bluuebunny/crossref_metadata_2025_split huggingface dataset:
Administration of platelets to ruptured abdominal aortic aneurysm patients before open surgery: a prospective, single‐blinded, randomised study
Authors: Lunen T. B. , Johansson P. I. , Jensen L. P. , Homburg K. M. , Roeder O. C. , Lonn L. , Secher N. H. , Helgstrand U. , Carstensen M. , Jensen K. B. , Lange T. , Sillesen H. , Swiatek F. , Nielsen H. B. 
Published: May 2018

SUMMARYBackgroundIn patients undergoing open surgery for a ruptured abdominal aortic aneurysm (rAAA), survivors demonstrate a high platelet count, and proactive administration of platelets (and fresh frozen plasma) appears to influence mortality.ObjectivesThis trial investigated the effect of platelets administered before transport to surgery.MethodsIn a prospective study design, patients were randomised to receive platelets (intervention; n = 61) or no platelets (control; n = 61) before transport to vascular surgery from 11 local hospitals. The study was terminated when one of the vascular surgical centres implemented endovascular repair for rAAA patients.ResultsThirty days after surgery, mortality was 36% for patients with intervention vs 31% for controls (P = 0·32). Post‐operative thrombotic events (14 vs 15; P = 0·69), renal failure (11 vs 10; P = 0·15) and pulmonary insufficiency (34 vs 39; P = 0·15) were similar in the two groups of patients. No adverse reactions to platelet administration were observed. In addition, length of stay in the intensive care unit was unaffected by intervention.ConclusionsFor patients planned for open repair of a rAAA, we observed no significant effect of early administration of platelets with regard to post‐operative complications and stay in the ICU or in hospital and also no significant effect on mortality.
Diversity of Staphylococcus pseudintermedius in carriage sites and skin lesions of dogs with superficial bacterial folliculitis: potential implications for diagnostic testing and therapy
Authors: Larsen Rikke Friis , Boysen Lene , Jessen Lisbeth Rem , Guardabassi Luca , Damborg Peter 
Published: May 2018

BackgroundStaphylococcus pseudintermedius is genotypically diverse within the canine population and multiple strains may colonize individual dogs at any given time. If multiple strains with distinct antimicrobial resistance profiles are present in superficial bacterial folliculitis (SBF), sampling a single skin lesion for culture and antimicrobial susceptibility testing (AST) might be inadequate to select effective therapy.Hypothesis/ObjectivesTo investigate S. pseudintermedius diversity in carriage sites and lesions of dogs with SBF.AnimalsFourteen dogs with SBF.MethodsStaphylococcus pseudintermedius isolates obtained from perineum, gingiva and four to six skin lesions per dog were subjected to pulsed‐field gel electrophoresis (PFGE) and AST to assess diversity between lesions. For two dogs, 14–16 isolates per lesion were included in the analysis to assess diversity within lesions.ResultsAnalysis of one isolate per lesion revealed one to four strains displaying unique PFGE profiles, and up to three unique antimicrobial resistance (AMR) profiles for each dog. Multiple pustules from the same dog always harboured the same strain, whereas papules, crusts and collarettes did not. Up to four strains with distinct AMR profiles were isolated from the same lesion in two dogs. In 12 dogs, at least one carriage site strain also was represented in lesions.Conclusions and clinical importanceLesions of SBF may harbour multiple S. pseudintermedius strains with distinct antimicrobial resistance profiles. Pustules are the best target for bacterial culture. It remains unclear whether isolation of different strains from other lesion types is a consequence of contamination or co‐infection by multiple strains.
Assessment of porcine endogenous retrovirus transmission across an alginate barrier used for the encapsulation of porcine islets
Authors: Crossan Claire , Mourad Nizar I. , Smith Karen , Gianello Pierre , Scobie Linda 
Published: May 2018

AbstractBackgroundSubcutaneous implantation of a macroencapsulated patch containing human allogenic islets has been successfully used to alleviate type 1 diabetes mellitus (T1DM) in a human recipient without the need for immunosuppression. The use of encapsulated porcine islets to treat T1DM has also been reported. Although no evidence of pathogen transfer using this technology has been reported to date, we deemed it appropriate to determine if the encapsulation technology would prevent the release of virus, in particular, the porcine endogenous retrovirus (PERV).MethodsHEK293 (human epithelial kidney) and swine testis (ST) cells were co‐cultured with macroencapsulated pig islets embedded in an alginate patch, macroencapsulated PK15 (swine kidney epithelial) cells embedded in an alginate patch and free PK15 cells. Cells and supernatant were harvested at weekly time points from the cultures for up to 60 days and screened for evidence of PERV release using qRT‐PCR to detect PERV RNA and SG‐PERT to detect reverse transcriptase (RT).ResultsNo PERV virus, or evidence of PERV replication, was detected in the culture medium of HEK293 or pig cells cultured with encapsulated porcine islets. Increased PERV activity relative to the background was not detected in ST cells cultured with encapsulated PK15 cells. However, PERV was detected in 1 of the 3 experimental replicates of HEK293 cells cultured with encapsulated PK15 cells. Both HEK293 and ST cells cultured with free PK15 cells showed an increase in RT detection.ConclusionsWith the exception of 1 replicate, there does not appear to be evidence of transmission of replication competent PERV from the encapsulated islet cells or the positive control PK15 cells across the alginate barrier. The detection of PERV would suggest the alginate barrier of this replicate may have become compromised, emphasizing the importance of quality control when producing encapsulated islet patches.
The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on MIC Determination
Authors: Smith Kenneth P. , Kirby James E. 
Published: May 2018

ABSTRACT

The observed MIC may depend on the number of bacteria initially inoculated into the assay. This phenomenon is termed the inoculum effect (IE) and is often most pronounced for β-lactams in strains expressing β-lactamase enzymes. The Clinical and Laboratory Standards Institute (CLSI)-recommended inoculum is 5 × 10
5
CFU ml
−1
with an acceptable range of 2 × 10
5
to 8 × 10
5
CFU ml
−1
. IE testing is typically performed using an inoculum 100-fold greater than the CLSI-recommended inoculum. Therefore, it remains unknown whether the IE influences MICs during testing performed according to CLSI guidelines. Here, we utilized inkjet printing technology to test the IE on cefepime, meropenem, and ceftazidime-avibactam. First, we determined that the inkjet dispense volume correlated well with the number of bacteria delivered to microwells in 2-fold (
R
2
= 0.99) or 1.1-fold (
R
2
= 0.98) serial dilutions. We then quantified the IE by dispensing orthogonal titrations of bacterial cells and antibiotics. For cefepime-resistant and susceptible dose-dependent strains, a 2-fold increase in inoculum resulted in a 1.6 log
2
-fold increase in MIC. For carbapenemase-producing strains, each 2-fold reduction in inoculum resulted in a 1.26 log
2
-fold reduction in meropenem MIC. At the lower end of the CLSI-allowable inoculum range, minor error rates of 34.8% were observed for meropenem when testing a resistant-strain set. Ceftazidime-avibactam was not subject to an appreciable IE. Our results suggest that IE is sufficiently pronounced for meropenem and cefepime in multidrug-resistant Gram-negative pathogens to affect categorical interpretations during standard laboratory testing.
Carbapenem-Nonsusceptible Haemophilus influenzae with Penicillin-Binding Protein 3 Containing an Amino Acid Insertion
Authors: Kitaoka Kazuki , Kimura Kouji , Kitanaka Hiromitsu , Banno Hirotsugu , Jin Wanchun , Wachino Jun-ichi , Arakawa Yoshichika 
Published: May 2018

ABSTRACT

The prevalence of β-lactamase-negative ampicillin-resistant (BLNAR)
Haemophilus influenzae
has become a clinical concern. In BLNAR isolates, amino acid substitutions in penicillin-binding protein 3 (PBP3) are relevant to the β-lactam resistance. Carbapenem-nonsusceptible
H. influenzae
isolates have been rarely reported. Through antimicrobial susceptibility testing, nucleotide sequence analysis of
ftsI
, encoding PBP3, and the utilization of a collection of
H. influenzae
clinical isolates in our laboratory, we obtained a carbapenem-nonsusceptible clinical isolate (NUBL1772) that possesses an altered PBP3 containing V525_N526insM. The aim of this study was to reveal the effect of altered PBP3 containing V525_N526insM on reduced carbapenem susceptibility. After generating recombinant strains with altered
ftsI
, we performed antimicrobial susceptibility testing and competitive binding assays with fluorescent penicillin (Bocillin FL) and carbapenems. Elevated carbapenem MICs were found for the recombinant strain harboring the entire
ftsI
gene of NUBL1772. The recombinant PBP3 of NUBL1772 also exhibited reduced binding to carbapenems. These results demonstrate that altered PBP3 containing V525_N526insM influences the reduced carbapenem susceptibility. The revertant mutant lacking the V525_N526insM exhibited lower MICs for carbapenems than NUBL1772, suggesting that this insertion affects reduced carbapenem susceptibility. The MICs of β-lactams for NUBL1772 were higher than those for the recombinant possessing
ftsI
of NUBL1772. NUBL1772 harbored AcrR with early termination, resulting in low-level transcription of
acrB
and high efflux pump activity. These findings suggest that the disruption of AcrR also contributes to the reduced carbapenem susceptibility found in NUBL1772. Our results provide the first evidence that the altered PBP3 containing V525_N526insM is responsible for the reduced susceptibility to carbapenems in
H. influenzae
.
Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity
Authors: Yew Wing Wai , Chang Kwok Chiu , Chan Denise P. 
Published: May 2018

ABSTRACT
Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even, rarely, mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Covering only first-line antituberculosis drugs, this review addresses whether and how oxidative stress and, more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection, and preexisting liver disease. Importantly, these comorbid conditions are associated with oxidative stress and drugs related to antioxidants, especially those for management of mitochondrial dysfunction. Thus, the shared pathogenetic mechanism(s) for liver injury might be in operation due to disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. More translational research to unravel the pathogenesis, inclusive of the underlying molecular bases, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is clinical research pertaining to the advances in therapy, with antioxidants and beyond. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.
PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani
Authors: Habib Samar , El Andaloussi Abdeljabar , Elmasry Khaled , Handoussa Aya , Azab Manar , Elsawey Aliaa , Al-Hendy Ayman , Ismail Nahed 
Published: May 2018

ABSTRACTLeishmania donovaniis a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4+Th1 cell-mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate thatL. donovaniis able to elicit initial expansion of gamma interferon-producing CD4+Th1 and CD8+T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10+FOXP3+Treg and CD4+and CD8+T cells expressing PD1. Blocking of PDL-1 signalingin vivoresulted in restoration of protective type 1 responses by both CD4+and CD8+T cells, which resulted in a significant decrease in the parasite burden. Mechanistically, PDL-1 blocking inhibited autophagy, a cellular degradation process hijacked byLeishmaniato acquire host cell nutrients for their survival. Inhibition of autophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. Together, our findings show for the first time that anti-PDL-1 antibody is an effective therapeutic approach for restoration of effector arms of protective immunity against VL and subsequent parasite clearance.
Small Bottleneck Size in a Highly Multipartite Virus during a Complete Infection Cycle
Authors: Gallet Romain , Fabre Frédéric , Thébaud Gaël , Sofonea Mircea T. , Sicard Anne , Blanc Stéphane , Michalakis Yannis 
Published: May 2018

ABSTRACT

Multipartite viruses package their genomic segments independently and thus incur the risk of being unable to transmit their entire genome during host-to-host transmission if they undergo severe bottlenecks. In this paper, we estimated the bottleneck size during one infection cycle of
Faba bean necrotic stunt virus
(FBNSV), an octopartite nanovirus whose segments have been previously shown to converge to particular and unequal relative frequencies within host plants and aphid vectors. Two methods were used to derive this estimate, one based on the probability of transmission of the virus and the other based on the temporal evolution of the relative frequency of markers for two genomic segments, one frequent and one rare (segment N and S, respectively), both in plants and vectors. Our results show that FBNSV undergoes severe bottlenecks during aphid transmission. Further, even though the bottlenecks are always narrow under our experimental conditions, they slightly widen with the number of transmitting aphids. In particular, when several aphids are used for transmission, the bottleneck size of the segments is also affected by within-plant processes and, importantly, significantly differs across segments. These results indicate that genetic drift not only must be an important process affecting the evolution of these viruses but also that these effects vary across genomic segments and, thus, across viral genes, a rather unique and intriguing situation. We further discuss the potential consequences of our findings for the transmission of multipartite viruses.

IMPORTANCE
Multipartite viruses package their genomic segments in independent capsids. The most obvious cost of such genomic structure is the risk of losing at least one segment during host-to-host transmission. A theoretical study has shown that for nanoviruses, composed of 6 to 8 segments, hundreds of copies of each segment need to be transmitted to ensure that at least one copy of each segment was present in the host. These estimations seem to be very high compared to the size of the bottlenecks measured with other viruses. Here, we estimated the bottleneck size during one infection cycle of FBNSV, an octopartite nanovirus. We show that these bottlenecks are always narrow (few viral particles) and slightly widen with the number of transmitting aphids. These results contrast with theoretical predictions and illustrate the fact that a new conceptual framework is probably needed to understand the transmission of highly multipartite viruses.
The Case for an Expanded Concept of Trained Immunity
Authors: Cassone Antonio 
Published: May 2018

ABSTRACT

Trained immunity was originally proposed as a program of innate immunity memory by innate immunity cells of hematopoietic origin such as the monocytes/macrophages and the NK cells. Here I discuss some old and new data justifying this program and some specific, still unanswered, questions it raises regarding the model fungus
Candida albicans
and the chronic, inflammatory vulvovaginal disease it causes. Building upon this well-established program, the recent reports that epithelial cells of mammals can also acquire memory from previous stimulations, and the apparent intrinsic ability of many living cells from bacteria to mammals to learn from experience, I suggest an expansion of the concept of trained immunity to include all cells of different lineages with the potential of memorizing previous microbial encounters. This expansion would better fit the complexity of innate immunity and the role it plays in infectious and inflammatory diseases.
Wolbachia w
Stri Blocks Zika Virus Growth at Two Independent Stages of Viral Replication
Authors: Schultz M. J. , Tan A. L. , Gray C. N. , Isern S. , Michael S. F. , Frydman H. M. , Connor J. H. 
Published: May 2018

ABSTRACT

Mosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Coinfection of mosquitos with the bacterium
Wolbachia pipientis
from supergroup A is a recent strategy employed to reduce the capacity for major vectors in the
Aedes
mosquito genus to transmit viruses, including dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, a supergroup B
Wolbachia w
Stri, isolated from
Laodelphax striatellus
, was shown to inhibit multiple lineages of ZIKV in
Aedes albopictus
cells. Here, we show that
w
Stri blocks the growth of positive-sense RNA viruses DENV, CHIKV, ZIKV, and yellow fever virus by greater than 99.9%.
w
Stri presence did not affect the growth of the negative-sense RNA viruses LaCrosse virus or vesicular stomatitis virus. Investigation of the stages of the ZIKV life cycle inhibited by
w
Stri identified two distinct blocks in viral replication. We found a reduction of ZIKV entry into
w
Stri-infected cells. This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate in
Wolbachia
-infected cells. RNA transfection and metabolic labeling studies suggested that this replication defect is at the level of RNA translation, where we saw a 66% reduction in mosquito protein synthesis in
w
Stri-infected cells. This study’s findings increase the potential for application of
w
Stri to block additional arboviruses and also identify specific blocks in viral infection caused by
Wolbachia
coinfection.

IMPORTANCE
Dengue, Zika, and yellow fever viruses are mosquito-transmitted diseases that have spread throughout the world, causing millions of infections and thousands of deaths each year. Existing programs that seek to contain these diseases through elimination of the mosquito population have so far failed, making it crucial to explore new ways of limiting the spread of these viruses. Here, we show that introduction of an insect symbiont,
Wolbachia w
Stri, into mosquito cells is highly effective at reducing yellow fever virus, dengue virus, Zika virus, and Chikungunya virus production. Reduction of virus replication was attributable to decreases in entry and a strong block of virus gene expression at the translational level. These findings expand the potential use of
Wolbachia w
Stri to block viruses and identify two separate steps for limiting virus replication in mosquitos that could be targeted via microbes or other means as an antiviral strategy.
A Single-Domain Response Regulator Functions as an Integrating Hub To Coordinate General Stress Response and Development in Alphaproteobacteria
Authors: Lori C. , Kaczmarczyk A. , de Jong I. , Jenal U. 
Published: May 2018

ABSTRACT

The alphaproteobacterial general stress response is governed by a conserved partner-switching mechanism that is triggered by phosphorylation of the response regulator PhyR. In the model organism
Caulobacter crescentus
, PhyR was proposed to be phosphorylated by the histidine kinase PhyK, but biochemical evidence in support of such a role of PhyK is missing. Here, we identify a single-domain response regulator, MrrA, that is essential for general stress response activation in
C. crescentus
. We demonstrate that PhyK does not function as a kinase but accepts phosphoryl groups from MrrA and passes them on to PhyR, adopting the role of a histidine phosphotransferase. MrrA is phosphorylated by at least six histidine kinases that likely serve as stress sensors. MrrA also transfers phosphate to LovK, a histidine kinase involved in
C. crescentus
holdfast production and attachment, which also negatively regulates the general stress response. We show that LovK together with the response regulator LovR acts as a phosphate sink to redirect phosphate flux away from the PhyKR branch. In agreement with the biochemical data, an
mrrA
mutant is unable to activate the general stress response and shows a hyperattachment phenotype, which is linked to decreased expression of the major holdfast inhibitory protein HfiA. We propose that MrrA serves as a central phosphorylation hub that coordinates the general stress response with
C. crescentus
development and other adaptive behaviors. The characteristic bow-tie architecture of this phosphorylation network with MrrA as the central knot may expedite the evolvability and species-specific niche adaptation of this group of bacteria.

IMPORTANCE
Two-component systems (TCSs) consisting of a histidine kinase and a cognate response regulator are predominant signal transduction systems in bacteria. To avoid cross talk, TCSs are generally thought to be highly insulated from each other. However, this notion is based largely on studies of the HisKA subfamily of histidine kinases, while little information is available for the HWE and HisKA2 subfamilies. The latter have been implicated in the alphaproteobacterial general stress response. Here, we show that in the model organism
Caulobacter crescentus
an atypical FATGUY-type single-domain response regulator, MrrA, is highly promiscuous in accepting and transferring phosphoryl groups from and to multiple up- and downstream kinases, challenging the current view of strictly insulated TCSs. Instead, we propose that FATGUY response regulators have evolved in alphaproteobacteria as central phosphorylation hubs to broadly sample information and distribute phosphoryl groups between the general stress response pathway and other TCSs, thereby coordinating multiple cellular behaviors.