A potentially important role for t cells and regulatory t cells in Langerhans cell histiocytosis

Publication date: Available online 18 June 2018
Source:Clinical Immunology
Author(s): Jenée M. Mitchell, Stuart P. Berzins, George Kannourakis
Langerhans cell histiocytosis is characterized by lesions containing inflammatory immune cells, including myeloid cells and T cells. Patient mortality remains unacceptably high and new treatment options are required. Several LCH studies have identified aberrant frequencies of T cell subsets with potential immune regulatory properties. High numbers of Foxp3⁺ regulatory T cells and gamma-delta T cells have been reported in patients with LCH, although, the cause of their presence or their significance is not yet clear. This review describes the current understanding of how LCH develops and progresses, focusing on the growing evidence that regulatory T cell subsets may be important and discussing the exciting potential for harnessing these cells to treat LCH using immune based therapies.



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Examination of the cut-off values for a questionnaire used to evaluate asthma control in Japanese asthma patients

Publication date: Available online 18 June 2018
Source:Allergology International
Author(s): Yuji Tohda, Soichiro Hozawa, Hiroshi Tanaka
BackgroundThe Japan Asthma Control Survey (JACS) questionnaire, developed as a tool for measuring asthma control levels in Japanese asthma patients, was previously tested for its reliability and validity. However, many of the patients enrolled in the original validation study had mild asthma; thus a re-evaluation including severe cases was required to calculate more reliable cut-off values.MethodsPooled analysis of data from the original validation study and the subsequent medication guidance study including adult patients with severe asthma was conducted to calculate the JACS questionnaire cut-off values and to assess their sensitivity and specificity for identifying "well-controlled", "not well-controlled", and "poorly controlled" asthma as described in the Asthma Prevention and Management Guideline 2015 (JGL2015). The data were from 353 patients with mild to severe persistent asthma classified according to JGL2015.ResultsThe JACS questionnaire cut-off values were 8.0 (sensitivity, 67.9%; specificity, 81.9%) for "well-controlled" and "not well-controlled" and 4.8 (sensitivity, 85.3%; specificity, 53.3%) for "not well-controlled" and "poorly controlled".ConclusionsJACS cut-off values can be expected to be more useful for evaluating asthma control status in clinical practice and clinical research, thus improving asthma treatment, in Japan. This analysis was the original validation study (UMIN000016589) and the subsequent medication guidance study (UMIN000024353).



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Pediatric case with rice bran allergy induced by epicutaneous sensitization in a family rice shop

Publication date: Available online 18 June 2018
Source:Allergology International
Author(s): Yui Togashi, Naoko Inomata, Aki Suzuki, Amiko Hakuta, Michiko Aihara




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Transoral Thyroid and Parathyroid Surgery Vestibular Approach: A Framework for Assessment and Safe Exploration

Thyroid, Ahead of Print.


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Tired and Swollen: A Mono Mimic for Angioedema

Publication date: Available online 18 June 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Amie Nguyen, Sandra Christiansen




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Role of complement C5a and histones in septic cardiomyopathy

Publication date: Available online 18 June 2018
Source:Molecular Immunology
Author(s): Fatemeh Fattahi, Lynn M. Frydrych, Guowu Bian, Miriam Kalbitz, Todd J. Herron, Elizabeth A. Malan, Matthew J. Delano, Peter A. Ward
Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca²⁺]i-regulatory enzymes including sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2) and Na⁺/Ca²⁺ exchanger (NCX) as well as Na⁺/K⁺-ATPase in CMs. There is also evidence that CLP causes release of IL-1β via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).



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Common and rare genetic variants of complement components in human disease

Publication date: Available online 18 June 2018
Source:Molecular Immunology
Author(s): Elena Goicoechea de Jorge, Alberto López Lera, Rafael Bayarri-Olmos, Hugo Yebenes, Margarita Lopez-Trascasa, Santiago Rodríguez de Córdoba
Genetic variability in the complement system and its association with disease has been known for more than 50 years, but only during the last decade have we begun to understand how this complement genetic variability contributes to the development of diseases. A number of reports have described important genotype-phenotype correlations that associate particular diseases with genetic variants altering specific aspects of the activation and regulation of the complement system. The detailed functional characterization of some of these genetic variants provided key insights into the pathogenic mechanisms underlying these pathologies, which is facilitating the design of specific anti-complement therapies. Importantly, these analyses have sometimes revealed unknown features of the complement proteins. As a whole, these advances have delineated the functional implications of genetic variability in the complement system, which supports the implementation of a precision medicine approach based on the complement genetic makeup of the patients. Here we provide an overview of rare complement variants and common polymorphisms associated with disease and discuss what we have learned from them.



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In vitro activity of ceftolozane-tazobactam against Enterobacter cloacae complex clinical isolates with different {beta}-lactam resistance phenotypes [PublishAheadOfPrint]

The study evaluated the in vitro activity of ceftolozane-tazobactam (C/T) against 94 unique clinical isolates of Enterobacter cloacae complex (ECC). No difference was observed according to the ECC cluster. The in vitro activity greatly varied depending on the β-lactamase-producing profile: 100%, 67% and 19% of wild-type, ESBL-producing, and AmpC-overproducing strains were susceptible to C/T, respectively. The use of C/T could be of interest for the treatment of some infections caused by ESBL-producing AmpC-non-overexpressing ECC isolates.

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Activity of Telavancin against S. aureus isolated from cystic fibrosis patients including those with decreased susceptibility to Ceftaroline [PublishAheadOfPrint]

Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a worse clinical outcome with increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus has a dual mode of action causing inhibition of the peptidoglycan synthesis and membrane depolarization. CF-associated MRSA infections remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for complicated skin infections and hospital-acquired pneumonia, the activity against CF- associated S. aureus infections has not been investigated. In this work, we studied the activity of telavancin against CF S. aureus strains collected from diverse geographical CF centers in the USA. We found that telavancin-MIC90 was 0.06 μg/ml, 8-fold lower than ceftaroline or daptomycin and 25-fold lower than linezolid and vancomycin. We demonstrate that telavancin at serum-free concentrations has rapid bactericidal activity with a decrease of more than 3 log10 CFU/ml during the first 4 to 6 hours of treatment, performing better in this assay than vancomycin and ceftaroline, including S. aureus resistant to ceftaroline.

Telavancin resistance was infrequent (0.3%), although we found that it can occur in- vitro in both CF- and non-CF S. aureus strains by progressive passages with sub-inhibitory concentrations. Genetic analysis of telavancin in-vitro mutants showed gene polymorphisms in cell wall and virulence genes, and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for CF infections with potent in-vitro activity and low resistance potential.

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Cas9/CRISPR genome editing to demonstrate the contribution of Cyp51A Gly138Ser to azole resistance in Aspergillus fumigatus [PublishAheadOfPrint]

A pan-azole-resistant Aspergillus fumigatus strain with the cyp51A mutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containing cyp51A with the mutations were introduced along with Cas9 protein and single-guide RNA into the azole-resistant/susceptible strains. Recombinant strains showed increased susceptibility via the replacement of Ser138 by glycine. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using Cas9/CRISPR genome editing.

https://ift.tt/2lgxj2P

Pharmacokinetics of a pediatric tribendimidine dose-finding study to treat hookworm infection in African children [PublishAheadOfPrint]

Tribendimidine is a broad-spectrum anthelmintic available in China, which is currently being pursued for US Food and Drug Administration approval for soil-transmitted helminth infections. Pharmacokinetic (PK) studies with tribendimidine in children, the main target group for treatment programs, have not been conducted to date. In the framework of a dose-ranging study in hookworm infected school-aged children in Côte d'Ivoire, children were either treated with 100 mg, 200 mg, or 400 mg tribendimidine. Dried blood spot samples were collected up to 22 hours after treatment. The active metabolite, deacetylated amidantel (dADT) and its metabolite acylated dADT (adADT) were quantified using liquid chromatography tandem mass spectrometry. PK parameters were calculated using a noncompartmental model and univariate logistic regression was applied using maximal blood concentrations (C_max) and area under the blood concentration-time curve (AUC_0-22h) as predictors of drug efficacy. Dried blood spot samples of 101 children were analyzed. We observed a less than proportional and proportional exposure in dADT's median C_max and AUC_0-22h, respectively, following administration of 100 mg (C_max=853 ng/ml; AUC_0-22h =3,019 h*ng/ml) and 400 mg (C_max=2,275ng/ml; AUC_0-22h =12,530 h*ng/ml) tribendimidine. There were large, dose-independent variations in the time to C_max (T_max) and ratios of dADT to adADT. We did not detect an influence of C_max or AUC_0-22h of dADT or adADT on drug efficacy or adverse events. Since our study population was bearing hookworm infection of mainly low intensity, additional studies in heavy intensity infections might be required to confirm this observation.

https://ift.tt/2ylSoSV

A New Locus of Drug Resistance in the Human Cytomegalovirus UL56 Gene Revealed by in vitro Exposure to Letermovir and Ganciclovir [PublishAheadOfPrint]

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In 8 experiments, UL56 terminase gene mutations were detected beginning at 10 passages, including novel amino acid substitutions V236A, L328V and A365S, in a region previously associated with letermovir resistance. Outside this region, UL56 substitution C25F was detected at moderate drug concentrations in 2 experiments, as either the first detected mutation, or adding to a preexisting substitution V231L. In all cases, mutation at UL56 codon 325 conferring absolute letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of UL56 mutations. UL56 substitutions V236A, L328V and A365S were shown to confer borderline or low-grade letermovir resistance, while C25F conferred 5.4-fold increased letermovir resistance (EC50) by itself and 46-fold in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for letermovir resistance distinct from those previously described.

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Evaluation of the Adequacy of WHO revised Dosages of the First-Line Anti-Tuberculosis Drugs in Children with Tuberculosis using Population Pharmacokinetic Modeling and Simulations [PublishAheadOfPrint]

Optimal doses for anti-tuberculosis (TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosages ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) for at least 4 weeks had blood samples collected at pre-dose, 1, 2, 4, and 8-hours post-dose. Drug concentrations were determined by validated liquid chromatography mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, and the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by one-compartment model and that for INH and EMB by two-compartment model. C_max and AUC targets were based on published results in children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for N-acetyl transferase 2 non-slow (rapid and intermediate) acetylators in the lower weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB.

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Do fitness costs explain the rapid spread of kelch13-C580Y substitutions conferring artemisinin resistance? [PublishAheadOfPrint]

Fitness costs are key determinants of whether drug resistance alleles establish and how fast they spread within populations. More than 125 different kelch13 alleles, each containing a different amino acid substitution, have arisen in SE Asian malaria parasite (Plasmodium falciparum) populations under artemisinin selection over the past 15 years in a dramatic example of a soft selective event. However, just one of these alleles (C580Y) is now outcompeting other alleles in multiple different countries and is spreading towards fixation. Here we examine the fitness consequences of C580Y, relative to another less successful kelch13 mutation (R561H), to try to explain the distinctive dynamics of C580Y. We hypothesized that C580Y will show lower fitness costs relative to other kelch13 substitutions in the absence of artemisinin treatment. We used CRISPR/Cas9 methods to introduce single mutations (C580Y or R561H), or synonymous control edits into a wildtype parasite isolated on the Thailand-Myanmar border, conducted replicated head-to-head competition assays, and determined the outcome of competition using deep sequencing of kelch13 amplicons. Contrary to our predictions, these experiments reveal that C580Y carries higher fitness costs (s=0.15 ± 0.008 [1 s.e.]) than R561H (s=0.084 ± 0.005). Furthermore, R561H outcompetes C580Y in direct competition (s=0.065 ± 0.004). We conclude that fitness costs of C580Y in isolation are unlikely to explain the rapid spread of this substitution.

https://ift.tt/2lgXM0g

In vitro susceptibility of Burkholderia cepacia complex isolated from cystic fibrosis patients to ceftazidime-avibactam and ceftolozane-tazobactam [PublishAheadOfPrint]

We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. Highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Respectively, 81% and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam. For temocillin, ceftazidime, piperacillin-tazobactam and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.

https://ift.tt/2ywN5QT

Neisseria meningitidis antimicrobial resistance in Italy, 2006-2016 [PublishAheadOfPrint]

The aim of the study was to evaluate the antimicrobial susceptibility of 866 Neisseria meningitidis invasive strains during 11-years of surveillance in Italy. Two and six strains were resistant to ciprofloxacin and rifampin, respectively. Forty-five percent were penicillin intermediate (Pen^I) associated with hypervirulent serogroup C clonal complex 11. All the strains were susceptible to cephalosporins.

https://ift.tt/2lh7Cz7

Colistin heteroresistance and the involvement of the PmrAB regulatory system in Acinetobacter baumannii [PublishAheadOfPrint]

Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem and colistin is increasingly being used for last resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study is to investigate the role of the PmrAB regulatory pathway in laboratory-selected mutants representative of global epidemic strains. From three unrelated A. baumannii clinical strains (Sequence Type 2, 3 and 20), eight colistin resistant mutants were selected. Half of the mutants showed HR to colistin according to the reference method (Population Analysis Profiling), whereas the other half exhibited stable resistance. M12I mutation within pmrA and M308R, S144KLAGS and P170L mutations for pmrB, were associated with HR to colistin while T235I, A226T and P233S mutations within pmrB were associated with stable resistance. The transcripts levels of the pmrCAB operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I) displayed a compensatory mutation through ISAba1 mobilization within the pmrB gene that was associated with the loss of colistin resistance. The mutant resistance phenotype associated with T235I was partially restored in a trans-complementation assay turning to HR. The level of colistin resistance is correlated with the level of expression of pmrC in the trans-complemented strains. This report shows the role of different mutations in the PmrAB regulatory pathway and warns on the development of colistin HR that could be present but not easily detected through routine testing.

https://ift.tt/2ywNrab

Mutations in gyrA and gyrB in Moxifloxacin-Resistant Mycobacterium avium Complex and Mycobacterium abscessus Complex Clinical Isolates [PublishAheadOfPrint]

Data are limited on the frequency of gyrA and gyrB mutations in fluoroquinolone-resistant isolates of the Mycobacterium avium complex (MAC) and M. abscessus complex (MABC). In our analysis, we did not find any resistance-associated mutations in gyrA or gyrB in 105 clinical isolates of MAC or MABC, including 72 moxifloxacin-resistant isolates. Our findings suggest that mechanisms other than gyrA and gyrB mutations contribute to moxifloxacin resistance in these organisms.

https://ift.tt/2lg22gx

Extinction of Zika virus and Usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs [PublishAheadOfPrint]

Flaviviruses constitute an increasing source of public health concern with growing numbers of pathogens causing disease, and a geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there is currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides that have shown mutagenic activity against other RNA viruses – favipiravir, ribavirin and 5-fluorouracil – while they remain unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although both viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin) while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis, and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication, and the design of antiviral therapies based on lethal mutagenesis.

https://ift.tt/2ywMSNB

Molecular characterization of nasal MRSA isolates showing increasing prevalence of mupirocin resistance and associated multi-drug resistance following attempted decolonization. [PublishAheadOfPrint]

Sequential methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients following attempted mupirocin nasal decolonisation showed an increase in mupirocin resistance (MR) from 6.6% to 20%. MR isolates from patients who failed decolonization yielded indistinguishable spa types and carried multiple antimicrobial- and antiseptic-resistance genes, which may guide infection control and prevention.

https://ift.tt/2ljMh8s

Activity of RX-04 pyrrolocytosine protein synthesis inhibitors against multiresistant Gram-negative bacteria [PublishAheadOfPrint]

Pyrrolocytosines RX-04A-D are designed to bind to the bacterial 50S ribosomal subunit differently from currently-used antibiotics. The four analogs had broad anti-Gram-negative activity: RX-04A inhibited 94.7% of clinical Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa at 0.5-4 μg/ml, with no MICs >8 μg/ml. MICs for multi-resistant carbapenemase producers were up to two-fold higher than for control strains, with values ≥8 μg/ml for one Serratia isolate with porin and efflux lesions. mcr-1 did not affect MICs.

https://ift.tt/2tkXo4B

Genes and Proteins Involved in qnrS1 Induction [PublishAheadOfPrint]

Expression of the quinolone resistance gene qnrS1 is increased by quinolones, but, unlike induction of some other qnr genes, the bacterial SOS system is not involved and no lexA box is found upstream. Nonetheless, at least 205-bp of upstream sequence is required for induction to take place. An upstream sequence bound to beads trapped potential binding proteins from cell extracts that were identified by mass spectrometry as Dps, Fis, Ihf, Lrp, CysB, and YjhU. To further elucidate their role a reporter plasmid linking the qnrS1 upstream sequence to lacZ was introduced into cells of the Keio collection with single gene deletions and screened for lacZ expression. Mutants in ihfA and ihfB had decreased lacZ induction while induction in a cysB mutant was increased and dps, fis, lrp, yjhU and other mutants showed no change. The essential upstream sequence contains potential binding sites for Ihf and DnaA. A dnaA deletion could not be tested because it provides essential functions in cell replication, but increased dnaA expression decreased qnrS1 induction while decreased dnaA expression enhanced it implying a role for DnaA as a repressor. In a mobility shift assay purified IhfA, IhfB, and DnaA proteins (but not CysB) were shown to bind to the upstream segment. Induction decreased in a gyrA quinolone-resistant mutant indicating that GyrA also has a role. Thus, quinolones acting through proteins DnaA, GyrA, IhfA, and IhfB regulates expression of qnrS1.

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Thailandamide: a fatty acid synthesis antibiotic that is co-expressed with a resistant target gene. [PublishAheadOfPrint]

Microbes encode many uncharacterized gene clusters that may produce antibiotics and other bioactive small molecules. Methods for activating these genes are needed to explore their biosynthetic potential. A transposon containing an inducible promoter was randomly inserted into the genome of the soil bacterium Burkholderia thailandensis in order to induce antibiotic expression. This screen identified the polyketide/non-ribosomal peptide thailandamide as an antibiotic and discovered its regulator, AtsR. Mutants of Salmonella resistant to thailandamide had mutations in the accA gene for acetyl-CoA carboxylase, which is one of the first enzymes in the fatty acid synthesis pathway. A second copy of accA in the thailandamide synthesis gene cluster keeps B. thailandensis resistant to its own antibiotic. These genetic techniques will likely be powerful tools for discovering other unusual antibiotics.

https://ift.tt/2yp5GOs

Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis [PublishAheadOfPrint]

Over the past decade, the prevalence of infections involving Methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics has shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate 200 mg PO or IV once daily for 3 doses, with minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetics was performed using maximum-likelihood, expectation maximization method, and the disposition of TZD was described by a 2-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean (%CV) sputum-to-unbound plasma penetration ratio of 2.88 (50.3). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 L/h, 61.6 ± 6.94 L, and 1.04 ± 0.232 respectively. The total clearance is higher in CF patients when compared with healthy volunteers; however, it is similar to published data in patients with complicated skin and skin structure infections (cSSSI). This study demonstrates the oral bioavailability of tedizolid is excellent in patients with CF, and the plasma pharmacokinetics are similar to that reported for patients with cSSSI.

https://ift.tt/2lhUauU

Pharmacological inhibition of the vacuolar ATPase in bloodstream form Trypanosoma brucei rescues genetic knockdown of mitochondrial gene expression [PublishAheadOfPrint]

Trypanosomatid parasites cause diseases in humans and livestock. It was reported that partial inhibition of the vacuolar ATPase (V-ATPase) affects dependence of Trypanosoma brucei on its mitochondrial genome (kDNA), a target of the anti-trypanosomatid drug isometamidium. Here we report that V-ATPase inhibition with bafilomycin A1 (BafA) provides partial resistance to genetic knockdown of mitochondrial gene expression. BafA does not promote long-term survival after kDNA loss, but in its presence, isometamidium causes less damage to kDNA.

https://ift.tt/2ylSiL3

Population Pharmacokinetic Study of Amoxicillin-treated Burn Patients Hospitalized at a Tertiary Swiss Centre [PublishAheadOfPrint]

Objectives: To investigate the population pharmacokinetics (PK) of amoxicillin in ICU burn patients and the optimal dosage regimens.

Methods: Prospective study involving 21 consecutive burn patients receiving amoxicillin. PK data were analysed using non-linear mixed effects modelling. Monte-Carlo simulations assessed the influence of various amoxicillin dosage regimens with identified covariates on the probability to achieve a target (PTA) value of time during which free amoxicillin concentrations in plasma exceeded the minimal inhibitory concentration (fT>MIC).

Results: A two-compartment model best described the data. Creatinine clearance (CL_CR) and body weight (BW) influenced amoxicillin CL and central volume of distribution (V1), respectively. The median CL_CR (Cockcroft-Gault formula) was high (128 mL/min) with 25% of patients having CL_CR > 150 mL/min. The CL, V1 and t_1/2 values at steady-state for a patient with a CL_CR of 110 mL/min and BW of 70 kg were 13.6 L/h, 9.7 L and 0.8 h, respectively. Simulations showed that a target fT>MIC ≥ 50% was achieved (PTA > 90%) with standard amoxicillin dosage regimens (1-2 g q6-8 h) when the MIC was low (< 1 mg/L). However, increased dosages of up to 2 g/4 h were necessary in patients with augmented CL_R or higher MIC. Prolonging amoxicillin infusion from 30 min to 2 h had a favourable effect on target attainment.

Conclusion: This population analysis shows an increased amoxicillin CL and substantial CL PK variability in burn patients compared to literature data with non-burn patients. Situations of augmented CL_CR and/or high bacterial MIC target values may require dosage increases and longer infusion durations.

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Efficacy and Pharmacokinetics Evaluation of a Single Oral Dose of Afoxolaner against Sarcoptes scabiei in the Porcine Scabies Model for Human Infestation [PublishAheadOfPrint]

Scabies is a major and potentially growing public health problem worldwide with an unmet need for acaricidal agents with greater efficacy and improved pharmacological properties for its treatment. The objective of the present study was to assess the efficacy and describe the pharmacokinetics profile of a novel acaricide, afoxolaner (AFX), in a relevant experimental porcine model. Twelve pigs were experimentally infested and treated either with 2.5 mg/kg single dose oral AFX (n = 4), 0.2 mg/kg two-doses 8 days apart oral ivermectin (IVM, n = 4), or no treatment against scabies (n = 4). Response to treatment was assessed by reduction of mite counts in skin scrapings as well as clinical and pruritus scores over time. Plasma and skin pharmacokinetic profiles for both AFX and IVM were evaluated. AFX efficacy was 100% at days 8 and 14 post-treatment and remained unchanged until the study-end (day 45). IVM efficacy was 86% and 97% on days 8 and 14, respectively, with a few mites recovered at study-end. Clinical and pruritus scores decreased in both treated groups and remained constant in the control group. Plasma mean residence times (MRT) were 7.1±2.4 and 1.1±0.2 days for AFX and IVM, respectively. Skin MRT values were 16.2±16.9 and 2.7±0.5 days for AFX and IVM, respectively. Overall, a single oral dose of AFX was efficacious for the treatment of scabies in experimentally infested pigs and showed a remarkably long MRT in plasma and notably in the skin.

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Retrospondyloptosis of the Spine Secondary to Nonaccidental Trauma

Spinal fracture rates from NAT have been reported in

https://ift.tt/2tjKcwS

Prevalence of food allergens sensitization and food allergies in a group of allergic Honduran children

Food allergy is a public health problem that has increased in the last decade. Despite the increasing rates in children, quality data on the burden of these diseases is lacking particularly in developing count...

https://ift.tt/2JS394Y

CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases

Cell adhesion molecule 1 (CADM1) has been reported as a diagnostic marker for Adult T-cell leukemia/lymphoma (ATLL). Our study suggests that CADM1 is expressed not only in ATLL but also in mycosis fungoides (MF). CADM1 can be useful for differentiating MF from inflammatory skin disorders.

https://ift.tt/2lkfkZA

Prevalence of psoriatic arthritis in patients with psoriasis: A systematic review and meta-analysis of observational and clinical studies

Wide-ranging estimates have been reported for the occurrence of psoriatic arthritis in patients with psoriasis. We found an overall pooled prevalence of 19.7% for psoriatic arthritis in patients with psoriasis and 24.6% in patients with moderate-to-severe disease.Screening psoriasis patients for psoriatic arthritis may be warranted, especially for those with moderate-to-severe disease..

https://ift.tt/2MCvnhQ

Oral Immunotherapy for Food Allergy -The FAST perspective

Although the practical application of oral immunotherapy for food allergy (FOIT) is routine in Japan1 and common in Europe,2,3 it continues to be controversial in North America.4 It is not the intention of this report to engage in that polemic, but rather to acknowledge that there are at least dozens of allergists in North America treating thousands of food allergic patients with FOIT. We do not contend that collections of anecdotes are the same as data. We do believe, however, that questions arise in the day-to-day practice of food allergy treatment that must be addressed, but are unlikely to be the subject of prospective, controlled trials.

https://ift.tt/2JZE9YF

Heterogeneity and the origins of asthma

It is a well-known fact that there is significant heterogeneity in the origins of asthma in adults and children. This article examines the roots of asthma across the ages including atopy, the role of the microbiome and viral infections, along with comorbidities/confounders such as obesity, aspirin-exacerbated respiratory disease (AERD), neutrophilic asthma, cigarette smoking and the possibility of an asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome.

https://ift.tt/2I12CaM

Radiographic and histologic characterization of tongue base tissues obtained by transoral robotic surgery in patients with obstructive sleep apnea

Our aim was to radiographically and histologically characterize the tongue base tissues removed after robotic surgery and to analyze their relationship with polysomnographic measurements in obstructive sleep apnea.

https://ift.tt/2JZ6ivM

Clenched fist syndrome: a case report

The clenched fist syndrome/psycho-flexed hand, first described in the early 1980s, has not yet entered the major psychiatric textbooks. Curiously, the phenomenon has been illuminated mainly in journals and tex...

https://ift.tt/2tkuCRD

Perinodal Adipose Tissue Participates in Immune Protection through a Lymphatic Vessel-Independent Route [NOVEL IMMUNOLOGICAL METHODS]

Lymphatic vessels remove and transport excess interstitial fluid to lymph nodes (LNs) for fluid balance and immune protection. LNs are typically surrounded by perinodal adipose tissue (PAT). However, PAT is a blood vessel–rich but lymphatic-rare tissue; therefore, how excess fluid in PAT is removed remains unclear. Using C57BL/6 mice, fluorescent dye tracing and transmission electron microscopy results suggest that fluid in PAT can travel to the LN via collagen I⁺ channels (PAT-LN conduits), merge into a collagen-rich space between the PAT and LN capsule (PAT-LN sinus), and may enter the LN via the LN capsule–associated conduits. This newly identified route of fluid flow allows fluid to enter the draining LN even when the afferent lymphatic vessels are blocked, indicating that fluid trafficking in PAT-LN conduits is not dependent on functional lymphatic vessels. Similar to lymphatic vessels, PAT-LN conduits can deliver Ags to the LN for immune protection. Additionally, Staphylococcus aureus from intradermal or i.v. infection may use PAT-LN conduits to infect PAT and stimulate PAT immune protection. Our studies revealed a new route of material exchange between PAT and the LN. Ag accumulation and bacterial infection in PAT demonstrate that PAT not only provides energy and regulatory factors, but can also directly participate in immune protection, indicating a new immune function of PAT for host immunity.

https://ift.tt/2tjfW5j

Myeloid-Derived Suppressor Cells Impair B Cell Responses in Lung Cancer through IL-7 and STAT5 [TUMOR IMMUNOLOGY]

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity, affecting amino acid metabolism and T cell function in the tumor microenvironment. However, it is unknown whether MDSCs regulate B cell responses during tumor progression. Using a syngeneic mouse model of lung cancer, we show reduction in percentages and absolute numbers of B cell subsets including pro–, pre–, and mature B cells in the bone marrow (BM) of tumor-bearing mice. The kinetics of this impaired B cell response correlated with the progressive infiltration of MDSCs. We identified that IL-7 and downstream STAT5 signaling that play a critical role in B cell development and differentiation were also impaired during tumor progression. Global impairment of B cell function was indicated by reduced serum IgG levels. Importantly, we show that anti–Gr-1 Ab-mediated depletion of MDSCs not only rescued serum IgG and IL-7 levels but also reduced TGF-β1, a known regulator of stromal IL-7, suggesting MDSC-mediated regulation of B cell responses. Furthermore, blockade of IL-7 resulted in reduced phosphorylation of downstream STAT5 and B cell differentiation in tumor-bearing mice and administration of TGF-β–blocking Ab rescued these IL-7–dependent B cell responses. Adoptive transfer of BM-derived MDSCs from tumor-bearing mice into congenic recipients resulted in significant reductions of B cell subsets in the BM and in circulation. MDSCs also suppressed B cell proliferation in vitro in an arginase-dependent manner that required cell-to-cell contact. Our results indicate that tumor-infiltrating MDSCs may suppress humoral immune responses and promote tumor escape from immune surveillance.

https://ift.tt/2MCW068

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity [IMMUNE REGULATION]

Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5–induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention.

https://ift.tt/2tkc1F4

Correction: NK Cells Influence Both Innate and Adaptive Immune Responses after Mucosal Immunization with Antigen and Mucosal Adjuvant [CORRECTIONS]

https://ift.tt/2MCwyhe

Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease [INNATE IMMUNITY AND INFLAMMATION]

Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament–binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.

https://ift.tt/2Mza4gW

Genome-Wide Posttranscriptional Dysregulation by MicroRNAs in Human Asthma as Revealed by Frac-seq [SYSTEMS IMMUNOLOGY]

MicroRNAs are small noncoding RNAs that inhibit gene expression posttranscriptionally, implicated in virtually all biological processes. Although the effect of individual microRNAs is generally studied, the genome-wide role of multiple microRNAs is less investigated. We assessed paired genome-wide expression of microRNAs with total (cytoplasmic) and translational (polyribosome-bound) mRNA levels employing subcellular fractionation and RNA sequencing (Frac-seq) in human primary bronchoepithelium from healthy controls and severe asthmatics. Severe asthma is a chronic inflammatory disease of the airways characterized by poor response to therapy. We found genes (i.e., isoforms of a gene) and mRNA isoforms differentially expressed in asthma, with novel inflammatory and structural pathophysiological mechanisms related to bronchoepithelium disclosed solely by polyribosome-bound mRNAs (e.g., IL1A and LTB genes or ITGA6 and ITGA2 alternatively spliced isoforms). Gene expression (i.e., isoforms of a gene) and mRNA expression analysis revealed different molecular candidates and biological pathways, with differentially expressed polyribosome-bound and total mRNAs also showing little overlap. We reveal a hub of six dysregulated microRNAs accounting for ~90% of all microRNA targeting, displaying preference for polyribosome-bound mRNAs. Transfection of this hub in bronchial epithelial cells from healthy donors mimicked asthma characteristics. Our work demonstrates extensive posttranscriptional gene dysregulation in human asthma, in which microRNAs play a central role, illustrating the feasibility and importance of assessing posttranscriptional gene expression when investigating human disease.

https://ift.tt/2MAeIeA

Innate Nutritional Immunity [BRIEF REVIEWS]

Iron (Fe) is an essential micronutrient for both microbes and their hosts. The biologic importance of Fe derives from its inherent ability to act as a universal redox catalyst, co-opted in a variety of biochemical processes critical to maintain life. Animals evolved several mechanisms to retain and limit Fe availability to pathogenic microbes, a resistance mechanism termed "nutritional immunity." Likewise, pathogenic microbes coevolved to deploy diverse and efficient mechanisms to acquire Fe from their hosts and in doing so overcome nutritional immunity. In this review, we discuss how the innate immune system regulates Fe metabolism to withhold Fe from pathogenic microbes and how strategies used by pathogens to acquire Fe circumvent these resistance mechanisms.

https://ift.tt/2tjfTGF

Original Ligand for LT{beta}R Is LIGHT: Insight into Evolution of the LT/LT{beta}R System [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The lymphotoxin (LT)/LTβ receptor (LTβR) axis is crucial for the regulation of immune responses and development of lymphoid tissues in mammals. Despite the importance of this pathway, the existence and function of LT and LTβR remain obscure for nonmammalian species. In this study, we report a nonmammalian LTβR and its ligand. We demonstrate that TNF-New (TNFN), which has been considered orthologous to mammalian LT, was expressed on the cell surface as a homomer in vitro. This different protein structure indicates that TNFN is not orthologous to mammalian LTα and LTβ. Additionally, we found that LTβR was conserved in teleosts, but the soluble form of recombinant fugu LTβR did not bind to membrane TNFN under the circumstance tested. Conversely, the LTβR recombinant bound to another ligand, LIGHT, similar to that of mammals. These findings indicate that teleost LTβR is originally a LIGHT receptor. In the cytoplasmic region of fugu LTβR, recombinant fugu LTβR bound to the adaptor protein TNFR-associated factor (TRAF) 2, but little to TRAF3. This difference suggests that teleost LTβR could potentially activate the classical NF-B pathway with a novel binding domain, but would have little ability to activate an alternative one. Collectively, our results suggested that LIGHT was the original ligand for LTβR, and that the teleost immune system lacked the LT/LTβR pathway. Acquisition of the LT ligand and TRAF binding domain after lobe-finned fish may have facilitated the sophistication of the immune system and lymphoid tissues.

https://ift.tt/2MAyEy4

CD4 T Cell Affinity Diversity Is Equally Maintained during Acute and Chronic Infection [ANTIGEN RECOGNITION AND RESPONSES]

TCR affinity for peptide MHC dictates the functional efficiency of T cells and their propensity to differentiate into effectors and form memory. However, in the context of chronic infections, it is unclear what the overall profile of TCR affinity for Ag is and if it differs from acute infections. Using the comprehensive affinity analysis provided by the two-dimensional micropipette adhesion frequency assay and the common indirect affinity evaluation methods of MHC class II tetramer and functional avidity, we tracked IA^b GP_61–80–specific cells in the mouse model of acute (Armstrong) and chronic (clone 13) lymphocytic choriomeningitis virus infection. In each response, we show CD4 T cell population affinity peaks at the effector phase and declines with memory. Of interest, the range and average relative two-dimensional affinity was equivalent between acute and chronic infection, indicating chronic Ag exposure did not skew TCR affinity. In contrast, functional and tetramer avidity measurements revealed divergent results and lacked a consistent correlation with TCR affinity. Our findings highlight that the immune system maintains a diverse range in TCR affinity even under the pressures of chronic Ag stimulation.

https://ift.tt/2t6ft76

Effects of Influenza on Alveolar Macrophage Viability Are Dependent on Mouse Genetic Strain [INFECTIOUS DISEASE AND HOST RESPONSE]

Secondary bacterial coinfections following influenza virus pose a serious threat to human health. Therefore, it is of significant clinical relevance to understand the immunological causes of this increased susceptibility. Influenza-induced alterations in alveolar macrophages (AMs) have been shown to be a major underlying cause of the increased susceptibility to bacterial superinfection. However, the mechanisms responsible for this remain under debate, specifically in terms of whether AMs are depleted in response to influenza infection or are maintained postinfection, but with disrupted phagocytic activity. The data presented in this article resolves this issue by showing that either mechanism can differentially occur in individual mouse strains. BALB/c mice exhibited a dramatic IFN-–dependent reduction in levels of AMs following infection with influenza A, whereas AM levels in C57BL/6 mice were maintained throughout the course of influenza infection, although the cells displayed an altered phenotype, namely an upregulation in CD11b expression. These strain differences were observed regardless of whether infection was performed with low or high doses of influenza virus. Furthermore, infection with either the H1N1 A/California/04/2009 (CA04) or H1N1 A/PR8/1934 (PR8) virus strain yielded similar results. Regardless of AM viability, both BALB/c and C57BL/6 mice showed a high level of susceptibility to postinfluenza bacterial infection. These findings resolve the apparent inconsistencies in the literature, identify mouse strain–dependent differences in the AM response to influenza infection, and ultimately may facilitate translation of the mouse model to clinical application.

https://ift.tt/2t7LGuV

CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease [AUTOIMMUNITY]

CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2–deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2–deficient mice. CD8 T cells express the B cell follicle–localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality.

https://ift.tt/2thVfGI

Innate Recognition of the Microbiota by TLR1 Promotes Epithelial Homeostasis and Prevents Chronic Inflammation [MUCOSAL IMMUNOLOGY]

There is cross-talk between the intestinal epithelium and the microbiota that functions to maintain a tightly regulated microenvironment and prevent chronic inflammation. This communication is partly mediated through the recognition of bacterial proteins by host-encoded innate receptors, such as TLRs. However, studies examining the role of TLR signaling on colonic homeostasis have given variable and conflicting results. Despite its critical role in mediating immunity during enteric infection of the small intestine, TLR1-mediated recognition of microbiota-derived ligands and their influence on colonic homeostasis has not been well studied. In this study, we demonstrate that defective TLR1 recognition of the microbiome by epithelial cells results in disruption of crypt homeostasis specifically within the secretory cell compartment, including a defect in the mucus layer, ectopic Paneth cells in the colon, and an increase in the number of rapidly dividing cells at the base of the crypt. As a consequence of the perturbed epithelial barrier, we found an increase in mucosal-associated and translocated commensal bacteria and chronic low-grade inflammation characterized by an increase in lineage-negative Sca1⁺Thy1^hi innate lymphoid-like cells that exacerbate inflammation and worsen outcomes in a model of colonic injury and repair. Our findings demonstrate that sensing of the microbiota by TLR1 may provide key signals that regulate the colonic epithelium, thereby limiting inflammation through the prevention of bacterial attachment to the mucosa and exposure to the underlying immune system.

https://ift.tt/2t7LEmN

TRIM29 Negatively Regulates the Type I IFN Production in Response to RNA Virus [INNATE IMMUNITY AND INFLAMMATION]

The innate immunity is critically important in protection against virus infections, and in the case of RNA viral infections, the signaling mechanisms that initiate robust protective innate immunity without triggering autoimmune inflammation remain incompletely defined. In this study, we found the E3 ligase TRIM29 was specifically expressed in poly I:C–stimulated human myeloid dendritic cells. The induced TRIM29 played a negative role in type I IFN production in response to poly I:C or dsRNA virus reovirus infection. Importantly, the challenge of wild-type mice with reovirus led to lethal infection. In contrast, deletion of TRIM29 protected the mice from this developing lethality. Additionally, TRIM29^–/– mice have lower titers of reovirus in the heart, intestine, spleen, liver, and brain because of elevated production of type I IFN. Mechanistically, TRIM29 was shown to interact with MAVS and subsequently induce its K11-linked ubiquitination and degradation. Taken together, TRIM29 regulates negatively the host innate immune response to RNA virus, which could be employed by RNA viruses for viral pathogenesis.

https://ift.tt/2t7SMiY

IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo [CLINICAL AND HUMAN IMMUNOLOGY]

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte–derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF–driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.

https://ift.tt/2MAeILC

Pillars Article: T-Cell Apoptosis Detected In Situ during Positive and Negative Selection in the Thymus. Nature. 1994. 372: 100-103 [PILLARS OF IMMUNOLOGY]

https://ift.tt/2tdCrtd

Differential Roles of LT{beta}R in Endothelial Cell Subsets for Lymph Node Organogenesis and Maturation [IMMUNE SYSTEM DEVELOPMENT]

Cellular cross-talk mediated by lymphotoxin αβ–lymphotoxin β receptor (LTβR) signaling plays a critical role in lymph node (LN) development. Although the major role of LTβR signaling has long been considered to occur in mesenchymal lymphoid tissue organizer cells, a recent study using a VE-cadherin^creLtbr^fl/fl mouse model suggested that endothelial LTβR signaling contributes to the formation of LNs. However, the detailed roles of LTβR in different endothelial cells (ECs) in LN development remain unknown. Using various cre transgenic mouse models (Tek^cre, a strain targeting ECs, and Lyve1^cre, mainly targeting lymphatic ECs), we observed that specific LTβR ablation in Tek^cre+ or Lyve1^cre+ cells is not required for LN formation. Moreover, double-cre–mediated LTβR depletion does not interrupt LN formation. Nevertheless, Tek^creLtbr^fl/fl mice exhibit reduced lymphoid tissue inducer cell accumulation at the LN anlagen and impaired LN maturation. Interestingly, a subset of ECs (VE-cadherin⁺Tek^cre-low/neg ECs) was found to be enriched in transcripts related to hematopoietic cell recruitment and transendothelial migration, resembling LN high ECs in adult animals. Furthermore, endothelial Tek was observed to negatively regulate hematopoietic cell transmigration. Taken together, our data suggest that although Tek^cre+ endothelial LTβR is required for the accumulation of hematopoietic cells and full LN maturation, LTβR in VE-cadherin⁺Tek^cre-low/neg ECs in embryos might represent a critical portal-determining factor for LN formation.

https://ift.tt/2t7gM5M

MicroRNA-302 Cluster Downregulates Enterovirus 71-Induced Innate Immune Response by Targeting KPNA2 [INNATE IMMUNITY AND INFLAMMATION]

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus–induced IFN expression by targeting NF-B-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy.

https://ift.tt/2thV5PC

Survival of Mice with Gastrointestinal Acute Radiation Syndrome through Control of Bacterial Translocation [IMMUNOTHERAPY AND VACCINES]

Macrophages (M) with the M2b phenotype (Pheno2b-M) in bacterial translocation sites have been described as cells responsible for the increased susceptibility of mice with gastrointestinal acute radiation syndrome to sepsis caused by gut bacteria. In this study, we tried to reduce the mortality of mice exposed to 7–10 Gy of gamma rays by controlling Pheno2b-M polarization in bacterial translocation sites. MicroRNA-222 was induced in association with gamma irradiation. Pheno2b-M polarization was promoted and maintained in gamma-irradiated mice through the reduction of a long noncoding RNA growth arrest–specific transcript 5 (a CCL1 gene silencer) influenced by this microRNA. Therefore, the host resistance of 7–9-Gy gamma-irradiated mice to sepsis caused by bacterial translocation was improved after treatment with CCL1 antisense oligodeoxynucleotide. However, the mortality of 10-Gy gamma-irradiated mice was not alleviated by this treatment. The crypts and villi in the ileum of 10-Gy gamma-irradiated mice were severely damaged, but these were markedly improved after transplantation of intestinal lineage cells differentiated from murine embryonic stem cells. All 10-Gy gamma-irradiated mice given both of the oligodeoxynucleotide and intestinal lineage cells survived, whereas all of the same mice given either of them died. These results indicate that high mortality rates of mice irradiated with 7–10 Gy of gamma rays are reducible by depleting CCL1 in combination with the intestinal lineage cell transplantation. These findings support the novel therapeutic possibility of victims who have gastrointestinal acute radiation syndrome for the reduction of their high mortality rates.

https://ift.tt/2ymlEJr

IL-36{alpha} from Skin-Resident Cells Plays an Important Role in the Pathogenesis of Imiquimod-Induced Psoriasiform Dermatitis by Forming a Local Autoamplification Loop [INNATE IMMUNITY AND INFLAMMATION]

IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6^–/– mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6^–/– mice showed similar susceptibility to dextran sodium sulfate–induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6^–/– mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36), but not Il1f8 (IL-36β), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1β, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1β, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling–induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.

https://ift.tt/2ymlj9D

Formation of Immune Complexes with a Tetanus-Derived B Cell Epitope Boosts Human T Cell Responses to Covalently Linked Peptides in an Ex Vivo Blood Loop System [IMMUNOTHERAPY AND VACCINES]

Enhancing T cell responses against both viral and tumor Ags requires efficient costimulation and directed delivery of peptide Ags into APCs. Long peptide vaccines are considered favorable vaccine moieties from a clinical perspective, as they can harbor more than one immunogenic epitope enabling treatment of a broader target population. In addition, longer peptides are not extracellularly loaded on MHC class I; rather, they require intracellular processing and will thereby be presented to T cells mainly by professional APCs, thereby avoiding the risk of tolerance induction. The drawback of peptide vaccines regardless of peptide length is that naked peptides are not actively targeted to and taken up by APCs, and the standard nonconjugated adjuvant-peptide mixtures do not ensure cotargeting of the two to the same APC. We have identified a tetanus toxin–derived B cell epitope that can mediate the formation of immune complexes in the presence of circulating Abs. In this study, we show that these immune complexes improve both Ag uptake by APCs (blood monocytes and CD1c⁺ dendritic cells) and consequently improve CD8⁺ T cell recall responses in a human ex vivo blood loop system. The uptake of the peptide conjugate by blood monocytes is dependent on Abs and the complement component C1q. We envision that this strategy can be used to facilitate active uptake of Ags into APCs to improve T cell responses against pathogens or cancer.

https://ift.tt/2MwowX7

Alex Haller, Founder of Pediatric Surgery at Johns Hopkins, Pioneer of Pediatric Trauma Care, Dies At 91

J. Alex Haller Jr., M.D., a trailblazing pioneer in pediatric surgery, pediatric trauma treatment and biomedical ethics who transformed the practice of pediatric care at Johns Hopkins and throughout the nation, died on June 13 in Glencoe, Maryland. He was 91.

https://ift.tt/2I1SmPB

The Optimal Dose of Sevoflurane Via Anaconda® in Post-operative Patient Underwent Head & Neck Surgery

Condition:   Patients Who Needs Sedation After Head & Neck Surgery
Interventions:   Procedure: Naso-tracheal group;   Procedure: tracheostomy group
Sponsor:   Yonsei University
Recruiting

https://ift.tt/2t40RVY

Postural Garment Versus Exercises for Women With Cervical Pain

Conditions:   Posture;   Cervical Pain
Interventions:   Other: Exercises;   Device: Posture garment
Sponsor:   University of Andorra
Recruiting

https://ift.tt/2M2pI3c

The Role of Surgical Debridement in Cases of Refractory Malignant Otitis Externa

Abstract

Malignant Otitis externa is a necrotizing condition of external ear involving causing the osteomyelitis of the bone and surrounding soft tissue leading to multiple cranial nerve palsies. Though most patients respond to oral ciprofloxacin but due to emerging resistance cases of refractory malignant otitis externa which are unresponsive to antibiotic therapy for at least 6 weeks are being encountered lately. A study of 20 patients of refractory malignant otitis Externa was conducted at a tertiary care centre in north India; 10 patients were randomly allotted in group A and group B each. Group A was subjected to i/v ceftazidine 1 gm bd with oral ciprofloxacin 750 mg bd and Group B was subjected to surgical debridement with oral ciprofloxacin 750 mg bd. The improvement in symptoms was tabulated and statistical analysis was done using Mann–Whitney U test. There was better resolution of nocturnal pain in patients of group B who underwent surgical debridement although existing facial palsy didn't improve in both the groups. The improvement of symptoms in group B was statistically significant with P ≤ 0.05. We strongly recommend the role of surgical debridement in cases of refractory malignant otitis externa to relieve the patient of nocturnal pain. As the sample size of the study is small we are looking forward to the compilation of a multi institutional data so that a consensus on definitive protocol in cases unresponsive to oral multidrug therapy can be established.

https://ift.tt/2tioHwe

Kimura’s Disease: A Rare Cause of Parotid Swelling

Abstract

Kimura's disease also known as subcutaneous angioblastic lymphoid hyperplasia with peripheral eosinophilia is a rare clinicopathological entity. It is a chronic granulomatous disease of unknown etiology. The clinical presentation varies from subcutaneous swellings of the head and neck region with regional lymphadenopathy with salivary gland involvement to systemic manifestations like nephrotic syndrome. The clinical features are mild, rarely life threatening. The present article is a case report of Kimura's disease presenting as multiple swellings at the left temporal region, left parotid and bilateral post auricular region. Though the lesion is benign, the cosmetic disfigurement caused by the swellings was of significant concern to our patient. MRI Scan was suggestive of a parotid swelling extending into the temporal and post auricular region of the left side. Surgical modality of treatment was adopted- Superficial Parotidectomy with excision of subcutaneous swellings. Histopathological examination confirmed the diagnosis of Kimura's disease. The mode of presentation as multiple large swellings with the involvement of the parotid gland created a diagnostic dilemma, hence this article intends to consider Kimura's disease as a rare but possible cause of a parotid swelling.

https://ift.tt/2lhYpXy

Study the Effect of Tubotympanic Disease on Bone Conduction Threshold

Abstract

Tubo-tympanic disease of middle ear cleft can temporarily detoriate the bone conduction threshold specially in higher frequency in long standing cases. It mainly affects the inertial ossicular component of the bone conduction mechanism. (1) Study the effect of tubotympanic disease on bone conduction threshold (SN loss). (2) Study the duration of the disease on bone conduction threshold. 84 cases of tubotympanic disease were taken for the study. There pre-operative PTA was done and effect of the disease on the bone conduction threshold was noted. Results were analyzed by using analysis of variance. The significance level α was taken 0.05 as at marginally significant, 0.01 significant and 0.001 as highly significant. The bone conduction at all frequencies increased significantly P < 0.05 with duration of ear discharge. The differences in the bone conduction at all frequencies amongst normal ears were significantly lower as compared to the diseased ear. Duration of ear discharge and type of hearing loss reveals that in patients with ear discharge less than 11 years there were 24 (77.41%) subjects with conductive hearing loss, 1 (3.22%) subject with mixed hearing loss. As the duration increased 11–20 years, the cases of conductive hearing loss decreased 13 (56.52%) and cases of mixed hearing loss increased to 3 (13.04%). In patients with ear discharge of > 21 years conductive subjects were 19 (63.33%) and subjects with mixed hearing loss increased to 5 (33.33%) cases. The average hearing loss and the average bone conduction threshold increases as the duration of disease increases. In patients of safe CSOM who have poor BCT, it is the higher frequencies which are more affected.

https://ift.tt/2tgcMPG