Evaluation of the frequency of food allergens based on skin prick test in children in Kurdistan Province – Iran

Publication date: Available online 24 July 2017
Source:Allergologia et Immunopathologia
Author(s): R. Kalmarzi, P. Ataee, Gh. Homagostar, M. Tagik, E. Ghaderi, W. Kooti
IntroductionFood allergy refers to abnormal reactions of the body caused by an immune system response to food. This study was conducted aiming to investigate allergy to food allergens in children with food allergies.Materials and methodsThis study was conducted as a cross-sectional one on 304 children aged six months to seven years with food allergies admitted to the tertiary referral hospital in Kurdistan Province – Iran, during 2014–2015. All the patients were examined for skin prick test using 49 allergens. Finally, the obtained data were analysed using SPSS15 and chi-square and t tests.ResultsThe highest percentage of occurrence of bump reaction (wheal) and redness (flare) was due to the consumption of fish, eggs, tomatoes, and cocoa. Moreover, the lowest rate of wheal and flare was caused by exposure to allergens like latex, tea, malt, and wheat flour. The reaction most created due to the consumption of foods was flare which was higher among under three-year-olds group (p<0.05), and between the sexes, girls showed the most common allergic reactions (p<0.05).ConclusionSince food allergy has a high prevalence in children, it should be considered with great interest. Considering that avoiding food allergens is the first step in the treatment of food allergies, the present study may be a useful guide in this regard.



http://ift.tt/2tVg7BO

Cross-Linking Furan-Modified Kisspeptin-10 to the KISS Receptor

http://ift.tt/2tVkixw

Site-selective peptide and protein labelling & crosslinking

http://ift.tt/2tFIqZY

Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma

Thyroid , Vol. 0, No. 0.


http://ift.tt/2eJgdL8

Comparison of the Seventh and Eighth Editions of the American Joint Committee on Cancer/Union for International Cancer Control Tumor-Node-Metastasis Staging System for Differentiated Thyroid Cancer

Thyroid , Vol. 0, No. 0.


http://ift.tt/2eJfHNc

PMab-52: Specific and Sensitive Monoclonal Antibody Against Cat Podoplanin for Immunohistochemistry

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy , Vol. 0, No. 0.


http://ift.tt/2usiK1y

Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


http://ift.tt/2vDA7ee

Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-Abdominal Abscess Model [PublishAheadOfPrint]

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents. Yet, their clinical effectiveness is highly variable with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption/ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic dose. However, CD101 but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs may be limited by penetration at the site of infection, which have implications for clinical outcomes and emergence of resistance in patients with IAC.

http://ift.tt/2tEXZRC

Multicenter Evaluation of Ceftazidime-avibactam and Ceftolozane-tazobactam Inhibitory Activity against Meropenem Non-Susceptible P. aeruginosa from Blood, Respiratory Tract and Wounds [PublishAheadOfPrint]

The recent escalation of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of this class of compounds for this prevalent healthcare associate pathogen. Herein, we compared the in-vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem non-susceptible Pseudomonas aeruginosa non-duplicate clinical isolates from 34 US hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood or wound) and non-susceptibility to other β-lactam antimicrobials was considered. An extensive genotypic search for enzymatically-driven β-lactam resistance mechanisms revealed the exclusive presence of VIM among only 4% of the subset of isolates non-susceptible to ceftazidime-avibactam, ceftolozane-tazobactam or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem non-susceptible Pseudomonas aeruginosa. Further in-vitro and in-vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multi-drug resistant Pseudomonas aeruginosa.

http://ift.tt/2tVxAdy

Benzoxazoles, phthalazinones, and arylurea-based compounds with IMPDH-independent antibacterial activity against Francisella tularensis [PublishAheadOfPrint]

Francisella tularensis is the causative agent of tularemia and a potential biowarfare agent. The virulence of F. tularensis is decreased by deletion of guaB, the gene encoding inosine monophosphate dehydrogenase (IMPDH), suggesting that this enzyme is a target for antibacterial design. Here we report that F. tularensis growth is blocked by inhibitors of bacterial IMPDHs. Seventeen compounds from two different frameworks, designated D and Q, display antibacterial activity with minimum inhibitory concentrations less than 1 μM. These compounds are also active against intracellular infections. Surprisingly, antibacterial activity does not correlate with IMPDH inhibition. In addition, the presence of guanine does not affect the antibacterial activity of most compounds, nor does the deletion of guaB. These observations suggest that antibacterial activity derives from inhibition of another target(s). Moreover, D compounds only display antibacterial activity against F. tularensis, suggesting the presence of a unique target or uptake mechanism. A guaB mutant resistant to compound D73 contained a missense mutation (Gly45Cys) in nuoB, which encodes a subunit of bacterial complex I. Over-expression of the mutant nuoB conferred resistance to D73 in both wild-type and guaB strains. This strain was not resistant to Q compounds, suggesting that a different off-target mechanism operates for these compounds. Several Q compounds are also effective against Mycobacterium tuberculosis, where a second target has also been implicated in addition to IMPDH. The fortuitous presence of multiple targets with overlapping structure-activity relationships presents an intriguing opportunity for the development of robust antibiotics that may avoid the emergence of resistance.

http://ift.tt/2tUX9eO

Clinical Characteristics and Treatment Outcomes of Patients with Acquired Macrolide-resistant Mycobacterium abscessus Lung Disease [PublishAheadOfPrint]

Macrolide antibiotics are mainstays in the treatment of lung disease due to the Mycobacterium abscessus complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant M. abscessus subspecies abscessus (hereafter M. abscessus). This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of M. abscessus. We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant M. abscessus lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form, and two (15%) patients had the fibrocavitary form of the disease. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for M. abscessus, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range: 16.0--43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at positions 2058 (n = 10) or 2059 (n = 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with M. abscessus lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant M. abscessus lung disease.

http://ift.tt/2tFeoFt

Emergence of mcr-1 in Raoultella ornithinolytica and Escherichia coli from retail vegetables, China [PublishAheadOfPrint]

The presence of mcr-1 among Enterobacteriaceae isolates collected from retail vegetables in China between 2015 and 2016 were investigated. Two Raoultella ornithinolytica and seven Escherichia coli strains recovered from lettuce and tomato samples were identified as MCR-1-producers. Similar to isolates from animals and humans, the mcr-1 gene was located on the IncHI2/ST3, IncI2 or IncX4 plasmids. The presence of MCR-1-producing organisms in ready-to-eat food samples represents a serious risk for human health.

http://ift.tt/2tFusHt

Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis [PublishAheadOfPrint]

AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis. In this study we describe the population pharmacokinetics of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug susceptible TB. Patients were randomized to four doses (500 mg once daily, 1200 mg once daily, 500 mg twice daily and 800 mg twice daily). Patients were intensively sampled on day 1 and 14. AZD-5847 pharmacokinetics were best described with a two compartment system with tlag for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PKPD of AZD-5847, linezolid and sutezolid. AZD 5847 PKPD in terms of both fAUC/MIC and fT>MIC was less favorable compared to linezolid and sutezolid. This could help explain the poor bactericidal activity for AZD-5847 in the recent phase II study.

http://ift.tt/2tFsabu

In vitro drug susceptibility of bedaquiline, delamanid, linezolid, clofazimine, moxifloxacin, and gatifloxacin against extensively drug -resistant tuberculosis from Beijing, China [PublishAheadOfPrint]

Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore in vitro drug susceptibility of bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MXF), and gatifloxacin (GAT) against 90 XDR-TB strains isolated from patients in China. We also described the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD and BDQ was found in 82 (91.1%), 76 (84.4%), 5 (5.6%), 5 (5.6%), 4 (4.4%) and 3 (3.3%) isolates among the XDR-TB strains, respectively. The most frequent mutations conferring fluoroquinolone resistance occurred in codon 94 of gyrA gene (57.8%), and the strains with these mutations (69.2%) were associated with high-level MFX-resistance compared to strains with mutations in codon 90 (25.0%, P<0.01). All the 5 CLO-resistant isolates exhibited >=4-fold upward shifts in BDQ minimal inhibitory concentration, which were attributed to mutations of codons 53 (60.0%) and 157 (20.0%) in Rv0678 gene. Additionally, mutation in codon 318 of fbiC gene was identified as the sole mutation related to DMD resistance. In conclusion, our data demonstrate that the XDR-TB strains exhibit strikingly high proportion of resistance to the current anti-TB drugs, whereas BDQ, DMD, LZD and CLO exhibit excellent in vitro activity against XDR-TB in a National TB Center of China. The extensive cross-resistance between OFX and later-generation fluoroquinolones indicates that MFX and GAT may have difficulty in producing the desired effect for XDR-TB patients under current settings.

http://ift.tt/2tV2fYk

Multicenter and international study of MIC/MEC distributions for definition of epidemiological cutoff values (ECVs) for species of Sporothrix identified by molecular methods [PublishAheadOfPrint]

Clinical and Laboratory Standards Institute (CLSI) conditions for testing the susceptibilities of pathogenic Sporothrix species to antifungal agents are based on a collaborative study that evaluated five clinically relevant isolates of Sporothrix schenckii sensu lato and some antifungal agents. With the advent of molecular identification, there are two basic needs: to confirm the suitability of these testing conditions for all agents and Sporothrix species and to establish species-specific epidemiologic cutoff values (ECVs) or breakpoints (BPs) for these species. We collected available CLSI MICs/MECs of amphotericin B, five triazoles, terbinafine, flucytosine and caspofungin for 301 Sporothrix schenckii sensu stricto, 486 S. brasiliensis, 75 S. globosa and 13 S. mexicana molecularly identified isolates. Data were obtained in 17 independent laboratories (Australia, Europe, India, South Africa, South and North America) using conidial inoculum suspensions and 48-72 h of incubation at 35°C. Sufficient and suitable data (modal MICs within 2-fold concentrations) allowed the proposal of the following ECVs for S. schenckii and S. brasiliensis, respectively: amphotericin B 4 and 4 μg/ml, itraconazole 2 and 2 μg/ml; posaconazole 2 and 2 μg/ml; and voriconazole 64 and 32 μg/ml; ketoconazole and terbinafine ECVs for S. brasiliensis were 2 and 0.12 μg/ml, respectively. Insufficient or unsuitable data precluded the calculation of ketoconazole and terbinafine ECVs for S. schenckii as well as ECVs for S. globosa and S. mexicana or any other antifungal agent. These ECVs could aid the clinician in identifying potentially resistant isolates (non-wild type) less likely to respond to therapy.

http://ift.tt/2tEN5vj

Assessment of bactericidal drug activity and treatment outcome in a mouse tuberculosis model using a clinical Beijing strain [PublishAheadOfPrint]

Objectives: Mycobacterium tuberculosis Beijing strains are associated with lower treatment success rates in tuberculosis patients. In contrast, laboratory strains such as H37Rv are often used in preclinical tuberculosis models. Therefore, we explored the impact of using a clinical Beijing strain on treatment outcome in our mouse tuberculosis model. Additionally, the predictive value of bactericidal activity on treatment outcome was assessed.

Methods: BALB/c mice were infected with a Beijing strain and treated with one of ten different combinations of conventional anti-TB drugs. Bactericidal activity was assessed by determining reductions in mycobacterial load after 7, 14 and 28 days and after 2, 3 and 6 months of treatment. Treatment outcome was evaluated after a 6-months treatment-course and was based on lung culture-status 3 months post-treatment.

Results: None of the anti-TB drug regimens tested could achieve 100% treatment success. Treatment outcome depended critically on rifampicin. Four non-rifampicin-containing regimens showed 0% treatment success compared to success rates ranging between 81-95% for six rifampicin-containing regimens. Bactericidal activity was only predictive for treatment outcome after 3 months of treatment.

Conclusion: Our data advocate the use of multiple mycobacterial strains, including a Beijing strain, to increase the translational value of mouse TB models evaluating treatment outcome. Additionally, our findings support the notion that bactericidal activity in the first two months of treatment, as measured in clinical phase IIa/b trials, has limited predictive value for tuberculosis treatment outcome, thus emphasizing the need for better parameters to guide future phase-IIII trials.

http://ift.tt/2tUNyok

Oxidative stress response tips the balance in Aspergillus terreus AmB resistance [PublishAheadOfPrint]

In this study we characterize the impact of antioxidative enzymes in AmB resistant (ATR) and rare susceptible (ATS) clinical A. terreus isolates. We elucidate the expression profiles of superoxide dismutases (SODs) and catalases (CATs) encoding genes, enzymatic activity of SODs, superoxide anion production and signaling pathways involved in oxidative stress response (OSR) under AmB treatment in ATS and ATR strains. We show that ATR possess almost doubled basal SOD activity compared to ATS and that ATR exhibits an enhanced OSR, with significantly higher sod2 mRNA levels and significantly increased cat transcripts in ATR upon AmB treatment. In particular, inhibition of SOD- and CAT proteins rendered resistant isolates considerably susceptible to the drug in vitro. In conclusion, this study shows that Sods and Cats are crucial for AmB resistance in A. terreus and targeting the OSR might offer new treatment perspectives for resistant species.

http://ift.tt/2tF0X8P

Transfersomal phage cocktail: an effective treatment against methicillin resistant S.aureus (MRSA) mediated Skin and Soft tissue infections (SSTIs) [PublishAheadOfPrint]

Emergence of drug resistance has rekindled the interest in phage therapy as an alternative treatment option. Its potency, safety and proven efficacy is worth noting. However, phage therapy still suffers from issues of poor stability, narrow spectrum and poor pharmacokinetic profile. It therefore becomes essential to look into the use of Drug Delivery Systems (DDS) for efficient delivery of lytic phages in vivo. For the first time, the present study has evaluated the use of nano-structured lipid based carriers i.e. Transfersomes as transdermal delivery systems for encapsulating MRSA phage cocktail. Further, therapeutic potential of the encapsulated phage cocktail has been studied in resolving experimental soft tissue infection in rats. Results from in vitro stability as well as in vivo phage titer experiments indicate that transfersome entrapped phage cocktail showed better persistence and stability than free phages. Besides this, rats administered with transfersome entrapped phage cocktail resolved the experimental thigh infection within a period of seven days, unlike the twenty-day time period required for untreated animals. The findings of the present study advocate the use of transferosme as delivery agents for enhancing the stability and in vivo persistence of the encapsulated phages. In addition, this study also highlights the advantage offered by transfersome encapsulated phages in providing better therapeutic option than free phage in treating skin and soft tissue infection. Transfersome entrapped phage cocktail was able to protect all test animals (with no mortality) even when administered at a delay of twelve-hour post infection unlike free phages, thus making this treatment option more suitable in clinical settings.

http://ift.tt/2tUYimp

Co-administration of allopurinol to increase anti-mycobacterial efficacy of pyrazinamide: evaluation in a whole-blood bactericidal activity model [PublishAheadOfPrint]

Co-administering pyrazinamide (PZA) with the xanthine oxidase inhibitor, allopurinol, increases systemic levels of the active metabolite, pyrazinoic acid (POA), but effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10mg/kg or 25mg/kg) and the same dose 7 days later co-administered with allopurinol (100mg daily, 2 days before to 1 day after PZA dose). Blood was drawn at intervals to 48 hours after each PZA dose and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units (CFU) after 72 hours incubation. Allopurinol increased POA AUC (AUC_(0-8) 18.32h*μg/mL versus 24.63h*μg/mL for PZA alone versus PZA+allopurinol respectively; p<0.001) and C_max (2.81μg/mL versus 4.00μg/mL; p<0.001). There was no effect of allopurinol on mean cumulative WBA (0.01±0.02logCFU versus 0.00±0.02logCFU for PZA alone versus PZA+allopurinol respectively; p=0.49). Higher systemic POA levels were associated with greater WBA (p <0.001) but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA in spite of a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Co-administration of allopurinol does not appear to be a useful strategy for increasing efficacy of PZA in clinical practice.

http://ift.tt/2tFou9k

Effect of Rifampin on the Single-Dose Pharmacokinetics of Oral Cabotegravir in Healthy Subjects [PublishAheadOfPrint]

Introduction: Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection.

Methods: This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir. Subjects received a single oral dose of cabotegravir 30 mg on Day 1 followed by plasma sampling on Days 1 to 8. Treatment with once-daily oral rifampin 600 mg occurred on Days 8 to 28. Subjects received a second dose of cabotegravir 30 mg on Day 21 followed by pharmacokinetic sampling on Days 21 to 28.

Results: Fifteen subjects were enrolled and completed the study. Rifampin decreased cabotegravir area under the concentration-time curve over infinite time and half-life by 59% and 57%, respectively, whereas oral clearance was increased by 2.4-fold. The maximum plasma concentration of cabotegravir was unaffected by coadministration with rifampin. All adverse events were mild in severity, with chromaturia attributed to rifampin observed in all subjects.

DISCUSSION: Rifampin induction of cabotegravir metabolism resulted in increased cabotegravir oral clearance and significantly decreased cabotegravir exposures. Rifampin is expected to increase cabotegravir clearance following long-acting injectable administration. Concomitant administration of rifampin with oral and long-acting formulations of cabotegravir is not recommended currently without further study.

http://ift.tt/2tF0XWn

A cationic polymer that shows high antifungal activity against diverse human pathogens [PublishAheadOfPrint]

Invasive fungal diseases are generally difficult to treat and often fatal. The therapeutic agents available to treat fungi are limited, and there is a critical need for new agents to combat these deadly infections. Antifungal compound development has been hindered by the challenge of creating agents that are highly active against fungal pathogens but not toxic to the host. Host-defense peptides (HDPs) are produced by eukaryotes as a component of the innate immune response to pathogens and have served as inspiration for the development of many new antibacterial compounds. HDP mimics, however, have largely failed to exhibit potent and selective antifungal activity. Here, we present an HDP-like nylon-3 copolymer that is effective against diverse fungi while displaying only mild to moderate toxicity toward mammalian cells. This polymer is active on its own and in synergy with existing antifungal drugs against multiple species of Candida and Cryptococcus, reaching levels of efficacy comparable to those of the clinical agents amphotericin B and fluconazole in some cases. In addition, the polymer acts synergistically with azoles against different species of Aspergillus, including some azole-resistant strains. These findings indicate that nylon-3 polymers are a promising lead for development of new antifungal therapeutic strategies.

http://ift.tt/2tF45RT

Psoriasis: a mixed autoimmune and autoinflammatory disease

Yun Liang | Mrinal K Sarkar | Lam C Tsoi | Johann E Gudjonsson

http://ift.tt/2vDtxEI

The immunopathology of dengue and Zika virus infections

Abigail Culshaw | Juthathip Mongkolsapaya | Gavin R Screaton

http://ift.tt/2urdjjm

Germinal center enhancement by extended antigen availability

Kimberly M Cirelli | Shane Crotty

http://ift.tt/2urI0VO

Top Reviewers

Publication date: July–August 2017
Source:American Journal of Otolaryngology, Volume 38, Issue 4





http://ift.tt/2gYwBb7

Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis [INNATE IMMUNITY AND INFLAMMATION]

von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic ADAMTS13 deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the AP of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release, and complement activation.

http://ift.tt/2gXW3xJ

Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death [TRANSPLANTATION]

Nucleotide-binding oligomerization domain (Nod)–containing proteins Nod1 and Nod2 play important roles in the innate immune response to pathogenic microbes, but mounting data suggest these pattern recognition receptors might also play key roles in adaptive immune responses. Targeting Nod1 and Nod2 signaling pathways in T cells is likely to provide a new strategy to modify inflammation in a variety of disease states, particularly those that depend on Ag-induced T cell activation. To better understand how Nod1 and Nod2 proteins contribute to adaptive immunity, this study investigated their role in alloantigen-induced T cell activation and asked whether their absence might impact in vivo alloresponses using a severe acute graft versus host disease model. The study provided several important observations. We found that the simultaneous absence of Nod1 and Nod2 primed T cells for activation-induced cell death. T cells from Nod1 x 2^–/– mice rapidly underwent cell death upon exposure to alloantigen. The Nod1 x 2^–/– T cells had sustained p53 expression that was associated with downregulation of its negative regulator MDM2. In vivo, mice transplanted with an inoculum containing Nod1 x 2^–/– T cells were protected from severe graft versus host disease. The results show that the simultaneous absence of Nod1 and Nod2 is associated with accelerated T cell death upon alloantigen encounter, suggesting these proteins might provide new targets to ameliorate T cell responses in a variety of inflammatory states, including those associated with bone marrow or solid organ transplantation.

http://ift.tt/2gXVLa7

Menin Controls the Memory Th2 Cell Function by Maintaining the Epigenetic Integrity of Th2 Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Posttranslational modifications of histones are well-established epigenetic modifications that play an important role in gene expression and regulation. These modifications are partly mediated by the Trithorax group (TrxG) complex, which regulates the induction or maintenance of gene transcription. We investigated the role of Menin, a component of the TrxG complex, in the acquisition and maintenance of Th2 cell identity using T cell–specific Menin-deficient mice. Our gene expression analysis revealed that Menin was involved in the maintenance of the high expression of the previously identified Th2-specific genes rather than the induction of these genes. This result suggests that Menin plays a role in the maintenance of Th2 cell identity. Menin directly bound to the Gata3 gene locus, and this Menin-Gata3 axis appeared to form a core unit of the Th2-specific gene regulatory network. Consistent with the phenotype of Menin-deficient Th2 cells observed in vitro, Menin deficiency resulted in the attenuation of effector Th2 cell–induced airway inflammation. In addition, in memory Th2 (mTh2) cells, Menin was found to play an important role in the maintenance of the expression of Th2-specific genes, including Gata3, Il4, and Il13. Consequently, Menin-deficient mTh2 cells showed an impaired ability to recruit eosinophils to the lung, resulting in the attenuation of mTh2 cell–induced airway inflammation. This study confirmed the critical role of Menin in Th2 cell–mediated immune responses.

http://ift.tt/2gXVRhZ

Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus [INFECTIOUS DISEASE AND HOST RESPONSE]

Zika virus (ZIKV) is a mosquito-borne and sexually transmitted flavivirus that is associated with fetal CNS-damaging malformations during pregnancy in humans. This study documents the viral kinetics and immune responses in rhesus macaques infected with a clinical ZIKV Brazilian isolate. We evaluated the viral kinetics and immune responses induced after an i.v. infection with a Brazilian ZIKV clinical isolate (HS-2015-BA-01) in rhesus macaques for up to 142 d. ZIKV-specific Ab-secreting cells, germinal center reactions, and monocyte, dendritic cell, NK, and T cell frequencies were monitored. ZIKV loads were readily detected in plasma (until day 5 or 7), semen and urine (until days 7 and 14), and saliva (until day 42), but the viremia was rapidly controlled. No detectable clinical manifestations were observed. However, lymph node hyperplasia was clearly visible postviremia but was associated with low frequencies of ZIKV-specific Ab-secreting cells in lymph nodes and bone marrow, correlating with low Ab titers. CD14⁺/CD16^– monocytes and myeloid CD11c^hi dendritic cells decreased in blood, whereas NK and T cell numbers were only marginally altered during the course of the study. ZIKV infection caused a significant lymphoid tissue activation but limited induction of ZIKV-specific B cells, suggesting that these parameters need to be considered for ZIKV vaccine design.

http://ift.tt/2gXW4Sj

Dietary Salt Exacerbates Experimental Colitis [INNATE IMMUNITY AND INFLAMMATION]

The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10–deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10–deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium. This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD.

http://ift.tt/2gXW2Kb

Activation of Mouse Tcrb: Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR β (Tcrb) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites. An outstanding issue in understanding T cell gene expression programs is whether RUNX1 and ETS1 have independent functions in enhancer activation that can be dissected from cooperative binding. We now show that RUNX1 is sufficient to activate the endogenous mouse Eβ element and its neighboring 25 kb region by independently tethering this TF without coincidental ETS1 binding. Moreover, RUNX1 is sufficient for long-range promoter-Eβ looping, nucleosome clearance, and robust transcription throughout the Tcrb recombination center, spanning both DβJβ clusters. We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding, can compensate for the loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of recombination center promoters.

http://ift.tt/2gXVTq7

Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease [MUCOSAL IMMUNOLOGY]

Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg⁺) mice to SHS from postnatal day (PND) 3–21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed Scnn1b-Tg⁺ (FA-Tg⁺) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed Scnn1b-Tg⁺ (SHS-Tg⁺) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg⁺ mice exhibited marked mucus obstruction and Th2 responses, SHS-Tg⁺ mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, Th2 responses, and delayed bacterial clearance in SHS-Tg⁺ mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg⁺ mice, the SHS-Tg⁺ mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished Th2 response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.

http://ift.tt/2gXDHNd

Correction: DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia [CORRECTIONS]

http://ift.tt/2gXVKD5

Inflammasome and Fas-Mediated IL-1{beta} Contributes to Th17/Th1 Cell Induction in Pathogenic Bacterial Infection In Vivo [INNATE IMMUNITY AND INFLAMMATION]

CD4⁺ Th cells play crucial roles in orchestrating immune responses against pathogenic microbes, after differentiating into effector subsets. Recent research has revealed the importance of IFN- and IL-17 double-producing CD4⁺ Th cells, termed Th17/Th1 cells, in the induction of autoimmune and inflammatory diseases. In addition, Th17/Th1 cells are involved in the regulation of infection caused by the intracellular bacterium Mycobacterium tuberculosis in humans. However, the precise mechanism of Th17/Th1 induction during pathogen infection is unclear. In this study, we showed that the inflammasome and Fas-dependent IL-1β induces Th17/Th1 cells in mice, in response to infection with the pathogenic intracellular bacterium Listeria monocytogenes. In the spleens of infected wild-type mice, Th17/Th1 cells were induced, and expressed T-bet and Rort. In Pycard^–/– mice, which lack the adaptor molecule of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain), Th17/Th1 induction was abolished. In addition, the Fas-mediated IL-1β production was required for Th17/Th1 induction during bacterial infection: Th17/Th1 induction was abolished in Fas^–/– mice, whereas supplementation with recombinant IL-1β restored Th17/Th1 induction via IL-1 receptor 1 (IL-1R1), and rescued the mortality of Fas^–/– mice infected with Listeria. IL-1R1, but not apoptosis-associated speck-like protein containing a caspase recruitment domain or Fas on T cells, was required for Th17/Th1 induction, indicating that IL-1β stimulates IL-1R1 on T cells for Th17/Th1 induction. These results indicate that IL-1β, produced by the inflammasome and Fas-dependent mechanisms, contributes cooperatively to the Th17/Th1 induction during bacterial infection. This study provides a deeper understanding of the molecular mechanisms underlying Th17/Th1 induction during pathogenic microbial infections in vivo.

http://ift.tt/2eJ7UyO

Defining the Kinetics, Phenotype, and Function of T Cells Induced by Mycobacterium tuberculosis: Pillar of Immunity to Tuberculosis [PILLARS OF IMMUNOLOGY]

http://ift.tt/2eJ8CMw

Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice [INNATE IMMUNITY AND INFLAMMATION]

During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN-α/β) are induced in inflammatory conditions associated with increased alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-α/β receptor is required for inflammation-induced alloimmunization. Additionally, mitochondrial antiviral signaling protein–mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic-polycytidylic acid–induced IFN-α/β production and alloimmunization. We further report that IFN-α, in the absence of an adjuvant, is sufficient to induce RBC alloimmunization. These findings raise the possibility that patients with IFN-α/β–mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies.

http://ift.tt/2eJ8gFG

Retraction: Hypoxia-Inducible Factor (HIF) 1{alpha} Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance [LETTERS OF RETRACTION]

http://ift.tt/2eJ1Zd3

Here, There, and Anywhere? Arguments for and against the Physical Plasma Cell Survival Niche [BRIEF REVIEWS]

To maintain Ab titers, individual plasma cells must survive for extended periods, perhaps even for the life of the host. Although it is clear that plasma cell survival requires cell extrinsic signals, the nature and source of these signals remains open for debate. It is commonly postulated that plasma cells only gain access to these signals within specialized regulatory microenvironments, or niches, in the bone marrow or in the gut. In this review we discuss current concepts and information surrounding plasma cell survival niches, and consider two opposing models to explain long-term serologic immunity.

http://ift.tt/2eJ8BIs

Cutting Edge: Eosinophils Undergo Caspase-1-Mediated Pyroptosis in Response to Necrotic Liver Cells [CUTTING EDGE]

Many chronic liver disorders are characterized by dysregulated immune responses and hepatocyte death. We used an in vivo model to study the immune response to necrotic liver injury and found that necrotic liver cells induced eosinophil recruitment. Necrotic liver induced eosinophil IL-1β and IL-18 secretion, degranulation, and cell death. Caspase-1 inhibitors blocked all of these responses. Caspase-1–mediated cell death with accompanying cytokine release is the hallmark of a novel form of cell death termed pyroptosis. To confirm this response in a disease model, we isolated eosinophils from the livers of Schistosoma mansoni–infected mice. S. mansoni eggs lodge in the hepatic sinusoids of infected mice, resulting in hepatocyte death, inflammation, and progressive liver fibrosis. This response is typified by massive eosinophilia, and we were able to confirm pyroptosis in the infiltrating eosinophils. This demonstrated that pyroptosis is a cellular pathway used by eosinophils in response to large-scale hepatic cell death.

http://ift.tt/2gXWfgr

IFN-{gamma}-Expressing Th17 Cells Are Required for Development of Severe Ocular Surface Autoimmunity [MUCOSAL IMMUNOLOGY]

Th17 cells are critical effectors mediating the ocular surface autoimmunity in dry eye disease (DED). Increased IFN- has also been implicated in DED; however, it remains unclear to what extent Th1 cells contribute to DED pathogenesis. In this study, we investigated the cellular source of IFN- and assessed its contribution to corneal epitheliopathy in DED mice. We discovered a significant IL-17A⁺IFN-⁺ (Th17/1) population and determined that these cells are derived from Th17 precursors. Adoptive transfer of Th17/1, but not Th1, cells confers the disease to naive recipients as effectively as do Th17 cells alone. DED-induced IL-12 and IL-23 are required for in vivo transition of pathogenic Th17 cells to IFN- producers. Furthermore, using IFN-–deficient Th17 cells, we demonstrate the disease-amplifying role of Th17-derived IFN- in DED pathogenesis. These results clearly demonstrate that Th17 cells mediate ocular surface autoimmunity through both IL-17A and IFN-.

http://ift.tt/2eJ27t3

Activation of Human Basophils by A549 Lung Epithelial Cells Reveals a Novel IgE-Dependent Response Independent of Allergen [ALLERGY AND OTHER HYPERSENSITIVITIES]

Evidence for epithelial cell (EC)–derived cytokines (e.g., thymic stromal lymphopoietin [TSLP]) activating human basophils remains controversial. We therefore hypothesize that ECs can directly activate basophils via cell-to-cell interaction. Basophils in medium alone or with IL-3 ± anti-IgE were coincubated with TSLP, IL-33, or IL-25. Analogous experiments cocultured basophils (1–72 h) directly with EC lines. Supernatants were tested for mediators and cytokines. Abs targeting receptors were tested for neutralizing effects. Lactic acid (pH 3.9) treatment combined with passive sensitization tested the role of IgE. Overall, IL-33 augmented IL-13 secretion from basophils cotreated with IL-3, with minimal effects on histamine and IL-4. Conversely, basophils (but not mast cells) released histamine and marked levels of IL-4/IL-13 (10-fold) when cocultured with A549 EC and IL-3, without exogenous allergen or IgE cross-linking stimuli. The inability to detect IL-33 or TSLP, or to neutralize their activity, suggested a unique mode of basophil activation by A549 EC. Half-maximal rates for histamine (4 h) and IL-4 (5 h) secretion were slower than observed with standard IgE-dependent activation. Ig stripping combined with passive sensitization ± omalizumab showed a dependency for basophil-bound IgE, substantiated by a requirement for cell-to-cell contact, aggregation, and FcRI-dependent signaling. A yet unidentified IgE-binding lectin associated with A549 EC is implicated after discovering that LacNAc suppressed basophil activation in cocultures. These findings point to a lectin-dependent activation of basophil requiring IgE but independent of allergen or secreted cytokine. Pending further investigation, we predict this unique mode of activation is linked to inflammatory conditions whereby IgE-dependent activation of basophils occurs despite the absence of any known allergen.

http://ift.tt/2eIKV7d

Involvement of NK Cells in IL-28B-Mediated Immunity against Influenza Virus Infection [INNATE IMMUNITY AND INFLAMMATION]

IL-28B is a member of the newly discovered type III IFN family and exhibits unique antiviral properties compared with other family members. NK cells play a critical role in defending against viruses; however, little is known about the role of IL-28B in NK cell function. In a mouse model of influenza A virus (mouse adapted influenza A/PR/8/34 strain) infection, long-term overexpression of IL-28B induced by hepatocyte-specific gene delivery exerted a strong antiviral effect in the presence of NK cells. In IL-28B–overexpressing wild-type mice, the percentages and absolute numbers of NK cells in the spleen, liver, and lung were markedly increased, with higher proliferation and accelerated NK cell maturation based on phenotypes staining with CD11b and CD27 or CD11b and KLRG1. Furthermore, the effect of IL-28B on NK cells was macrophage dependent, as confirmed in an in vitro coculture assay and in in vivo macrophage- or alveolar macrophage–depletion experiments. Transwell studies demonstrated that CFSE-labeled NK cell proliferation was driven, in a dose-dependent manner, by unknown soluble factor(s) secreted by IL-28B–stimulated alveolar macrophages, without requiring direct cell–cell contact. An understanding of the NK cell–promoting features of IL-28B will facilitate future clinical application of this cytokine.

http://ift.tt/2eJ8jBm

Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice [INNATE IMMUNITY AND INFLAMMATION]

Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.

http://ift.tt/2eIKMkb

Suppression of Lipopolysaccharide-Induced Inflammatory Response by Fragments from Serum Amyloid A [INNATE IMMUNITY AND INFLAMMATION]

Serum amyloid A (SAA) is known as an acute-phase protein and a biomarker for inflammatory diseases. Published studies have shown that SAA possesses proinflammatory cytokine-like activity and is chemotactic for phagocytes, but the structural basis for these activities remains unidentified. In this article, we report that truncated SAA1 proteins lacking N- and C-terminal sequences exhibit reduced proinflammatory activity and strongly suppress LPS-induced expression of IL-1β, IL-6, and TNF-α in macrophages. A truncated SAA1 containing aa 11–58 was examined further and found to facilitate p38 MAPK phosphorylation while reducing LPS-stimulated phosphorylation of ERK and JNK. In LPS-challenged mice, aa 11–58 reduced the severity of acute lung injury, with significantly less neutrophil infiltration in the lungs and attenuated pulmonary expression of IL-1β, IL-6, and TNF-α. Coadministration of aa 11–58 markedly improved mouse survival in response to a lethal dose of LPS. A potent induction of IL-10 was observed in a TLR2-dependent, but TLR4-independent, manner in macrophages stimulated with aa 11–58. However, the aa 11–58 fragment of SAA1 was unable to induce chemotaxis or calcium flux through formyl peptide receptor 2. These results indicate that the N- and C-terminal sequences contain structural determinants for the proinflammatory and chemotactic activities of SAA1, and their removal switches SAA1 to an anti-inflammatory role. Given that proteolytic processing of SAA is associated with the pathological changes in several diseases, including secondary amyloidosis, our findings may shed light on the structure–function relationship of SAA1 with respect to its role in inflammation.

http://ift.tt/2eIqFCF

B Cell-Extrinsic Myd88 and Fcer1g Negatively Regulate Autoreactive and Normal B Cell Immune Responses [ANTIGEN RECOGNITION AND RESPONSES]

MyD88 and FcR common -chain (Fcer1g, FcR) elicit proinflammatory responses to exogenous Ags. Deletion of these receptors in autoimmune models has generally led to reduced overall disease. In B cells, Myd88 is required for anti-DNA and anti-RNA autoantibody responses, whereas Fcer1g is not expressed in these cells. The roles of these receptors in myeloid cells during B cell autoimmune activation remain less clear. To investigate the roles of Myd88 and Fcer1g in non-B cells, we transferred anti–self-IgG (rheumatoid factor) B cells and their physiologic target Ag, anti-chromatin Ab, into mice lacking Fcer1g, Myd88, or both and studied the extrafollicular plasmablast response. Surprisingly, we found a markedly higher and more prolonged response in the absence of either molecule; this effect was accentuated in doubly deficient recipients, with a 40-fold increase compared with wild-type recipients at day 10. This enhancement was dependent on CD40L, indicating that Myd88 and FcR, presumably on myeloid APCs, were required to downregulate T cell help for the extrafollicular response. To extend the generality, we then investigated a classic T cell–dependent response to (4-hydroxy-3-nitrophenyl)acetyl conjugated to chicken globulin and found a similar effect. Thus, these results reveal novel regulatory roles in the B cell response for receptors that are typically proinflammatory.

http://ift.tt/2gXBIbI

Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The T cell repertoire is a function of thymic V(D)J rearrangement and of peripheral selection. The mature repertoire embodies TCR sequences that are important for survival and can identify important structural aspects of the TCR. Analysis of the circulating TCRBV19 CD8 T cell repertoire showed that a majority of NDN-encoded CDR3 amino acid motifs start at CDR3 position four, well within the V region. Rearrangement at this position indicates that the DNA hairpin loop is not opened at the position adjacent to the recombination signal sequence, but rather is trimmed back three or more bases. In this article, we show that the rearrangement frequency distribution within the V region reveals selection on CDR3 position four. The selection is already established in single-positive CD8 thymocytes. Crystal structures reveal a possible basis for this selection due to the location of this residue in a bend that positions the remaining portion of CDR3 to interact with the peptide and MHC. Examination of other TCRBV families also shows selection for rearrangement within the V region of a number of genes and for CD8 and CD4 cells. The exact profile of rearrangement within the V region appears to be V gene specific. The frequent observation of side chains associated with turn motifs at CDR3 positions three and four fits with the structural need for a bend. The data are discussed in terms of the generation of a structural turn motif, the rearrangement mechanism, and selection of the repertoire on the peptide and MHC.

http://ift.tt/2eJ29Bb

On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes [AUTOIMMUNITY]

Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic β cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R^–/–) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R^+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R^–/– mice. This is likely due to an increase in the frequency of mTGFβ⁺Foxp3^int regulatory T cells and the persistence of CD206⁺ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R^+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.

http://ift.tt/2eJ8vk4

CD36 and Platelet-Activating Factor Receptor Promote House Dust Mite Allergy Development [MUCOSAL IMMUNOLOGY]

Over 89% of asthmatic children in underdeveloped countries demonstrate sensitivity to house dust mites (HDMs). The allergic response to HDMs is partially mediated by epithelial cell–derived cytokines that activate group 2 innate lymphoid cells, induce migration and activation of dendritic cells, and promote effector differentiation of HDM-specific TH2 cells. However, the contribution of innate receptor engagement on epithelial or dendritic cells by HDMs that ultimately mediates said innate and adaptive allergic responses is poorly understood. We and other investigators have demonstrated that HDMs express phosphorylcholine (PC) moieties. The major PC receptors involved in immune responses include CD36 and platelet-activating factor receptor (PAFR). Because CD36 and PAFR are expressed by epithelial cells and dendritic cells, and expression of these receptors is higher in human asthmatics, we determined whether engagement of CD36 or PAFR on epithelial or dendritic cells contributes to HDM allergy development. Testing bone marrow chimeric mice revealed that CD36 engagement on radioresistant cells and PAFR engagement on radioresistant and radiosensitive cells in the lung promote allergic responses to HDMs. Additionally, passive anti–PC IgM Abs administered intratracheally with HDMs decreased allergen uptake by epithelial cells and APCs in the lungs of C57BL/6 mice but not CD36^–/– or PAFR^–/– mice. These results show that CD36 and PAFR are important mediators of HDM allergy development and that inhibiting HDM engagement with PC receptors in the lung protects against allergic airway disease.

http://ift.tt/2eJ23tj

IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus [CLINICAL AND HUMAN IMMUNOLOGY]

The IL-23/IL-17 pathway is important in multiple autoimmune diseases, but its effect on lupus pathology remains unclear, with opposing trials in murine models of the disease. In this study, we show a disease activity–related upregulation of serum IL-23 and IL-23 receptor in patients with systemic lupus erythematosus (SLE) as compared with healthy controls. When added in SLE T cell in vitro cultures, IL-23 induced IL-17 and limited IL-2 production, whereas T follicular helper and double negative (DN) T cells significantly expanded. To further dissect the role of IL-23 in the expression of autoimmunity and related pathology, we generated IL-23 receptor–deficient MRL.lpr mice. These IL-23R^–/–MRL.lpr mice displayed attenuated lupus nephritis with a striking decrease in the accumulation of DN T cells in the kidneys and secondary lymphoid organs. Moreover, T cells from IL-23R^–/–MRL.lpr mice produced increased amounts of IL-2 and reduced amounts of IL-17 compared with T cells from wild type animals. In vitro IL-23 treatment promoted IL-17 production and downregulated IL-2 production. The IL-23R^–/–MRL.lpr had fewer T follicular helper cells, B cells, and plasma cells, leading to decreased production of anti-dsDNA Abs. Our results show that IL-23 accounts for the main aspects of human and murine lupus including the expansion of DN T cells, decreased IL-2, and increased IL-17 production. We propose that blockade of IL-23 should have a therapeutic value in patients with SLE.

http://ift.tt/2gXSfwh

Effects of deoxynivalenol (DON) and its microbial biotransformation product deepoxy-deoxynivalenol (DOM-1) on a trout, pig, mouse, and human cell line

Abstract

Deoxynivalenol (DON), a trichothecene produced by various Fusarium species, is one of the most prevalent food- and feed-associated mycotoxins. The effects of DON and deepoxy-deoxynivalenol (DOM-1) were assessed in five different cell lines from different tissues and species starting from the first line of defense, the trout gill (RTgill-W1) and pig intestinal cells (IPEC-1 and IPEC-J2) over immune cells, as second line of defense (mouse macrophages RAW 264.7) to human liver cells (HepG2). Viability was assessed with a WST-1 assay, except for RTgill-W1, where a neutral red (NR) and sulforhodamine B (SRB) assay was performed. Additionally, more sensitive parameters, such as interleukin-, nitric oxide (NO)-, and albumin-release were determined. Viability was affected by DON at concentrations starting at 10 μmol/L (RTgill-W1), 0.9 μmol/L (IPEC-1), 3.5 μmol/L (IPEC-J2), and 0.9 μmol/L (HepG2), whereas DOM-1 did not have such an effect. Additionally, NO was decreased (0.84 μmol/L DON), whereas interleukin (IL)-6 was increased (0.42 μmol/L DON) in lipopolysaccharide (LPS)-stimulated DON-, but not DOM-1-treated RAW cells. Tumor necrosis factor (TNF)-α release, however, was not affected. Interestingly, albumin secretion of HepG2 cells was decreased by both DON and DOM-1 but at a much higher concentration for DOM-1 (228 versus 0.9 μmol/L for DON). 98.9% of DOM-1 was retrieved by liquid chromatography tandem mass spectrometry at the end of the experiment, proving its stability. In this study, IL-6 was the most sensitive parameter, followed by NO and albumin release and viability for HepG2 and IPEC-1.

http://ift.tt/2uQNF8I

Tips on Finding a Reputable Plastic Surgeon for Patient Referral

Drs Granick and Lee share their personal views on becoming plastic surgeons and offer resources on where to find reputable ones for patient referrals.
Medscape Plastic Surgery

http://ift.tt/2uizdDH

Protective antibodies against HSP60 for autoimmune inflammatory diseases

Publication date: Available online 24 July 2017
Source:Clinical Immunology
Author(s): Rina Ulmansky, Yaakov Naparstek




http://ift.tt/2vC7myS

Radiological Evaluation of Cochlear Orientation and Its Implications in Cochlear Implantation

Abstract

To test whether there are variations in cochlear orientation with respect to age and sex, and its relevance in cochlear implant surgery. Implant otologists rely upon the anatomic landmarks including the facial recess and round window niche and round window membrane for accessibility and placement of electrode array into scala tympani of basal turn of cochlea. Anecdotally, surgeons note variations in cochlear orientation with respect to age. Cochlear orientation studied radiologically by pre-operative CT scan of temporal bone can guide a Surgeon's approach to cochlear implantation. To investigate the changes in cochlear orientation with respect to age and sex; and its relevance in cochlear implantation. A retrospective analytical study was performed on CT scans of temporal bones in patients (of our hospital from July 2013 to January 2015 i.e. for a period of 18 months) with no congenital or radiological abnormalities of cochlea. The basal turn angulations of cochlea varied with age and majority of change occurred during early age. The basal turn angulations of cochlea in difficult situations during cochlear implantation were correlated with the data. There is a significant variation in cochlear orientation as measured radiologically by basal turn angulations relative to midsagittal plane. The more obtuse and acute basal turn angulations have implications like difficulty in cochleostomy and electrode placement during cochlear implantation.

http://ift.tt/2eImarH

Invordering inkomstenbelastingen

http://ift.tt/2usHEMR

Normal carboxyhaemoglobin level in carbon monoxide poisoning treated with hyperbaric oxygen therapy

Throughout the world both intentional and inadvertent exposure to carbon monoxide (CO) remains an important public health issue. While CO poisoning can be lethal, the morbidity is predominantly due to nervous system injury. A previously healthy 22-year-old woman was found unconscious at home by her sister. Her parents were found dead in the house with a recent history of a dysfunctional furnace. She was presumed to have CO poisoning despite an initial carboxyhaemoglobin level of 2.5%. Patient had both clinical and radiological evidence of neurological damage. However, with multiple sessions of hyperbaric oxygen (HBO) therapy she recovered to a near normal functional status. There is no consensus that exists among treating physicians about the role of hyperbaric oxygen in management of neurological injury. The case described here has significant neurological damage related to CO exposure but improved after HBO therapy.

http://ift.tt/2uQK36e

Case of a strangulated right paraduodenal fossa hernia in a malrotated gut

We report an unusual case of a strangulated internal hernia resulting from a right paraduodenal fossa hernia (PDH) in the context of bowel malrotation. There are few documented cases of PDHs associated with a concomitant gut malrotation. Emergency laparotomy was performed based on clinical and radiological. Intraoperatively, the proximal jejunum was seen to enter a hernia sac formed by an aberrant duodenojejunal flexure located to the right of the aorta. This was presumed to be a strangulated internal hernia of the paraduodenal recess in a malrotated gut. The hernia neck was widened and the sac obliterated to allow reduction of the contents. On reduction and warming, the insulted small bowel appeared viable and returned to the abdominal cavity without resection.

http://ift.tt/2usDrZz

Silent tracheobronchial chondritis in a patient with a delayed diagnosis of relapsing polychondritis

Relapsing polychondritis is a very rare autoimmune disease characterised by a relapsing inflammation of hyaline, elastic and fibrous cartilaginous tissues. The incidence is estimated to be between 3.5 and 4.5 per million people per year. Clinical signs and symptoms can be very subtle, and if left undiagnosed for a prolonged period, airway involvement can cause fibrosis of the tracheobronchial wall, leading to a fixed tracheobronchial stenosis. Eventually, this can progress to life-threatening tracheobronchomalacia due to irreversible damage and loss of tissue integrity. We report an elderly man who presented with recurrent bilateral ear inflammation and intermittent polyarthritis who was diagnosed with relapsing polychondritis with asymptomatic involvement of his large airways.

http://ift.tt/2uRaiJP

Unusual genitourinary tract activity

A 23-year-old woman presented to the emergency department after manually inserting foreign bodies into the urinary bladder through her urethra. A plain abdominal film of the kidneys, ureters and bladder confirmed three radio-opaque densities in the urinary bladder. She was taken to the operating room where cystourethroscopy was performed. At cystoscopy 2 'corn-on-the-cob' skewers and 1 battery were identified but were too large to be retrieved safely with a grasper through the protective sheath. The objects were grasped with a 'sponge-holding forceps' (placed alongside the cystoscope) and extracted one at a time. A psychiatric consultation was sought and the patient was diagnosed and treated for borderline personality disorder. Unusual genitourinary activity (UGUA) has been described for several centuries and is characterised by the deposition of foreign objects in the genitalia.¹ The most common incentive for UGUA is sexual stimulation, but psychiatric disorders and intoxication are also associated.² Management involves retrieval of foreign bodies and evaluation of psychosocial factors.

http://ift.tt/2uQR0Eu

Dengue fever presenting as cauda equina syndrome

Description

Dengue is an arboviral disease transmitted by Aedes sp. mosquitoes. A wide spectrum of illness is observed, ranging from dengue fever to dengue shock syndrome. The common neurological complications noted are encephalitis and encephalopathy. Haemorrhagic complications due to thrombocytopenia can result in various neurological sequelae.1 We report a case of dengue fever with spontaneous spinal hematoma presenting as cauda equina syndrome.

A 47-year-old man presented with moderate grade fever and arthralgia for 5 days. On day 6 of illness, he got admitted with complaints of lower backache, urinary retention, bilateral lower limb weakness and numbness below ankle. This was followed by reduced perianal sensations. On clinical examination, the patient was found to have MRC grade 4/5 power in extensor hallucis longus and ankle plantar flexors. The ankle reflexes were absent bilaterally with other deep tendon reflexes being normal. Babinski reflex was negative. The patient had...

http://ift.tt/2uQXcMX

Radiological Evaluation of Cochlear Orientation and Its Implications in Cochlear Implantation

Abstract

To test whether there are variations in cochlear orientation with respect to age and sex, and its relevance in cochlear implant surgery. Implant otologists rely upon the anatomic landmarks including the facial recess and round window niche and round window membrane for accessibility and placement of electrode array into scala tympani of basal turn of cochlea. Anecdotally, surgeons note variations in cochlear orientation with respect to age. Cochlear orientation studied radiologically by pre-operative CT scan of temporal bone can guide a Surgeon's approach to cochlear implantation. To investigate the changes in cochlear orientation with respect to age and sex; and its relevance in cochlear implantation. A retrospective analytical study was performed on CT scans of temporal bones in patients (of our hospital from July 2013 to January 2015 i.e. for a period of 18 months) with no congenital or radiological abnormalities of cochlea. The basal turn angulations of cochlea varied with age and majority of change occurred during early age. The basal turn angulations of cochlea in difficult situations during cochlear implantation were correlated with the data. There is a significant variation in cochlear orientation as measured radiologically by basal turn angulations relative to midsagittal plane. The more obtuse and acute basal turn angulations have implications like difficulty in cochleostomy and electrode placement during cochlear implantation.

http://ift.tt/2eImarH

Effects of Combined Surgery on Obstructive Sleep Apnea in Obese Patients: an Open-label Randomized Controlled Clinical Trial

Condition:   To Compare the Difference of AHI Variation Between LSG and Combined Surgery
Interventions:   Procedure: Laparoscopic sleeve gastrectomy（LSG）;   Procedure: Uvulopalatopharyngoplasty(UPPP) and Adenoidectomy/Tonsillectomy
Sponsor:   Bing Wang
Not yet recruiting - verified July 2017

http://ift.tt/2vShRNL

New Modalities for Detection of Oropharyngeal Cancer

Conditions:   Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma;   Oropharynx Cancer;   Base of Tongue Carcinoma;   Tonsil Cancer
Interventions:   Device: Transcervical Oropharyngeal Ultrasound;   Procedure: Oral Rinse Collection;   Procedure: Blood Draw
Sponsors:   Vanderbilt University Medical Center;   American Cancer Society, Inc.
Recruiting - verified July 2017

http://ift.tt/2uPZdcw

Cricopharyngeal Dysfunction and Esophageal Diverticulum

Conditions:   Zenker's Esophageal Diverticulum;   Cricopharyngeal Dysfunction;   Progressive Dysphagia
Intervention:   Other: open, transcervical versus rigid endoscopic treatment
Sponsor:   University of Cincinnati
Recruiting - verified July 2017

http://ift.tt/2vS8gGK

NCI-COG Pediatric MATCH trial to test targeted drugs in childhood cancers

The nationwide precision medicine trial will enroll children and adolescents with advanced cancers that haven't responded to standard therapy to explore treatments targeted at specific genetic mutations.

http://ift.tt/2tuJUSw

A murine intestinal intraepithelial NKp46-negative innate lymphoid cell population characterized by group 1 properties

The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal V gamma 3 T cells, intestinal intraepithelial CD8 alpha alpha(+) T lymphocytes, and CD49a(+) liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8 alpha alpha, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8 alpha cells, and intraepithelial ILC1. Importantly, NKp46(-)CD8 alpha alpha(-)Ly49E(+) cells produce interferon (IFN)-gamma, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.

http://ift.tt/2vBamLT

Tenascin-C downregulates Wnt inhibitor Dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model

The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic beta-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.

http://ift.tt/2uqcyHv

A negative selection scheme for tobacco protoplast-derived cells expressing the T-DNA gene 2

http://ift.tt/2upI8Fm

The graphical determination of operating conditions for chromatographic sequences

Salisbury, RS; (2007) The graphical determination of operating conditions for chromatographic sequences. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2uPSvTV

Patients with Huntington's disease pioneered human stereotactic neurosurgery 70 years ago

Hariz, M; Tabrizi, SJ; (2017) Patients with Huntington's disease pioneered human stereotactic neurosurgery 70 years ago. Brain (In press).

http://ift.tt/2usuAqZ

The functional role of extracellular nucleotides in the renal tubule

Vekaria, RM; (2006) The functional role of extracellular nucleotides in the renal tubule. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2uQhp5T

The foundation of a theory of translation built on the semiotics of C.S. Peirce

Stecconi, U; (2006) The foundation of a theory of translation built on the semiotics of C.S. Peirce. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2usVSO0

The effects of lipid lowering treatment on the arterial wall and renal function in patients with peripheral arterial disease

Youssef, FA; (2006) The effects of lipid lowering treatment on the arterial wall and renal function in patients with peripheral arterial disease. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2uPUKGB

The effects of intrinsic and extrinsic factors on neural stem cell populations

Scott, CE; (2007) The effects of intrinsic and extrinsic factors on neural stem cell populations. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2usqUW1

The effect of left hemisphere brain tumours and their resection on speech production and visual processing

Lloyd-Smith, A; (2008) The effect of left hemisphere brain tumours and their resection on speech production and visual processing. Doctoral thesis, UCL (University College London).

http://ift.tt/2uPKtu6

Decadal trends in the diurnal variation of galactic cosmic rays observed using neutron monitor data

Thomas, S; Owens, M; Lockwood, M; Owen, CJ; (2017) Decadal trends in the diurnal variation of galactic cosmic rays observed using neutron monitor data. Annales Geophysicae , 35 pp. 825-838. 10.5194/angeo-35-825-2017 . Green open access

http://ift.tt/2usGfpC

The development of social cognitive processes during adolescence

Thompson, SS; (2007) The development of social cognitive processes during adolescence. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2uPPXF6

The development of inhibitory mechanisms in spinal pain pathways

Harrop, JE; (2006) The development of inhibitory mechanisms in spinal pain pathways. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2usBdcX

Feasibility and Acceptability of self sampling kits to increase the uptake of HIV testing among black Africans in the United Kingdom: The HAUS Study

Burns, FM; Seguin, M; Dodds, C; Mugweni, E; McDaid, L; Flowers, P; Wayal, S; Burns, FM; Seguin, M; Dodds, C; Mugweni, E; McDaid, L; Flowers, P; Wayal, S; Zomer, E; Weatherburn, P; Fakoya, I; Hartney, T; McDonagh, L; Hunter, R; Young, I; Khan, S; Fremantle, N; Chwuala, J; Sachikonye, M; Anderson, J; Singh, S; Nastouli, E; Rait, G; - view fewer (2017) Feasibility and Acceptability of self sampling kits to increase the uptake of HIV testing among black Africans in the United Kingdom: The HAUS Study. Health Technology Assessment (In press).

http://ift.tt/2uPPXoA

The characteristics of hard targets in SAR imagery

Bennett, AJ; (2007) The characteristics of hard targets in SAR imagery. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2usQeLE

Who’s Who in the Delivery Room?

Join us for Belly to Baby as Abby goes through the admission and discharge process at Barnes-Jewish Hospital.

The post Who's Who in the Delivery Room? appeared first on ChildrensMD.

http://ift.tt/2uPEZzu

Paediatric chest wall trauma causing delayed presentation of ventricular arrhythmia

This report describes a paediatric patient presenting with haemodynamically stable non-sustained ventricular tachycardia 1 day after minor blunt chest trauma. Initial laboratory studies, chest X-ray and echocardiography were normal; however, cardiac MRI revealed precordial haematoma, myocardial contusion and small pericardial effusion. Throughout her hospital course, she remained asymptomatic aside from frequent couplets and triplets of premature ventricular contractions. Ectopy was controlled with oral verapamil. This case highlights how significant cardiac injury may be missed with standard diagnostic algorithms.

http://ift.tt/2usm8YO

An unusual presentation of a benign pancreatic lesion containing amyloid

We present a unique case of a benign pancreatic lesion which was positive for amyloid in a 55-year-old female patient without systemic amyloidosis. Further testing revealed islet-type amyloid polypeptide (or amylin), a protein found in various diseases such as diabetes, insulinoma and pancreatic adenocarcinoma—none of which was seen in our patient.

http://ift.tt/2uQJEAV

Lipoma of superior vena cava: a rare occurrence

Most benign primary cardiac tumours are myxomas; non-myxomatous tumours are less common but comprise a wide variety. Cardiac lipoma is a rare non-myxomatous variety. A 70-year-old Caucasian woman with right breast cancer status postpartial mastectomy underwent surveillance MRI of the breast and was found to have a possible right atrial (RA) mass. She also reported frequent headaches and palpitations. She underwent a transoesophageal echocardiogram which showed a 2.6x1.6x1.6 cm echogenic mass at the superior vena cava (SVC) and RA junction. She was anticoagulated for a possible thrombus without resolution. Surgical excision was undertaken in view of ongoing symptoms and partial occlusion of the SVC. Intraoperatively, a 2–3 cm smoothly textured lobulated mass was found and histopathology showed adipose tissue consistent with lipoma. The postoperative course was uneventful, and the patient was discharged in stable condition.

http://ift.tt/2vSxCnQ

Benign paroxysmal positional vertigo (BPPV) diagnosis and treatment in an elite professional football (soccer) player

A 33-year-old male professional football player suffered from acute-onset dizziness following a lower limb soft tissue treatment in prone lying. Symptoms included spinning vertigo lasting for 30's, headache, visual vertigo and disorientation. Clinical examination of balance and vestibular systems confirmed a left posterior canalithiasis benign paroxysmal positional vertigo (BPPV) and excluded other central and peripheral causes of dizziness. Two cycles of a left Epley manoeuvre were performed. An Epley manoeuvre abolished the BPPV and negated the need for medication. The player was able to return to play without dizziness within 24 hours completely symptom free. BPPV can be successfully identified and treated in elite football players and they can see a return to training and games within 24 hours. There are no epidemiology studies for this group of elite athletes either male or female despite increased occupational risk factors.

http://ift.tt/2uZR99q

Q fever prosthetic joint infection

Coxiella burnetii is the causative pathogen of the zoonotic infection Q fever. Most patients with Q fever experience a non-specific febrile illness, hepatitis or pneumonia. Q fever has recently been described as a cause of prosthetic joint septic arthritis, but remains very uncommonly reported. We present a case of Q fever prosthetic joint septic arthritis that has responded to a combination of two-stage surgical exchange and prolonged medical treatment with doxycycline and hydroxychloroquine.

http://ift.tt/2vSyCYZ

Soft tissue laceration caused by lower extremity intraosseous access insertion in an obese patient

Description

Intravenous access placement in the obese could be challenging due to unreliable anatomical landmarks and impact overall care. Intraosseous (IO) access remains a quick and reliable alternative to emergent intravenous access.1 2 The adult IO demonstrates an excellent safety profile with serious complications, such as compartment syndrome, osteomyelitis and skin abscesses, occurring in less than 1% of insertions.3

An 85-year-old woman presented with septic shock due to lobar pneumonia. Physical examination revealed a dehydrated, hypotensive, morbidly obese woman with anasarca and lower extremity lymphoedema. After several failed peripheral intravenous access attempts, IO access was achieved using the Arrow® EZ-IO® system, 2 cm distal and slightly medial to the tibial tuberosity in the right lower extremity during first attempt by an experienced emergencist without difficulties. The IO needle length was 45 mm and its gauge 15 Ga. EZ-IO® stabiliser dressing was not used during placement. IO...

http://ift.tt/2v0lwwq

Importance of temporal changes in myocardial strain in Takotsubo cardiomyopathy

Strain imaging is a sensitive marker of myocardial dysfunction and may be underused in Takotsubo cardiomyopathy (TC). We present a case of biventricular TC in which early improvement in left ventricular longitudinal strain predated subsequent improvement in ejection fraction. Early temporal patterns of strain of the left and right ventricles have not previously been described in TC. Our case illustrates how strain can be a sensitive marker for myocardial dysfunction and recovery in TC. Increased use of strain in TC may have further implications on prognosis and management.

http://ift.tt/2vSq30r

Apical ballooning (takotsubo) syndrome with concurrent ST-segment elevation myocardial infarction

We present the case of a 61-year-old woman admitted with chest pain and an ECG demonstrating ST-segment elevation in the lateral leads. Emergency coronary angiography demonstrated an occluded obtuse marginal branch. Percutaneous intervention was unsuccessful as the lesion could not be crossed with a wire. Left ventriculography and transthoracic echocardiography demonstrated hypokinesis of the entire apex but preserved contractility of the basal segments, consistent with a diagnosis of apical ballooning syndrome (ABS). Cardiac MRI demonstrated myocardial oedema in all mid to apical segments, with a left ventricular ejection fraction (LVEF) of 38%. Repeat study at 5 months demonstrated an infarct in the distribution of the occluded artery with late gadolinium enhancement, consistent with a diagnosis of a lateral wall myocardial infarction and an improvement in the LVEF to 51%. The case illustrates the novel observation that ABS and acute myocardial infarction may rarely occur simultaneously.

http://ift.tt/2v09FOT

Atypical presentation of Parsonage-Turner syndrome confounded by surgical rotator cuff injury

Parsonage-Turner syndrome (PTS) is a rare neuropathy that commonly presents as unexpected severe shoulder and arm pain that eventually subsides while weakness or paralysis ensues. During exceptions to this classic presentation, confirming PTS can be challenging. Alternative causes of upper extremity pain may confound the diagnostic algorithm. Moreover, objective findings from necessary diagnostic tests depend on when those tests are performed. We present an atypical onset of PTS, whereby the initial presentation of severe neuropathic pain was preceded by mild shoulder pain that should decrease one's clinical suspicion for PTS. This milder pain coincided with the presence of a rotator cuff injury, whereby surgical intervention preceded impending paralysis and hindered postoperative rehabilitation. Physicians should be aware of the possibility of atypical presentations of PTS in hopes of avoiding either untimely surgery or delays in diagnosis.

http://ift.tt/2vSNab0

Primary bilateral adrenal nodular disease with Cushing's syndrome: varying aetiology

Primary adrenal disorders contribute 20%â"30% of patients with endogenous Cushing's syndrome. Most of the primary adrenal diseases are unilateral and include adenoma and adrenocortical carcinoma, whereas bilateral adrenal lesions are uncommon and include primary pigmented nodular adrenocortical disease, primary bilateral macronodular adrenocortical hyperplasia, isolated micronodular adrenocortical disease, bilateral adenomas or carcinomas, and rarely pituitary adrenocorticotropic hormone-dependent adrenal nodular disease. Cyclic adenosine monophosphate-dependent protein kinase A signalling is the major activator of cortisol secretion in primary adrenal nodular disorders. We report two cases of bilateral adrenal nodular disease with endogenous Cushing's syndrome, including one each of primary pigmented nodular adrenocortical disease and primary bilateral macronodular adrenocortical hyperplasia.

http://ift.tt/2uZR7OQ

A rare case of fatal meningoencephalitis with septic thromboembolism due to otitis media: a forensic case and review of literature

Description

Meningitis is an inflammatory syndrome involving the meninges, and it manifests with headache and stiff neck. On the contrary, encephalitis refers to the inflammation of the brain parenchyma. The causative pathogens can be manifold though, except for immunocompromised patients; in literature, there are no cases of meningoencephalitis caused by bacteria usually present in the bowel.

We report the case of a 40-year-old man. Following an earache, the man went to the hospital. In anamnesis, the man reported a chronic otitis media for many years, and clinicians, noting auricular bleeding, advised local antibiotic treatment. The next day, he had fever, treated with paracetamol. After 3 days, following the worsening of the clinical condition, the man returned to the hospital where physicians detected temporal and spatial disorientation, neck stiffness and fever of 39.5°C. Despite medical therapy, the man died after a few hours. An autopsy was performed. It showed an abscess...

http://ift.tt/2vSG4nf

Awakening with amantadine from a persistent vegetative state after subarachnoid haemorrhage

We report the case of a 36-year-old woman with a subarachnoid haemorrhage (SAH) caused by a rupture of a right-sided middle cerebral artery aneurysm and subsequent malignant infarction of the right hemisphere leading to a persistent vegetative state and severe spastic tetraparesis with recurrent myocloni. Nine months after disease onset, the patient was transferred to our department for diagnostic and therapeutic re-evaluation. The poor clinical condition could not be explained by the brain lesion caused by the SAH or infarction. Moreover, glucose metabolism was normal in brain regions not affected by SAH and infarction as shown by positron emission tomography with ¹⁸F-fluorodeoxyglucose. We terminated baclofen and reduced antiepileptics known to impair vigilance and cognitive functions. However, only after starting amantadine treatment we observed a stunning awakening of the patient fully orientated within days. Our findings warrant trials to investigate amantadine in the treatment of unresponsive wakefulness syndromes due to acute central nervous system diseases.

http://ift.tt/2v0bBqU

An unusual case of interstitial lung disease in a patient with cardiopulmonary syndrome as the initial presentation of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a very rare disorder with only approximately 600 cases reported in the literature. ECD has been recently reclassified as a histiocytic dendritic cell neoplasm. The clinical spectrum ranges from asymptomatic tissue accumulation of histiocytes to invasive tissue infiltration, which can cause fulminant multisystem failure. It typically presents with bone pain and constitutional symptoms. Extraosseous manifestations are not uncommon. ECD-associated interstitial lung disease has been described in 20%-35% of patients. Diagnosis is primarily by tissue biopsy and immunohistochemistry showing xanthogranulomas composed of foamy histiocytes that stain positive for CD68, CD14 and CD163 and negative for CD1á and langerin. We report a case of ECD in a young man with cardiopulmonary involvement who presented with haemoptysis and dyspnoea.

http://ift.tt/2vSrfkg

Klippel-Trenaunay syndrome: diagnosis in a neonate

Description

A male newborn was evaluated due to a port-wine stain. Mother, 40 years old, father and brother were healthy. Gestation was uneventful. Amniocentesis revealed a normal male karyotype. A caesarean delivery was performed at 38 weeks. First physical examination showed a port-wine stain affecting the abdomen, back and left limb (figure 1) and hypertrophy of the affected limb. A biopsy was performed and histological findings revealed capillary malformations. Therefore, a Klippel-Trenaunay syndrome was diagnosed. Abdominal and lower limb doppler ultrasound and brain MRI excluded other vascular abnormalities. He was followed by a multidisciplinary team. At 9 months, there was a slight difference in the length of legs and the circumference of thighs (figure 2).

Figure 1

A port-stain affecting the abdomen and left limb at first physical examination of the neonate.

Figure 2

Appearance of the...

http://ift.tt/2v0b9cj

Reconstruction of urethra using appendix in a patient with cloacal malformation

We report a case of 21-year-old young woman with congenital cloacal malformation. She was operated at the age of 1.5 years separating the rectum from common opening as a two-stage repair. She was incontinent in the earlier part of her life but she became continent to some extent later in early adulthood. She presented with urinary stress incontinence following delivery of dead fetus of 6 months. She underwent multiple investigations revealing common opening of bladder neck and vagina. A multidisciplinary evaluation was done and she underwent closure of common channel and neourethra reconstruction using pedicled appendix. Patient was continent and voiding by herself on discharge.

http://ift.tt/2vSvRHj

Trans-scaphoid perilunate fracture dislocation: 'notjust a scaphoid fracture

Description

Perilunate dislocations are uncommon high-energy injuries which are missed in approximately 25% of cases on initial presentation.1 We present the X-rays of a 25-year-old man who fell from a height of approximately 2 metres onto an extended wrist. Plain radiographs (figure 1) show classical signs of a trans-scaphoid perilunate fracture dislocation. Pre-reduction, he had median nerve symptoms which settled with reduction and elevation. Reduction was performed in the emergency department with analgesia/sedation.

Figure 1

Posteroanterior and lateral pre-reduction radiographs of the wrist.

The sequence of events in this injury is well described: (1) the force begins radially and passes through the scaphoid causing it to fracture; (2) the force is transmitted ulnarly through the lunocapitate interval, and the lunate projects through the space of Poirier (between the intercarpal ligaments volar to the bones); (3) the distal portion...

http://ift.tt/2v0njl4

Patient-reported outcome measures (PROMs): enhancing decision making and follow-up

A case presentation of patient undergoing elective total knee replacement. Patient-reported outcome measures prospectively collected electronically pre and postoperatively allowed real-time review, aiding follow-up and reducing the need for clinical, face-to-face follow-up.

http://ift.tt/2v01Rge

Angioscopic observation of an atherosclerotic coronary aneurysm without yellow plaque

Description

A-58-year-old man with diabetes mellitus was admitted to our hospital with angina following physical effort. Coronary CT angiography (CCTA) revealed a saccular coronary aneurysm at the left main trunk bifurcation and a significant stenosis at the middle portion of the calcified left anterior descending artery (LAD) (figure 1). Invasive coronary angiography showed a large coronary aneurysm (12.3x11.0 mm) arising from the ostial LAD and stenoses in the middle of the LAD and in the middle of the left circumflex artery (figure 2). Intravascular ultrasound showed a severely calcified LAD, as shown on CCTA; however, it failed to reveal the entire picture with regard to the aneurysm because of the limited echo depth. Non-obstructive angioscopy (NOA)1 was performed to investigate the intimal injury of the aneurysm and demonstrated a rough, salmon-pink coloured surface without the presence of thrombus or atheromatous yellow plaque

http://ift.tt/2vSJFkY

Silicone implant incompatibility syndrome (SIIS) in a 57-year-old woman with unilateral silicone breast implant

Since the 1960s, silicone implants have been used for breast augmentations, both cosmetically and in reconstructive surgery. Tissue exposed to silicone can react with multiple adverse advents. Autoimmune/inflammatory syndrome induced by adjuvants due to silicone exposure from ruptured silicone implants can lead to different interstitial lung manifestations predominantly with granuloma evolvement, leading to the so-called silicone implant incompatibility syndrome (SIIS). This case describes a 57-year-old woman with multiple lung infiltrations and a left-sided breast implant. The implant had been replaced twice, once due to implant rupture 36 years ago. The nodular infiltrates could not be related to infection, malignancy, interstitial lung disease, vasculitis or connective tissue disorder, and it was concluded that the nodular infiltrations were of inflammatory origin due to an autoimmune response secondary to the silicone implants (SIIS). After explantation, the patient's symptoms subsided and her physical condition has remarkably improved.

http://ift.tt/2v02WVw

Moving Onward?: Secondary Movers on the Fringes of Refugee Mobility in Kakuma Refugee Camp, Kenya

This article examines the migration-asylum nexus in the microcosm of Kakuma Refugee Camp in Kenya by focusing on refugees and asylum seekers who move onward from a first refuge, in Central-East Africa. By drawing on qualitative ethnographic field research in Kakuma, the article outlines how such "secondary movements" cause many anxieties, as the distinction between refugees and migrants is blurred by motivations that are not exclusively protection related. Based on a Foucauldian analysis of power and discourse, we arguethat this creates a contested social and semantic space wherein all actors struggle to uphold the rigid distinction. Additionally, by combining the strengths of migration studies' consideration for policy categories and mobility studies' holistic perspective toward migration, the article aims to further deepen academic interaction between two literature traditions in order to enhance our understanding of how mobility is "shaped" and "lived" by people in wartime situations.

http://ift.tt/2vANT1n

Disruption of a horizontally transferred phytoene desaturase abolishes carotenoid accumulation and diapause inTetranychus urticae

http://ift.tt/2uQ5qFm

The Aryans and the Ancient System of Caste

http://ift.tt/2uPNyKD

Universal historiography as process? Shaping monastic memories in the eleventh-century Chronicle of Saint-Vaast

http://ift.tt/2usDSTM

β2-Adrenergic receptors protect axons during energetic stress but do not influence basal glio-axonal lactate shuttling in mouse white matter

http://ift.tt/2uPI2YD

Handboek psychofarmacotherapie

Deze derde editie van het Handboek Psychofarmacotherapie bevat een grondige herziening van de bestaande data en aanvulling met meer recente wetenschappelijke gegevens en aanbevelingen. Het accent ligt op de farmacologische aspecten van de diverse aangehaalde farmaca en minder op de theoretische achtergrond van de ziektebeelden. Het gebruik van overzichtelijke schema's, beslissingsbomen, en overzichtelijke tabellen werd aangemoedigd voor deze nieuwe editie. Naast evidence based literatuur;, wordt ook gekeken naar eigen opinies en standpunten berustend op individuele ervaring (expert opinion). Er werden een aantal nieuwe hoofdstukken ingevoegd zoals de farmacologische benadering van ADHD en autisme, educatie in correct psychofarmacagebruik, ethiek van het voorschrijven, de toekomstperspectieven van de farmacogenetica, het interpreteren van onderzoek- en studieresultaten en een kort historisch overzicht van deze nog relatief jonge discipline. Het Handboek Psychofarmacotherapie is geschikt als handboek in het (hoger) onderwijs en als naslagwerk. Het is een leidraad voor de geneesheer in opleiding (psychiaters, maar ook huisartsen en neurologen), de apotheker, de farmaceutische industrie en alle professionelen geïnteresseerd in de materie. Een uitgave in samenwerking met BCNBP (Belgian College of Neuropsychopharmacology and Biological Psychiatry - www.bcnbp.org).

http://ift.tt/2uQgv9g

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and alpha(2B)-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p < 0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.

http://ift.tt/2usHSUx

Laser capture microdissection in forensic research: a review

In forensic sciences, short tandem repeat (STR) analysis has become the prime tool for DNA-based identification of the donor(s) of biological stains and/or traces. Many traces, however, contain cells and, hence, DNA, from more than a single individual, giving rise to mixed genotypes and the subsequent difficulties in interpreting the results. An even more challenging situation occurs when cells of a victim are much more abundant than the cells of the perpetrator. Therefore, the forensic community seeks to improve cell-separation methods in order to generate single-donor cell populations from a mixed trace in order to facilitate DNA typing and identification. Laser capture microdissection (LCM) offers a valuable tool for precise separation of specific cells. This review summarises all possible forensic applications of LCM, gives an overview of the staining and detection options, including automated detection and retrieval of cells of interest, and reviews the DNA extraction protocols compatible with LCM of cells from forensic samples.

http://ift.tt/2uPFWI0

Laser microdissection in forensic sciences

Laser capture microdissection (LCM) is a valuable tool in forensic sciences. In cases of sexual assault, spermatozoa recovered from postcoital samples can be automatically screened after staining with Sperm HY-LITER™. Male cells from male/female mixtures can be automatically screened after fluorescence in situ hybridization in suspension (S-FISH) by using Y-chromosome-specific probes. In both cases, male cells were isolated using LCM and DNA analysis was performed. Full DNA profiles could consistently be obtained from as little as 30 spermatozoa and 10 male cells respectively, which proves that staining with Sperm HY-LITER™ as well as S-FISH had no significant influence on DNA recovery.

http://ift.tt/2ussWFH

Research Shows One Aspect of the Affordable Care Act Has No Significant Impact on Emergency Department Patient Visits

As the debate surrounding the Affordable Care Act (ACA) looms in the U.S. Congress, Johns Hopkins researchers are weighing in on one aspect of the law. In 2014, as part of the ACA, Maryland was one of the states that expanded eligibility for its Medicaid program. One of the proposed benefits of expanding Medicaid under the ACA was a reduction in emergency department patient visits. However, some research prior to the ACA implementation found new Medicaid enrollees increased their visits to the emergency department.

http://ift.tt/2tujvEx

Antibody reactivity against Helicobacter pylori proteins in a sample of the Spanish adult population in 2008-2013

Abstract

Background

Differences in Helicobacter pylori protein expression have been related to the risk of severe gastric diseases. In Spain, a marked geographic pattern in gastric cancer mortality has long been reported. Objective: To characterize antibody reactivity patterns against 16 H. pylori proteins, by age, sex, and region of birth, in a large sample of the Spanish adult population.

Materials and Methods

Antibody reactivity was quantified by H. pylori multiplex serology in a sample from the control group of the multicase-control study MCC-Spain. For this analysis, 2555 population-based controls were included. Each participant was classified as seropositive or seronegative for each protein according to specific cutoffs. Overall H. pylori seroprevalence was defined as positivity against ≥4 proteins. Descriptive analyses by age, sex, and region of birth were performed for both seroprevalence and seroreactivity (continuous measure). Differences among groups were tested by logistic and linear regression models.

Results

Overall H. pylori seroprevalence increased with age in both sexes. For ages 55-74, seroprevalence was lower in women than in men (84% vs 92%, P<.001). Region of birth explained 7% of the variability in seroprevalence. Among H. pylori seropositive subjects, proteins with the highest seroprevalence were GroEL, NapA, HP231, and Omp. Seropositivity for most of the proteins increased or remained stable with age, rising mainly for CagA, GroEL, and HyuA in women. A clear cohort effect was not observed.

Conclusions

This is the first study to describe the antibody patterns against 16 H. pylori proteins in the Spanish population. We found variability in the H. pylori antibody profiles according to both individual factors such as age and sex, and environmental factors such as the region of birth. The slightness of the reduction in seropositivity with decreasing age highlights the ongoing importance of this infection.

http://ift.tt/2usIWaW

Odontogenic Fungal Maxillary Sinusitis: A Case Report of a Displaced Dental Foreign Body

Abstract

Odontogenic etiology accounts for 10–12% of cases of maxillary sinusitis. Although uncommon, direct spread of dental infections into the maxillary sinus is possible due to the close relationship of the maxillary posterior teeth to the maxillary sinus. An odontogenic infection is a polymicrobial aerobic–anaerobic infection, with anaerobes out numbering the aerobes. Diagnosis requires a thorough dental and clinical evaluation, including radiographs. Management of sinus disease of odontogenic origin often requires medical treatment with appropriate antibiotics, surgical drainage when indicated, and treatment to remove the offending dental etiology. A 35-year-old, non-smoking woman visited our clinic, with a history of 6 months of facial pain, purulent nose discharge, and a foul taste in her mouth. The patient was otherwise healthy. Nasal endoscopy showed purulent discharge coming from the left middle meatus with a congested nasal mucosa and with a past history of dental treatments. CT PNS showed fractured free floating and an impacted foreign body through the premolar tooth and a right maxillary polyp with evidence of similar dental procedure done bilaterally. Functional endoscopic sinus surgery with extraction of the affected tooth and closure of oroantral fistula was done. The association between an odontogenic condition and maxillary sinusitis requires a thorough dental examination of patients with sinusitis. Concomitant management of the dental origin and the associated sinusitis will ensure complete resolution of the infection and may prevent recurrences and complications. A combination of a medical and surgical approach is generally required for the treatment of odontogenic sinusitis. An endoscopic shaver-assisted approach to is a reliable, minimally invasive method associated with less morbidity and lower incidence of complications.

http://ift.tt/2vSa824