bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic effectiveness of calcineurin inhibitors in canine vesicular cutaneous lupus erythematosus
Authors: Banovic Frane , Robson David , Linek Monika , Olivry Thierry 
Published: April 2017

BackgroundOral and topical calcineurin inhibitors (CIs) have been reported to lead to complete lesion remission in several dogs with vesicular cutaneous lupus erythematosus (VCLE).ObjectivesTo report retrospectively on the effectiveness and adverse effects of systemic (ciclosporin) and/or topical (tacrolimus/pimecrolimus) CIs in 11 dogs with VCLE.MethodsInclusion criteria were: (i) presence of characteristic annular, polycyclic or serpiginous ulcerations distributed over the groin, axillae and/or ventral abdomen; (ii) a histopathological diagnosis of VCLE (i.e. a lymphocyte‐rich interface dermatitis with vesiculation); (iii) treatment that included CIs for at least eight weeks; and (iv) follow‐up until death/euthanasia or for a minimum of 12 months post‐diagnosis.ResultsInitial therapy included the avoidance of excessive sun exposure, oral glucocorticoids [six of 11 dogs (55%); progressively tapered over a month] and once daily ciclosporin [11 dogs (100%); median 5.8 mg/kg]. A complete remission (CR) of signs occurred between days 35 and 70 after starting CIs in eight dogs (73%); increasing ciclosporin dosage and adding topical tacrolimus induced a CR in two additional dogs (18%). Relapses were common when doses were tapered or discontinued. With the exception of three dogs that were euthanized, clinical signs were maintained in CR with oral ciclosporin (eight of eight dogs treated, 100%) or topical tacrolimus/pimecrolimus (four of eight dogs; 50%) with a median follow‐up of 2.9 years.Conclusions and clinical importanceThese observations support CIs as the preferable therapeutic alternatives to long‐term immunosuppression with oral glucocorticoids in dogs with VCLE.
In Vitro
Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae
Authors: Huang Dennis , Yu Brenda , Diep John K. , Sharma Rajnikant , Dudley Michael , Monteiro Jussimara , Kaye Keith S. , Pogue Jason M. , Abboud Cely Saad , Rao Gauri G. 
Published: April 2017

ABSTRACT

The multidrug resistance profiles of
Klebsiella pneumoniae
carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the
in vitro
activity of polymyxin B and minocycline combination therapy against six KPC-2-producing
K. pneumoniae
isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing
K. pneumoniae
is dependent on polymyxin B susceptibility. Further
in vitro
and animal studies must be performed to fully evaluate the efficacy of this drug combination.
Emergence and Evolution of Multidrug-Resistant Klebsiella pneumoniae with both
bla
KPC
and
bla
CTX-M
Integrated in the Chromosome
Authors: Huang Weihua , Wang Guiqing , Sebra Robert , Zhuge Jian , Yin Changhong , Aguero-Rosenfeld Maria E. , Schuetz Audrey N. , Dimitrova Nevenka , Fallon John T. 
Published: April 2017

ABSTRACT

The extended-spectrum-β-lactamase (ESBL)- and
Klebsiella pneumoniae
carbapenemase (KPC)-producing
Enterobacteriaceae
represent serious and urgent threats to public health. In a retrospective study of multidrug-resistant
K. pneumoniae
, we identified three clinical isolates, CN1, CR14, and NY9, carrying both
bla
CTX-M
and
bla
KPC
genes. The complete genomes of these three
K. pneumoniae
isolates were
de novo
assembled by using both short- and long-read whole-genome sequencing. In CR14 and NY9,
bla
CTX-M
and
bla
KPC
were carried on two different plasmids. In contrast, CN1 had one copy of
bla
KPC-2
and three copies of
bla
CTX-M-15
integrated in the chromosome, for which the
bla
CTX-M-15
genes were linked to an insertion sequence, IS
Ecp1
, whereas the
bla
KPC-2
gene was in the context of a Tn
4401a
transposition unit conjugated with a PsP3-like prophage. Intriguingly, downstream of the Tn
4401a-bla
KPC-2
-prophage genomic island, CN1 also carried a clustered regularly interspaced short palindromic repeat (CRISPR)-
cas
array with four spacers targeting a variety of
K. pneumoniae
plasmids harboring antimicrobial resistance genes. Comparative genomic analysis revealed that there were two subtypes of type I-E CRISPR-
cas
in
K. pneumoniae
strains and suggested that the evolving CRISPR-
cas
, with its acquired novel spacer, induced the mobilization of antimicrobial resistance genes from plasmids into the chromosome. The integration and dissemination of multiple copies of
bla
CTX-M
and
bla
KPC
from plasmids to chromosome depicts the complex pandemic scenario of multidrug-resistant
K. pneumoniae
. Additionally, the implications from this study also raise concerns for the application of a CRISPR-
cas
strategy against antimicrobial resistance.
Demonstrating the Protective Efficacy of the Novel Fluoroquinolone Finafloxacin against an Inhalational Exposure to Burkholderia pseudomallei
Authors: Barnes Kay B. , Hamblin Karleigh A. , Richards Mark I. , Laws Thomas R. , Vente Andreas , Atkins Helen S. , Harding Sarah V. 
Published: April 2017

ABSTRACT

Burkholderia pseudomallei
is the causative agent of melioidosis, a serious disease endemic in Southeast Asia and Northern Australia. Antibiotic treatment is lengthy and relapse often occurs. Finafloxacin is a novel fluoroquinolone with increased antibacterial activity in acidic conditions in contrast to other fluoroquinolones which demonstrate reduced activity at a lower pH. Therefore, finafloxacin may have improved efficacy against
B. pseudomallei
, which can survive within host cells where the local pH is acidic.
In vitro
analysis was performed using MICs, minimal bactericidal concentrations (MBCs), time-kill assays, persister cell assays, and macrophage assays. Finafloxacin showed increased bactericidal activity at pH 5 in comparison to pH 7 and ciprofloxacin at pH 5.
In vivo
studies in BALB/c mice included pharmacokinetic studies to inform an appropriate dosing regimen. Finafloxacin efficacy was evaluated in an inhalational murine model of melioidosis where antibiotic treatment was initiated at 6 or 24 h postchallenge and continued for 14 days, and mice were observed for 63 days. The survival of infected mice following 14 days of treatment was 80%, 60% or 0% for treatments initiated at 6 h and 60%, 30% or 0% for treatments initiated at 24 h for finafloxacin, co-trimoxazole, or ciprofloxacin, respectively. In summary, finafloxacin has increased bactericidal activity for
B. pseudomallei
under acidic conditions
in vitro
and improves survival in a murine model of melioidosis compared with those for ciprofloxacin. Furthermore, finafloxacin improves bacteriological clearance compared with that of co-trimoxazole, suggesting it may offer an effective postexposure prophylaxis against
B. pseudomallei
.
Candida guilliermondii Complex Is Characterized by High Antifungal Resistance but Low Mortality in 22 Cases of Candidemia
Authors: Marcos-Zambrano Laura Judith , Puig-Asensio Mireia , Pérez-García Felipe , Escribano Pilar , Sánchez-Carrillo Carlos , Zaragoza Oscar , Padilla Belén , Cuenca-Estrella Manuel , Almirante Benito , Martín-Gómez M. Teresa , Muñoz Patricia , Bouza Emilio , Guinea Jesús 
Published: April 2017

ABSTRACT

The objectives of our study were to describe the characteristics of patients with
Candida guilliermondii
candidemia and to perform an in-depth microbiological characterization of isolates and compare them with those of patients with
C. albicans
candidemia. We described the risk factors and outcomes of 22 patients with candidemia caused by the
C. guilliermondii
complex. Incident isolates were identified using molecular techniques, and susceptibility to fluconazole, anidulafungin, and micafungin was studied. Biofilm formation was measured using the crystal violet assay (biomass production) and the XTT reduction assay (metabolic activity), and virulence was studied using the
Galleria mellonella
model. Biofilm formation was compared with that observed for
C. albicans
. The main conditions predisposing to infection were malignancy (68%), immunosuppressive therapy (59%), and neutropenia (18%). Clinical presentation of candidemia was less severe in patients infected by the
C. guilliermondii
complex than in patients infected by
C. albicans
, and 30-day mortality was lower in
C. guilliermondii
patients (13.6% versus 33.9%, respectively;
P
= 0.049). Isolates were identified as
C. guilliermondii
sensu stricto
(
n
= 17) and
Candida fermentati
(
n
= 5). The isolates produced biofilms with low metabolic activity and moderate biomass. The
G. mellonella
model showed that
C. guilliermondii
was less virulent than
C. albicans
(mean of 6 days versus 1 day of survival, respectively;
P
< 0.001). Patients with candidemia caused by the
C. guilliermondii
complex had severe and debilitating underlying conditions. Overall, the isolates showed diminished susceptibility to fluconazole and echinocandins, although poor biofilm formation and the low virulence were associated with a favorable outcome.
Effects on the QT Interval of a Gatifloxacin-Containing Regimen versus Standard Treatment of Pulmonary Tuberculosis
Authors: Olliaro Piero L. , Merle Corinne , Mthiyane Thuli , Bah Boubacar , Kassa Ferdinand , Amukoye Evans , N′Diaye Alimatou , Perronne Christian , Lienhardt Christian , McIlleron Helen , Fielding Katherine 
Published: April 2017

ABSTRACT

The effects on ventricular repolarization—recorded on the electrocardiogram (ECG) as lengthening of the QT interval—of acute tuberculosis and those of standard and alternative antituberculosis regimens are underdocumented. A correction factor (QTc) is introduced to make the QT independent of the heart rate, translating into the slope of the regression line between QT and heart rate being close to zero. ECGs were performed predosing and 1 to 5 h postdosing (month 1, month 2, and end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampin and isoniazid for 6 months and pyrazinamide and ethambutol for 2 months; “control”) or a test regimen with gatifloxacin, rifampin, and isoniazid given for 4 months (pyrazinamide for the first 2 months) as part of the OFLOTUB study, a randomized controlled trial conducted in five African countries. Drug levels were measured at steady state (month 1) in a subset of patients. We compared treatment effects on the QTc and modeled the effect of individual drugs' maximum concentrations of drug in serum (
C
max
) on the Fridericia-corrected QT interval. A total of 1,686 patients were eligible for the correction factor analysis of QT at baseline (mean age, 30.7 years; 27% female). Median heart rate decreased from 96/min at baseline to 71/min at end of treatment, and body temperature decreased from 37.2 to 36.5°C. Pretreatment, the nonlinear model estimated the best correction factor at 0.4081 in between Bazett's (0.5) and Fridericia's (0.33) corrections. On treatment, Fridericia (QTcF) was the best correction factor. A total of 1,602 patients contributed to the analysis of QTcF by treatment arm. The peak QTcF value during follow-up was >480 ms for 21 patients (7 and 14 in the test and control arms, respectively) and >500 ms for 9 patients (5 and 4, respectively), corresponding to a risk difference of −0.9% (95% confidence interval [CI], −2.0% to 2.3%;
P
= 0.12) and 0.1% (95% CI, −0.6% to 0.9%;
P
= 0.75), respectively, between the test and control arms. One hundred six (6.6%) patients had a peak measurement change from baseline of >60 ms (adjusted between-arm difference, 0.8%; 95% CI, −1.4% to 3.1%;
P
= 0.47). No evidence was found of an association between
C
max
of the antituberculosis drugs 1 month into treatment and the length of QTcF. Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appears to carry a sizable risk of QT prolongation in patients with newly diagnosed pulmonary tuberculosis. This is to date the largest data set studying the effects of antituberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT00216385.)
Evaluation of a Multidrug Assay for Monitoring Adherence to a Regimen for HIV Preexposure Prophylaxis in a Clinical Study, HIV Prevention Trials Network 073
Authors: Zhang Yinfeng , Clarke William , Marzinke Mark A. , Piwowar-Manning Estelle , Beauchamp Geetha , Breaud Autumn , Hendrix Craig W. , Cloherty Gavin A. , Emel Lynda , Rose Scott , Hightow-Weidman Lisa , Siegel Marc , Shoptaw Steven , Fields Sheldon D. , Wheeler Darrell , Eshleman Susan H. 
Published: April 2017

ABSTRACT
Daily oral tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC) is a safe and effective intervention for HIV preexposure prophylaxis (PrEP). We evaluated the performance of a qualitative assay that detects 20 antiretroviral (ARV) drugs (multidrug assay) in assessing recent PrEP exposure (detection limit, 2 to 20 ng/ml). Samples were obtained from 216 Black men who have sex with men (208 HIV-uninfected men and 8 seroconverters) who were enrolled in a study in the United States evaluating the acceptability of TDF-FTC PrEP (165 of the uninfected men and 5 of the seroconverters accepted PrEP). Samples from 163 of the 165 HIV-uninfected men who accepted PrEP and samples from all 8 seroconverters were also tested for tenofovir (TFV) and FTC using a quantitative assay (detection limit for both drugs, 0.31 ng/ml). HIV drug resistance was assessed in seroconverter samples. The multidrug assay detected TFV and/or FTC in 3 (1.4%) of the 208 uninfected men at enrollment, 84 (40.4%) of the 208 uninfected men at the last study visit, and 1 (12.5%) of the 8 seroconverters. No other ARV drugs were detected. The quantitative assay confirmed all positive results from the multidrug assay and detected TFV and/or FTC in 9 additional samples (TFV range, 0.65 to 16.5 ng/ml; FTC range, 0.33 to 14.6 ng/ml). Resistance mutations were detected in 4 of the 8 seroconverter samples. The multidrug assay had 100% sensitivity and specificity for detecting TFV and FTC at drug concentrations consistent with daily PrEP use. The quantitative assay detected TFV and FTC at lower levels, which also might have provided protection against HIV infection.
Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus
Authors: Elmwall Jonas , Kwiecinski Jakub , Na Manli , Ali Abukar Ahmed , Osla Veronica , Shaw Lindsey N. , Wang Wanzhong , Sävman Karin , Josefsson Elisabet , Bylund Johan , Jin Tao , Welin Amanda , Karlsson Anna 
Published: April 2017

ABSTRACTStaphylococcus aureusis a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a β-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates ofS. aureuscaused galectin-3 degradation. Similar proteolytic capacities were found inStaphylococcus epidermidisisolates but not inStaphylococcus saprophyticus. Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression onS. aureusvirulence was studied in a murine skin infection model. In galectin-3+/+mice, SspB-expressingS. aureuscaused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3−/−mice, which overall showed smaller lesion sizes than the galectin-3+/+animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.
Cues from the Membrane: Bacterial Glycerophospholipids
Authors: Dalebroux Zachary D. 
Published: April 2017

ABSTRACT

In this issue of the
Journal of Bacteriology
, V. W. Rowlett et al. unveil new
Escherichia coli
circuitry linking membrane glycerophospholipid (GPL) homeostasis to bacterial stress response and adaptation mechanisms (J Bacteriol 199:e00849-16, 2017,
https://doi.org/10.1128/JB.00849-16
). Glycerophospholipids comprise critical components of the dual-membrane envelope of Gram-negative bacteria and participate in many processes. The new evidence suggests that, in some instances, distinct
E. coli
GPL molecules function for distinct biochemistry and bacteria sense perturbations in membrane GPL concentrations to coordinate survival strategies. Understanding GPL sensing and remodeling mechanisms will be important moving forward, given the breadth of function for these molecules in bacteriology.
Pseudomonas aeruginosa-Derived Rhamnolipids and Other Detergents Modulate Colony Morphotype and Motility in the Burkholderia cepacia Complex
Authors: Bernier Steve P. , Hum Courtney , Li Xiang , O'Toole George A. , Magarvey Nathan A. , Surette Michael G. 
Published: April 2017

ABSTRACT

Competitive interactions mediated by released chemicals (e.g., toxins) are prominent in multispecies communities, but the effects of these chemicals at subinhibitory concentrations on susceptible bacteria are poorly understood. Although
Pseudomonas aeruginosa
and species of the
Burkholderia cepacia
complex (Bcc) can exist together as a coinfection in cystic fibrosis airways,
P. aeruginosa
toxins can kill Bcc species
in vitro
. Consequently, these bacteria become an ideal
in vitro
model system to study the impact of sublethal levels of toxins on the biology of typical susceptible bacteria, such as the Bcc, when exposed to
P. aeruginosa
toxins. Using
P. aeruginosa
spent medium as a source of toxins, we showed that a small window of subinhibitory concentrations modulated the colony morphotype and swarming motility of some but not all tested Bcc strains, for which rhamnolipids were identified as the active molecule. Using a random transposon mutagenesis approach, we identified several genes required by the Bcc to respond to low concentrations of rhamnolipids and consequently affect the ability of this microbe to change its morphotype and swarm over surfaces. Among those genes identified were those coding for type IVb-Tad pili, which are often required for virulence in various bacterial pathogens. Our study demonstrates that manipulating chemical gradients
in vitro
can lead to the identification of bacterial behaviors relevant to polymicrobial infections.

IMPORTANCE
Interspecies interactions can have profound effects on the development and outcomes of polymicrobial infections. Consequently, improving the molecular understanding of these interactions could provide us with new insights on the possible long-term consequences of these chronic infections. In this study, we show that
P. aeruginosa
-derived rhamnolipids, which participate in Bcc killing at high concentrations, can also trigger biological responses in
Burkholderia
spp. at low concentrations. The modulation of potential virulence phenotypes in the Bcc by
P. aeruginosa
suggests that these interactions contribute to pathogenesis and disease severity in the context of polymicrobial infections.
Sports injuries and illnesses in first-year physical education teacher education students
Authors: van Beijsterveldt Anne-Marie , Richardson Angelo , Clarsen Benjamin , Stubbe Janine 
Published: April 2017

Background/aimWe aimed to investigate the magnitude and characteristics of injuries and illnesses in Dutch physical education teacher education (PETE) students.MethodsDuring the first 21 weeks of the academic year, 245 first-year students registered their health problems online using the Oslo Sports Trauma Research Centre (OSTRC) Questionnaire on Health Problems.ResultsA total of 276 injuries, 140 illnesses and 69 unclassified health problems were reported. We found an injury incidence rate of 11.7 injuries per 1000 hours (95% CI 10.4 to 13.2). Injury characteristics were: 42% overuse injuries, 62% causing absence from sports (median injury time loss=2 days) and 64% reinjuries. Most injuries were located at the knee, lower leg (anterior) and ankle. The duration of the illnesses was short (<1 week).Summary and conclusionsWe implemented a new registration method in the PETE academic programme. The results show that the risk for health problems is high for PETE students. Prevention is necessary, and to decrease injuries prevention programmes should focus on the lower extremities.
A novel treadmill protocol for exercise testing in children: the British Columbia Children’s Hospital protocol
Authors: Duff D Kathryn , De Souza Astrid M , Human Derek G , Potts James E , Harris Kevin C 
Published: April 2017

BackgroundExercise testing in children is widely recommended for a number of clinical and prescriptive reasons. Many institutions continue to use the Bruce protocol for treadmill testing; however, with its incremental changes in speed and grade, it has challenges for practical application in children. We have developed a novel institutional protocol (British Columbia Children’s Hospital (BCCH)), which may have better utility in paediatric populations.AimTo determine if our institutional protocol yields similar peak responses in minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER), metabolic equivalents (METS) and heart rate (HR) when compared with the traditional Bruce protocol.MethodsOn two different occasions, 70 children (boys=33; girls=37) aged 10–18 years completed an exercise test on a treadmill using each of the protocols. During each test, metabolic gas exchange parameters were measured. HR was monitored continuously during exercise using an HR monitor.ResultsPhysiological variables were similar between the two protocols (median (IQR); rs): VE (L/min) (BCCH=96.7 (72.0–110.2); Bruce=99.2 (75.6–120.0); rs=0.95), peak VO2(mL/min) (BCCH=2897 (2342–3807); Bruce=2901 (2427–3654); rs=0.94) and METS (BCCH=16.2 (14.8–17.7); Bruce=16.4 (14.7–17.9); rs=0.89). RERs were similar (BCCH=1.00 (0.96–1.02); Bruce=1.03 (0.99–1.07); rs=0.48). Total exercise time (in seconds) was longer for the BCCH protocol: BCCH=915 (829–1005); Bruce=810 (750-919); rs=0.67.ConclusionThe BCCH protocol produces similar peak exercise responses to the Bruce protocol and provides an alternative for clinical exercise testing in children.