A Practical Approach for the Verification and Determination of Site- and Trimester-Specific Reference Intervals for Thyroid Function Tests in Pregnancy

Thyroid, Ahead of Print.


http://bit.ly/2DSC8JM

Cochlear implantation as a treatment for single-sided deafness and asymmetric hearing loss: a randomized controlled evaluation of cost-utility

Abstract

Background

Single-sided deafness (SSD) and asymmetric hearing loss (AHL) have recently been proposed as a new indication for cochlear implantation. There is still no recommended treatment for these hearing deficits, and most options considered rely on the transfer of sound from the poor ear to the better ear, using Contralateral Routing of the Signal (CROS) hearing aids or bone conduction (BC) devices. In contrast, cochlear implantation allows the poor ear to be stimulated and binaural hearing abilities to be partially restored. Indeed, most recently published studies have reported an improvement in the spatial localisation of an incoming sound and better speech recognition in noisy environments after cochlear implantation in SSD/AHL subjects. It also provides consistent relief of tinnitus when associated. These encouraging hearing outcomes raise the question of the cost-utility of this expensive treatment in an extended indication.

Methods

The final endpoint of this national multicentre study is to determine the incremental cost-utility ratio (ICUR) of cochlear implantation in comparison to the current standard of care in France through simple observation, using a randomised controlled trial. Firstly, the study comprises a prospective and descriptive part, where 150 SSD/AHL subjects try CROS hearing aids and a BC device for three weeks each. Secondly, the choice is made between CROS hearing aids, BC implanted device and cochlear implantation. Hearing outcomes and quality of life measurements are described after 6 months for the subjects who chose CROS, BC or declined any option. The subjects who opt for cochlear implantation are randomised between one group where the cochlear implant is inserted without delay and one group of simple initial observation. Hearing outcomes and quality of life measurements are compared after 6 months.

Discussion

The present study was designed to assess the efficiency of cochlear implantation in SSD/AHL. A favourable cost-utility ratio in this extended indication would strengthen the promising clinical results and justify a reimbursement by the health insurance. The efficiency of other options (CROS, BC) will also be described.

Trial registration

This research has been registered in ClinicalTrials.gov (http://www.clinicaltrials.gov/), the 29th July 2014 under the n°NCT02204618.

http://bit.ly/2UGSSsW

Whole genome sequencing for drug resistance profile prediction in Mycobacterium tuberculosis [Mechanisms of Resistance]

Whole genome sequencing allows rapid detection of drug-resistant Mycobacterium tuberculosis isolates. However, the availability of high-quality data linking quantitative phenotypic drug susceptibility testing (DST) and genomic data has thus far been limited.

We determined drug resistance profiles of 176 genetically diverse clinical M. tuberculosis isolates from Democratic Republic of the Congo, Ivory Coast, Peru, Thailand and Switzerland by quantitative phenotypic DST for 11 antituberculous drugs using the BD BACTEC MGIT 960 system and 7H10 agar dilution to generate a cross-validated phenotypic DST readout. We compared DST results with predicted drug resistance profiles inferred by whole genome sequencing.

Classification of strains by the two phenotypic DST methods into resistotype/wild type populations was concordant in 73-99 % of cases, depending on the drug. Our data suggests that the established critical concentration (5 mg/L) for ethambutol resistance (MGIT 960 system) is too high and may misclassify strains as susceptible, compared to 7H10 agar dilution. Increased minimal inhibitory concentrations were explained by mutations identified by whole genome sequencing. Using whole genome sequences, we were able to predict quantitative drug resistance levels for the majority of drug resistance mutations. Predicting quantitative levels of drug resistance by whole genome sequencing was partially limited due to incompletely understood drug resistance mechanisms. The overall sensitivity and specificity of whole genome-based DST were 86.8 % and 94.5 %, respectively.

Despite some limitations, whole genome sequencing has the potential to infer resistance profiles without the need for time-consuming phenotypic methods.

http://bit.ly/2SuameP

In Vitro Activity of Tebipenem (SPR859) Against Penicillin-Binding Proteins of Gram-negative and Gram-positive Bacteria [Mechanisms of Action]

Tebipenem (SPR859) is the microbiologically active form of SPR994, tebipenem-pivoxil, an orally available carbapenem with activity against extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae. Measurement of the relative binding of SPR859 to the bacterial cell targets revealed that it is a potent inhibitor of multiple penicillin-binding proteins (PBPs), but primarily a Gram-negative PBP2 inhibitor, similar to other compounds in this class. These data support further clinical development of SPR994.

http://bit.ly/2GoFciy

Impact of Pre-existing Hepatitis C Virus Genotype 6 NS3, NS5A and NS5B Polymorphisms on Their In Vitro Susceptibility to Inhibition by Direct-Acting Antiviral Agents [Antiviral Agents]

HCV genotype (GT)-6 is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with HCV GT-6a where high response rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the US HCV database were compared and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Pre-existing resistance-associated substitutions (RASs) to NS3 protease (A156V, D168E) and NS5B nucleotide (L159F, S282C) inhibitors were rare (<4%). Pre-existing RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (EC₉₀ range 119-2032nM) compared with susceptibilities against a GT-6a consensus replicon (EC₉₀ range 0.1-19nM). These L28 RASs pre-existed in combination with R30S (EC₉₀[lsqb]L28A-R30S[rsqb] ≥720nM or EC₉₀[lsqb]L28T-R30S[rsqb] ≥128nM against tested DAAs) or as L28T-L31I (EC₉₀[lsqb]tested DAAs[rsqb] >5000nM) and were detected in evaluated GT-6b or -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Monitoring of response rates in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is therefore suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

http://bit.ly/2Srf3WM

"Resurrecting old {beta}-lactams": the potent inhibitory activity of temocillin against multi-drug resistant Burkholderia spp. isolates from the United States [Mechanisms of Resistance]

Burkholderia spp. are opportunistic human pathogens that infect persons with cystic fibrosis and the immunocompromised. Burkholderia spp. express class A and C β-lactamases, which are transcriptionally regulated by PenR_A through linkage to cell wall metabolism and β-lactam exposure. The potency of temocillin, a 6-methoxy-β-lactam was tested against a panel of multi-drug resistant (MDR) Burkholderia spp. In addition, the mechanistic basis of temocillin activity was assessed and compared to ticarcillin. Susceptibility testing with temocillin and ticarcillin was conducted, as well as biochemical analysis of the PenA1 class A β-lactamase and AmpC1 class C β-lactamase. Molecular dynamics simulations (MDS) were performed using PenA1 with temocillin and ticarcillin. The majority (86.7%) of 150 MDR Burkholderia strains were susceptible to temocillin, while only 4% of the strains were susceptible to ticarcillin. Neither temocillin nor ticarcillin induced bla expression. Ticarcillin was hydrolyzed by PenA1 (k_cat/K_m = 1.7±0.2 μM^-1s^-1), while temocillin was slow to form a favorable complex (K_iapp = ~2 mM). Ticarcillin and temocillin were both potent inhibitors of AmpC1, with K_{i app} values of 4.9±1.0 μM and 4.3±0.4 μM, respectively. MDS of PenA revealed that ticarcillin is in an advantageous position for acylation and deacylation. Conversely, with temocillin, active site residues K73 and S130 are rotated and the catalytic water molecule is displaced, thereby slowing acylation and allowing the 6-methoxy of temocillin to block deacylation. Temocillin is a β-lactam with potent activity against Burkholderia spp. as it does not induce bla expression and is poorly hydrolyzed by endogenous β-lactamases.

http://bit.ly/2GoF9TU

An in vitro Mechanistic Study of the Distribution of Lascufloxacin into the Epithelial Lining Fluid [Pharmacology]

The present study aimed to clarify the mechanism underlying the high distribution of lascufloxacin in epithelial lining fluid (ELF). Involvement of transporters was examined by transcellular transport across Calu-3 and transporter-overexpressing cells; the binding of lascufloxacin to ELF components was examined by an organic solvent-water partitioning system that employed pulmonary surfactant and phospholipids. Transcellular transport across the transporter-overexpressing cells indicated lascufloxacin to be a substrate of both P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP); therefore, its transport across Calu-3 cells was inhibited by P-gp and BCRP inhibitors. However, permeability and efflux ratios of lascufloxacin were similar to those of the other quinolones with relatively low ELF distribution, indicating the existence of another mechanism for lascufloxacin distribution in ELF. Amongst pulmonary surfactants, which are a primary component of ELF, lascufloxacin preferentially bound to phosphatidylserine (PhS) from several phospholipids, and the binding was significantly higher than that for other quinolones. This binding was saturable with two apparent classes of binding sites, and inhibited by some weakly basic drugs, indicating the presence of an ionic bond. In conclusion, the results of this study suggest that the binding of lascufloxacin to PhS in the pulmonary surfactant is the major mechanism of the high distribution of lascufloxacin in the ELF.

http://bit.ly/2SsXOnX

Cefepime Pharmacokinetics in Critically Ill Pediatric Patients Receiving Continuous Renal Replacement Therapy [Pharmacology]

This retrospective study included pediatric intensive care unit patients receiving continuous venovenous hemodiafiltration (CVVHDF) being treated with cefepime. Free drug concentration time above one and four times a presumed MIC of 8 mcg/mL were calculated. Four patients received doses ranging from 48 to 64 mg/kg/dose every six to twelve hours. Three patients achieved 100% fT>1xMIC with the fourth achieving 98% fT>1xMIC. Therapeutic drug monitoring should be considered for critically ill patients receiving cefepime on CVVHDF.

http://bit.ly/2GoEMJ0

A FASII inhibitor prevents staphylococcal evasion of daptomycin by inhibiting phospholipid decoy production [Mechanisms of Action]

Daptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus. We have shown recently that S. aureus can evade daptomycin by releasing phospholipid decoys that sequester and inactivate the antibiotic, leading to treatment failure. Since phospholipid release occurs via an active process, we hypothesised that it could be inhibited, thereby increasing daptomycin efficacy. To identify opportunities for therapeutic interventions that block phospholipid release, we first determined how the host environment influenced the release of phospholipids and inactivation of daptomycin by S. aureus. The addition of certain host-associated fatty acids to the growth medium enhanced phospholipid release. However, in serum, the sequestration of fatty acids by albumin restricted their availability to S. aureus sufficiently to prevent their use in the generation of released phospholipids. This finding implied that in host tissues S. aureus may be completely dependent upon endogenous phospholipid biosynthesis to generate lipids for release, providing a target for therapeutic intervention. To test this, we exposed S. aureus to AFN-1252, an inhibitor of the staphylococcal FASII fatty acid biosynthetic pathway, together with daptomycin. AFN-1252 efficiently blocked daptomycin-induced phospholipid decoy production, even in the case of isolates resistant to AFN-1252, which prevented the inactivation of daptomycin and resulted in sustained bacterial killing. In turn, daptomycin prevented the fatty acid-dependent emergence of AFN-1252-resistant isolates in vitro. In summary, AFN-1252 significantly enhances daptomycin activity against S. aureus in vitro by blocking the production of phospholipid decoys, whilst daptomycin blocks the emergence of resistance to AFN-1252.

http://bit.ly/2SxqJXU

Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis [Experimental Therapeutics]

Candida albicans, the causative agent of mucosal infections including oropharyngeal candidiasis (OPC) as well as bloodstream infections is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron-limitation using deferasirox (an FDA approved iron chelator for treatment of patients with iron overload) during murine OPC; and assessed deferasirox-treated C. albicans for its interaction with human oral epithelial (OE), neutrophils, and antimicrobial peptides. Therapeutic deferasirox treatment significantly reduced salivary iron levels while a non-significant reduction in fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model, resulted in significant reduction of C. albicans colony forming units (CFU)/g of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans harvested from tongues of animals undergoing preventive treatment had differential expression of 106 genes, including those involved in iron metabolism, adhesion, and response to host innate immunity. Moreover, deferasirox-treated C. albicans cells had two-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress); and reduced adhesion and invasion of OE cells, in vitro. Thus deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence.

http://bit.ly/2GoEJNk

Impact of an antimicrobial stewardship intervention on within and between patient daptomycin resistance evolution in vancomycin-resistant Enterococcus faecium. [Clinical Therapeutics]

Vancomycin-resistant Enterococcus (VRE) is a leading cause of hospital acquired infection, with limited treatment options. Resistance to one of the few remaining drugs, daptomycin, is a growing clinical problem, and has previously been described in this hospital. In response to increasing resistance, an antimicrobial stewardship intervention was implemented to reduce hospital-wide use of daptomycin. To assess the impact of the intervention, daptomycin prescribing patterns and clinically-reported culture results from VRE faecium blood stream infections (BSI) from 2011 through 2017 were retrospectively extracted and the impact of the intervention was estimated using interrupted time series analysis. We corrected for a change in MIC testing methodology by retesting 262 isolates using E-test and broth microdilution. Hospital-wide and within-patient resistance patterns of corrected daptomycin MICs are reported. Our data show that daptomycin prescriptions decreased from an average of 287 days of therapy/month pre-intervention, to 151 days of therapy/month post-intervention. Concurrently, the proportion of patients experiencing an increase in daptomycin minimum inhibitory concentration (MIC) during an infection declined from 14.6% (7/48 patients) in 2014 to 1.9% (1/54 patients) in 2017. Hospital-wide resistance to daptomycin also decreased in the post-intervention period, but this was not maintained. This study shows that an antimicrobial stewardship guided intervention reduced daptomycin use and improved individual level outcomes but had only transient impact on the hospital-level trend.

http://bit.ly/2StsiGv

Negative impact of carbapenem methylation on the reactivity of {beta}-lactams for cysteine acylation revealed by quantum calculations and kinetic analyses [Chemistry; Biosynthesis]

The Ldt_fm L,D-transpeptidase mediates resistance to most β-lactam antibiotics in Enterococcus faecium by replacing classical peptidoglycan polymerases. The catalytic Cys of Ldt_fm is rapidly acylated by β-lactams belonging to the carbapenem class but not by penams and cephems. We previously reported quantum calculations and kinetic analyses for Ldt_fm and showed that the inactivation profile is not determined by differences in drug binding (K_D values in the 50-80 mM range). Here, we analyze the reaction of a Cys sulfhydryl with various β-lactams in the absence of the enzyme environment in order to compare the intrinsic reactivity of drugs belonging to the penam, cephem, and carbapenem classes. For this purpose, we synthesized cyclic Cys-Asn to generate a soluble molecule with a sulfhydryl closely mimicking a cysteine in a polypeptide chain thereby avoiding free reactive amino and carboxyl groups. Computational studies identified a thermodynamically favored pathway involving a concerted rupture of the β-lactam amide bond and formation of an amine anion. Energy barriers indicated that the drug reactivity was the highest for non-methylated carbapenems, intermediate for methylated carbapenems and cephems, and the lowest for penams. Electron withdrawing groups were key reactivity determinants by enabling delocalization of the negative charge of the amine anion. Acylation rates of cCys-Asn determined by spectrophotometry revealed the same order in the reactivity of β-lactams. We concluded that the rate of Ldt_fm acylation is largely determined by the β-lactam reactivity with one exception as the enzyme catalytic pocket fully compensated for the detrimental effect of carbapenem methylation.

http://bit.ly/2GouSXH

Abrogation of triazole resistance upon deletion of CDR1 in a clinical isolate of Candida auris [Mechanisms of Resistance]

Candida auris has rapidly emerged as a healthcare-associated and multidrug-resistant pathogen of global concern. In this work, we examined the relative expression of the four C. auris genes with the highest degree of homology to C. albicans CDR1 and MDR1 among three triazole-resistant clinical isolates, as compared to the triazole-susceptible genome reference clinical isolate. We subsequently utilized a novel Cas9-mediated system for genetic manipulations to delete C. auris CDR1 and MDR1 in both a triazole-resistant clinical isolate and the susceptible reference strain, and observed MIC for all clinically available triazoles decreased as much as 128-fold in the CDR1 deletion strains. The findings of this work reveal for the first time that both C. auris CDR1 and MDR1 are more highly expressed among triazole-resistant clinical isolates of C. auris, and that the overexpression of CDR1 is a significant contributor to clinical triazole resistance.

http://bit.ly/2Suag74

In vitro antimicrobial activity of diacerein on 76 gram-positive cocci isolates from bacterial keratitis patients and an in vivo study of diacerein eye drops on Staphylococcus aureus keratitis in mice [Experimental Therapeutics]

Bacterial keratitis is an aggressive infectious corneal disease. With the continuing rise in antibiotic resistance and a decline in the discovery of new antibiotics, new antimicrobial drugs are now required. In the present study, we determined the antibacterial activity of diacerein, an anti-inflammatory drug, against 76 Gram-positive cocci isolated from bacterial keratitis patients in vitro and anti-Staphylococcus aureus activity in mouse bacterial keratitis model in vivo. The minimum inhibitory concentrations (MICs) of diacerein were tested using the broth microdilution method in vitro. A BALB/c Staphylococcus aureus keratitis animal model was selected and the corneal clinical observation, viable bacteria and Hematoxylin-eosin and Gram staining of infected corneas were measured to evaluate antibacterial efficacy of diacerein eye drops in vivo. An in vivo eye irritation study was carried out by a modified Draize test in rabbits. Our in vitro results showed that diacerein possesses satisfactory antibacterial activity against the majority of Gram-positive cocci (60/76), including all 57 tested Staphylococcus and 3 Enterococcus. The in vivo experiment showed that diacerein eye drops reduced bacterial load and improved ocular clinical scores after topical administration of diacerein drops on infected corneas. The ocular irritation test revealed that diacerein eye drop had excellent ocular tolerance. These results indicated that diacerein possesses in vivo anti-Staphylococcus aureus activity. We suggest that diacerein is a possible topically administered drug for Staphylococcus aureus-infected patients, especially those with ocular surface inflammatory disorders.

http://bit.ly/2GoEB0i

Clinical and Molecular Characteristics of qacA/B-Positive Methicillin-resistant Staphylococcus aureus Causing Bloodstream Infections [Epidemiology and Surveillance]

The increasing use of chlorhexidine for methicillin-resistant Staphylococcus aureus (MRSA) decolonization has raised concerns about the emergence of resistance to these agents. However, the clinical significance of MRSA positive for the qacA/B-chlorhexidine tolerance genes has not been established. We investigated the clinical features and predictive factors of MRSA bloodstream infection (BSI) isolates, caused by qacA/B-positive MRSA, from 2010 to 2016 at a tertiary hospital in South Korea. A total of 246 MRSA BSI isolates were included; 71 (28.9%) isolates carried qacA/B. The annual frequency of qacA/B-positive MRSA bacteremia did not change significantly over the study period. Patients infected with qacA/B-positive MRSA had common risk factors for healthcare-associated infections, including prior antibiotic use, central venous catheterization in situ, intensive-care-unit-acquired bacteremia, and nosocomial infection. The qacA/B-positive isolates were also associated with an increasing chlorhexidine MIC and resistance to non-β-lactam antibiotics. The qacA/B-positive isolates were more likely to belong to sequence type 5 (ST5), which is a common healthcare-associated MRSA strain in South Korea. In multivariable analyses, qacA/B-positive MRSA isolates were found to be associated with agr dysfunction (aOR, 6.45; 95% CI, 2.59–16.10), ST5 MRSA strain (aOR 4.96; 95% CI, 1.85–13.26), nosocomial infection (aOR, 4.88; 95% CI, 2.20–10.83), and antibiotic use within the previous 3 months (aOR, 2.59; 95% CI, 1.20–5.59). These findings suggest that the microbiological features of qacA/B carriage may provide a selective advantage for specific MRSA strains in hospital environments.

http://bit.ly/2SxqwUC

Viability Screen of LOPAC1280 Reveals Tyrosine Kinase Inhibitor Tyrphostin A9 as a Novel Partner Drug for Artesunate Combinations to Target the Plasmodium falciparum Ring Stage [Experimental Therapeutics]

The emergence of artemisinin-resistant P. falciparum poses a major threat to current frontline artemisinin combination therapies. Artemisinin resistance is widely associated with mutations in the PfKelch13 propeller region leading to delayed parasite clearance and increased survival of early ring stage parasites. There is therefore a need to discover novel drugs that are effective against artemisinin-resistant P. falciparum. In view of this, our study aims to identify compounds from the Library of Pharmacologically Active Compounds¹²⁸⁰ (LOPAC¹²⁸⁰) that could increase the efficacy of artesunate and be used as a potential partner drug for treatment against artemisinin-resistant falciparum malaria. By using a modified ring stage survival assay, we performed a high throughput screening of 1280 compounds from the LOPAC library in combination with artesunate against P. falciparum IPC 5202 field isolate harboring R539T mutation at the PfKelch13 propeller region. The potencies of the hits were determined through dose-dependent isobologram analyses against both IPC 5202 and CamWT_C580Y field isolates; the latter with more prevalent C580Y mutation characteristic of artemisinin resistance. We identified tyrphostin A9 with synergistic and additive activity against both parasite strains when dosed in combination with artesunate. These findings provide promising novel artesunate combinations that can target the P. falciparum artemisinin resistant ring stage and insights that may aid in a better understanding of the mechanism involved in ART resistance.

http://bit.ly/2GoEx0y

Pooled population pharmacokinetic analysis of tribendimidine for the treatment of Opisthorchis viverrini infections [Clinical Therapeutics]

Opisthorchiasis, caused by the food-borne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao PDR, pharmacokinetic samples from 125 adult and adolescent O. viverrini patients treated with 400 mg tribendimidine were obtained following the design of an sparse sampling scheme at 20 min, 2, 7.75, 8 and 30 h after treatment, using dried blood spot sampling. Pharmacokinetic data for the metabolites dADT and adADT were pooled with data from two previous dose-ascending trials and evaluated using nonlinear mixed-effects modelling. The observed pharmacokinetic data were described using a flexible transit absorption model for the active metabolite dADT followed by one-compartment disposition models for both metabolites. Significant covariates were age, body weight, formulation, and breaking of the enteric coating on the tablets. There were significant associations between O. viverrini cure and both dADT C_max and AUC (p-values <0.001), with younger age associated with a higher probability of cure. Modelling and simulation of exposures in a patients with different weight and age combinations showed that an oral single dose of 400 mg tribendimidine attained therapeutic success in over 90% of adult patients. Our data confirmed that tribendimidine could be a valuable novel alternative to the standard treatment praziquantel for the treatment of O. viverrini infections.

http://bit.ly/2Sxqvjw

An update on clinical safety of adalimumab in treating psoriasis: A systematic review and meta‐analysis based on 20 randomized controlled trials

Summary

Purpose

The current meta‐analysis was conducted to better evaluate the role of adalimumab for patients with psoriasis in terms of its safety profile on the basis of eligible randomized controlled trials (RCTs).

Methods

The following electronic databases such as Cochrane, PubMed, and Embase database involving the index words were screened and identified for qualified studies updated to December 2018. Associated publications and sources were hand‐searched for more related details. To further analyze the main outcomes, the odds ratio (OR) and mean difference (MD) with its 95% confidence interval (95% CI) were utilized.

Results

There were a total of 20 RCTs involving respective 3795 and 3266 patients in the adalimumab and control group that met our inclusion criteria. According to the aggregated results, the adalimumab group was highly associated with significant improvement in the incidence of adverse event (AE), infection, and injection site reaction on comparison of the control group. Nevertheless, no remarkable differences were found between the two study groups in terms of the incidence of serious AE, serious infection as well as the discontinuation of study drug caused by AE.

Conclusion

Adalimumab was proved to be linked to higher incidence of AE, infection, and injection site reaction during the therapy process of psoriasis based on high‐quality RCTs. In addition, there was no association between adalimumab therapy and serious AE, serious infection and the discontinuation of study drug caused by AE in patients harboring psoriasis according to eligible RCTs.

http://bit.ly/2RF7oQ3

Capecitabine-induced bilateral ectropion: A rare ocular manifestation requiring surgical intervention

Sedat Tatar, Can E Yalçın, Billur Sezgin, Ayşe Y Taş, Orkun Müftüoğlu, Selahattin Özmen

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):241-244

It has been established that many chemotherapeutic agents are associated with a variety of ocular side effects. As an antineoplastic agent, 5-fluorouracil (5-FU) is the chemotherapeutic agent that is frequently linked with cicatricial ectropion. Capecitabine is a prodrug of 5-FU and has a more favorable side effect profile than 5-FU. Frequent side effects of capecitabine include gastrointestinal events and hand–foot–mouth syndrome; cicatricial ectropion is rather uncommon. Enzyme deficiencies affecting the capecitabine metabolism have been reported to be associated with exaggerated generalized systemic and cutaneous side effects; however, there are no cases in the literature reporting capecitabine-induced isolated bilateral-progressive ectropion. Although cessation of the agent is frequently sufficient for the treatment of ectropion, close follow-up is indicated in such patients as permanent damage may occur if the problem is left untreated. We report a case of capecitabine-induced bilateral cicatricial ectropion refractory to treatment cessation, ultimately requiring surgical treatment.

http://bit.ly/2Twf60R

Injection lipolysis: A systematic review of literature and our experience with a combination of phosphatidylcholine and deoxycholate over a period of 14 years in 1269 patients of Indian and South East Asian origin

Mohan K Thomas, James A D'Silva, Ateesh J Borole

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):222-228

Background: Phosphatidylcholine and deoxycholate (PC–DC) injections have been used as nonsurgical alternatives to liposuction. DC as a constituent for lipolysis has recently been approved by the US Food and Drug Administration. Aim: PC and DC have independently been used in lipolysis. We hereby present a systematic review of literature on injection lipolysis and share our experience of using DC in combination with PC for injection lipolysis. We have retrospectively evaluated the effects of PC–DC treatments in varied age groups, both sexes, and over different target areas. Materials and Methods: This study spans over 14 years wherein 1269 patients of different age groups and sex were treated with injection lipolysis with PC–DC combination. The PC–DC cocktail injection was given to all patients for an average four sessions every 4 weeks, and the results were assessed after 8 weeks from the last session. Results: The effects were best appreciated over the face (malar, jawline, and submental areas) and upper arm, whereas average effect was observed on the thighs and around the knees. We have also used lipolysis as a primary modality as well as a touch-up modality following liposuction. The results are better appreciated in primary lipolysis. The need for follow-up sessions (1–2 sessions) of lipolysis and the quantification of results in subsequent sessions reveal that maximal improvement is achieved in the first session. Conclusion: PC–DC cocktail used for lipolysis as a local administration is effective for reducing unwanted fat. It shows great efficacy in treating localized fat, especially over the face and bra roll in the women of younger age group (20–30 years).

http://bit.ly/2BiKIje

Overview of medical therapies and phototherapy in vitiligo based on their pathogenetic action and the role of platelet-rich plasma

Kabir Sardana, Gunjan Verma

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):167-168



http://bit.ly/2TAHYFm

Learning from the past, gleaning into future

Venkataram Mysore, Manjot K Marwah

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):165-166



http://bit.ly/2BiKDvW

Logic of hair transplantation

Aniketh Venkataram, Venkataram Mysore

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):169-172

Hair transplant is a seemingly illogical process wherein we are using a small number of hairs to cover a large area of baldness. This is possible if one understands the logic of this equation. Understanding the pattern of hair distribution, and the sequence of balding, helps us learn the limitations of this technique and give the best possible results to the patient. In this article, we aim to give an understanding of all the processes associated with hair transplantation and the logic behind the same.

http://bit.ly/2Ty4oGX

Is prophylactic immunosuppressive therapy for patients with a history of postsurgical pyoderma gangrenosum necessary?

Christina Nicole Canzoneri, Dustin L Taylor, Daniel J Freet

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):234-236

Postsurgical pyoderma gangrenosum (PSPG) is a rare but serious surgical complication with a predilection for the breast and abdomen. Immunosuppression is the mainstay of treatment of PSPG. In addition, it has become a common practice for clinicians to prophylactically treat patients with a history of PSPG with corticosteroids or immunomodulators during subsequent operative procedures to prevent recurrence. Although many practitioners have reported successful outcomes with these measures, currently no protocol exists for prophylactic perioperative therapy. Here, we present the clinical course and 10-year follow-up of a woman who developed PSPG after undergoing body-contouring surgery, subsequently underwent multiple operative procedures without prophylactic immunosuppression, and has not experienced recurrence of PSPG. This case suggests that prophylactic therapy may not be necessary in all patients with a history of PSPG and shows that further research into the use of perioperative immunosuppression to prevent PSPG recurrence may be warranted.

http://bit.ly/2BlB8Mz

Controversies in hair transplantation

Muthuvel Kumaresan, Venkatram Mysore

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):173-181

Hair transplantation being a relatively new field, several aspects raise issues and controversies. The issues refer to both ethics and evidence and how practitioners and the community need to deal with them. This article deals with few of such diverse issues as follicular unit transplantation versus follicular unit excision, safe donor area, platelet-rich plasma, and minimum qualification for performing hair transplantation.

http://bit.ly/2TvWIoT

“Jigsaw puzzle” advancement flap

Maria M Sanches, Ana I Pinto, Paulo L Filipe, Joao M Silva

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):248-249



http://bit.ly/2BiKdFY

Complications in hair transplantation

Amit S Kerure, Narendra Patwardhan

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):182-189

Hair transplantation is a relatively safe surgery and is associated with very few complications. It is a cosmetic surgery so the complications may impact social and psychological aspect of the patient. Every hair transplantation surgeon should be aware of possible complications and techniques for the prevention and techniques of their management. Most of the complications are avoidable and can be minimized by proper surgical technique and wound care. Counseling and discussion with the patient before surgery help in proper planning and avoid patient dissatisfaction. Every patient should be individualized, planned, and operated with an aim to zero-down the complications and complaints.

http://bit.ly/2Tx9cfU

Fractional carbon dioxide laser in combination with topical corticosteroid application in resistant alopecia areata: A case series

Imran Majid, Shazia Jeelani, Saher Imran

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):217-221

Introduction: Intradermal steroid injections are used as treatment option in resistant alopecia areata. However, it is difficult and quite painful to treat large areas of alopecia with this modality. Objective: To assess the efficacy and safety profile of a combination of fractional carbon dioxide (CO2) treatment followed by topical corticosteroid application in resistant alopecia areata. Materials and Methods: Ten cases of resistant alopecia areata who had not responded to multiple treatment modalities were treated with fractional CO2 laser followed by topical application of triamcinolone spray (10mg/mL) on the resistant lesions. Patients received 4–8 sessions that were repeated at an interval of 3–4 weeks. Response to treatment was assessed on a quartile physician assessment scale and labeled as excellent (>75% regrowth), good (50%–75% regrowth), fair (26%–50% response), and poor (<25% regrowth). Results: Eight of these ten cases completed the treatment process. Seven of these eight patients had complete recovery of the area treated. One patient however did not show good response even after four sessions. No significant adverse effects were noted in any of the patients. Conclusion: Fractional CO2 laser in combination with topical triamcinolone can prove to be an effective treatment option in resistant alopecia areata.

http://bit.ly/2Bl0x9r

Donor harvesting: Strip dissection

Kapil Dua, Shraddha Uprety, Aman Dua

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):190-194

Hair transplant is a constantly evolving science. From the time that it was conceived by Dr. Norman Orentreich to the present state, the procedure of hair transplant has undergone multiple advancements. In this article, we discuss in brief regarding the strip follicular unit transplantation. We summarize the major points regarding the procedure of strip follicular unit transplantation along with some nuggets of experience that we have gathered over time. We briefly deal with the indications, anesthesia, procedure, and complications of strip follicular unit transplantation and some special scenarios like the repeat excision of strip.

http://bit.ly/2TyPuAo

Deoxycholate (ATX-101) mixed with lidocaine to minimize pain/discomfort in nonsurgical treatment of submental fullness appearance

Raffaele Rauso

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):229-233

In the present study pain/discomfort reduction in submental fullness treatment with the injections of a DC based drug (ATX-101, Allergan, Dublin, Ireland) premixed with lidocaine 2% on a sample of 12 patients retrospectively evaluated has been performed All patients indicated improvement in skin tightening from the 2nd month postinjection. Three patients had minor ecchymoses at the injection sites, which resolved spontaneously within 10 days posttreatment. One patient experienced dysesthesia of the treated area, which lasted approximately 40 days and resolved spontaneously. No other complications—such as nerve paresis or alopecia—were recorded. No patient required analgesic drugs postinjection.

http://bit.ly/2BiK1Xa

Donor harvesting: Follicular unit excision

Anil K Garg, Seema Garg

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):195-201

FUE or follicular unit excision is one of the methods for hair follicle harvesting in hair transplantation. FUE involves harvesting hairs from the donor area, under local anesthesia which is most commonly the scalp but occasionally beard, chest and other parts of the body, using a circular punch less than a mm, mounted on a manual handle or a motorized hand device or more recently a robotic device.First hair transplant was done by Dr Shoji Okuda in 1937. The term "follicular unit extraction" was coined by William Rassman in 2002. The modern era of FUE begins with the work of several surgeons Woods, Rassman, Cole, Harris and Rose. FUE has gone through various stages of development from manual to motorized and blunt to sharp, serrated trumpet and flared punches. Now the use of the robot in FUE with extraction and incision making is also in use.In 2017 nomenclature committee headed by Parsa Mohebi of ISHRS, recommended the term "FOLLICULAR UNIT EXCISION" is most appropriate as it explains the two steps of the process: incision and extraction and incision is done by a physician. FUE is a surgeon based time-consuming procedure with the long learning curve. Use of motorized device and sharp punches has certainly helped to increase speed in an experienced hand. FUE method of hair transplant is the most demanding procedure. If done properly it is a safe procedure. with the experience, use of better quality of instrument the disadvantages of FUE like transection can be reduced. The above informations were collected from various papers published in authentic journals and textbooks.

http://bit.ly/2Ty7ET0

Impacted foreign bodies in the maxillofacial region–A series of three cases

Pulkit Khandelwal, Vikas Dhupar, Francis Akkara, Neha Hajira

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):237-240

Penetrating injuries to the maxillofacial region are very common. Foreign bodies embedded deep in the maxillofacial region due to these injuries pose a challenge to an oral and maxillofacial surgeon. These objects may become a potent source of pain and infection. Early diagnosis of these foreign bodies can be achieved by the use of plain radiographs, ultrasonography, computed tomographic scans, and magnetic resonance imaging. Once diagnosed and located, these foreign bodies should be removed. Here, we report three such cases where early diagnosis of these foreign bodies embedded in the maxillofacial region lead to their early and successful removal without complications.

http://bit.ly/2BiKhp6

Recipient area

Manjot K Marwah, Venkataram Mysore

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):202-210

Recipient area is the canvas in a hair transplant surgery, where the surgeon can truly display his artistic creativity and deliver an aesthetic masterpiece, after all hair transplantation is as much about art as science. There are four main steps in dealing with the recipient area. Marking the hairline and estimation of grafts is the most important steps to give a natural look. There are multiple anatomical markers that need to be addressed while drawing a hairline. The second step is the anesthesia and it should be as painless as possible. This is followed by implantation, which can be achieved by various techniques. There are multiple technicalities to be considered while implanting, such as density, angle, and direction. Once implantation is done, the final step is appropriate postoperative care. Each of these steps has been discussed in detail in this chapter.

http://bit.ly/2TAHXBi

Asymptomatic pinkish-red nodule over the posterolateral tongue

Mahima Agrawal, Sidharth Sonthalia, Abhijeet K Jha, Mohamad Goldust

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):245-247

A young otherwise healthy male presented with asymptomatic pinkish-red nodule over postero-lateral tongue with the suspicion of having developed oral cancer. Biopsy from the lesion showed multiple circumscribed nodules in the lamina propria comprised of numerous oval and spindle-shaped cells. Abundant lymphatic tissue with germinal centres were also observed. Differentials included mucosal neuroma, traumatic neuroma, subgemmal neurogenous plaque, neurofibroma, and lingual tonsils. This quiz discusses the diagnosis and approach to the differential diagnoses in such a clinical setting.

http://bit.ly/2BkxOBw

A randomized controlled, single-observer blinded study to determine the efficacy of topical minoxidil plus microneedling versus topical minoxidil alone in the treatment of androgenetic alopecia

Muriki K Kumar, Arun C Inamadar, Aparna Palit

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):211-216

Background: Androgenetic alopecia (AGA) is the most common form of hair loss in adults, which is generally progressive in the absence of treatment. As a head full of healthy hair adds to the cosmetic appeal of the individual, the consequences of AGA are predominantly psychological. Currently, topical minoxidil is the first-line treatment for AGA. Many adjuvant treatment modalities have been used synergistically with minoxidil. Microneedling is one among such adjuvant treatments, which works by various mechanisms to stimulate the dermal papillary cells that play a key role in hair growth. Aim: To compare the efficacy of microneedling along with topical minoxidil and topical minoxidil alone in the treatment of AGA in men. Materials and Methods: Sixty-eight men with Norwood–Hamilton grade III and IV AGA were recruited for the study. After randomization, one group was treated with weekly microneedling and twice daily application of 5% minoxidil solution and the other group was treated with twice daily application of 5% minoxidil solution alone. Global photographs were taken at baseline (pretreatment) and at end of the study duration. Trichoscopic images were taken from a targeted fixed area before treatment (baseline) and at end of the therapy from where hair count was also carried out. The two primary efficacy parameters were assessed: increase in the hair count from that of the baseline and patient self-assessment of hair growth at the end of the study. Results: The mean increase in hair count in the targeted area of one square inch at the end of the treatment was significantly greater for the combination treatment group (12.52/inch2) compared to that for the minoxidil alone group (1.89/inch2). Four patients in the "microneedling plus topical minoxidil" group reported a 50% improvement versus none in the "minoxidil alone" group. Conclusion: Our study showed that the combination of microneedling and topical minoxidil treatment was superior compared to topical minoxidil alone with regard to increase in the hair count and patient satisfaction, although the response achieved was not cosmetically significant.

http://bit.ly/2TwIMLk

Chemical peeling for nail disorders: Author response to the published comment

Deepashree Daulatabad, Soni Nanda, Chander Grover

Journal of Cutaneous and Aesthetic Surgery 2018 11(4):250-251



http://bit.ly/2DS9s3M

Cochlear implantation as a treatment for single-sided deafness and asymmetric hearing loss: a randomized controlled evaluation of cost-utility

Single-sided deafness (SSD) and asymmetric hearing loss (AHL) have recently been proposed as a new indication for cochlear implantation. There is still no recommended treatment for these hearing deficits, and ...

http://bit.ly/2UHSWZt

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of melanoma families and whether performance improvements can be achieved.

http://bit.ly/2RG7O8S

Pigments in American Tattoo Inks and their Propensity to Elicit Allergic Contact Dermatitis

Tattoos have become increasingly common in the United States. Historically, tattoo inks were comprised of metallic pigments which had the potential to cause allergic contact dermatitis. Data have been lacking on the current use of these pigments in tattoo ink.

http://bit.ly/2S9ko5D

Incidence and Risk of Photosensitivity with Targeted Anticancer Therapies

http://bit.ly/2S6OyGN

Intralesional sodium stibogluconate under inhaled anesthesia for the treatment of cutaneous leishmaniasis in children: A retrospective cohort

http://bit.ly/2UEXFLx

Liposuction-like Sclerotherapy Technique: a Deep Approach to Superficial Lymphatic Malformation

http://bit.ly/2S9kom9

The Hydroxychloroquine–Interferon Gamma Release Assay Question: TB or not TB?

http://bit.ly/2UEmFm8

Early Detection of Acral Melanoma: A Review of Clinical, Dermoscopic, Histopathologic, and Molecular Characteristics

Acral lentiginous melanoma is a distinct subtype of melanoma on acral skin. Patient presentation at later stages as well as delayed diagnosis by physicians contribute to a worse associated prognosis and survival rate. Despite our progress on understanding the key features of this disease, the diagnosis of early stage acral melanoma is still challenging. It is essential to integrate clinical, dermoscopic, and histological findings in the diagnosis of acral lentiginous melanoma. In addition, molecular studies can be helpful.

http://bit.ly/2RApLpz

Determining patient preferences and willingness to pay related to scar length and appearance following skin cancer treatment on the face and trunk: A multi-center discrete choice experiment

http://bit.ly/2UEmDe0

Coffee, tea, caffeine, and risk of non-melanoma skin cancer in a Chinese population: The Singapore Chinese Health Study

1.Although studies in Caucasians suggest that caffeine may reduce the risk of non-melanoma skin cancer (NMSC), studies among darker-skinned populations are lacking. 2.We showed that intake of coffee or caffeine may reduce the risk of squamous cell and basal cell carcinomas among Chinese in Singapore.

http://bit.ly/2WJpLHF

Recommendations for the definition, evaluation, and treatment of nail psoriasis in adult patients with no or mild skin psoriasis: a dermatologist and nail expert group consensus

Nail involvement in psoriasis is common, and the severity of it does not always parallel the intensity of cutaneous disease.We created a consensus group, of which the aim was to provide practical recommendations for the treatment of nail psoriasis in patients without skin psoriasis, or with mild skin lesions with no indication for a systemic treatment. This collaborative process was conducted by an international panel of dermatologists with special expertise in nail disorders, using a formal consensus methodology.

http://bit.ly/2t70Pw4

Whats Bred in the Bone: Calcium Channels in Lymphocytes [BRIEF REVIEWS]

Calcium (Ca²⁺) is an important second messenger in lymphocytes and is essential in regulating various intracellular pathways that control critical cell functions. Ca²⁺ channels are located in the plasma membrane and intracellular membranes, facilitating Ca²⁺ entry into the cytoplasm. Upon Ag receptor stimulation, Ca²⁺ can enter the lymphocyte via the Ca²⁺ release-activated Ca²⁺ channel found in the plasma membrane. The increase of cytosolic Ca²⁺ modulates signaling pathways, resulting in the transcription of target genes implicated in differentiation, activation, proliferation, survival, and apoptosis of lymphocytes. Along with Ca²⁺ release-activated Ca²⁺ channels, several other channels have been found in the membranes of T and B lymphocytes contributing to key cellular events. Among them are the transient receptor potential channels, the P2X receptors, voltage-dependent Ca²⁺ channels, and the inositol 1,4,5-trisphosphate receptor as well as the N-methyl-d-aspartate receptors. In this article, we review the contributions of these channels to mediating Ca²⁺ currents that drive specific lymphocyte functions.

http://bit.ly/2UG7WHs

Leishmania donovani Induces Autophagy in Human Blood-Derived Neutrophils [INFECTIOUS DISEASE AND HOST RESPONSE]

Neutrophils, the essential components of the innate immune system, are recruited in large numbers to the pathogen site of entry. Several pathogens induce neutrophil autophagy; however, function of autophagic events during Leishmania parasite infection remain unknown. In this article, we report a finding that is new, to our knowledge, of how Leishmania-induced human polymorphonuclear neutrophil (hPMN) autophagy regulates the silent mode of parasite transfer to macrophages by influencing the engulfment of infected cells. Leishmania infection induced a time-dependent autophagy increase responsive to block by 3-methyladenine but sensitive to ULK1/2 inhibition only after 3 h. This suggested the prevalence of canonical autophagy during later hours, ULK1/2 inhibition being able to block only canonical autophagy. Interaction of Rubicon and Beclin-1 at 1 h postinfection affirmed the prevalence of noncanonical autophagy during early infection. There was a reduction in macrophage uptake of parasite-exposed hPMNs treated with 3-methyladenine or ULK1/2 inhibitor, suggesting the involvement of both noncanonical and canonical autophagy in neutrophil engulfment. Autophagy inducer rapamycin augmented neutrophil engulfment by macrophages. Redistribution of hPMN surface CD47 encouraged neutrophil uptake. Activation of ERK, phosphoinositide 3-kinase, and NADPH oxidase–mediated reactive oxygen species generation were induced after parasite binding. The lpg1-knockout parasites expressing defective lipophosphoglycan did not induce autophagy, indicating that lipophosphoglycan is necessary for interaction with the neutrophils. Autophagy induction was TLR2/4 independent because the receptor blockade did not interfere with infection-induced autophagy. In summary, the engulfment of neutrophils by the macrophages was influenced by the escalation of hPMN autophagy, which is an important event during Leishmania infection.

http://bit.ly/2UE1hgT

A Prime-Pull-Amplify Vaccination Strategy To Maximize Induction of Circulating and Genital-Resident Intraepithelial CD8+ Memory T Cells [MUCOSAL IMMUNOLOGY]

Recent insight into the mechanisms of induction of tissue-resident memory (T_RM) CD8⁺ T cells (CD8⁺ T_RM) enables the development of novel vaccine strategies against sexually transmitted infections. To maximize both systemic and genital intraepithelial CD8⁺ T cells against vaccine Ags, we assessed combinations of i.m. and intravaginal routes in heterologous prime-boost immunization regimens with unrelated viral vectors. Only i.m. prime followed by intravaginal boost induced concomitant strong systemic and intraepithelial genital-resident CD8⁺ T cell responses. Intravaginal boost with vectors expressing vaccine Ags was far superior to intravaginal instillation of CXCR3 chemokine receptor ligands or TLR 3, 7, and 9 agonists to recruit and increase the pool of cervicovaginal CD8⁺ T_RM. Transient Ag presentation increased trafficking of cognate and bystander circulating activated, but not naive, CD8⁺ T cells into the genital tract and induced in situ proliferation and differentiation of cognate CD8⁺ T_RM. Secondary genital CD8⁺ T_RM were induced in the absence of CD4⁺ T cell help and shared a similar TCR repertoire with systemic CD8⁺ T cells. This prime-pull-amplify approach elicited systemic and genital CD8⁺ T cell responses against high-risk human papillomavirus type 16 E7 oncoprotein and conferred CD8-mediated protection to a vaccinia virus genital challenge. These results underscore the importance of the delivery route of nonreplicating vectors in prime-boost immunization to shape the tissue distribution of CD8⁺ T cell responses. In this context, the importance of local Ag presentation to elicit genital CD8⁺ T_RM provides a rationale to develop novel vaccines against sexually transmitted infections and to treat human papillomavirus neoplasia.

http://bit.ly/2UD9nX3

Characterization of Subpopulations of Chicken Mononuclear Phagocytes That Express TIM4 and CSF1R [INNATE IMMUNITY AND INFLAMMATION]

The phosphatidylserine receptor TIM4, encoded by TIMD4, mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 mAbs in combination with CSF1R reporter transgenes to dissect the function of TIM4 in the chick (Gallus gallus). During development in ovo, TIM4 was present on the large majority of macrophages, but expression became more heterogeneous posthatch. Blood monocytes expressed KUL01, class II MHC, and CSF1R-mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4^– monocytes. In liver, highly phagocytic TIM4^hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R-mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R-mApple was detected in liver TIM4^lo and TIM4^– cells, which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R alongside high levels of FLT3, MHCII, XCR1, and other markers associated with conventional dendritic cells in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4^hi phagocytes coexpressed many receptors involved in apoptotic cell recognition. TIM4^lo cells appear to be a subpopulation of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of dendritic cell–like cells.

http://bit.ly/2UE1ctB

Cutting Edge: HDAC3 Protects Double-Positive Thymocytes from P2X7 Receptor-Induced Cell Death [CUTTING EDGE]

Intricate life-versus-death decisions are programmed during T cell development, and the regulatory mechanisms that coordinate their activation and repression are still under investigation. In this study, HDAC3-deficient double-positive (DP) thymocytes exhibit a severe decrease in numbers. The thymic cortex is rich in ATP, which is released by macrophages that clear apoptotic DP thymocytes that fail to undergo positive selection. We demonstrate that HDAC3 is required to repress expression of the purinergic receptor P2X7 to prevent DP cell death. HDAC3-deficient DP thymocytes upregulate the P2X7 receptor, increasing sensitivity to ATP-induced cell death. P2rx7/HDAC3-double knockout mice show a partial rescue in DP cell number. HDAC3 directly binds to the P2rx7 enhancer, which is hyperacetylated in the absence of HDAC3. In addition, RORt binds to the P2rx7 enhancer and promotes P2X7 receptor expression in the absence of HDAC3. Therefore, HDAC3 is a critical regulator of DP thymocyte survival and is required to suppress P2X7 receptor expression.

http://bit.ly/2Sf6BLa

Cadmium Induces Glomerular Endothelial Cell-Specific Expression of Complement Factor H via the -1635 AP-1 Binding Site [INNATE IMMUNITY AND INFLAMMATION]

Cadmium (Cd) is an environmental toxin that induces nephrotoxicity. Complement factor H (CFH), an inhibitor of complement activation, is involved in the pathogenesis of various renal diseases. In this study, we investigated the effects of Cd on CFH production by the kidney. In C57B6/J mice, an increased CFH level was found in renal blood and glomerular endothelial cells after Cd treatment. In vitro, Cd induces an increased CFH secretion and mRNA expression in human renal glomerular endothelial cells but not in human podocytes or human mesangial cells. Cd activates the JNK pathway and increases c-Jun and c-Fos in human renal glomerular endothelial cells. A JNK inhibitor, SP600125, specifically abolishes Cd-induced CFH production. By chromatin immunoprecipitation assay and EMSA, the –1635 AP-1 motif on human CFH promoter was identified as the binding element for c-Jun and c-Fos. In a luciferase activity assay, mutation of the AP1 site eliminates Cd-induced increase of CFH promoter activity. Thus, the –1635 AP-1 motif on the CFH promoter region mediates Cd-inducible CFH gene expression.

http://bit.ly/2UHzEDO

Cutting Edge: ICOS-Deficient Regulatory T Cells Display Normal Induction of Il10 but Readily Downregulate Expression of Foxp3 [CUTTING EDGE]

The ICOS pathway has been implicated in the development and functions of regulatory T (Treg) cells, including those producing IL-10. Treg cell–derived IL-10 is indispensable for the establishment and maintenance of intestinal immune homeostasis. We examined the possible involvement of the ICOS pathway in the accumulation of murine colonic Foxp3- and/or IL-10–expressing cells. We show that ICOS deficiency does not impair induction of IL-10 by intestinal CD4 T cells but, instead, triggers substantial reductions in gut-resident and peripherally derived Foxp3⁺ Treg cells. ICOS deficiency is associated with reduced demethylation of Foxp3 CNS2 and enhanced loss of Foxp3. This instability significantly limits the ability of ICOS-deficient Treg cells to reverse ongoing inflammation. Collectively, our results identify a novel role for ICOS costimulation in imprinting the functional stability of Foxp3 that is required for the retention of full Treg cell function in the periphery.

http://bit.ly/2UE1vEL

In This Issue [IN THIS ISSUE]

http://bit.ly/2SdFy2R

Neutrophil Cathepsin G Regulates Dendritic Cell Production of IL-12 during Development of CD4 T Cell Responses to Antigens in the Skin [ALLERGY AND OTHER HYPERSENSITIVITIES]

Contact hypersensitivity (CHS) is a CD8 T cell–mediated response to hapten skin sensitization and challenge. Sensitization of wild-type (WT) mice induces hapten-reactive effector CD8 T cells producing IFN- and IL-17– and IL-4–producing CD4 T cells that cannot mediate CHS. Although CXCR2-dependent Ly6G⁺ (neutrophil) cell recruitment into hapten-challenged skin is required to direct effector CD8 T cell infiltration into the challenge site to elicit CHS, 2,4-dinitrofluorobenezene (DNFB) sensitization of CXCR2^–/– mice and neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 T cells producing IFN- and IL-17. CD4 T cell–mediated CHS responses were not generated during DNFB sensitization of neutrophil-depleted WT mice treated with anti–IL-12 mAb or neutrophil-depleted IL-12^–/– mice. Neutrophil depletion during DNFB sensitization of WT mice markedly increased IL-12–producing hapten-primed dendritic cell numbers in the skin-draining lymph nodes. Sensitization of mice lacking the neutrophil serine protease cathepsin G (CG)–induced hapten-reactive CD4 and CD8 T cells producing IFN- and IL-17 with elevated and elongated CHS responses to DNFB challenge. Induction of CHS effector CD4 T cells producing IFN- in neutrophil-depleted WT mice was eliminated by s.c. injection of active, but not inactivated, CG during sensitization. Thus, hapten skin sensitization induces neutrophil release of CG that systemically inhibits hapten-presenting dendritic cell production of IL-12 and the development of hapten-reactive CD4 T cells to IFN-–producing CHS effector cells.

http://bit.ly/2SbzRCo

Immune Cell Infiltration into the Eye Is Controlled by IL-10 in Recoverin-Induced Autoimmune Retinopathy [AUTOIMMUNITY]

Autoimmune retinopathy (AIR) is a treatable condition that manifests in acute and progressive vision loss in patients. It has recently been determined that AIR is associated with an imbalance of T_H1 versus regulatory T cell immunity toward the retinal protein, recoverin. This study describes a new murine model to understand the immunopathology of AIR and its association with T cell responses toward recoverin. Immunization of C57BL/6 mice with recoverin resulted in ocular inflammation including infiltration of CD4⁺ and CD8⁺ T lymphocytes, B cells, and CD11b⁺Ly6C⁺ inflammatory monocytes in the eyes. Production of IFN- and IL-17 from T cells was exacerbated in IL-10 knockout (KO) mice and kinetics of disease development was accelerated. Infiltration of T cells and inflammatory monocytes into the eyes dramatically increased in recoverin-immunized IL-10 KO mice. An immunodominant peptide of recoverin, AG-16, was capable of inducing disease in IL-10 KO mice and resulted in expansion of AG-16 tetramer-specific CD4⁺ T cells in lymphoid organs and eyes. Adoptive transfer of recoverin-stimulated cells into naive mice was sufficient to induce AIR, and immunization of B cell–deficient mice led to a milder form of the disease. This model supports the hypothesis that recoverin-specific T cell responses are major drivers of AIR pathogenesis and that IL-10 is an important factor in protection.

http://bit.ly/2UE1u3F

Angiogenic Host Defense Peptide AG-30/5C and Bradykinin B2 Receptor Antagonist Icatibant Are G Protein Biased Agonists for MRGPRX2 in Mast Cells [INNATE IMMUNITY AND INFLAMMATION]

AG-30/5C is an angiogenic host defense peptide that activates human mast cells (MC) via an unknown mechanism. Using short hairpin RNA–silenced human MC line LAD2 and stably transfected RBL-2H3 cells, we demonstrate that AG-30/5C induces MC degranulation via Mas-related G protein–coupled receptor X2 (MRGPRX2). Most G protein–coupled receptors signal via parallel and independent pathways mediated by G proteins and β-arrestins. AG-30/5C and compound 48/80 induced similar maximal MC degranulation via MRGPRX2, which was abolished by pertussis toxin. However, compound 48/80 induced a robust β-arrestin activation as determined by transcriptional activation following arrestin translocation (Tango), but AG-30/5C did not. Overnight culture of MC with compound 48/80 resulted in reduced cell surface MRGPRX2 expression, and this was associated with a significant decrease in subsequent MC degranulation in response to compound 48/80 or AG-30/5C. However, AG-30/5C pretreatment had no effect on cell surface MRGPRX2 expression or degranulation in response to compound 48/80 or AG-30/5C. Icatibant, a bradykinin B₂ receptor antagonist, promotes MC degranulation via MRGPRX2 and causes pseudoallergic drug reaction. Icatibant caused MC degranulation via a pertussis toxin–sensitive G protein but did not activate β-arrestin. A screen of the National Institutes of Health Clinical Collection library led to the identification of resveratrol as an inhibitor of MRGPRX2. Resveratrol inhibited compound 48/80–induced Tango and MC degranulation in response to compound 48/80, AG-30/5C, and Icatibant. This study demonstrates the novel finding that AG-30/5C and Icatibant serve as G protein–biased agonists for MRGPRX2, but compound 48/80 signals via both G protein and β-arrestin with distinct differences in receptor regulation.

http://bit.ly/2UAmVmi

The Autoimmune Susceptibility Gene C5orf30 Regulates Macrophage-Mediated Resolution of Inflammation [AUTOIMMUNITY]

Genetic variants in C5orf30 have been associated with development of the autoimmune conditions primary biliary cirrhosis and rheumatoid arthritis. In rheumatoid arthritis, C5orf30 expression is cell-specific, with highest expression found in macrophages and synovial fibroblasts. C5orf30 is highly expressed in inflamed joints and is a negative regulator of tissue damage in a mouse model of inflammatory arthritis. Transcriptomic analysis from ultrasound-guided synovial biopsy of inflamed joints in a well characterized clinical cohort of newly diagnosed, disease-modifying antirheumatic drugs–naive rheumatoid arthritis patients was used to determine the clinical association of C5orf30 expression with disease activity. A combined molecular and computational biology approach was used to elucidate C5orf30 function in macrophages both in vitro and in vivo. Synovial expression of C5orf30 is inversely correlated with both clinical measures of rheumatoid arthritis disease activity and with synovial TNF mRNA expression. C5orf30 plays a role in regulating macrophage phenotype and is differentially turned over in inflammatory and anti-inflammatory macrophages. Inhibition of C5orf30 reduces wound healing/repair–associated functions of macrophages, reduces signaling required for resolution of inflammation, and decreases secretion of anti-inflammatory mediators. In an animal model of wound healing (zebrafish), C5orf30 inhibition increases the recruitment of macrophages to the wound site. Finally, we demonstrate that C5orf30 skews macrophage immunometabolism, demonstrating a mechanism for C5orf30-mediated immune regulation.

http://bit.ly/2S7WpUu

Growth Factor-like Gene Regulation Is Separable from Survival and Maturation in Antibody-Secreting Cells [SYSTEMS IMMUNOLOGY]

Recurrent mutational activation of the MAP kinase pathway in plasma cell myeloma implicates growth factor–like signaling responses in the biology of Ab-secreting cells (ASCs). Physiological ASCs survive in niche microenvironments, but how niche signals are propagated and integrated is poorly understood. In this study, we dissect such a response in human ASCs using an in vitro model. Applying time course expression data and parsimonious gene correlation network analysis (PGCNA), a new approach established by our group, we map expression changes that occur during the maturation of proliferating plasmablast to quiescent plasma cell under survival conditions including the potential niche signal TGF-β3. This analysis demonstrates a convergent pattern of differentiation, linking unfolded protein response/endoplasmic reticulum stress to secretory optimization, coordinated with cell cycle exit. TGF-β3 supports ASC survival while having a limited effect on gene expression including upregulation of CXCR4. This is associated with a significant shift in response to SDF1 in ASCs with amplified ERK1/2 activation, growth factor–like immediate early gene regulation and EGR1 protein expression. Similarly, ASCs responding to survival conditions initially induce partially overlapping sets of immediate early genes without sustaining the response. Thus, in human ASCs growth factor–like gene regulation is transiently imposed by niche signals but is not sustained during subsequent survival and maturation.

http://bit.ly/2UGlTVP

A Functional Idiotype/Anti-Idiotype Network Is Active in Genetically Gluten-Intolerant Individuals Negative for Both Celiac Disease-Related Intestinal Damage and Serum Autoantibodies [AUTOIMMUNITY]

An unbalance between Abs that recognize an autoantigen (idiotypes; IDs) and Igs that bind such Abs (anti-IDs) is considered a functional event in autoimmune disorders. We investigated the presence of an ID/anti-ID network in celiac disease (CD), a condition in which antitissue transglutaminase 2 (TG2) Abs are suspected to contribute to CD pathogenesis. To characterize the ID side, we reproduced by in vitro yeast display the intestine-resident Abs from CD and control patients. These TG2-specific IDs were used to identify potential anti-IDs in the serum. We observed elevated titers of anti-IDs in asymptomatic patients with predisposition to CD and demonstrated that anti-ID depletion from the serum restores a detectable humoral response against TG2. Our study provides an alternative approach to quantify CD-related autoantibodies in cases that would be defined "negative serology" with current diagnostic applications. Therefore, we suggest that developments of this technology could be designed for perspective routine tests.

http://bit.ly/2UG7OHY

Cyclic Dinucleotide-Adjuvanted Dengue Virus Nonstructural Protein 1 Induces Protective Antibody and T Cell Responses [IMMUNOTHERAPY AND VACCINES]

Endothelial dysfunction and vascular leak, pathogenic hallmarks of severe dengue disease, are directly triggered by dengue virus (DENV) nonstructural protein 1 (NS1). Previous studies have shown that immunization with NS1, as well as passive transfer of NS1-immune serum or anti-NS1 mAb, prevent NS1-mediated lethality in vivo. In this study, we evaluated the immunogenicity and protective capacity of recombinant DENV NS1 administered with cyclic dinucleotides (CDNs), potent activators of innate immune pathways and highly immunogenic adjuvants. Using both wild-type C57BL/6 mice and IFN-α/β receptor–deficient mice, we show that NS1-CDN immunizations elicit serotype-specific and cross-reactive Ab and T cell responses. Furthermore, NS1-CDN vaccinations conferred significant homotypic and heterotypic protection from DENV2-induced morbidity and mortality. In addition, we demonstrate that high anti-NS1 Ab titers are associated with protection, supporting the role of humoral responses against DENV NS1 as correlates of protection. These findings highlight the potential of CDN-based adjuvants for inducing Ab and T cell responses and validate NS1 as an important candidate for dengue vaccine development.

http://bit.ly/2S7WpDY

Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells [IMMUNE REGULATION]

Although the methylation status of histone H3K27 plays a critical role in CD4⁺ T cell differentiation and its function, the role of Utx histone H3K27 demethylase in the CD8⁺ T cell–dependent immune response remains unclear. We therefore generated T cell–specific Utx^flox/flox Cd4-Cre Tg (Utx KO) mice to determine the role of Utx in CD8⁺ T cells. Wild-type (WT) and Utx KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8⁺ T cells. There was no significant difference in the number of Ag-specific CD8⁺ T cells upon primary infection between WT and Utx KO mice. However, Utx deficiency resulted in more Ag-specific CD8⁺ T cells upon secondary infection. Adoptive transfer of Utx KO CD8⁺ T cells resulted in a larger number of memory cells in the primary response than in WT. We observed a decreased gene expression of effector-associated transcription factors, including Prdm1 encoding Blimp1, in Utx KO CD8⁺ T cells. We confirmed that the trimethylation level of histone H3K27 in the Prdm1 gene loci in the Utx KO cells was higher than in the WT cells. The treatment of CD8⁺ T cells with Utx-cofactor α-ketoglutarate hampered the memory formation, whereas Utx inhibitor GSK-J4 enhanced the memory formation in WT CD8⁺ T cells. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8⁺ T cells by epigenetically regulating the gene expression. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8⁺ T cells.

http://bit.ly/2S6u7ts

Ablation and Inhibition of the Immunoproteasome Catalytic Subunit LMP7 Attenuate Experimental Abdominal Aortic Aneurysm Formation in Mice [INNATE IMMUNITY AND INFLAMMATION]

Low–molecular mass protein 7 (LMP7) is a proteolytic subunit of the immunoproteasome that is involved in regulating inflammatory responses. However, the role of LMP7 in the pathogenesis of abdominal aortic aneurysm (AAA) remains unknown. In this study, ApoE knockout (KO) or LMP7/ApoE double KO (dKO) mice were infused with angiotensin II (Ang II, 1000 ng/kg per minute) for up to 28 d. We found that LMP7 expression was significantly upregulated in AAA tissues from ApoE KO mice and human patients. Moreover, Ang II infusion markedly increased the incidence and severity of AAA in ApoE KO mice, which was considerably reduced in LMP7/ApoE dKO mice. Histological alterations, including aortic wall thickening, collagen deposition, elastin fragmentation, and vascular smooth muscle cell apoptosis in AAA tissue of ApoE KO mice, were also significantly attenuated in LMP7/ApoE dKO mice. Interestingly, LMP7/ApoE dKO mice showed a marked reduction of infiltration of CD3⁺ T cells, especially CD4⁺ T cells in AAA tissues compared with ApoE KO mice. Moreover, ablation of LMP7 substantially inhibited the differentiation of CD4⁺ T cells into Th1 and Th17 cells by reducing the activation of multiple transcriptional factors. We also investigated the effects of an LMP7-specific inhibitor PR-957 (also known as ONX 0914) on AAA formation in ApoE KO mice. PR-957 treatment could reduce the AAA incidence and severity. In conclusion, our results provide, to our knowledge, novel evidence that ablation or pharmacological inhibition of LMP7 attenuates Ang II–induced AAA formation, and LMP7 might be a novel therapeutic target for treating AAA in humans.

http://bit.ly/2SdC3sX

ADAR1 Is Required for Dendritic Cell Subset Homeostasis and Alveolar Macrophage Function [IMMUNE REGULATION]

RNA editing by adenosine deaminases acting on dsRNA (ADAR) has become of increasing medical relevance, particularly because aberrant ADAR1 activity has been associated with autoimmunity and malignancies. However, the role of ADAR1 in dendritic cells (DC), representing critical professional APCs, is unknown. We have established conditional murine CD11c Cre-mediated ADAR1 gene ablation, which did not induce general apoptosis in CD11c⁺ cells but instead manifests in cell type–specific effects in DC subpopulations. Bone marrow–derived DC subset analysis revealed an incapacity to differentiate CD103 DC⁺ in both bulk bone marrow and purified pre-DC lineage progenitor assays. ADAR1 deficiency further resulted in a preferential systemic loss of CD8⁺/CD103⁺ DCs, revealing critical dependency on ADAR1, whereas other DC subpopulations were moderately affected or unaffected. Additionally, alveolar macrophages were depleted and dysfunctional, resembling pulmonary alveolar proteinosis. These results reveal an unrecognized role of ADAR1 in DC subset homeostasis and unveils the cell type–specific effects of RNA editing.

http://bit.ly/2UE1oJl

C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro [INNATE IMMUNITY AND INFLAMMATION]

The classical pathway of complement (CP) can mediate C3 opsonization of Ags responsible for the costimulation and activation of cognate B lymphocytes. In this manner, the complement system acts as a bridge between the innate and adaptive immune systems critical for establishing a humoral response. However, aberrant complement activation is often observed in autoimmune diseases in which C3 deposition on self-antigens may serve to activate self-reactive B cell clones. In this study, we use BIVV009 (Sutimlimab), a clinical stage, humanized mAb that specifically inhibits the CP-specific serine protease C1s to evaluate the impact of upstream CP antagonism on activation and proliferation of normal and autoimmune human B cells. We report that BIVV009 significantly inhibited complement-mediated activation and proliferation of primary human B cells. Strikingly, CP antagonism suppressed human Ig–induced activation of B cells derived from patients with rheumatoid arthritis. These results suggest that clinical use of CP inhibitors in autoimmune patients may not only block complement-mediated tissue damage, but may also prevent the long-term activation of autoimmune B cells and the production of autoantibodies that contribute to the underlying pathologic condition of these diseases.

http://bit.ly/2S9q3ca

Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells [IMMUNE REGULATION]

CD4 Th cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. CD4 T cells differentiate into distinct Th effector or regulatory subsets in response to signals delivered to them during the course of infection. Ikaros is a transcription factor that is expressed in blood cells from the level of the hematopoietic stem cell. It is required for normal thymic T cell development and serves as a tumor suppressor, as lack of Ikaros in developing lymphoid cells results in leukemia. To study the role of Ikaros in CD4 T cell differentiation and function, an Ikaros conditional knockout mouse was developed such that Ikaros expression was deleted specifically in mature T cells, thus avoiding defects observed in germline Ikaros mutant mice. Using this model system, we have shown that in the absence of Ikaros, CD4 T cells are able to attain Th1, Th2, and Th17, but not inducible regulatory T, cell fates. However, they show enhanced expression of a cohort of proinflammatory cytokines, resulting in differentiation of Th17 cells with a phenotype that has been associated with autoimmunity and pathological inflammation. In addition, we define Ikaros as a repressor of the gene program associated with the response to type I IFNs, another key pathway whose deregulation is linked to autoimmunity. Taken together, these data definitively define Ikaros as a critical regulator at the center of the inflammatory response in T cells and highlight a potential role in suppressing autoimmunity.

http://bit.ly/2SbtaAi

Levels of horse allergen Equ C 4 in dander and saliva from ten horse breeds

Abstract

Background

Horses are an important source of allergens, but the distribution of horse allergens is poorly understood. Five horse allergens have been identified, Equ c 1‐4 and 6. Equ c 4 seems to be an important allergen, with an IgE‐binding frequency of 77% in horse‐sensitized individuals.

Objectives

The aim of this study was to investigate levels of horse allergen Equ c 4 in dander, saliva and urine from ten horse breeds.

Method: The study population included 170 horses (87 mares, 27 stallions, 56 geldings) from ten breeds. Horse dander, saliva and urine samples were collected. Levels of horse allergen Equ c 4 were quantified using a two‐site sandwich ELISA (mAb 103 and 14G4) and were expressed as Equ c 4 U/μg protein.

Results

The horse allergen Equ c 4 was present in all dander and saliva samples from ten horse breeds, with high within‐breed and inter‐breed variations; GM values were 639 Equ c 4 U /μg protein (range 5 – 15264) for dander and 39.5 (4 – 263) for saliva. Equ c 4 was found in 19/21 urine samples. Adjusted for age, sex and changes over time, no differences between breeds could be seen in dander, while in saliva the North Swedish horse showed lower levels of Equ c 4 than any other breed. The levels of Equ c 4 protein in dander and saliva were significantly higher in samples from stallions compared to mares and geldings, independent of breed.

Conclusions & Clinical Relevance

The results show a high variability in allergen levels of Equ c 4 in dander and saliva both within and between breeds. Significantly higher levels were found in stallions compared to mares and geldings, independent of breed. Results suggest that none of the horse breeds studied can be recommended for individuals allergic to Equ c 4.

This article is protected by copyright. All rights reserved.

http://bit.ly/2Tvxqar

Alopecic patches of the scalp: a variant of primary cutaneous follicle center B‐cell lymphoma reported in a series of 14 cases

Abstract

Primary cutaneous follicle center lymphoma (PCFCL) is the most frequent primary cutaneous B‐cell lymphoma. It presents usually with erythematous papules, plaques and tumors that predominate on the head, neck and upper trunk. The evolution is indolent but relapses are frequent. Atypical presentations of PCFCL have been occasionally described, such as diffuse facial erythema, one case of scarring alopecia (1), macular lesions, including 2 cases of scarring alopecia (2), miliary agminated papules (3), or extensive telangiectasia of the scalp (4). The incidence and prognosis of these atypical forms are unknown.

This article is protected by copyright. All rights reserved.

http://bit.ly/2WP3U1s

A deep convolutional neural network for the diagnosis of thyroid nodules on ultrasound

Abstract

Background

We designed a deep convolutional neural network (CNN) to diagnose thyroid malignancy on ultrasound (US) and compared the diagnostic performance of CNN with that of experienced radiologists.

Methods

Between May 2012 and February 2015, 589 thyroid nodules in 519 patients were diagnosed as benign or malignant by surgical excision. Experienced radiologists retrospectively reviewed the US of the thyroid nodules in a test set. CNNs were trained and tested using retrospective data of 439 and 150 US images, respectively. Diagnostic performances were compared between the two groups.

Results

Of the 589 thyroid nodules, 396 were malignant and 193 were benign. The area under the curve (AUC) for diagnosing thyroid malignancy was 0.805‐0.860 for radiologists. The AUCs for diagnosing thyroid malignancy for the three CNNs were 0.845, 0.835, and 0.850. There was no significant difference in AUC between radiologists and CNNs.

Conclusions

CNNs showed comparable diagnostic performance compared to experienced radiologists in differentiating thyroid malignancy on US.

http://bit.ly/2BdGWI7

Stepwise approach towards adoption of allergen immunotherapy for allergic rhinitis and asthma patients in daily practice in Belgium: a BelSACI-Abeforcal-EUFOREA statement

Allergic rhinitis (AR) affects 23–30% of the European population with equal prevalence reported in Belgium. Despite guidelines on the correct use of effective treatment, up to 40% of AR patients remain uncontr...

http://bit.ly/2Sur9hO

Using Data Mining Techniques to Examine Domestic Violence Topics on Twitter

Violence and Gender, Ahead of Print.


http://bit.ly/2S9XLOD

Treatment of oral cancers during pregnancy: a case-based discussion

Malignancies occur in approximately 1:1000 pregnancies; the most common being breast (46%) and hematological (18%) malignancies. Oral cancers account for only 2% of all cancers in pregnant women, and there are...

http://bit.ly/2UGyacY

Pressure induced tissue resection in the larynx: A preliminary canine study

Objectives

The application of laser (light amplification by stimulated emission of radiation) energy in the larynx relies on thermal injury. The impact of this injury on adjacent tissue can be undesirable. Attempts have been made to limit the extent and range of injury to adjacent tissue. The O‐Pel Surgical System (Precise Light Surgical, Inc., Campbell, CA), a new technology, utilizes kinetic energy through Pressure Induced Tissue Resection (PITR) (Precise Light Surgical, Inc.) to cut tissue, theoretically eliminating injury to adjacent tissue. The purpose of this study was to evaluate the PSL in canine vocal folds.

Methods

Four dogs underwent PITR incisions (4 mJ pulses at 200 Hz) on their vocal folds, through mucosa into the muscle. The animals were sacrificed at days 0, 3, 7, and 21 days postsurgery. The larynges were harvested and histology was performed with hematoxylin and eosin, Masson trichrome, and Verhoeff‐van Gieson.

Results

At day 0, focal denudation of the epithelium and coagulation necrosis in the lamina propria and adjacent connective tissue are noted. On days 3 and 7, an inflammatory infiltrate of neutrophils is seen within the lamina propria and surrounding connective tissue with minimal edema and early deposition of collagen. At day 21, the mucosa is completely regenerated with the area of previous PITR into the muscle replaced with thick bundles of collagen.

Conclusion

The unique PITR characteristics offer a potentially unique cutting technology for laryngeal microsurgery. The current canine study suggests appropriate and rapid healing. With refinements of the tip size of the probe and adjustment of energy, PITR will likely be an appropriate alternate to traditional lasers in laryngeal surgery.

Level of Evidence

NA. Laryngoscope, 2019

http://bit.ly/2SsWMZg

Toripalimab or Placebo With Paclitaxel and Cisplatin in Esophageal Squamous Cell Carcinoma

Condition:   Advanced or Metastatic Esophageal Squamous Cell Cancer Without Previous Systemic Chemotherapy
Intervention:   Biological: JS001
Sponsor:   Shanghai Junshi Bioscience Co., Ltd.
Recruiting

http://bit.ly/2I3HMx5

TreatmENT of AnastomotiC Leakage After Esophagectomy

Conditions:   Esophageal Cancer;   Esophageal Neoplasms
Intervention:   Other: Intervantions for anastomotic leakage after esophagectomy
Sponsors:   Radboud University;   Dutch Upper-GI Cancer Audit group (DUCA);   Oesophago-Gastric Anastomosis Audit (OGAA)
Not yet recruiting

http://bit.ly/2t5qNQw

Radiotherapy, Carboplatin/Paclitaxel and Nivolumab for High Risk HPV-related Head and Neck Cancer

Condition:   Oropharynx Squamous Cell Carcinoma
Interventions:   Drug: Nivolumab;   Drug: Carboplatin;   Drug: Paclitaxel;   Radiation: Radiation Therapy
Sponsors:   University of Michigan Rogel Cancer Center;   Bristol-Myers Squibb
Not yet recruiting

http://bit.ly/2HPI6iB

TPST-1120 as Monotherapy and in Combination With (Nivolumab, Docetaxel or Cetuximab) in Subjects With Advanced Cancers

Conditions:   Hepatocellular Carcinoma;   Metastatic Castration Resistant Prostate Cancer;   Renal Cell Carcinoma;   Non-small Cell Lung Cancer;   Colorectal Cancer;   Squamous Cell Carcinoma of Head and Neck;   Triple-Negative Breast Cancer;   Urothelial Carcinoma;   Cholangiocarcinoma;   GastroEsophageal Cancer;   Pancreatic Cancer;   Sarcoma
Interventions:   Drug: Part 1 TPST-1120;   Drug: Part 2a TPST-1120 + nivolumab;   Drug: Part 2b TPST-1120 + docetaxel;   Drug: Part 2c TPST-1120 + cetuximab;   Drug: Part 3 TPST-1120;   Drug: Part 4a TPST-1120 + nivolumab;   Drug: Part 4b TPST-1120 + docetaxel;   Drug: Part 4c TPST-1120 + cetuximab
Sponsor:   Tempest Therapeutics
Not yet recruiting

http://bit.ly/2G8dbMR

Safety and Efficacy of KY1044 and Atezolizumab in Advanced Cancer

Conditions:   Squamous Cell Carcinoma of Head and Neck;   Non-small Cell Lung Cancer;   Hepatocellular Carcinoma;   Esophageal Cancer;   Gastric Cancer;   Melanoma;   Renal Cell Carcinoma;   Pancreatic Cancer;   Cervical Cancer;   Triple Negative Breast Cancer;   Advanced Cancer
Interventions:   Drug: KY1044;   Drug: KY1044 and atezolizumab
Sponsor:   Kymab Limited
Recruiting

http://bit.ly/2D7Dm2g

Photon Therapy Versus Proton Therapy in Early Tonsil Cancer.

Condition:   Tonsil Cancer
Intervention:   Radiation: Radiotherapy
Sponsor:   Lund University Hospital
Recruiting

http://bit.ly/2GeoFi7

PD-L1 ImagiNg to prediCt Durvalumab Treatment Response in HNSCC

Condition:   Head and Neck Cancer
Interventions:   Diagnostic Test: PD-L1 imaging;   Drug: Durvalumab
Sponsors:   Radboud University;   AstraZeneca
Not yet recruiting

http://bit.ly/2D9Ywwy

Left to their own devices: the everyday realities of one-to-one classrooms

Selwyn, N; Nemorin, S; Bulfin, S; Johnson, NF; (2017) Left to their own devices: the everyday realities of one-to-one classrooms. Oxford Review of Education , 43 (3) pp. 289-310. 10.1080/03054985.2017.1305047 . Green open access

http://bit.ly/2GbUOGI

Optomechanics outside the lab: Prototyping and field-testing a whispering gallery mode accelerometer

Li, YL; Barker, PF; (2018) Optomechanics outside the lab: Prototyping and field-testing a whispering gallery mode accelerometer. In: Frontiers in Optics / Laser Science, OSA Technical Digest (Optical Society of America). OSA Publishing: Washington DC, USA.

http://bit.ly/2D9f3AV

Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

Jacquillet, G; Unwin, RJ; (2019) Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi). Pflügers Archiv - European Journal of Physiology , 471 (1) pp. 83-98. 10.1007/s00424-018-2231-z . Green open access

http://bit.ly/2G8wVA7

Aff-Wild: Valence and Arousal 'in-the-wild' Challenge

Zafeiriou, S; Kollias, D; Nicolaou, MA; Papaioannou, A; Zhao, G; Kotsia, I; (2017) Aff-Wild: Valence and Arousal 'in-the-wild' Challenge. In: 2017 IEEE Conference on Computer Vision and Pattern Recognition Workshops (CVPRW). (pp. pp. 1980-1987). IEEE Green open access

http://bit.ly/2Dak2kX

AgeDB: the first manually collected, in-the-wild age database

Moschoglou, S; Papaioannou, A; Sagonas, C; Deng, J; Kotsia, I; Zafeiriou, S; (2017) AgeDB: the first manually collected, in-the-wild age database. In: 2017 IEEE Conference on Computer Vision and Pattern Recognition Workshops (CVPRW). (pp. pp. 1997-2005). IEEE Green open access

http://bit.ly/2Geo5kr

Modern Heritage, the Other, and the Anthropocene

Denison, EB; (2018) Modern Heritage, the Other, and the Anthropocene. Built Heritage , 2 (4) pp. 31-41.

http://bit.ly/2D5mUzC

National Women Against Pit Closures: gender, trade unionism and community activism in the miners' strike, 1984–5

Sutcliffe-Braithwaite, Florence; Thomlinson, Natalie; (2018) National Women Against Pit Closures: gender, trade unionism and community activism in the miners' strike, 1984–5. Contemporary British History , 32 (1) pp. 78-100. 10.1080/13619462.2017.1408540 .

http://bit.ly/2Geo3sP

Carbonate delta drift: A new sediment drift type

Blättler, CL; Guo, JA; Haffen, S; Horozal, S; Inoue, M; Jovane, L; Kroon, D; ... Young, JR; + view all Blättler, CL; Guo, JA; Haffen, S; Horozal, S; Inoue, M; Jovane, L; Kroon, D; Lanci, L; Laya, JC; Mee, ALH; Nakakuni, M; Nath, BN; Niino, K; Petruny, LM; Pratiwi, SD; Slagle, AL; Su, X; Swart, PK; Wright, JD; Yao, Z; Young, JR; - view fewer (2018) Carbonate delta drift: A new sediment drift type. Marine Geology , 401 pp. 98-111. 10.1016/j.margeo.2018.04.011 .

http://bit.ly/2Dd86Pk

Using a 3D collagen matrix to deliver respiratory progenitor cells to decellularized trachea in vivo

Hamilton, N; Hynds, R; Gowers, K; Tait, A; Butler, C; Hopper, C; Burns, A; ... Janes, SM; + view all Hamilton, N; Hynds, R; Gowers, K; Tait, A; Butler, C; Hopper, C; Burns, A; Birchall, M; Lowdell, M; Janes, SM; - view fewer (2019) Using a 3D collagen matrix to deliver respiratory progenitor cells to decellularized trachea in vivo. Tissue Engineering Part C: Methods 10.1089/ten.TEC.2018.0241 . (In press).

http://bit.ly/2GaM43Q

Fast sampling from Wiener posteriors for image data with dataflow engines

Jeffrey, N; Heavens, A; Fortio, PD; (2018) Fast sampling from Wiener posteriors for image data with dataflow engines. Astronomy and Computing , 25 pp. 230-237. 10.1016/j.ascom.2018.10.001 . Green open access

http://bit.ly/2D5mOYM

Image-based Remapping of Material Appearance

Sztrajman, A; Krivánek, J; Wilkie, A; Weyrich, T; (2017) Image-based Remapping of Material Appearance. In: Klein, R and Rushmeier, HE, (eds.) Proceedings of the Eurographics Workshop on Material Appearance Modeling (MAM2017). (pp. pp. 5-8). Eurographics Association: Helsinki, Finland. Green open access

http://bit.ly/2G6myws

Large-scale ultrasound simulations using the hybrid OpenMP/MPI decomposition

Jaros, J; Nikl, V; Treeby, BE; (2015) Large-scale ultrasound simulations using the hybrid OpenMP/MPI decomposition. In: (Proceedings) EASC '15 Proceedings of the 3rd International Conference on Exascale Applications and Software. (pp. pp. 115-119). ACM Green open access

http://bit.ly/2D8KETz

Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor

Buechler, J; Salinas, PC; (2018) Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor. Frontiers in Synaptic Neuroscience , 10 , Article 38. 10.3389/fnsyn.2018.00038 . Green open access

http://bit.ly/2GaVLPP

The hidden role of the subsurface for cities

Tann, LVD; Metje, N; Admiraal, H; Collins, B; (2018) The hidden role of the subsurface for cities. Proceedings of the Institution of Civil Engineers - Civil Engineering , 171 (6) , Article 1700028. 10.1680/jcien.17.00028 . Green open access

http://bit.ly/2D5mPfi

Analysis of energy consumption in Hunan Province (China) using a LMDI method based LEAP model

Wang, P; Wang, C; Hu, Y; Liu, Z; (2017) Analysis of energy consumption in Hunan Province (China) using a LMDI method based LEAP model. In: Yan, J and Wu, J and Li, H, (eds.) Energy Procedia. (pp. pp. 3160-3169). Elsevier Green open access

http://bit.ly/2G7BJWl

Information‐anchored sensitivity analysis: theory and application

Cro, S; Carpenter, JR; Kenward, MG; (2019) Information‐anchored sensitivity analysis: theory and application. Journal of the Royal Statistical Society: Series A (Statistics in Society) , 182 (2) pp. 623-645. 10.1111/rssa.12423 . Green open access

http://bit.ly/2D6xcj5

Spinal Muscular Atrophy, types I and II: What are the differences in body composition and resting energy expenditure?

Bertoli, S; De Amicis, R; Mastella, C; Pieri, G; Giaquinto, E; Battezzati, A; Leone, A; Bertoli, S; De Amicis, R; Mastella, C; Pieri, G; Giaquinto, E; Battezzati, A; Leone, A; Baranello, G; - view fewer (2017) Spinal Muscular Atrophy, types I and II: What are the differences in body composition and resting energy expenditure? Clinical Nutrition , 36 (6) pp. 1674-1680. 10.1016/j.clnu.2016.10.020 . Green open access

http://bit.ly/2G6mixu

A New Method for Measuring Bell-Shaped Chest Induced by Impaired Ribcage Muscles in Spinal Muscular Atrophy Children

LoMauro, A; Banfi, P; Mastella, C; Alberti, K; Baranello, G; Aliverti, A; (2018) A New Method for Measuring Bell-Shaped Chest Induced by Impaired Ribcage Muscles in Spinal Muscular Atrophy Children. Frontiers in Neurology , 9 , Article 703. 10.3389/fneur.2018.00703 . Green open access

http://bit.ly/2D4KZ9H

GPU-Accelerated Simulation of Elastic Wave Propagation

Kadlubiak, K; Jaros, J; Treeby, BE; (2018) GPU-Accelerated Simulation of Elastic Wave Propagation. In: Smari, WW and Zinedine, K, (eds.) Proceedings of 2018 International Conference on High Performance Computing & Simulation (HPCS). (pp. pp. 188-195). IEEE: Orleans, France. Green open access

http://bit.ly/2G99cj1

Passive Radar for Opportunistic Monitoring in E-Health Applications

Li, W; Tan, B; Piechocki, R; (2018) Passive Radar for Opportunistic Monitoring in E-Health Applications. IEEE Journal of Translational Engineering in Health and Medicine , 6 , Article 2800210. 10.1109/JTEHM.2018.2791609 . Green open access

http://bit.ly/2D5XFx8

Intrascleral Fixation of an Intraocular Lens through the Pars Plana Prevents Corneal Endothelial Damage

We report two cases of aphakia in whom an intraocular lens (IOL) was intrasclerally fixated through the pars plana to minimize further corneal endothelial damage. A modified lock-and-lead technique was used. A sclerotomy and scleral incision were made 2.5 mm from the limbus. A 24-G catheter needle was used for penetration of the leading haptic, and two ultrathin 30-G needles were used to bury the ends of the haptics. The scleral incision was sutured with 8-0 nylon. Corneal endothelial cells were preserved after surgery. Neither intra- nor postoperative complications were observed. Intrascleral fixation of an IOL through the pars plana effectively minimizes further damage to corneal endothelial cells in select cases.
Case Rep Ophthalmol 2019;10:53–60

http://bit.ly/2GlbQlg

Treatment of oral cancers during pregnancy: a case-based discussion

Abstract

Background

Malignancies occur in approximately 1:1000 pregnancies; the most common being breast (46%) and hematological (18%) malignancies. Oral cancers account for only 2% of all cancers in pregnant women, and there are no standard guidelines for the treatment of oral cancer during pregnancy.

Methods

Between 2007 and 2014, our department managed 1109 patients with oral cancers; four (0.4%) had tongue carcinomas during pregnancy. These cases were retrospectively reviewed.

Results

The four women were aged 29–39 (median 32.5) years. Two underwent partial glossectomy at 39 and 40 weeks' gestation, respectively, one received radiotherapy at 17 weeks' gestation, and one underwent supraomohyoid neck dissection and hemi-glossectomy with a forearm flap reconstruction.

Conclusion

In addition to tumor factors, the wishes of the patient and her family, gestational age, and fetal and maternal conditions are important factors in deciding on a treatment protocol. Moreover, treatment decisions require multidisciplinary approach.

http://bit.ly/2MNDgRY

Facilitating Lifelong Learning Through Vocational Education and Training: Promoting Inclusion and Opportunities for Young People

Kersh, N; Huegler, N; (2018) Facilitating Lifelong Learning Through Vocational Education and Training: Promoting Inclusion and Opportunities for Young People. In: McGrath, S and Mulder, M and Papier, J and Suart, R, (eds.) Handbook of Vocational Education and Training: Developments in the Changing World of Work. Springer: Cham, Switzerland.

http://bit.ly/2MLX9c7

Marketing Renewable Energy in the United Kingdom

Spataru, C; Arcuri, B; (2017) Marketing Renewable Energy in the United Kingdom. In: Herbes, C and Friege, C, (eds.) Marketing Renewable Energy: Concepts, Business Models and Cases. (pp. 331-344). Springer: Cham, Switzerland.

http://bit.ly/2DQINnJ

On Becoming A Cyborg: A Reflection On Articulation Work, Embodiment, Agency and Abelism

Rode, JA; (2018) On Becoming A Cyborg: A Reflection On Articulation Work, Embodiment, Agency and Abelism. In: Langdon, P and Lazar, J and Heylighen, A and Dong, H, (eds.) Breaking Down Barriers: Usability, Accessibility and Inclusive Design. (pp. pp. 239-249). Springer: Cham, Switzerland.

http://bit.ly/2MOLKbs

Microscale bioprocessing platform for the evaluation of membrane filtration processes for primary recovery

Rayat, Andrea Chielou May Elumbaring; (2011) Microscale bioprocessing platform for the evaluation of membrane filtration processes for primary recovery. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://bit.ly/2DQIGbN

Drops, Jets and High-Resolution 3D Printing: Fundamentals and Applications

Caulfield, R; Fang, F; Tiwari, MK; (2018) Drops, Jets and High-Resolution 3D Printing: Fundamentals and Applications. In: Basu, S and Agarwal, A and Mukhopadhyay, A and Patel, C, (eds.) Applications Paradigms of Droplet and Spray Transport: Paradigms and Applications. (pp. 123-162). Springer: Singapore.

http://bit.ly/2MOaSiH

Serious Frivolity: Exploring Play in UK Secondary Mathematics Classrooms

Lake, E; (2017) Serious Frivolity: Exploring Play in UK Secondary Mathematics Classrooms. In: Andra, C and Brunetto, D and Levenson, E and Liljedahl, P, (eds.) Teaching and Learning in Maths Classrooms: Emerging Themes in Affect-related Research: Teachers' Beliefs, Students' Engagement and Social Interaction. (pp. 59-69). Springer: Cham, Switzerland.

http://bit.ly/2DQIyJl

The Global Ambitions of Irish Universities: Internationalizing Practices and Emerging Stratification in the Irish Higher Education Sector

Courtois, ADM; (2018) The Global Ambitions of Irish Universities: Internationalizing Practices and Emerging Stratification in the Irish Higher Education Sector. In: Bloch, R and Paradeise, C and Mitterle, A and Tobias, P, (eds.) Universities and the Production of Elites. Discourses, Policies, and Strategies of Excellence and Stratification in Higher Education. Palgrave Macmillan: Cham, Switzerland.

http://bit.ly/2MNvcAy

Anticipatory Mobile Digital Health: Towards Personalised Proactive Therapies and Prevention Strategies

Pejovic, V; Mehrotra, A; Musolesi, M; (2017) Anticipatory Mobile Digital Health: Towards Personalised Proactive Therapies and Prevention Strategies. In: Nadin, M, (ed.) Anticipation and Medicine. (pp. 253-267). Springer: Cham, Switzerland. Green open access

http://bit.ly/2DTpWbY

How Low Can We Go? The Implications of Delayed Ratcheting and Negative Emissions Technologies on Achieving Well Below 2 °C

Winning, M; Pye, S; Glynn, J; Scamman, D; Welsby, D; (2018) How Low Can We Go? The Implications of Delayed Ratcheting and Negative Emissions Technologies on Achieving Well Below 2 °C. In: Giannakidis, G and Karlsson, K and Labriet, M and Ó Gallachó, B, (eds.) Limiting Global Warming to Well Below 2 °C: Energy System Modelling and Policy Development. (pp. 51-65). Springer: Cham, Switzerland.

http://bit.ly/2MM31lq

Making sense of data: fact and value

Standish, P; (2016) Making sense of data: fact and value. Pedagogika , 6/2016 pp. 622-637. 10.14712/23362189.2016.367 .

http://bit.ly/2DQIkBZ

Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP)

Singh, RB; Agarwal, A; Agrawal, R; Sagoo, MS; Aggarwal, K; Gupta, V; (2019) Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP). In: Gupta, V and Nguyen, QD and LeHoang, P and Herbort, CPH, (eds.) The Uveitis Atlas. Springer: New Delhi, India. (In press).

http://bit.ly/2MMxGz6

25-Hydroxyvitamin D variability within-person due to diurnal rhythm and illness: a case report

Vitamin D nutrition research requires accurate measures of circulating 25-hydroxyvitamin D. Our objectives were to test whether a diurnal fluctuation in blood-spot concentrations of 25-hydroxyvitamin D can be ...

http://bit.ly/2HPuhRb

Activation of Group 2 innate lymphoid cells after allergen challenge in asthmatics

Publication date: Available online 4 February 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Carla Winkler, Thomas Hochdörfer, Elisabeth Israelsson, Annemarie Hasselberg, Anders Cavallin, Kristofer Thörn, Daniel Muthas, Shervin Shojaee, Katrin Lueer, Meike Mueller, Jenny Mjösberg, Outi Vaarala, Jens Hohlfeld, Katerina Pardali

Abstract

Background

Group 2 innate lymphoid cells (ILC2) are effective producers of IL-5 and IL-13 during allergic inflammation and bridge the innate and adaptive immune response. ILC2 are increased in asthmatics compared to healthy controls. So far human data describing their phenotype during acute allergic inflammation in the lung is incomplete.

Objectives

This study aims to characterize and compare blood- and lung-derived ILC2 before and after segmental allergen challenge in mild to moderate asthmatic individuals with high blood eosinophil levels (≥300/μl).

Methods

ILC2 were isolated from blood and bronchoalveolar lavage (BAL) before and after segmental allergen challenge. Cells were sorted by flow cytometry, cultured and analyzed for cytokine release or migration, and sequenced for RNA expression.

Results

ILC2 were nearly absent in the alveolar space under baseline conditions but increased significantly after allergen challenge (P < 0.05) , whilst at the same time ILC2 numbers in blood were reduced (P<0.05). Prostaglandin D₂ (PGD₂) and CXCL12 levels in BAL correlated with decreased ILC2 numbers in blood (P = 0.004, respective P = 0.024). After allergen challenge several genes promoting type 2 inflammation were higher expressed in BAL compared to blood ILC2, while blood ILC2 remain unactivated.

Conclusion

ILC2 accumulate at the site of allergic inflammation and are recruited from the blood. Their transcriptional and functional activation pattern promote type 2 inflammation.

http://bit.ly/2WNWo70