bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Vancomycin Susceptibility of Methicillin-Susceptible Staphylococcus aureus Has No Significant Impact on Mortality but Results in an Increase in Complicated Infection
Authors: Sullivan Sean B. , Austin Eloise D. , Stump Stephania , Mathema Barun , Whittier Susan , Lowy Franklin D. , Uhlemann Anne-Catrin 
Published: May 2017

ABSTRACT

Methicillin-susceptible
Staphylococcus aureus
(MSSA) bloodstream infections (BSIs) often lead to severe complications despite the availability of effective antibiotics. It remains unclear whether elevated vancomycin MICs are associated with worse outcomes. We conducted a 2-year retrospective cohort study (
n
= 252) of patients with MSSA BSIs at a tertiary care hospital. We defined reduced vancomycin susceptibility (RVS) as a Microscan MIC of 2 mg/liter. All strains were genotyped (
spa
) and assessed for
agr
functionality. Multivariable logistic regression models were used to examine the impact of RVS phenotype and strain genotype on 30-day all-cause mortality and complicated bacteremia (metastatic spread, endovascular infection, or duration ≥3 days). One-third of patients (84/252) were infected with RVS isolates. RVS Infections were more frequently associated with metastatic or embolic sites of infection (36% versus 17%,
P
< 0.001), and endovascular infection (26% versus 12%,
P
= 0.004). These infections occurred more often in patients with fewer underlying comorbidities (Charlson comorbidity index of ≥3 [73% versus 88%,
P
= 0.002]). Genotyping identified 127
spa
-types and 14 Spa-clonal complexes (Spa-CCs). Spa-CC002 and Spa-CC008 were more likely to exhibit the RVS phenotype versus other Spa-CCs (OR = 2.2,
P
< 0.01). The RVS phenotype was not significantly associated with 30-day mortality; however, it was associated with complicated bacteremia (adjusted odds ratio of 2.35 [range, 1.26 to 4.37];
P
= 0.007) in adjusted analyses. The association of RVS strains with complicated infection and fewer underlying comorbidities suggests the phenotype as a potential marker of strain virulence in MSSA BSIs. The RVS phenotype itself was not a significant predictor of mortality in this patient cohort. Further studies are necessary to explore this host-pathogen relationship.
Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study
Authors: Steens Jean-Marc , Scherrer Didier , Gineste Paul , Barrett P. Noel , Khuanchai Supparatpino , Winai Ratanasuwan , Ruxrungtham Kiat , Tazi Jamal , Murphy Robert , Ehrlich Hartmut 
Published: May 2017

ABSTRACT

We investigated the safety and antiviral effects of an anti-HIV compound (ABX464) with a unique mechanism of viral replication inhibition. This was a randomized, double-blind, placebo-controlled, dose-ranging study in treatment-naive HIV-infected patients. Participants were assigned to eight groups; each group included eight subjects receiving either the study compound, ABX464 (
n
= 6), or the corresponding placebo (
n
= 2), according to a randomization code. The first dose administered was 25 mg, given once or 3 times a day over a 2- to 3-week period. Ascending doses of up to 150 mg were delivered after review of the safety data. The primary objective of the study was to assess the safety and tolerability of ABX464 after repeated oral administrations in subjects infected by HIV. Sixty-six subjects were enrolled and were randomized. Sixty-three subjects completed the study according to the study protocol. Twenty-one adverse events (AEs) were reported by 7 subjects out of 16 (44%) who received placebo, and 158 AEs were reported by 39 subjects out of 50 (78%) who received the study drug. In the ABX464 treatment group, all of these adverse events were mild to moderate. No subjects discontinued treatment due to drug-related AEs. Administration of ABX464 at up to 150 mg once a day was safe and well tolerated in HIV-infected subjects. An efficacy signal with respect to a reduction of the viral load by ABX464 was detected, mainly in subjects treated at the highest dose. Further studies will be required to demonstrate antiviral effects in HIV-infected subjects in combination with other antiretroviral therapies. (This study is registered on the ClinicalTrials.gov website under registration no. NCT02452242.)
Controlled Release of Plectasin NZ2114 from a Hybrid Silicone-Hydrogel Material for Inhibition of Staphylococcus aureus Biofilm
Authors: Klein Kasper , Grønnemose Rasmus Birkholm , Alm Martin , Brinch Karoline Sidelmann , Kolmos Hans Jørn , Andersen Thomas Emil 
Published: May 2017

ABSTRACT

Staphylococcus aureus
is a major human pathogen in catheter-related infections. Modifying catheter material with interpenetrating polymer networks is a novel material technology that allows for impregnation with drugs and subsequent controlled release. Here, we evaluated the potential for combining this system with plectasin derivate NZ2114 in an attempt to design an
S. aureus
biofilm-resistant catheter. The material demonstrated promising antibiofilm properties, including properties against methicillin-resistant
S. aureus
, thus suggesting a novel application of this antimicrobial peptide.
Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensis and Its Inhibitory Effect on Topoisomerase 1B
Authors: Velásquez Angela Maria Arenas , Ribeiro Willian Campos , Venn Vutey , Castelli Silvia , Camargo Mariana Santoro de , de Assis Renata Pires , de Souza Rodrigo Alves , Ribeiro Aline Rimoldi , Passalacqua Thaís Gaban , da Rosa João Aristeu , Baviera Amanda Martins , Mauro Antonio Eduardo , Desideri Alessandro , Almeida-Amaral Elmo Eduardo , Graminha Marcia A. S. 
Published: May 2017

ABSTRACT

Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the
Leishmania
genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and
N
,
N
′-dimethylbenzylamine (Hdmba) against
Leishmania amazonensis
. The compound [Pd(dmba)(μ-N
3
)]
2
(CP2) inhibits promastigote growth (50% inhibitory concentration [IC
50
] = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in
in vitro
incubated macrophages (IC
50
= 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 μM). In addition, CP2 was also active against
T. cruzi
intracellular amastigotes (IC
50
= 2.3 ± 0.5 μM, selective index = 225), an indication of its potential for use in Chagas disease therapy.
In vivo
assays using
L. amazonensis
-infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit
Leishmania donovani
topoisomerase 1B (
Ld
topo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.)
Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae
Authors: Kaku Norihito , Kosai Kosuke , Takeda Kazuaki , Uno Naoki , Morinaga Yoshitomo , Hasegawa Hiroo , Miyazaki Taiga , Izumikawa Koichi , Mukae Hiroshi , Yanagihara Katsunori 
Published: May 2017

ABSTRACT

OP0595 (RG6080) is a novel diazabicyclooctane that inhibits class A and C serine beta-lactamases. Although the combination of OP0595 and cefepime (FEP) showed good
in vitro
activity against extended-spectrum-beta-lactamase (ESBL)-producing pathogens, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown
in vivo
. In this study, we investigated the efficacy and pharmacokinetics of the combination therapy of OP0595 and FEP in a mouse model of pneumonia caused by
Klebsiella pneumoniae
harboring SHV- and CTX-M-9-type ESBLs. The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of body weight of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day. The MIC of FEP against the bacteria was 8 mg/liter and markedly improved to 0.06 mg/liter with the addition of 0.5 mg/ml of OP0595. In the survival study, the combination of FEP and OP0595 significantly improved the survival rate compared with that reported with either OP0595 or FEP alone (
P
< 0.001). The number of bacteria in the lungs and blood significantly decreased in the combination therapy group compared to that reported for the monotherapy groups (
P
< 0.001). In addition, the
in vivo
effect depended on the dose of FEP. However, pharmacokinetic analysis revealed that the percentage of time above MIC remained constant when increasing the dose of FEP in combination with 20 mg/kg of OP0595. The results of our study demonstrated the
in vivo
effectiveness of the combination of OP0595 and FEP.
Global Transcriptional Response to Organic Hydroperoxide and the Role of OhrR in the Control of Virulence Traits in Chromobacterium violaceum
Authors: Previato-Mello Maristela , Meireles Diogo de Abreu , Netto Luis Eduardo Soares , da Silva Neto José Freire 
Published: May 2017

ABSTRACT

A major pathway for the detoxification of organic hydroperoxides, such as cumene hydroperoxide (CHP), involves the MarR family transcriptional regulator OhrR and the peroxidase OhrA. However, the effect of these peroxides on the global transcriptome and the contribution of the OhrA/OhrR system to bacterial virulence remain poorly explored. Here, we analyzed the transcriptome profiles of
Chromobacterium violaceum
exposed to CHP and after the deletion of
ohrR
, and we show that OhrR controls the virulence of this human opportunistic pathogen. DNA microarray and Northern blot analyses of CHP-treated cells revealed the upregulation of genes related to the detoxification of peroxides (antioxidant enzymes and thiol-reducing systems), the degradation of the aromatic moiety of CHP (oxygenases), and protection against other secondary stresses (DNA repair, heat shock, iron limitation, and nitrogen starvation responses). Furthermore, we identified two upregulated genes (
ohrA
and a putative diguanylate cyclase with a GGDEF domain for cyclic di-GMP [c-di-GMP] synthesis) and three downregulated genes (hemolysin, chitinase, and collagenase) in the
ohrR
mutant by transcriptome analysis. Importantly, we show that OhrR directly repressed the expression of the putative diguanylate cyclase. Using a mouse infection model, we demonstrate that the
ohrR
mutant was attenuated for virulence and showed a decreased bacterial burden in the liver. Moreover, an
ohrR
-diguanylate cyclase double mutant displayed the same virulence as the wild-type strain. In conclusion, we have defined the transcriptional response to CHP, identified potential virulence factors such as diguanylate cyclase as members of the OhrR regulon, and shown that
C. violaceum
uses the transcriptional regulator OhrR to modulate its virulence.
Microbiomes of Site-Specific Dental Plaques from Children with Different Caries Status
Authors: Richards Vincent P. , Alvarez Andres J. , Luce Amy R. , Bedenbaugh Molly , Mitchell Mary Lyn , Burne Robert A. , Nascimento Marcelle M. 
Published: May 2017

ABSTRACTThe oral microbiota associated with the initiation and progression of dental caries has yet to be fully characterized. The Human Oral Microbe Identification Using Next-Generation Sequencing (HOMINGS) approach was used to analyze the microbiomes of site-specific supragingival dental plaques from children with different caries status. Fifty-five children (2 to 7 years of age) were assessed at baseline and at 12 months and grouped as caries free (CF), caries active with enamel lesions (CAE), and caries active with dentin carious lesions (CA). Plaque samples from caries-free tooth surfaces (PF) and from enamel carious lesions (PE) and dentin carious lesions (PD) were collected. 16S community profiles were obtained by HOMINGS, and 408 bacterial species and 84 genus probes were assigned. Plaque bacterial communities showed temporal stability, as there was no significant difference in beta diversity values between the baseline and 12-month samples. Irrespective of collection time points, the microbiomes of healthy tooth surfaces differed substantially from those found during caries activity. All pairwise comparisons of beta diversity values between groups were significantly different (P< 0.05), except for comparisons between the CA-PF, CAE-PE, and CA-PE groups.Streptococcusgenus probe 4 andNeisseriagenus probe 2 were the most frequently detected taxa across the plaque groups, followed byStreptococcus sanguinis, which was highly abundant in CF-PF. Well-known acidogenic/aciduric species such asStreptococcus mutans,Scardovia wiggsiae,Parascardovia denticolens, andLactobacillus salivariuswere found almost exclusively in CA-PD. The microbiomes of supragingival dental plaque differ substantially among tooth surfaces and children of different caries activities. In support of the ecological nature of caries etiology, a steady transition in community species composition was observed with disease progression.
SaeRS Is Responsive to Cellular Respiratory Status and Regulates Fermentative Biofilm Formation in Staphylococcus aureus
Authors: Mashruwala Ameya A. , Gries Casey M. , Scherr Tyler D. , Kielian Tammy , Boyd Jeffrey M. 
Published: May 2017

ABSTRACT

Biofilms are multicellular communities of microorganisms living as a quorum rather than as individual cells. The bacterial human pathogen
Staphylococcus aureus
uses oxygen as a terminal electron acceptor during respiration. Infected human tissues are hypoxic or anoxic. We recently reported that impaired respiration elicits a
p
rogrammed
c
ell
l
ysis (PCL) phenomenon in
S. aureus
leading to the release of cellular polymers that are utilized to form biofilms. PCL is dependent upon the AtlA murein hydrolase and is regulated, in part, by the SrrAB two-component regulatory system (TCRS). In the current study, we report that the SaeRS TCRS also governs fermentative biofilm formation by positively influencing AtlA activity. The SaeRS-modulated factor fibronectin-binding protein A (FnBPA) also contributed to the fermentative biofilm formation phenotype. SaeRS-dependent biofilm formation occurred in response to changes in cellular respiratory status. Genetic evidence presented suggests that a high cellular titer of phosphorylated SaeR is required for biofilm formation. Epistasis analyses found that SaeRS and SrrAB influence biofilm formation independently of one another. Analyses using a mouse model of orthopedic implant-associated biofilm formation found that both SaeRS and SrrAB govern host colonization. Of these two TCRSs, SrrAB was the dominant system driving biofilm formation
in vivo
. We propose a model wherein impaired cellular respiration stimulates SaeRS via an as yet undefined signal molecule(s), resulting in increasing expression of AtlA and FnBPA and biofilm formation.
Recruitment of Neutrophils Mediated by Vγ2 γδ T Cells Deteriorates Liver Fibrosis Induced by Schistosoma japonicum Infection in C57BL/6 Mice
Authors: Zheng Li , Hu Yuan , Wang Yanjuan , Huang Xibao , Xu Yuxin , Shen Yujuan , Cao Jianping 
Published: May 2017

ABSTRACTConventional adaptive T cell responses contribute to the pathogenesis ofSchistosoma japonicuminfection, leading to liver fibrosis. However, the role of gamma-delta (γδ) T cells in this disease is less clear. γδ T cells are known to secrete interleukin-17 (IL-17) in response to infection, exerting either protective or pathogenic functions. In the present study, mice infected withS. japonicumare used to characterize the role of γδ T cells. Combined with the infection ofS. japonicum, an extremely significant increase in the percentage of neutrophils in the CD45+cells was detected (from approximately 2.45% to 46.10% in blood and from 0.18% to 7.34% in spleen). Further analysis identified two different γδ T cell subsets that have different functions in the formation of granulomas inS. japonicum-infected mice. The Vγ1 T cells secrete gamma interferon (IFN-γ) only, while the Vγ2 T cells secrete both IL-17A and IFN-γ. Both subtypes lose the ability to secrete cytokine during the late stage of infection (12 weeks postinfection). When we depleted the Vγ2 T cells in infected mice, the percentage of neutrophils in blood and spleen decreased significantly, the liver fibrosis in the granulomas was reduced, and the level of IL-17A in the serum decreased (P< 0.05). These results suggest that duringS. japonicuminfection, Vγ2 T cells can recruit neutrophils and aggravate liver fibrosis by secreting IL-17A. This is the first report that a subset of γδ T cells plays a partial role in the pathological process of schistosome infection.
Inhibition of Staphylococcus aureus Cell Wall Biosynthesis by Desleucyl-Oritavancin: a Quantitative Peptidoglycan Composition Analysis by Mass Spectrometry
Authors: Chang James D. , Foster Erin E. , Thadani Aanchal N. , Ramirez Alejandro J. , Kim Sung Joon 
Published: May 2017

ABSTRACT

Oritavancin is a lipoglycopeptide antibiotic that exhibits potent activities against vancomycin-resistant Gram-positive pathogens. Oritavancin differs from vancomycin by a hydrophobic side chain attached to the drug disaccharide, which forms a secondary binding site to enable oritavancin binding to the cross-linked peptidoglycan in the cell wall. The mode of action of secondary binding site was investigated by measuring the changes in the peptidoglycan composition of
Staphylococcus aureus
grown in the presence of desleucyl-oritavancin at subinhibitory concentration using liquid chromatography-mass spectrometry (LC-MS). Desleucyl-oritavancin is an Edman degradation product of oritavancin that exhibits potent antibacterial activities despite the damaged
d
-Ala–
d
-Ala binding site due to its functional secondary binding site. Accurate quantitative peptidoglycan composition analysis based on 83 muropeptide ions determined that cell walls of
S. aureus
grown in the presence of desleucyl-oritavancin showed a reduction of peptidoglycan cross-linking, increased muropeptides with a tetrapeptide-stem structure, decreased
O
-acetylation of MurNAc, and increased
N
-deacetylation of GlcNAc. The changes in peptidoglycan composition suggest that desleucyl-oritavancin targets the peptidoglycan template to induce cell wall disorder and interferes with cell wall maturation.

IMPORTANCE
Oritavancin is a lipoglycopeptide antibiotic with a secondary binding site that targets the cross-linked peptidoglycan bridge structure in the cell wall. Even after the loss of its primary
d
-Ala–
d
-Ala binding site through Edman degradation, desleucyl-oritavancin exhibits potent antimicrobial activities through its still-functioning secondary binding site. In this study, we characterized the mode of action for desleucyl-oritavancin's secondary binding site using LC-MS. Peptidoglycan composition analysis of desleucyl-oritavancin-treated
S. aureus
was performed by determining the relative abundances of 83 muropeptide ions matched from a precalculated library through integrating extracted ion chromatograms. Our work highlights the use of quantitative peptidoglycan composition analysis by LC-MS to provide insights into the mode of action of glycopeptide antibiotics.
Neurolysis with Amniotic Membrane Nerve Wrapping for Treatment of Secondary Wartenberg Syndrome: A Preliminary Report
Authors: Gaspar Michael P. , Kane Patrick M. , Vosbikian Michael M. , Ketonis Constantinos , Rekant Mark S. 
Published: May 2017

Background: Entrapment of the superficial sensory branch of the radial nerve (SRN) commonly results in debilitating pain of the dorsoradial wrist. Symptom relief following SRN neurolysis is often incomplete or temporary due to recurrent perineural scarring.Methods: We performed a retrospective review with prospective follow-up of all patients with SRN neuropathy who were treated with neurolysis and nerve wrapping using an amnion-based allograft adhesion barrier over a one-year interval. Measured outcomes included pain rated by Visual Analog Scale (VAS) and Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) functional outcome scores.Results: Three females satisfied inclusion. At mean follow-up of 28.9 months, all three patients exhibited improved pain (mean VAS change −4.7 ± 0.6), function (mean QuickDASH change −40 ± 5), and subjective satisfaction. No adverse events or reactions to the implanted tissue occurred.Conclusions: SRN entrapment neuropathy was safely and effectively treated with neurolysis and amnion nerve wrapping in this small series. Use of this technique for perineural scar prevention warrants additional study in larger groups of patients and in other upper extremity entrapment neuropathies.
The Effect of Psychological Factors on the Outcomes of Carpal Tunnel Release: A Systematic Review
Authors: Park Jin Woo , Gong Hyun Sik , Rhee Seung Hwan , Kim Jihyeung , Lee Young Ho , Baek Goo Hyun 
Published: May 2017

Background: Several studies report that psychological factors are associated with outcomes of carpal tunnel release. However, interpretation of the association is difficult as there are diverse outcome parameters and patient expectations are different. We performed a systematic review to assess the relationships between psychological factors and the various outcome parameters. Methods: We identified 611 papers and selected 8 papers that fit the inclusion criteria. Psychological factors assessed were anxiety, depression, pain catastrophizing, coping, and mental health status. Outcomes of interest included satisfaction and measures of perceived level of function, pain, and physical measures of recovery. Results: For satisfaction and perceived level of function as the outcome, three studies reported a significant association, one study found an association approaching a value of significance, and one study reported no association. For pain as the outcome, two studies reported a significant association. For physical measures, one study reported no association. Conclusions: This systematic review found that depression correlates with postoperative pain, but that the association is less clear between psychological factors and outcomes such as satisfaction, perceived level of symptom and function, and physical measures of recovery. As pain may not be a primary symptom or outcome of CTS, we consider that the current literature does not strongly support the association between psychological factors and outcomes of CTR. This review could be of benefit during preoperative counseling in patients with psychological disturbances.