Innate function of house dust mite allergens: robust enzymatic degradation of extracellular matrix at elevated pH

Exposure to the house dust mite Dermatophagoides pteronyssinus (D.p.) increases the risk for developing allergic diseases in humans and their best friends, the dogs. Here, we explored whether this allergenic mite...

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Flow cytometry-based diagnosis of primary immunodeficiency diseases

Publication date: Available online 3 July 2017
Source:Allergology International
Author(s): Hirokazu Kanegane, Akihiro Hoshino, Tsubasa Okano, Takahiro Yasumi, Taizo Wada, Hidetoshi Takada, Satoshi Okada, Motoi Yamashita, Tzu-wen Yeh, Ryuta Nishikomori, Masatoshi Takagi, Kohsuke Imai, Hans D. Ochs, Tomohiro Morio
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs.Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.



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Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation [PublishAheadOfPrint]

Pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical PK studies of drugs administered during ECMO are scarce and proper dosing adjustment is yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. PK samples were collected from ten adult patients, and a population PK analysis as well as simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 hours using a trough concentration target of >10 μg/mL for mild to moderate infections and of >15 μg/mL for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. Presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) 600 mg and a maintenance dose (MD) 400 mg for ECMO patients not receiving CRRT; and a LD 800 mg and a MD 600 mg for those receiving CRRT. For severe infections, an optimal dose was a LD 1000 mg and a MD 800 mg for ECMO patients not receiving CRRT; and a LD 1200 mg and a MD 1000 mg for those receiving CRRT. In conclusion, higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO.

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In Vivo Emergence of Resistance to Novel Cephalosporin-{beta}-lactamase Inhibitor Combinations Through the Duplication of the Amino Acid D149 from OXA-2 {beta}-lactamase (OXA-539) in ST235 Pseudomonas aeruginosa [PublishAheadOfPrint]

Resistance development to novel cephalosporin-β-lactamase inhibitor combinations during ceftazidime treatment of a surgical infection by Pseudomonas aeruginosa was investigated. Both, initial (97C2) and final (98G1) isolates, belonged to the high-risk clone ST235 and were resistant to carbapenems (oprD-), fluoroquinolones (GyrA-T83I, ParC-S87L) and aminoglycosides (aacA7/aacA8/aadA6). 98G1 additionally showed resistance to ceftazidime, ceftazidime-avibactam and ceftolozane-tazobactam. Sequencing identified bla_OXA-2 in 97C2, but 98G1 contained a 3-bp insertion leading to the duplication of the key residue D149 (designated OXA-539). Evaluation of PAO1 transformants producing cloned OXA-2 or OXA-539 confirmed that D149 duplication was the cause of resistance. Active surveillance of the emergence of resistance to these new valuable agents is warranted.

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Assessment of clinical pharmacokinetic drug-drug interaction of antimalarial drugs {alpha}/{beta}-arteether and sulfadoxine-pyrimethamine [PublishAheadOfPrint]

The antimalarial drugs combination therapy is now being widely used for treatment of uncomplicated malaria. The objective of the present study was to investigate the effects of co-administration of intramuscular α/β-arteether (AE) and oral sulfadoxine-pyrimethamine (SP) on the pharmacokinetic properties of each drug as a drug–drug interaction study to support developing the fixed-dose combination therapy. Single-dose, open-label, crossover clinical trial was conducted in healthy adult Indian male volunteers (18–45 years, n=13), received single dose of AE, SP and combination dose of AE and SP. Blood samples were collected upto 21 days post administration and concentrations of α-arteether, β-arteether, sulfadoxine and pyrimethamine were determined by using validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were calculated and statistically analyzed to calculate geometric mean ratio and confidence interval. Following single dose co-administration of intramuscular AE and oral SP, the pharmacokinetic properties of α/β-arteether were not significantly affected, and α/β-arteether had no significant effect on the pharmacokinetic properties of SP in these selected groups of healthy volunteers. However, more investigations would be needed to explore this further.

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A novel 6-benzyl ether benzoxaborole is active against Mycobacterium tuberculosis in vitro [PublishAheadOfPrint]

We identified a novel 6-benzyl ether benzoxaborole with potent activity against Mycobacterium tuberculosis. The compound had a minimum inhibitory concentration of 2 μM in liquid medium. The compound was also able to prevent growth on solid medium at 0.8 μM and was active against intracellular bacteria (IC₅₀ = 3.6 μM) without cytotoxicity against eukaryotic cells (IC₅₀ >100 μM). We isolated resistant mutants (MIC ≥100 μM), which had mutations in Rv1683, Rv3068c and Rv0047c.

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OXA-244-producing Escherichia coli isolates: a challenge for clinical microbiology laboratories [PublishAheadOfPrint]

OXA-244 is a single point mutant derivative of OXA-48 displaying reduced carbapenemase activity. Here, we report microbiological features of 7 OXA-244-producing E. coli isolates. Only one isolate grew on the ChromID® CARBA SMART medium (bioMérieux), but 6/7 grew on ChromID® ESBL medium (bioMérieux), as they co-produced either an extended spectrum β-lactamase and or a plasmid-encoded cephalosporinase. The production of a carbapenemase was detected in 57.1%, 71.4%, 71.4%, and 100% of the E. coli isolates using the Carba NP test, the RAPIDEC® CARBA NP (bioMérieux), a MALDI-TOF MS hydrolysis assay (Bruker), and OXA-48 K-SeT® (Coris bioconcept), respectively. Our results indicate that OXA-244-producing E. coli isolates are difficult to detect, which may lead to their silent spread.

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