Disease outbreaks are considered to be the main constraint to aquaculture development. The disadvantages of widespread use of antibiotics have been realized in whole animal production industry including aquaculture. Thus there is increasing demand for developing alternative disease control strategies. The heat shock protein 70 (HSP70) were discovered as a potential candidate for the development of a new disease control approach. This thesis evaluates a novel anti-‐infective strategy to control vibriosis and WSSV in aquaculture. More specifically, investigations were performed to elucidate the role of recombinant heat shock protein 70 (Hsp 70), derived from a prokaryotic source, in generating an immune response and to instigate protection against pathogenic Vibrio campbellii and White Spot Syndrome virus (WSSV). Firstly, the role of bacterial HSP70 (DnaK) as an efficient immuno-stimulant in L. vannamei was verified by including a chemically synthetic, microbial contaminants free DnaK fragment peptide (DnaK442-‐491) as control. Secondly, in order to evaluate the acute immune stimulatory effect of DnaK in L. vannamei, regulation of four important immune-‐related gene groups (prophenoloxidase, transglutaminase, penadins, endogenous HSP70) were monitored 12h after DnaK intramuscular injection. Significantly responding genes were selected as immune markers for subsequent study. Subsequently, the priming effect of bacterial HSP70 DnaK against V. campbellii and WSSV infection was evaluated. Thesis demonstrated that pre-‐treatment of L. vannamei with the DnaK, followed by a non-lethal V. campbellii challenge affected the transcription of 3 immune marker genes, TGase-‐1, proPO-‐2 and lvHSP70. Similarly, we tested the hypothesis that DnaK can prime the immune system of L.vannamei to cope with a viral infection (WSSV). Transcriptions of two immune related genes, TGase-‐1 and proPO-‐2, were quantified within 12 hpp. Strong synergistic effects induced by both DnaK and WSSV on TGase-‐1 and proPO-‐2 were exhibited. In conclusion, the results presented in this thesis indicate a possible role for DnaK as an immune priming agent in L. vannamei against V. campbellii and WSSV infections.
http://ift.tt/2suKaRM
Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 19 Ιουνίου 2017
Priming the immune system of Litopenaeus vannamei with bacterial heat shock protein 70 homologue DnaK against Vibrio campbellii and white spot syndrome virus (WSSV) infection
Efficacy of a high-observation protocol in major head and neck cancer surgery: A prospective study
ABSTRACT
Background
The purpose of this study was to optimize an existing clinical care pathway (CCP) for head and neck cancer with a high-observation protocol (HOP) and to determine the effect on length of intensive care unit (ICU) admission and length of stay in hospital (LOS).
Methods
The HOP mandated initiation of spontaneous breathing trials before the conclusion of the surgery, weaning of sedation, and limiting mechanical ventilation. All patients with head and neck cancer undergoing primary surgery on the HOP were compared to a historical cohort regarding length of ICU admission, ICU readmissions, and LOS.
Results
Ninety-six and 52 patients were observed in "historical" and "HOP" cohorts. The length of ICU admission (1.9 vs 1.2 days; p = .021), LOS (20.3 vs 14.1 days; p = .020), and ICU readmissions (10.4% vs 1.9%; p = .013) were significantly decreased in the "HOP" cohort.
Conclusion
Rapid weaning of sedation and limiting mechanical ventilation may contribute to a shorter length of ICU admission and LOS, as well as decreased ICU readmissions. © 2017 Wiley Periodicals, Inc. Head Neck, 2017
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High Gpx1 expression predicts poor survival in laryngeal squamous cell carcinoma
Several studies have demonstrated that abnormal glutathione peroxidases 1 (Gpx1) expression can influence the biological behavior of malignant cells. However, the roles of Gpx1 in laryngeal squamous cell carcinoma (LSCC) remain unknown. The purpose of this study is to analyze the Gpx1 expression and prognostic significance in LSCC patients.
http://ift.tt/2tndU31
Metabolic control and periodontal treatment decreases elevated oxidative stress in the early phases of type 1 diabetes onset
Source:Archives of Oral Biology, Volume 82
Author(s): Cüneyt A. Aral, Özlem Nalbantoğlu, Bilge G. Nur, Mustafa Altunsoy, Kübra Aral
ObjectiveRecently, increasing concern has been focused on the contribution of oxidative stress in the pathology of periodontal disease and diabetes mellitus. Firstly, the present study aimed to analyze gingival crevicular fluid (GCF), salivary, and serum oxidative status in children with type 1 diabetes mellitus (T1DM) at diagnosis and systemically healthy children with and without gingivitis. Additionally, the diabetic patients were reevaluated after diabetes and periodontal treatment.DesignThe study groups were composed of 32 T1DM patients at diagnosis, and age- and gender-matched thirty-six systemically healthy children with (G) and without (H) gingivitis. The diabetic patients who took insulin therapy (1.5 units/kg/day totally) and periodontal treatment (oral hygiene education with professional scaling) were reevaluated after 3 months. The levels of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were recorded.ResultsGCF, salivary, and serum OSI were elevated in group T1DM compared to the other groups at baseline (p<0.05), and decreased in group T1DM at reevaluation compared to baseline (p<0.05). GCF OSI was positively correlated with periodontal clinical parameters (p<0.05). Glycated hemoglobin was positively correlated with GCF TOS (r=0.302, p=0.007), GCF OSI (r=0.346, p=0.002), salivary TOS (r=0.326, p=0.046), and serum TOS (r=0.239, p=0.044).ConclusionThe instability in the oxidative status that accompanies diabetes may be considered a significant pathogenic factor of diabetes-related periodontal inflammation.
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Mucoepidermoid carcinoma-associated expression of MUC5AC, MUC5B and mucin-type carbohydrate antigen sialyl-Tn in the parotid gland
Source:Archives of Oral Biology, Volume 82
Author(s): Johannes H. Matse, Wiresh K. Bharos, Enno C.I. Veerman, Elisabeth Bloemena, Jan G.M. Bolscher
ObjectivesThe aberrant expression of mucins and mucin-type carbohydrates has been described in many types of cancer, including mucoepidermoid carcinoma (MEC), a malignant salivary gland tumor. In this study, we examined the aberrant expression patterns of mucins (MUC1, MUC4, MUC5AC and MUC5B), simple mucin-type carbohydrate antigens (Tn, sialyl-Tn and T) and mature carbohydrate antigens (Lewisa and sulfo-Lewisa antigens) in MEC originating from the parotid gland, which normally does not secrete mucins.DesignWe conducted an immunohistochemical study to investigate the presence of mucins and carbohydrates in 24 MEC samples originating from the parotid gland and in surrounding normal tissue of the same gland in comparison 6 samples of normal salivary glands. The expression levels were compared with respect to the histological grading. Furthermore, 24 MEC samples from non-parotid salivary glands were included.ResultsWe observed loss of topology of membrane-bound MUC1 and MUC4, and de novo expression of MUC5AC, MUC5B and sialyl-Tn in MEC that originated in the parotid gland. Furthermore, mucins MUC1, MUC4 and carbohydrate antigens Tn, sialyl-Tn, T, Lewisa and sulfo-Lewisa were overexpressed in MEC samples compared to surrounding normal salivary gland tissues. MUC1 was expressed in both low- and high grade MECs, whereas MUC4 was not expressed in high grade MECs of the parotid gland.ConclusionDuring the development of MEC in the parotid gland, the genes for gel-forming secretory mucins are switched on. Besides these MEC tissues overexpress short oligosaccharides, suggesting that the glycosylation machinery is altered.
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Stimulatory effect of Aggregatibacter actinomycetemcomitans DNA on proinflammatory cytokine expression by human gingival fibroblasts
Publication date: October 2017
Source:Archives of Oral Biology, Volume 82
Author(s): Uriel Soto-Barreras, Gabriela Cortés-Sandoval, Ruben Dominguez-Perez, Alejandra Loyola-Leyva, Panfilo-Raymundo Martinez-Rodriguez, Juan Pablo Loyola-Rodriguez
ObjectiveWhile different virulence factors have been reported of Aggregatibacter actinomycetemcomitans (Aa), there is little information about the stimulatory effect of its DNA. The main purpose of this study was to assess the inflammatory response of human gingival fibroblasts (HGFs) stimulated with A. actinomycetemcomitans DNA.DesignCytokine levels of IL-6, IL-1α and TNF-α were measured on the supernatant of HGFs activated with 10, 25, 50 and 100μg/ml DNA of Aa during 24h. Primary cultures of HGFs were infected with Aa and its DNA at different times and concentrations to compare its cytotoxic effect. Cell damage and adhesion of Aa to HGFs were evaluated under light microscopy and Scanning electron microscopy respectively.ResultsThere was a statistical difference (p<0.05) in cytokine expression in HGFs activated by bacterial DNA with a dose dependent on IL-6 expression and a significantly elevated expression of IL-1α and TNF-α compared to Human DNA negative control. Substantial morphological alterations were observed after infection of A. actinomycetemcomitans in HGFs but not with bDNA exposure. Aggregatibacter actinomycetemcomitans showed a high rate of adhesion and cell damage to HGFs after 30min.ConclusionsGenomic DNA of A. actinomycetemcomitans could be a factor in the pathogenesis of periodontitis that might play a major role in the inflammatory response.
Graphical abstract
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Quantitative study of the proportion of the pore volume of human fluorotic enamel filled by resin infiltrant
Source:Archives of Oral Biology, Volume 82
Author(s): Frederico Barbosa de Sousa, Isabel Maria Porto Lelis, Regina Célia Bressan Queiroz Figueiredo, Andressa Cavalcanti Pires, Raquel Fernanda Gerlach
AimCapillarity theory predicts that the pore volume infiltrated by a liquid in a body with tubular capillaries is directly proportional to the capillary radius. The expected volume available for infiltration is the loosely bound water volume, which can be related to the capillary radii. We tested the hypothesis that the proportion of the pore volume infiltrated by resin infiltrant (Vratioresin) is correlated and agrees with the proportion of the pore volume with loosely bound water (Vratioa2).DesignSeven human fluorotic third molars (4 unerupted and 3 erupted; TF scores 4 to 7; fluoride content of inner coronal dentin ranged from 143 to 934μg Fluoride/g) were prepared and resin infiltration was performed during 10min in fluorotic enamel ground sections. Penetration depths were measured (polarizing microscopy and CLSM) and mineral volume and non-mineral volumes were measured at histological points (n=92) along transversal lines traced from the enamel surface to the enamel-dentin junction.ResultsNo well-mineralized surface layer was found. Infiltration depths ranged from 250μm to 900μm. Vratioresin ranged from 1.8 to 17.7% (mean of 10.13%±4.1%), was lower than Vratioa2 (p<0 Hedge's g=1.51, 95% CI: 1.18/1.83), and correlated positively with Vratioa2 (R=0.684; 95% CI: 0.557/0.780) and negatively with the air volume remained after infiltration (R=−0.79; 95% CI: −0.698/−0.780). Vratioa2 exceeded Vratioresin in 5% (1/4 of Vratioa2) on average.ConclusionVratioa2 and Vratioresin correlated well, but lacked good agreement. Organic matter, firmly bound water and air remained in enamel pores after resin infiltration.
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Potential chemotherapeutic effects of diosgenin, zoledronic acid and epigallocatechin-3-gallate on PE/CA-PJ15 oral squamous cancer cell line
Source:Archives of Oral Biology, Volume 82
Author(s): Eduardo Pons-Fuster López, Qin-tong Wang, Wei Wei, Pia López Jornet
ObjectiveTo study the potential chemotherapeutic effects of Diosgenin, zoledronic acid and Epigallocatechin-3-gallate on oral squamous cell cancer (OSCC).Materials and methodsCell viability, migration, apoptosis and cell cycle evaluation assays were performed in order to assess the effects of different doses of Diosgenin, zoledronic acid and Epigallocatechin-3-gallate on the PE/CA-PJ15 cell line.ResultsDoses of 100μM of diosgenin or zoledronic acid reduced cell viability significantly after 72h (p<0.001), as well as increasing apoptosis (p<0.05 and p<0.01 respectively). All three agents reduced cell migration and altered the cell cycle, each at a different phase of the cycle.Conclusionwhile DG and ZA reduced cell viability, increased apoptosis, inhibited cell migration and modified the cell cycle in different ways, EGCG only modified the cell cycle and reduced cell migration. These agents present a potential chemotherapeutic effect on PE/CA-PJ15 OSSC cell line, which have to be further studied.
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The absence of CD56 expression can differentiate papillary thyroid carcinoma from other thyroid lesions
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
http://ift.tt/2sNtPLh
The absence of CD56 expression can differentiate papillary thyroid carcinoma from other thyroid lesions
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Irregular Outcomes: Predictors of New Atrial Fibrillation After Noncardiac Surgery
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Determination of Perioperative Blood Loss: Accuracy or Approximation?
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Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study
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Treatment of experimental visceral leishmaniasis with single-dose liposomal amphotericin B - pharmacodynamics and biodistribution at different stages of disease [PublishAheadOfPrint]
Visceral leishmaniasis is a neglected tropical disease, which causes significant morbidity and mortality worldwide. Characterising the pharmacokinetics and pharmacodynamics of anti-leishmanial drugs in pre-clinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of AmBisome® in L. donovani infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome® >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 hours and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome® was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome® was administered at the advanced stage of infection and when compared to uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani infected livers and spleens. Taken together our data suggests that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single dose AmBisome® to L. donovani infected mice. Plasma levels were not reflective of changes in drug levels in tissues.
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Rapid and consistent evolution of colistin resistance in XDR Pseudomonas aeruginosa during morbidostat culture [PublishAheadOfPrint]
Colistin is a last resort antibiotic commonly used against multidrug-resistant strains of Pseudomonas aeruginosa. To investigate the potential for in-situ evolution of resistance against colistin and to map the molecular targets of colistin resistance, we exposed two P. aeruginosa isolates to colistin using a continuous culture device known as morbidostat. As a result, colistin resistance reproducibly increased 10-fold within ten days, and 100-fold within 20 days, along with highly stereotypic, yet strain specific mutation patterns. The majority of mutations hit the pmrAB two component signaling system and genes involved in lipopolysaccharide (LPS) synthesis, including lpxC, pmrE, and migA. We tracked the frequencies of all arising mutations by whole genome deep sequencing every 3-4 days to provide a detailed picture of the dynamics of resistance evolution, including competition and displacement among multiple resistant sub-populations. In seven out of 18 cultures, we observed mutations in mutS along with a mutator phenotype that seemed to facilitate resistance evolution.
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The impact of gyrB and eis mutations in improving second-line drug resistance detection among Mycobacterium tuberculosis isolates from Georgia [PublishAheadOfPrint]
SETTING: The country of Georgia has a high burden of multi- and extensively drug-resistant tuberculosis (XDR-TB).
OBJECTIVE: To evaluate whether the detection of mutations in gyrB and eis genes increased the sensitivity of detecting phenotypic resistance to ofloxacin and kanamycin or capreomycin as compared to use of the first generation MTBDRsl assay alone which evaluates for mutations in gyrA and rrs genes.
DESIGN: A retrospective study of storedMycobacterium tuberculosis isolates. All isolates underwent DNA sequencing of resistance determining regions.
RESULTS: Among 112 M. tuberculosisisolates with DNA extraction, targeted sequencing was successfully performed for each gene as follows:gyrA – 98%; gyrB – 96%; rrs – 93% and for the eis gene and its promoter - 93%.The specificity and hence positive predictive value ofgyrA and gyrB mutations for detecting ofloxacin resistance were 100%. The addition of gyrB mutations increased the sensitivity of phenotypic ofloxacin resistance detection by 13% (75 to 88%).All rrs resistant conferring mutations were A1401G and this mutation had a low sensitivity (40% and 18%) and high specificity (95% and 100%) in predicting phenotypic capreomycinand kanamycin resistance, respectively. The eisC-14T mutation increased the sensitivity of phenotypic kanamycin resistant by 9% (18 to 27%) and was found solely in kanamycin phenotypic resistance isolates.
CONCLUSIONS: Our data showed that the inclusion of eis C-14T and gyrB mutations in addition to mutations rrs and gyrAgenes improves the sensitivity of phenotypic ofloxacin and kanamycin resistance, respectively.
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A low molecular weight alginate oligosaccharide disrupts pseudomonal microcolony formation and enhances antibiotic effectiveness [PublishAheadOfPrint]
In chronic respiratory disease the formation of dense, 3-dimensional 'micro colonies' by Pseudomonas aeruginosa within the airway plays an important role in contributing to resistance to treatment. An in vitro biofilm model of pseudomonal microcolony formation using artificial sputum (AS) medium was established to study the effects of low molecular weight alginate oligomers (OligoG CF-5/20) on pseudomonal growth, microcolony formation and the efficacy of colistin. The studies employed clinical cystic fibrosis (CF) isolates (n=3) and reference non-mucoid and mucoid multi-drug resistant (MDR) CF isolates (n=7). Bacterial growth, biofilm development and disruption were studied using cell-viability assays and image analysis using scanning electron- and confocal laser scanning microscopy. Pseudomonal growth in AS medium was associated with increased ATP production (p<0.05) and the formation (at 48 h) of discrete (>10 μm) microcolonies. In conventional growth medium, colistin retained an ability to inhibit growth of planktonic bacteria, although the MIC was increased (0.1 to 0.4 μg/ml) in AS medium versus. In contrast, in an established biofilm model in the AS medium, the efficacy of colistin was decreased. OligoG CF-5/20 (≥2%) treatment however, induced dose-dependent biofilm disruption (p<0.05), and led to colistin retaining its antimicrobial activity (p<0.05). Whilst circular dichroism indicated that OligoG CF-5/20 did not change the orientation of the alginate carboxyl groups, mass-spectrometry demonstrated that the oligomers induced dose-dependent (>0.2%; p<0.05) reductions in pseudomonal quorum sensing signaling. These findings reinforce the potential clinical significance of microcolony formation in the CF lung, and highlight a novel approach to treat MDR pseudomonal infections.
http://ift.tt/2tHD8sw
Genome Evolution to Penicillin Resistance in Serotype 3 Streptococcus pneumoniae by Capsular Switching [PublishAheadOfPrint]
Streptococcus pneumoniae of serotype 3 was collected from cases of invasive pneumococcal disease (n = 124) throughout Japan from April 2010 to March 2013. A penicillin-resistant S. pneumoniae (PRSP) isolate from an adult patient, KK0981 of serotype 3, was identified among these strains. Whole-genome analysis characterized this PRSP as a recombinant strain derived from PRSP of serotype 23F with the cps-locus (20.3 kb) replaced by that of a penicillin-susceptible strain of serotype 3.
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Bactericidal and sterilizing activity of a novel regimen with bedaquiline, pretomanid, moxifloxacin and pyrazinamide in a murine model of tuberculosis [PublishAheadOfPrint]
New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) + pretomanid (PMD) + pyrazinamide (PZA) and of PMD + moxifloxacin (MXF) + PZA shorten the treatment duration necessary to prevent relapse by 2-3 and 1-2 months, respectively, compared with the current first-line regimen in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored to identify the optimal regimens and treatment times and to infer the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse free after two months of treatment. PZA could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA or BDQ from the beginning required approximately 0.5, 1 or 2 months of additional treatment to attain the same outcome.
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Genome wide analysis of the antimicrobial peptides in Python bivittatus and characterization of cathelicidins with potent antimicrobial activity and low cytotoxicity [PublishAheadOfPrint]
In this study, we sought to identify novel antimicrobial peptides (AMPs) in Python bivittatus through bioinformatic analyses of publicly available genome information and experimental validation. In our analysis of the python genome, we identified 29 AMP-related candidate sequences. Of these, we selected five cathelicidin-like sequences and subjected them to further in silico analyses. The results showed that these sequences likely have antimicrobial activity. The sequences were named Pb-CATH1–Pb-CATH5 according to their sequence similarity to previously reported snake cathelicidins. We predicted their molecular structure, and then chemically synthesized the mature peptide for three putative cathelicidins and subjected them to biological activity tests. Interestingly, all three peptides showed potent antimicrobial effects against Gram-negative bacteria, but very weak activity against Gram-positive bacteria. Remarkably, Pb-CATH4 showed potent activity against antibiotic-resistance clinical isolates and also possess very low hemolytic activity and cytotoxicity. Pb-CATH4 also showed considerable serum stability. Electron microscopic analysis indicated that Pb-CATH4 exerts its effects via toroidal pore preformation. Structural comparison of the cathelicidins identified in this study to previously reported ones revealed that these Pb-CATHs are representatives of a new group of reptilian cathelicidins lacking the acidic connecting domain. Furthermore, Pb-CATH4 possesses a completely different mature peptide sequence compared to previously described reptilian cathelicidins. These new AMPs may be candidates for the development of alternatives to or complements of antibiotics to control multi-drug resistant pathogens.
http://ift.tt/2tHwTVz
Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae [PublishAheadOfPrint]
We determined imipenem, imipenem-relebactam, ceftazidime and ceftazidime-avibactam minimum inhibitory concentrations (MICs) against 100 CRE isolates that underwent whole genome sequencing. KPCs were the most common carbapenemases. Forty-six isolates carried ESBLs. With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against MBL-producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (p<0.0001), and showed a trend to independent association with higher ceftazidime-avibactam MICs (p=0.07). Presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (p<0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity, and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.
http://ift.tt/2sJMzua
The combined effect of the Cfr methyltransferase and ribosomal protein L3 mutations on resistance to ribosome targeting antibiotics [PublishAheadOfPrint]
Several groups of antibiotics inhibit bacterial growth by binding to bacterial ribosomes. Mutations in the ribosomal protein L3 have been associated with resistance to linezolid and tiamulin, which both bind at the peptidyl transferase center in the ribosome. Resistance to these and other antibiotics also occurs through methylation of 23S ribosomal RNA at position A2503 by the methyltransferase Cfr. The mutations in L3 and the cfr gene have been found together in clinical isolates, raising the question whether they provide a combined effect on antibiotic resistance or growth. We transformed a plasmid borne cfr gene into an uL3 depleted E. coli strain containing either wild type L3 or one of the seven L3 mutations: G147R, Q148F, N149S, N149D, N149R, Q150L, or T151P expressed from plasmid coded rplC genes. The L3 mutations are well tolerated with small to moderate decreases in growth rate. The presence of Cfr has a very minor influence on growth rate. The resistance of the transformants against linezolid, tiamulin, florfenicol, and synercid was measured by minimum inhibitory concentration assays. The resistance from Cfr is in all cases stronger than the effects from the L3 mutations but various effects were obtained from the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. The susceptibility to linezolid and tiamulin varies highly between the L3 mutations while no significant effects are seen for florfenicol and synercid. This study underscores the complex interplay between various resistance mechanisms and cross-resistance, even from antibiotics with overlapping binding sites.
http://ift.tt/2tHIOCB
Bioavailability of lumefantrine is significantly enhanced with a novel formulation approach: A randomized, open-label pharmacokinetic study in healthy volunteers [PublishAheadOfPrint]
The artemether-lumefantrine combination requires food intake for optimal absorption of lumefantrine. In an attempt to enhance bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In Part 1, relative bioavailability of the two SDF variants was compared with the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In Part 2, pharmacokinetics of lumefantrine from both SDF variants was evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions.
The bioavailability of lumefantrine from SDF variant-1 and variant-2 increased up to ~48-fold and ~24-fold, respectively, relative to the conventional formulation. Both variants demonstrated positive food effect and less than proportional increase in exposure between 480 mg and 960 mg doses.
Most AEs were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant-2. No clinically-significant treatment-emergent changes were noted in vital signs, ECG, or laboratory blood assessments.
The Solid Dispersion Formulation enhances lumefantrine bioavailability to a significant extent and SDF variant-1 is superior to SDF variant-2.
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Identification of a novel antibacterial compound 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol active against persisters of Pseudomonas aeruginosa [PublishAheadOfPrint]
Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen as a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current report is focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group and, due to an increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells and elimination of these cells would therefore significantly improve patient outcome. In this study, a small-molecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters as compared to treatment with the antibiotic alone. Based on early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 106-fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel anti-persister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.
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{beta}-Lactam Antibiotics with a High Affinity for PBP2 Act Synergistically with the FtsZ-Targeting Agent TXA707 against Methicillin-Resistant Staphylococcus aureus [PublishAheadOfPrint]
Methicillin-resistant Staphylococcus aureus (MRSA) is a multi-drug resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. Here we present results that demonstrate differing extents of synergy between TXA707 and a broad range of β-lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each β-lactam, we determined the binding affinities of the β-lactam antibiotics for each of the four native penicillin binding proteins (PBPs) of S. aureus using a fluorescence anisotropy competition assay. A comparison of the resulting PBP binding affinities with our corresponding synergy results reveals that β-lactams with a high affinity for PBP2 afford the greatest degree of synergy with TXA707 against MRSA. In addition, we present fluorescence and electron microscopy studies that suggest a potential mechanism underlying the synergy between TXA707 and the β-lactam antibiotics. In this connection, our microscopy results show a disruption of septum formation in TXA707-treated MRSA cells, with a concomitant mislocalization of the PBPs from mid-cell to non-productive peripheral sites. Viewed as a whole, our results indicate that PBP2-targeting β-lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections.
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In Vitro Activity of Delafloxacin and Microbiological Response Against Fluoroquinolone Susceptible and Non-Susceptible S. aureus Isolates from two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) [PublishAheadOfPrint]
Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad spectrum in vitro activity, including Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and percent microbiological response in subjects infected with fluoroquinolone susceptible and non-susceptible S. aureus isolates was determined from two global Phase 3 studies of delafloxacin versus vancomycin plus aztreonam in ABSSSI. Patients were enrolled in 23 countries predominately in the US but also Eastern Europe, South America and Asia. The microbiological intent-to-treat population (MITT) included 1042 patients from which 685 S. aureus isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, N. Liberty, IA). Comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Non-susceptibility to these antibiotics was determined using CLSI breakpoints. S. aureus isolates were 33.7% levofloxacin non-susceptible (FQ-NS). The delafloxacin MIC90 values against levofloxacin non-susceptible S. aureus, MRSA and MSSA were all 0.25 μg/mL. Delafloxacin demonstrated high rates of microbiological response against FQ-NS isolates as well as isolates with documented mutations in the Quinolone Resistance Determining Region (QRDR). S. aureus were eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin treated patients. Similar eradication rates were observed for delafloxacin-treated subjects with levofloxacin non-susceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). 98.6% microbiological response rates were observed with delafloxacin treated subjects with S. aureus isolates with mutations in S84L in gyrA/S80Y in parC, the most commonly observed mutation in global phase 3 studies. The data suggest that delafloxacin could be a good treatment option for S. aureus ABSSSI isolates where high rates of ciprofloxacin and levofloxacin non-susceptibility are observed including MRSA.
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Antimicrobial Susceptibility Trends Among Staphylococcus aureus from United States Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program (2010-2016) [PublishAheadOfPrint]
We evaluated trends in Staphylococcus aureus antimicrobial susceptibility in United States hospitals in the 2010-2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. MRSA rates decreased from 50.0% (2010) to 42.2% (2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against MSSA and MRSA (97.2% susceptible) with no marked variations.
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Ceftazidime-Avibactam and Aztreonam an interesting strategy to Overcome {beta}-Lactam Resistance Conferred by Metallo-{beta}-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa [PublishAheadOfPrint]
We have read with great interest Marshal S. et al. regarding the efficacy of the ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) combination on metallo- β -lactamases producing Enterobacteriaceae (1)....
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Loss of C-5 sterol desaturase activity results in increased resistance to azole and echinocandin antifungals in a clinical isolate of Candida parapsilosis [PublishAheadOfPrint]
Among emerging non-albicans Candida species, C. parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatment of such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting the susceptibility of azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate including upregulation of ergosterol biosynthesis pathway genes ERG2, ERG5, ERG6, ERG11, ERG24, ERG25, and UPC2. Whole-genome sequencing revealed the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins.
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Topical antimicrobial treatments can elicit shifts to resident skin bacterial communities and reduce colonization by Staphylococcus aureus competitors [PublishAheadOfPrint]
The skin microbiome is a complex ecosystem with important implications for cutaneous health and disease. Topical antibiotics and antiseptics are often employed to preserve the balance of this population, and inhibit colonization by more pathogenic bacteria. Despite their widespread use, however, the impact of these interventions on broader microbial communities remains poorly understood. Here we report the longitudinal effects of topical antibiotics and antiseptics on skin bacterial communities and their role in Staphylococcus aureus colonization resistance. In response to antibiotics, cutaneous populations exhibited an immediate shift in bacterial residents, an effect that persisted for multiple days post-treatment. By contrast, antiseptics elicited only minor changes to skin bacterial populations, with few changes to the underlying microbiota. While variable in scope, both antibiotics and antiseptics were found to decrease colonization by commensal Staphylococcus spp. by sequencing- and culture-based methods, an effect which was highly dependent on baseline levels of Staphylococcus. Because Staphylococcus residents have been shown to compete with the skin pathogen S. aureus, we also tested whether treatment could influence S. aureus levels at the skin surface. We found that treated mice were more susceptible to exogenous association with S. aureus, and that precolonization with the same Staphylococcus residents that were previously disrupted by treatment could reduce S. aureus levels by over 100-fold. In all, this study indicates that antimicrobial drugs can alter skin bacterial residents, and that these alterations can have critical implications for cutaneous host defense.
http://ift.tt/2sJGuhm
Occurrence of clinically important lineages, including the ST131 C1-M27 subclone, among extended-spectrum {beta}-lactamase-producing Escherichia coli in wastewater [PublishAheadOfPrint]
Contamination of environmental waters by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBLEC) is of great concern. Wastewater treatment plants (WWTPs) and hospitals release large amounts of ESBLEC into the environment. In the present study, we isolated ESBLEC strains from wastewater collected from a WWTP and a hospital in Japan and performed whole-genome sequencing to characterize these strains. Genomic analysis of 54 strains (32 from the WWTP and 22 from hospital wastewater) revealed the occurrence of clinically important clonal groups with extraintestinal pathogenic E. coli status in both WWTP and hospital wastewater. Fine-scale phylogenetic analysis was performed to further characterize 15 sequence type 131 (ST131) complex strains (11 from the WWTP and 4 from hospital wastewater). These ST131 complex strains were comprised of different subgroups: clade A (n = 2), C1-M27 (n = 8), and C1 (non-C1-M27) (n = 1) for strains from the WWTP, and clade A (n = 2), C1-M27 (n = 1), and C1 (non-C1-M27) (n = 1) for strains from hospital wastewater. The results indicate that ESBLEC strains belonging to clinically important lineages, including the C1-M27 clade, may disseminate into the environment through wastewater, highlighting the need to monitor for antibiotic-resistance in wastewater.
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Pharmacokinetics, Safety, and Tolerability of Single Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers [PublishAheadOfPrint]
The pharmacokinetics, safety, and tolerability of intravenous (IV) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1 hour IV infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 hours after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g IV were: Cmax= 44.3 ± 7.6 and 370 ± 61.9 μg/mL, Tmax= 1.1 ± 0.05 and 1.08 ± 0.01 h, Vd= 29.7 ± 5.7 and 31.5 ± 10.4 liters, CL= 8.7 ± 1.7 and 7.8 ± 1.4 liters/h, CLR= 6.6 ± 1.9 and 6.3 ± 1.6 liters/h, AUC0-= 120 ± 28.5 and 1060 ± 192 μg⋅h/mL, and t1/2= 2.4 ± 0.4 and 2.8 ± 0.6 h, respectively. After oral administration the parameters were: Cmax= 26.8 ± 6.4 μg/mL, Tmax= 2.25 ± 0.4 h, Vd/F= 204 ± 70.7 liters, CL/F= 17 ± 4.7 liters/h, CLR= 6.5 ± 1.8 liters/h, AUC0-= 191 ± 57.6 μg⋅h/mL, and t1/2= 9.04 ± 4.5 h, respectively. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1 g IV dose. Approximately 74% and 80% of the 1 g and 8 g IV doses were excreted unchanged in the urine by 48 hours, compared to 37% after oral administration, with the majority of this excretion occurring by 12 hours regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of IV fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.
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Pyrazinamide susceptibility and pncA mutation profile of Mycobacterium tuberculosis among multi-drug resistant tuberculosis patients in Bangladesh [PublishAheadOfPrint]
Pyrazinamide (PZA) is a front line anti-tuberculosis (anti-TB) drug used in both first and second line treatment regimen. However, due to complex laboratory requirements, the PZA susceptibility test is rarely performed leading to the scarcity of data. Bangladesh is both a high TB and multi-drug resistant (MDR-TB) burden country but to our knowledge the published data on PZA susceptibility is limited, especially among MDR-TB patients. We aimed to analyze the PZA susceptibility pattern of Mycobacterium tuberculosis (MTB) isolates from MDR-TB patients and to correlate pncA mutation with PZA resistance in Bangladesh. A total of 169 confirmed MDR-TB isolates from a pool of specimens collected in a nationwide surveillance study were included in this analysis. All the isolates were tested for phenotypic PZA susceptibility in BACTEC MGIT culture medium and pncA gene was sequenced. We also correlated different clinical information and treatment outcomes with PZA susceptibility. We found that 45% isolates were phenotypically PZA resistant. The sequencing of pncA gene revealed high concordance (82.2%) with phenotypic results. A total of 64 different mutations were found and 9 isolates harbored multiple mutations. We detected 27 new pncA mutations. We did not find any significant correlation between different clinical categories, genetic lineage or treatment outcome groups with PZA susceptibility. Considering turnaround time, sequencing would be the more feasible option to determine PZA susceptibility and further studies to investigate the minimum inhibitory concentration of PZA should be conducted to figure out an effective dose of the drug.
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Inoperable infiltrative basal cell carcinoma successfully treated with vismodegib
Abstract
Basal cell carcinoma (BCC) is the most common skin cancer but usually has a good prognosis. However, there is a subset of BCC cases with a less favorable prognosis. For patients with locally advanced, recurrent or metastatic BCCs who are not suitable for surgery or radiotherapy, small-molecule drug inhibitors of hedgehog pathway are a new therapeutic opportunity. Here, we present a case of infiltrative BCC with multiple recurrences. Wide excision with reconstructive plastic surgery was performed initially with adjuvant radiotherapy. Due to multiple recurrences afterward, radiotherapy, topical imiquimod and oral itraconazole were used but were not effective. Finally, the patient was treated with vismodegib which led to a complete response. Moreover, the patient's symptoms due to the locally diffused cancer resolved.
http://ift.tt/2sN88ef
International Journal of Otolaryngology and Head & Neck Surgery Vol.6,No.3 (May 2017)
Coblation, Laryngeal Haemangioma, Propranolol
Paper Information Full Paper: PDF (Size:328KB)
DOI: 10.4236/ijohns.2017.63005
Altered Serum Lipids in the Cases of Head and Neck Cancer Associated with the Habit of Tobacco Consumption
Lipids, Cholesterol, Triglycerides, Head and Neck Cancer
Paper Information Full Paper: PDF (Size:488KB)
DOI: 10.4236/ijohns.2017.63006
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FDA Approves Delafloxacin (Baxdela) for Skin Infections
The new antibiotic works against both gram-positive and gram-negative bacteria, including MRSA.
FDA Approvals
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Transnasal endoscopic removal of bilateral postoperative maxillary cysts after aesthetic orthognathic ssurgery: Differences from that of Caldwell-Luc operations
Source:Auris Nasus Larynx
Author(s): Hyung Chae Yang, Sung Hoon Kang, Sung Ho Yoon, Hyong-Ho Cho
Postoperative maxillary cysts (PMCs) after orthognathic surgery are a rare disease condition. In this study, we reported first case of bilateral PMCs after cosmetic orthognathic surgery which was treated via the intranasal endoscopic approach. In addition, we compared the characteristics of PMCs after aesthetic orthognathic surgery with those of PMCs after Caldwell-Luc operation. We expect that this case will be helpful to surgeons who encounter similar cases.
http://ift.tt/2sQAnZb
Otolaryngology consultation tracheostomies and complex patient population
Source:American Journal of Otolaryngology
Author(s): Kristan P. Alfonso, Michael R. Kaufman, Emily V. Dressler, Meng Liu, Rony K. Aouad
PurposeTo assess for the differences in patients undergoing tracheostomy by the otolaryngology consult service versus other specialties.Materials and methodsA series of 1035 tracheostomies performed at our institution from January 2013 through November 2015 was retrospectively reviewed. Patient-related factors that contribute to procedural difficulty were reviewed.Results805 consecutive tracheostomies were included. Otolaryngology performed 176/805 (21.8%) tracheostomies as a consulting service. Morbidly obese patients were three times as likely to be referred to otolaryngology as other services (adjusted OR: 3.23; 95% CI: 2.21–4.72). Mean BMI was 36.38kg/m2 for Consults vs. 28.69kg/m2 for Others and morbidly obese patients had a mean BMI of 49.84kg/m2 vs. 42.68kg/m2 for Consults and Others respectively (p<0.001). Patients with upper airway compromise (8.5% of Consults vs. 1.6% for Others) had 5.5 times higher odds to be performed by otolaryngology (adjusted OR: 5.46; 95% CI: 2.24–13.28). Otolaryngology performed 81.8% of awake tracheostomies (n=9/11). There were significantly higher proportions of patients with diabetes, renal, pulmonary and cardiovascular disease in the Consults groups vs. Others (p<0.05).ConclusionsMore complex tracheostomies are being referred to and performed by otolaryngology at our institution. Difficult and challenging tracheostomies seem to be the "standard" for otolaryngologists.
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Triple Therapy Potent Approach in Aggressive Skin Cancer
Novel approach that recruits multiple pathways involved in a rare and aggressive skin cancer produces unprecedented responses to treatment.
Medscape Medical News
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Gamma-delta (γδ) T-cell lymphoma – another case unclassifiable by World Health Organization classification: a case report
We present a case of gamma-delta T-cell lymphoma that does not fit the current World Health Organization classifications.
http://ift.tt/2rOxOSO
SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions [IMMUNE REGULATION]
We previously showed that regulatory T cells (Tregs) from T cell–specific Socs1-deficient mice (Socs1fl/flLck-Cre+ mice) easily convert into Th1- or Th17-like cells (ex-Tregs), which lose Foxp3 expression and suppressive functions in vivo. Because Tregs in Socs1fl/flLck-Cre+ mice are constantly exposed to a large amount of inflammatory cytokines produced by non-Tregs in vivo, in this study we analyzed Treg-specific Socs1-deficient mice (Socs1fl/flFoxp3YFP-Cre mice). These mice developed dermatitis, splenomegaly, and lymphadenopathy that were much milder than those in Socs1fl/flLck-Cre+ mice. A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3–IFN-+ ex-Tregs in the tumor microenvironment and suppressed tumor growth. When transferred into Rag2–/– mice, Tregs from Socs1fl/flLck-Cre+ mice easily lost Foxp3 expression, whereas those from Socs1fl/flFoxp3YFP-Cre mice maintained Foxp3 expression. Although Tregs from Socs1fl/flLck-Cre+ mice produced IFN- after a 3-d culture in response to anti-CD3/CD28 Ab stimulation in vitro, Tregs from Socs1fl/flFoxp3YFP-Cre mice did not. This finding suggested that the inflammatory conditions in Socs1fl/flLck-Cre+ mice modified the born nature of Socs1-deficient Tregs. To investigate this mechanism, Tregs from Socs1fl/flFoxp3YFP-Cre mice were cultured with APCs from Socs1fl/flLck-Cre+ mice. These APCs facilitated STAT4 phosphorylation, IFN- production, and loss of Foxp3 expression in Tregs from Socs1fl/flFoxp3YFP-Cre mice in an IL-12–dependent manner. The results indicate that Socs1-deficient Tregs tend to convert into ex-Tregs under the inflammatory conditions in which APCs are highly activated, and that SOCS1 could be a useful target for enhancement of anti-tumor immunity.
http://ift.tt/2sPQs0S
Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+ T Cells [IMMUNE REGULATION]
Immune aging may underlie various aging-related disorders, including diminished resistance to infection, chronic inflammatory disorders, and autoimmunity. PD-1+ and CD153+ CD44high CD4+ T cells with features of cellular senescence, termed senescence-associated T (SA-T) cells, increasingly accumulate with age and may play a role in the immune aging phenotype. In this article, we demonstrate that, compared with young mice, the aged mouse environment is highly permissive for spontaneous proliferation of transferred naive CD4+ T cells, and it drives their transition to PD-1+ and CD153+ CD44high CD4+ T cells after extensive cell divisions. CD4+ T cells with essentially the same features as SA-T cells in aged mice are also generated from naive CD4+ T cells after extensive cell divisions under severe T-lymphopenic conditions by gamma irradiation or in developmental T cell defect, often in association with spontaneous germinal centers, as seen in aged mice. The increase in SA-T cells is significantly enhanced after thymectomy at the young adult stage, along with accelerated T cell homeostatic proliferation, whereas embryonic thymus implantation in the late adult stage markedly restricts the homeostatic proliferation of naive CD4+ T cells in the host and delays the increase in SA-T cells. Our results suggest that reduced T cell output due to physiologic thymic involution underlies the age-dependent accumulation of SA-T cells as a result of increasing homeostatic proliferation of naive CD4+ T cells. SA-T cells may provide a suitable biomarker of immune aging, as well as a potential target for controlling aging-related disorders.
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Low values of central venous oxygen saturation (ScvO2) during surgery and anastomotic leak of abdominal trauma patients
There is a well known relationship between hypoperfusion and postoperative complications like anastomotic leak. No studies have been done addressing this relationship in the context of abdominal trauma surgery...
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Do toddler's fractures of the tibia require evaluation and management by an orthopaedic surgeon routinely?.
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AMR launches campaign in opposition of EMS Workers Bill of Rights
American Medical Response SACRAMENTO, Calif. — Today, American Medical Response (AMR), California's largest provider of 911 emergency ambulance services, launched an online media campaign in opposition to AB 263, authored by Assemblyman Freddie Rodriguez. AB 263 places patient care at risk by seeking to restrict or eliminate private EMS providers from operating in the state. The standard ...
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Artery first approach for resecting ganglioneuroma encasing superior mesenteric artery
Publication date: Available online 17 June 2017
Source:Medical Journal Armed Forces India
Author(s): Jayant Kumar Banerjee, Ramanathan Saranga Bharathi, Rajat Jagani, Giriraj Singh
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Pulsed High Intensity Ultrasound Removes Calcified Buildup from Prosthetic Heart Valves
Image via: American College of Cardiology
Prosthetic heart valves that fit inside failed natural valves have now been used for years to treat thousands of patients. As time passes following implantation, the man-made valves tend to accumulate calcified debris over their leaflets. This slowly degrades their functionality and eventually requires revision procedures that may involve replacement of the prostheses, or valve-in-valve procedures that fit new prosthetic valves inside of old ones. A team of French researchers are proposing using pulsed cavitational ultrasound, also known as histotripsy, to clean the original implanted valves of the calcified buildup on their surfaces.
Histotripsy involves delivering pulses of high intensity ultrasound into tissue, breaking up the target material into different components. It's similar to lithotripsy used to smash kidney stones, but its effectiveness is due to the formation of microbubbles that actually interact with the targeted tissue.
To evaluate the effectiveness of this approach, the team got a hold of failed bioprosthetic heart valves (Carpentier-Edwards Perimount Magna) from patients undergoing explantation. These were either implanted into living sheep, to achieve the most realism, or evaluated in a special bath setup, which provided a long term easily monitored environment.
The researchers repeatedly applied pulsed cavitational ultrasound to the reimplanted valves and the valves in the bench-top apparatus, successfully reducing the calcification by about a half. This is a rather promising result, as revision procedures in already fragile patients can be both difficult and dangerous.
It is important to note that this research has not evaluated the safety of this approach in humans, which will be critical to make sure the treated valves maintain their integrity and that removed calcified material doesn't create even bigger problems downstream.
Study in JACC: Basic to Translational Science: Pulsed Cavitational Ultrasound Softening : A New Noninvasive Therapeutic Approach for Calcified Bioprosthetic Valve Stenosis…
Via: American College of Cardiology…
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Functional outcome after arthroscopic management of traumatic recurrent dislocation shoulder using Bankart repair and Remplissage techniques
Publication date: Available online 17 June 2017
Source:Medical Journal Armed Forces India
Author(s): Munish Sood, Amresh Ghai
BackgroundRecurrent dislocation shoulder is one of the common shoulder injuries encountered by the orthopedic surgeon in clinical practice. Bankart repair using the arthroscopic method has become one of the standard techniques in the management of recurrent dislocation shoulder. Remplissage technique can be used as adjunct to Bankart repair in certain conditions.MethodIn this case series, we have assessed the functional outcome and return to activity at midterm follow-up after arthroscopic management.Results51 patients with traumatic shoulder dislocation were operated using the shoulder arthroscopic technique. Rowe score improved significantly at the latest follow-up. No major complication was noticed in our case series.ConclusionThe shoulder arthroscopy procedure requires special instrumentation and expertise. We believe that this is a less invasive and safe procedure and provides an additional tool in the management of instabilities including in cases of complex recurrent dislocation of the shoulder.
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The psychological morbidity in the long term after war related bilateral lower limb amputation
Publication date: Available online 17 June 2017
Source:Medical Journal Armed Forces India
Author(s): Batool Mousavi, Mehdi Masoumi, Mohammadreza Soroush, Shekoufe Shahriar, Ali Firoozabadi
BackgroundTo determine the psychological morbidity in the long term after war related bilateral lower limb amputation.MethodsMental health status was determined by the Symptom Checklist-90-R (SCL-90-R) and a structured psychiatrist interview using Structured Clinical Interview for DSM Disorders-IV (SCID-IV) in 327 male amputees. The survey was 22.3 (SD=3.9) years after amputation. A one-sample t-test was conducted to compare our results with a survey carried out in a rural Iranian population.ResultsThe mean age of the participants was 42 years (SD=6.3). Only 22 persons had psychiatric diagnosis and were under treatment. The most common problems on SCL-90-R were somatization, obsessive-compulsive, interpersonal sensitivity, anxiety, and depression. Global severity index (GSI) of the bilateral lower limb amputees (BLLA) (0.88±0.63) was significantly higher than Iranian population (0.35±0.28) (p<0.001). BLLA had significantly higher scores in all subscales of Scl-90-R compared with general population (p<0.001). Of the total amputees about 39.1% (128 out 327) diagnosed with at least one psychiatric disorder in psychiatrist interview. About 83.9% (N=115) of the psychiatrist diagnosed disorders were new cases. Mood disorders 37.3% (depression 28.7%) and anxiety disorders 12.2% (obsessive compulsive disorder 9.8%) were the most common disorders in the study group. There was not any relationship between demographic variables and mental disorder (p>0.05).ConclusionThe high prevalence and especially the large proportion of undiagnosed mental disorders high-light the need for targeted and appropriate psychological interventions in this vulnerable population.
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Brain stem death certification protocol
Publication date: Available online 17 June 2017
Source:Medical Journal Armed Forces India
Author(s): Vikas Srivastava, Monish Nakra, Anand Shankar K., Pawan Dhull, R. Ramprasad, N.S. Lamba
Transplantation of Human Organs is guided by laid down specific Laws in India. The organs which are targeted to be transplanted are liver, kidney and cornea. The waiting list is enormous but the donor pool is meagre. This document has been made with a view that the donor pool can be enlarged by identifying patients who are 'Brain Dead' while still not having 'Cardiac Death'. The steps include the prerequisite conditions which must be satisfied by patients who have suspicion of being brain dead, detailed examination of the patient, confirmation of the Brain Death and Counselling of the relatives for organ donation.
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A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption
Abstract
Background
Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation.
Methods
We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption.
Results
We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC–MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption.
Conclusion
This novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption.
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Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4+ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes [SYSTEMS IMMUNOLOGY]
The significance of islet Ag-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior Ag exposure, inferred from expanded TCR clonotypes, and essential phenotypic properties in their transcriptomes. To test this, we developed single-cell RNA sequencing procedures for identifying TCR clonotypes and transcript phenotypes in individual T cells. We applied these procedures to analysis of islet Ag-reactive CD4+ memory T cells from the blood of T1D and HC individuals after activation with pooled immunodominant islet peptides. We found extensive TCR clonotype sharing in Ag-activated cells, especially from individual T1D subjects, consistent with in vivo T cell expansion during disease progression. The expanded clonotype from one T1D subject was detected at repeat visits spanning >15 mo, demonstrating clonotype stability. Notably, we found no clonotype sharing between subjects, indicating a predominance of "private" TCR specificities. Expanded clones from two T1D subjects recognized distinct IGRP peptides, implicating this molecule as a trigger for CD4+ T cell expansion. Although overall transcript profiles of cells from HC and T1D subjects were similar, profiles from the most expanded clones were distinctive. Our findings demonstrate that islet Ag-reactive CD4+ memory T cells with unique Ag specificities and phenotypes are expanded during disease progression and can be detected by single-cell analysis of peripheral blood.
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SLC46 Family Transporters Facilitate Cytosolic Innate Immune Recognition of Monomeric Peptidoglycans [INNATE IMMUNITY AND INFLAMMATION]
Tracheal cytotoxin (TCT), a monomer of DAP-type peptidoglycan from Bordetella pertussis, causes cytopathology in the respiratory epithelia of mammals and robustly triggers the Drosophila Imd pathway. PGRP-LE, a cytosolic innate immune sensor in Drosophila, directly recognizes TCT and triggers the Imd pathway, yet the mechanisms by which TCT accesses the cytosol are poorly understood. In this study, we report that CG8046, a Drosophila SLC46 family transporter, is a novel transporter facilitating cytosolic recognition of TCT, and plays a crucial role in protecting flies against systemic Escherichia coli infection. In addition, mammalian SLC46A2s promote TCT-triggered NOD1 activation in human epithelial cell lines, indicating that SLC46As is a conserved group of peptidoglycan transporter contributing to cytosolic immune recognition.
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Cutting Edge: Dual TCR{alpha} Expression Poses an Autoimmune Hazard by Limiting Regulatory T Cell Generation [CUTTING EDGE]
Despite accounting for 10–30% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an autoimmune hazard by allowing self-reactive TCRs to escape thymic selection. We revisited this hypothesis using the NOD murine model of type 1 diabetes. We bred NOD mice hemizygous at both TCRα and β (TCRα+/– β+/–) loci, rendering them incapable of producing dual TCR T cells. We found that the lack of dual TCRα expression skewed the insulin-specific thymocyte population toward greater regulatory T (Treg) cell commitment, resulting in a more tolerogenic Treg to conventional T cell ratio and protection from diabetes. These data support a novel hypothesis by which dual TCR expression can promote autoimmunity by limiting agonist selection of self-reactive thymocytes into the Treg cell lineage.
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IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis [MUCOSAL IMMUNOLOGY]
Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6–induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.
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TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement [INNATE IMMUNITY AND INFLAMMATION]
Induction of proinflammatory T cell immunity is augmented by innate dendritic cell (DC) maturation commonly initiated by TLR signaling. We demonstrate that ligation of TLR3, TLR4, and TLR9 induces murine DC production of complement components and local production of the anaphylatoxin C5a. In vitro, ex vivo, and in vivo analyses show that TLR-induced DC maturation, as assessed by surface phenotype, expression profiling by gene array, and functional ability to stimulate T cell responses, requires autocrine C3a receptor and C5a receptor (C3ar1/C5ar1) signaling. Studies using bone marrow chimeric animals and Foxp3-GFP/ERT2-Cre/dTomato fate-mapping mice show that TLR-initiated DC autocrine C3ar1/C5ar1 signaling causes expansion of effector T cells and instability of regulatory T cells and contributes to T cell–dependent transplant rejection. Together, our data position immune cell–derived complement production and autocrine/paracrine C3ar1/C5ar1 signaling as crucial intermediary processes that link TLR stimulation to DC maturation and the subsequent development of effector T cell responses.
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The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia.
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Aeroallergens Induce Reactive Oxygen Species Production and DNA Damage and Dampen Antioxidant Responses in Bronchial Epithelial Cells [ALLERGY AND OTHER HYPERSENSITIVITIES]
Exposure to environmental allergens is a major risk factor for asthma development. Allergens possess proteolytic activity that is capable of disrupting the airway epithelium. Although there is increasing evidence pointing to asthma as an epithelial disease, the underlying mechanism that drives asthma has not been fully elucidated. In this study, we investigated the direct DNA damage potential of aeroallergens on human bronchial epithelial cells and elucidated the mechanisms mediating the damage. Human bronchial epithelial cells, BEAS-2B, directly exposed to house dust mites (HDM) resulted in enhanced DNA damage, as measured by the CometChip and the staining of DNA double-strand break marker, H2AX. HDM stimulated cellular reactive oxygen species production, increased mitochondrial oxidative stress, and promoted nitrosative stress. Notably, expression of nuclear factor erythroid 2–related factor 2–dependent antioxidant genes was reduced immediately after HDM exposure, suggesting that HDM altered antioxidant responses. HDM exposure also reduced cell proliferation and induced cell death. Importantly, HDM-induced DNA damage can be prevented by the antioxidants glutathione and catalase, suggesting that HDM-induced reactive oxygen and nitrogen species can be neutralized by antioxidants. Mechanistic studies revealed that HDM-induced cellular injury is NADPH oxidase (NOX)-dependent, and apocynin, a NOX inhibitor, protected cells from double-strand breaks induced by HDM. Our results show that direct exposure of bronchial epithelial cells to HDM leads to the production of reactive oxygen and nitrogen species that damage DNA and induce cytotoxicity. Antioxidants and NOX inhibitors can prevent HDM-induced DNA damage, revealing a novel role for antioxidants and NOX inhibitors in mitigating allergic airway disease.
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Genetic coding variants in the niacin receptor, hydroxyl-carboxylic acid receptor 2, and response to niacin therapy.
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Genetics of pleiotropic effects of dexamethasone.
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Enhanced Effector Functions Due to Antibody Defucosylation Depend on the Effector Cell Fc{gamma} Receptor Profile [IMMUNOTHERAPY AND VACCINES]
Abs of the IgG isotype are glycosylated in their Fc domain at a conserved asparagine at position 297. Removal of the core fucose of this glycan greatly increases the affinity for FcRIII, resulting in enhanced FcRIII-mediated effector functions. Normal plasma IgG contains ~94% fucosylated Abs, but alloantibodies against, for example, Rhesus D (RhD) and platelet Ags frequently have reduced fucosylation that enhances their pathogenicity. The increased FcRIII-mediated effector functions have been put to use in various afucosylated therapeutic Abs in anticancer treatment. To test the functional consequences of Ab fucosylation, we produced V-gene–matched recombinant anti-RhD IgG Abs of the four different subclasses (IgG1–4) with and without core fucose (i.e., 20% fucose remaining). Binding to all human FcR types and their functional isoforms was assessed with surface plasmon resonance. All hypofucosylated anti-RhD IgGs of all IgG subclasses indeed showed enhanced binding affinity for isolated FcRIII isoforms, without affecting binding affinity to other FcRs. In contrast, when testing hypofucosylated anti-RhD Abs with FcRIIIa-expressing NK cells, a 12- and 7-fold increased erythrocyte lysis was observed with the IgG1 and IgG3, respectively, but no increase with IgG2 and IgG4 anti-RhD Abs. Notably, none of the hypofucosylated IgGs enhanced effector function of macrophages, which, in contrast to NK cells, express a complex set of FcRs, including FcRIIIa. Our data suggest that the beneficial effects of afucosylated biologicals for clinical use can be particularly anticipated when there is a substantial involvement of FcRIIIa-expressing cells, such as NK cells.
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T Follicular Helper Cell-Derived IL-4 Is Required for IgE Production during Intestinal Helminth Infection [INFECTIOUS DISEASE AND HOST RESPONSE]
IgE production plays a crucial role in protective as well as pathogenic type 2 immune responses. Although the cytokine IL-4 is required for the development of IgE-producing plasma cells, the source of IL-4 and cellular requirements for optimal IgE responses remain unclear. Recent evidence suggests that T follicular helper (Tfh) cells are the primary producer of IL-4 in the reactive lymph node during type 2 immune responses. As Tfh cells are also required for the development of plasmablasts derived from germinal center and extrafollicular sources, we hypothesized that this cell subset is essential for the IgE plasmablast response. In this study, we show that during intestinal helminth infection, IL-4 derived from Tfh cells is required for IgE class switching and plasmablast formation. Notably, early IgE class switching did not require germinal center formation. Additionally, Tfh cell–derived IL-4 was required to maintain the Th2 response in the mesenteric lymph nodes of infected mice. Collectively, our results indicate that IL-4–producing Tfh cells are central orchestrators of the type 2 immune response in the reactive lymph nodes during parasitic helminth infection.
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Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems [BRIEF REVIEWS]
Mucosal IgA or secretory IgA (SIgA) are structurally equipped to resist chemical degradation in the harsh environment of mucosal surfaces and enzymes of host or microbial origin. Production of SIgA is finely regulated, and distinct T-independent and T-dependent mechanisms orchestrate Ig α class switching and SIgA responses against commensal and pathogenic microbes. Most infectious pathogens enter the host via mucosal surfaces. To provide a first line of protection at these entry ports, vaccines are being developed to induce pathogen-specific SIgA in addition to systemic immunity achieved by injected vaccines. Mucosal or epicutaneous delivery of vaccines helps target the inductive sites for SIgA responses. The efficacy of such vaccines relies on the identification and/or engineering of vaccine adjuvants capable of supporting the development of SIgA alongside systemic immunity and delivery systems that improve vaccine delivery to the targeted anatomic sites and immune cells.
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Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing [BRIEF REVIEWS]
The healing of cutaneous wounds is dependent on the progression through distinct, yet overlapping phases of wound healing, including hemostasis, inflammation, proliferation, and resolution/remodeling. The failure of these phases to occur in a timely, progressive fashion promotes pathologic wound healing. The macrophage (M) has been demonstrated to play a critical role in the inflammatory phase of tissue repair, where its dynamic plasticity allows this cell to mediate both tissue-destructive and -reparative functions. The ability to understand and control both the initiation and the resolution of inflammation is critical for treating pathologic wound healing. There are now a host of studies demonstrating that metabolic and epigenetic regulation of gene transcription can influence M plasticity in wounds. In this review, we highlight the molecular and epigenetic factors that influence M polarization in both physiologic and pathologic wound healing, with particular attention to diabetic wounds.
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The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments [IMMUNE SYSTEM DEVELOPMENT]
The invariant chain (CD74) mediates assembly and targeting of MHC class II (MHCII) complexes. In endosomes, CD74 undergoes sequential degradation by different proteases, including cathepsin S (CatS) and the intramembrane protease signal peptide peptidase-like 2a (SPPL2a). In their absence, CD74 N-terminal fragments (NTFs) accumulate. In SPPL2a–/– B cells, such an NTF impairs endosomal trafficking and BCR signal transduction. In mice, this leads to a loss of splenic B cells beyond the transitional stage 1. To gain insight into CD74 determinants and the role of MHCII, we compared B cells from CatS–/–, SPPL2a–/–, and SPPL2a-MHCII double-deficient mice. We assessed differentiation of B cells in bone marrow and spleen and analyzed their endosomal morphology, BCR expression, and signal transduction. We demonstrate that MHCII is dispensable for the B cell phenotype of SPPL2a–/– mice, further supporting a CD74-intrinsic effect. Despite significant vacuolization of endosomal compartments similar to SPPL2a–/– B cells, CatS–/– traditional stage 1 B cells show unimpaired degradation of endocytic cargo, have intact BCR signaling, and do not exhibit any relevant defects in maturation. This could indicate that CD74 NTF–induced structural changes of endosomes are not directly involved in these processes. We further found that the block of CD74 degradation in CatS–/– B cells is incomplete, so that NTF levels are significantly lower than in SPPL2a–/– B cells. This suggests a dose dependency and threshold for the CD74 NTF–associated impairment of B cell signaling and maturation. In addition, different functional properties of the longer, MHCII-bound CD74 NTF could contribute to the milder phenotype of CatS–/– B cells.
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Cutting Edge: Origins, Recruitment, and Regulation of CD11c+ Cells in Inflamed Islets of Autoimmune Diabetes Mice [CUTTING EDGE]
In NOD mice, CD11c+ cells increase greatly with islet inflammation and contribute to autoimmune destruction of pancreatic β cells. In this study, we investigated their origin and mechanism of recruitment. CD11c+ cells in inflamed islets resembled classical dendritic cells based on their transcriptional profile. However, the majority of these cells were not from the Zbtb46-dependent dendritic-cell lineage. Instead, monocyte precursors could give rise to CD11c+ cells in inflamed islets. Chemokines Ccl5 and Ccl8 were persistently elevated in inflamed islets and the influx of CD11c+ cells was partially dependent on their receptor Ccr5. Treatment with islet Ag-specific regulatory T cells led to a marked decrease of Ccl5 and Ccl8, and a reduction of monocyte recruitment. These results implicate a monocytic origin of CD11c+ cells in inflamed islets and suggest that therapeutic regulatory T cells directly or indirectly regulate their influx by altering the chemotactic milieu in the islets.
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The Role of Shed PrPc in the Neuropathogenesis of HIV Infection [INFECTIOUS DISEASE AND HOST RESPONSE]
HIV-1 enters the CNS soon after peripheral infection and causes chronic neuroinflammation and neuronal damage that leads to cognitive impairment in 40–70% of HIV-infected people. The nonpathogenic cellular isoform of the human prion protein (PrPc) is an adhesion molecule constitutively expressed in the CNS. Previously, our laboratory showed that shed PrPc (sPrPc) is increased in the cerebrospinal fluid of HIV-infected people with cognitive deficits as compared with infected people with no impairment. In this article, we demonstrate that CCL2 and TNF-α, inflammatory mediators that are elevated in the CNS of HIV-infected people, increase shedding of PrPc from human astrocytes by increasing the active form of the metalloprotease ADAM10. We show that the consequence of this shedding can be the production of inflammatory mediators, because treatment of astrocytes with rPrPc increased secretion of CCL2, CXCL-12, and IL-8. Supernatants from rPrPc-treated astrocytes containing factors produced in response to this treatment, but not rPrPc by itself, cause increased chemotaxis of both uninfected and HIV-infected human monocytes, suggesting a role for sPrPc in monocyte recruitment into the brain. Furthermore, we examined whether PrPc participates in glutamate uptake and found that rPrPc decreased uptake of this metabolite in astrocytes, which could lead to neurotoxicity and neuronal loss. Collectively, our data characterize mediators involved in PrPc shedding and the effect of this sPrPc on monocyte chemotaxis and glutamate uptake from astrocytes. We propose that shedding of PrPc could be a potential target for therapeutics to limit the cognitive impairment characteristic of neuroAIDS.
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Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma [ALLERGY AND OTHER HYPERSENSITIVITIES]
Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.
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