PK/PD study of tigecycline in severely infected patients with continuous renal replacement therapy.

OBJECTIVE: The aim of this study was to analyze the pharmacokinetics/pharmacodynamics (PK/PD) of higher-dose tigecycline (100 mg q12h) in severely infected intensive care unit (ICU) patients receiving continuous renal replacement therapy (CRRT). MATERIALS AND METHODS: In this prospective single-center observational study, severely infected patients receiving intravenous tigecycline were enrolled. They were divided into a CRRT group (7 cases) and a non-CRRT group (9 cases). The blood samples and CRRT ultrafiltrate were collected. The drug concentration in each sample was determined by a HPLC-UV method. The pharmacokinetic parameters were simulated and calculated with DAS 2.0. The PK/PD parameters were evaluated according to published data. The registration number of this study is NCT02931526 in ClinicalTrials.gov. RESULTS: In the non-CRRT group, Cmax, Cmin, and AUC0-24 were 1.00 ± 0.66 µg×mL-1, 0.20 ± 0.12 µg×mL-1, and 22.12 ± 14.46 µg×h×mL-1, respectively. The clinical efficiency was 55.6%, and the bacterial clearance rate was 77.8%. In the CRRT group, Cmax, Cmin, and AUC0-24 were 0.96 ± 0.31 µg×mL-1, 0.22 ± 0.12 µg×mL-1, and 19.90 ± 8.14 µg×h×mL-1, respectively. The clinical efficiency was 28.6%, and the bacterial clearance rate was 28.6%. The individual differences of tigecycline plasma concentrations in our study were widely variable, and the differences of the two groups' PK/PD parameters had no statistical significance (p < 0.05). CONCLUSION: CRRT may have had little influence in tigecycline metabolism in our study, and therapeutic drug monitoring needs to be introduced for critically ill patients because of various pharmacokinetic parameters.

Open-source genomic analysis of Shiga-toxin-producing E. coli O104:H4.

An outbreak caused by Shiga-toxin­producing Escherichia coli O104:H4 occurred in Germany in May and June of 2011, with more than 3000 persons infected. Here, we report a cluster of cases associated with a single family and describe an open-source genomic analysis of an isolate from one member of the family. This analysis involved the use of rapid, bench-top DNA sequencing technology, open-source data release, and prompt crowd-sourced analyses. In less than a week, these studies revealed that the outbreak strain belonged to an enteroaggregative E. coli lineage that had acquired genes for Shiga toxin 2 and for antibiotic resistance.

Whole-genome sequence of Klebsiella pneumonia strain LCT-KP214.

Klebsiella pneumoniae is a gram-negative, nonmotile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium found in the normal flora of the mouth, skin, and intestines. Here we present the fine-draft genome sequence of K. pneumoniae strain LCT-KP214, which originated from K. pneumoniae strain CGMCC 1.1736.

Draft genome sequences of two Legionella dumoffii strains, TEX-KL and NY-23.

Legionella (Fluoribacter) dumoffii is one of the agents causing Legionnaires' disease. Here, we used Illumina second-generation sequencing technology to decipher for the first time the whole-genome sequences of two strains of this species, TEX-KL and NY-23. The assembly results for both strains consist of one chromosome and two plasmids.

Homeobox-A13 acts as a functional prognostic and diagnostic biomarker via regulating P53 and Wnt signaling pathways in lung cancer.

BACKGROUND: The prognosis of lung cancer patients is poor without useful prognostic and diagnostic biomarker. To search for novel prognostic and diagnostic markers, we previously found homeobox-A13 (HOXA13) as a promising candidate in lung cancer. OBJECTIVE: To determine the precisely clinical feature, prognostic and diagnostic value, possible role and mechanism of HOXA13. METHODS: Gene-expression was explored by real-time quantitative-PCR, western-blot and tissue-microarray. The associations were analyzed by Chi-square test, Kaplan-Meier and Cox-regression. The roles and mechanisms were evaluated by MTS, EdU, transwell, xenograft tumor and luciferase-reporter assays. RESULTS: HOXA13 expression is increased in tumors, and correlated with age of patients. HOXA13 expression is associated with unfavorable overall survival and relapse-free survival of patients in four cohorts. Interestingly, HOXA13 has different prognostic significance in adenocarcinoma (ADC) and squamous-cell carcinoma (SCC), and is a sex- and smoke-related prognostic factor only in ADC. Importantly, HOXA13 can serve as a diagnostic biomarker for lung cancer, especially for SCC. HOXA13 can promote cancer-cell proliferation, migration and invasion in vitro, and facilitate tumorigenicity and tumor metastasis in vivo. HOXA13 acts the oncogenic roles on tumor growth and metastasis by regulating P53 and Wnt/ß-catenin signaling activities in lung cancer. CONCLUSIONS: HOXA13 is a new prognostic and diagnostic biomarker associated with P53 and Wnt/ß-catenin signaling pathways.

Continuous positive airway pressure improves respiratory mechanics and efficiency of neural drive in stable COPD: an exploratory study.

BACKGROUND: Continuous positive airway pressure (CPAP) is a major treatment strategy for severe chronic obstructive pulmonary disease (COPD), especially with respiratory failure. However, it remains inconclusive whether CPAP affects respiratory mechanics and neural drive in stable COPD patients without respiratory failure. METHODS: Twenty-two COPD patients without respiratory failure received CPAP starting from 4 to 10 cmH2O in 1 cmH2O increments. Respiratory pattern, end expiatory lung volume (EELV), dynamic PEEPi (PEEPidyn), airway resistance (Raw), pressure-time product of diaphragmatic pressure (PTPdi) and esophageal pressure (PTPeso), root mean square (RMS) of diaphragm electromyogram (EMGdi) and ratio of ventilation (Ve) to EMGdi (i.e., Ve/RMS) were measured before and at each level of continue positive airway pressure (CPAP). A subgroup analysis was performed between patients with and without inspiratory muscle weakness. RESULTS: Nineteen patients completed the treatment. The respiratory pattern improved significantly after CPAP. Raw, PTPdi, and Pdi decreased significantly. ΔEELV decreased at 4 cmH2O (P<0.05), but increased significantly at >8 cmH2O. PEEPidyn decreased from 2.18±0.98 to 1.37±0.55 cmH2O. RMS increased while Ve/RMS improved significantly after CPAP (P<0.05). Besides, CPAP could significantly improve respiratory mechanics in patients with inspiratory muscle weakness. CONCLUSIONS: CPAP improves respiratory pattern, PEEPi, Raw, work of breathing and efficiency of neural drive in COPD patients without respiratory failure, but easily increases dynamic pulmonary hyperinflation. These effects on respiratory mechanics are significant in patients with inspiratory muscle weakness.

A double-layered zinc(II) coordination polymer with the ligand 3,5-bis(carboxylatomethoxy)benzoate.

In the title compound, poly[hexaaquabis[mu(4)-3,5-bis(carboxylatomethoxy)benzoato]trizinc(II)], [Zn(3)(C(11)H(7)O(8))(2)(H(2)O)(6)](n), there are two crystallographically distinct Zn(II) cations which are bridged by polycarboxylate ligands in a mu(4)-bridging mode. A pair of ligands bridges adjacent Zn atoms to give centrosymmetric dimetal building blocks which act as four-connected nodes to be further interlinked into a two-dimensional double-layered framework with (4,4) topology. Other Zn atoms, lying on inversion centres, occupy the cavities of this topological structure. This submission shows a versatile polycarboxylate ligand with rigid and flexible functional groups, the co-operation and complementarity of which would meet the coordination requirements of a variety of topological structures.

{µ-trans-N,N'-Bis[(diphenyl-phosphan-yl)meth-yl]benzene-1,4-diamine-κP:P'}bis-{(acetonitrile-κN)[dipyrido[3,2-a:2',3'-c]phenazine-κN,N]copper(I)} bis-(tetra-fluoridoborate).

In the centrosymmetric dinuclear title compound, [Cu(2)(C(2)H(3)N)(2)(C(18)H(10)N(4))(2)(C(32)H(30)N(2)P(2))](BF(4))(2), the Cu(I) centre is coordinated by two N atoms from a dipyridophenazine ligand, one P atom from an N,N'-bis-[(diphenyl-phosphan-yl)meth-yl]benzene-1,4-diamine (bpbda) ligand, and one N atom from an acetonitrile mol-ecule in a distorted tetra-hedral geometry. The bpbda ligand, lying on an inversion center, bridges two Cu(I) centres into a Z-shaped complex. Intra-molecular π-π inter-actions between the dipyridophenazine ligand and the benzene ring of the bpbda ligand are observed [centroid-centroid distance = 3.459 (3) Å]. The crystal structure also involves inter-molecular π-π inter-actions between the dipyridophenazine ligands [centroid-centroid distance = 3.506 (3) Å], which lead to a one-dimensional supra-molecular structure.

Tetra-aqua-bis(2-methyl-benzimidazolium-1,3-diacetato-κO)zinc(II) tetra-hydrate.

The asymmetric unit of the title compound, [Zn(C(12)H(11)N(2)O(4))(2)(H(2)O)(4)]·4H(2)O, contains one-half of the complex mol-ecule and two uncoordin-ated water mol-ecules. The four water O atoms in the equatorial plane around the Zn(II) centre ( symmetry) form a distorted square-planar arrangement, while the distorted octa-hedral coordination geometry is completed by the O atoms of the zwitterionic 2-methyl-benzimidazolium-1,3-diacetate ligands in the axial positions. The benzimidazole ring system is planar, with a maximum deviation of 0.041 (3) Å. Intra-molecular O-H⋯O hydrogen bonding results in the formation of a non-planar six-membered ring. In the crystal structure, strong intra- and inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into a three-dimensional network. π-π contacts between benzimidazole rings [centroid-centroid distance = 3.899 (1) Å] may further stabilize the structure.

A coordination polymer of CdCl2 with the novel zwitterionic dicarboxylate ligand 2,2'-(2-methylbenzimidazolium-1,3-diyl)diacetate (pda).

The title compound, poly[chlorido[mu(4)-2,2'-(2-methylbenzimidazolium-1,3-diyl)diacetato]cadmium(II)], [Cd(C(12)H(11)N(2)O(4))Cl](n), is an undulating two-dimensional polymer consisting of a paddlewheel Cd(2)(CO(2))(4) cluster which lies on an inversion centre. These paddlewheel clusters act as four-connected square building units interlinked via bridging zwitterionic dicarboxylate ligands into a corrugated layer which is consolidated by pi-pi interactions between benzene rings of benzimidazole groups. Neighbouring layers are further assembled via interlayer pi-pi interactions into a three-dimensional supramolecular structure. The key feature of this study is the synthesis of a paddlewheel-based polymer constructed with a novel multifunctional zwitterionic dicarboxylate ligand.

Procalcitonin levels in patients with positive blood culture, positive body fluid culture, sepsis, and severe sepsis: a cross-sectional study.

BACKGROUND: Numerous investigations on procalcitonin (PCT) have been carried out, although few with large sample size. To deal with the complexity of sepsis, an understanding of PCT in heterogeneous clinical conditions is required. METHODS: Hospitalized patients aged 10-79 years were included in this retrospective and cross-sectional study. PCT tests were assayed within 2 days of blood culture. RESULTS: A total of 2952 cases (from 2538 patients) were enrolled in this study, including 440 cases in the 'positive BC' group, 123 cases in the 'positive body fluid culture' group, and 2389 cases in the 'negative all culture' group. Median PCT values were 4.53 ng/ml, 2.95 ng/ml, and 0.49 ng/ml, respectively. Median PCT values in the gram-negative BC group and gram-positive BC group, respectively, were 6.99 ng/ml and 2.96 ng/ml. Median PCT values in the 'positive hydrothorax culture' group, 'positive ascites culture' group, 'positive bile culture' group, and 'positive cerebrospinal fluid culture' group, respectively, were 1.39 ng/ml, 8.32 ng/ml, 5.98 ng/ml, and 0.46 ng/ml. In all, 357 cases were classified into the 'sepsis' group, 150 of them were classified into the 'severe sepsis' group. Median PCT values were 5.63 ng/ml and 11.06 ng/ml, respectively. CONCLUSIONS: PCT could be used in clinical algorithms to diagnose positive infections and sepsis. Different PCT levels could be related to different kinds of microbemia, different infection sites, and differing severity of sepsis.

[Intensive hemoperfusion and long-term hemofiltration for treatment of paraquat poisoning: a case report].

OBJECTIVE: A 20-year-old male patient was admitted in our department 14 h after paraquat poisoning at the dose of about 50 mL. The patient underwent intensive hemoperfusion for 2 h (3 times a day) for 9 consecutive days and received continuous renal replacement therapy (CRRT) in the mode of continuous veno-venous hemofiltration (CVVH) for 10 consecutive days in addition to routine medications. The biochemical indexes were monitored during the therapy. After the treatment, paraquat concentrations in the blood and urine were decreased, and the patient's urine volume (UV) increased, serum creatinine (Cr) level decreased, and the oxygenation index became normal. Dynamic CT scan showed no obvious pulmonary fibrosis. The patient was followed up for 6 months after discharge and no complaint of discomforts was reported. This case suggests that early intensive hemoperfusion and long-term CVVH may help improve the prognosis after paraquat poisoning.

Mutation spectrum of six genes in Chinese phenylketonuria patients obtained through next-generation sequencing.

BACKGROUND: The identification of gene variants plays an important role in the diagnosis of genetic diseases. METHODOLOGY/PRINCIPAL FINDINGS: To develop a rapid method for the diagnosis of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency, we designed a multiplex, PCR-based primer panel to amplify all the exons and flanking regions (50 bp average) of six PKU-associated genes (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP). The Ion Torrent Personal Genome Machine (PGM) System was used to detect mutations in all the exons of these six genes. We tested 93 DNA samples from blood specimens from 35 patients and their parents (32 families) and 26 healthy adults. Using strict bioinformatic criteria, this sequencing data provided, on average, 99.14% coverage of the 39 exons at more than 70-fold mean depth of coverage. We found 23 previously documented variants in the PAH gene and six novel mutations in the PAH and PTS genes. A detailed analysis of the mutation spectrum of these patients is described in this study. CONCLUSIONS/SIGNIFICANCE: These results were confirmed by Sanger sequencing. In conclusion, benchtop next-generation sequencing technology can be used to detect mutations in monogenic diseases and can detect both point mutations and indels with high sensitivity, fidelity and throughput at a lower cost than conventional methods in clinical applications.