bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic Effects of Antimicrobial Peptides and Antibiotics against Clostridium difficile
Authors: Nuding Sabine , Frasch Tina , Schaller Martin , Stange Eduard F. , Zabel Lutz T. 
Published: July 2014

ABSTRACT

Accelerating rates of health care-associated infections caused by
Clostridium difficile
, with increasing recurrence and rising antibiotic resistance rates, have become a serious problem in recent years. This study was conducted to explore whether a combination of antibiotics with human antimicrobial peptides may lead to an increase in antibacterial activity. The
in vitro
activities of the antimicrobial peptides HBD1 to HBD3, HNP1, HD5, and LL-37 and the antibiotics tigecycline, moxifloxacin, piperacillin-tazobactam, and meropenem alone or in combination against 10 toxinogenic and 10 nontoxinogenic
C. difficile
strains were investigated. Bacterial viability was determined by flow cytometry and toxin production by enzyme-linked immunosorbent assay (ELISA). When combined at subinhibitory concentrations, antimicrobial peptides and antibiotics generally led to an additive killing effect against toxinogenic and nontoxinogenic
C. difficile
strains. However, LL-37 and HBD3 acted in synergism with all the antibiotics that were tested. Electron microscopy revealed membrane perturbation in bacterial cell walls by HBD3. In 3 out of 10 toxinogenic strains, HBD3, LL-37, piperacillin-tazobactam, and meropenem administration led to an increased toxin release which was not neutralized by the addition of HNP1. Antimicrobial peptides increase the bacterial killing of antibiotics against
C. difficile
regardless of the antibiotics' mode of action. Membrane perturbation in or pore formation on the bacterial cell wall may enhance the uptake of antibiotics and increase their antibacterial effect. Therefore, a combination of antibiotics with antimicrobial peptides may represent a promising novel approach to the treatment of
C. difficile
infections.
Musculoskeletal Safety Outcomes of Patients Receiving Daptomycin with HMG-CoA Reductase Inhibitors
Authors: Bland Christopher M. , Bookstaver P. Brandon , Lu Z. Kevin , Dunn Brianne L. , Rumley Kathey Fulton 
Published: July 2014

ABSTRACT

Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (
P
= 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (
P
= 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (
P
= 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population.
Antistaphylococcal Activity of Oritavancin and Its Synergistic Effect in Combination with Other Antimicrobial Agents
Authors: Lin Gengrong , Pankuch Glenn , Appelbaum Peter C. , Kosowska-Shick Klaudia 
Published: July 2014

ABSTRACT

Oritavancin exhibited
in vitro
activity against 169 strains of vancomycin-susceptible, methicillin-resistant
Staphylococcus aureus
(MRSA) with MICs ranging from 0.03 to 1 μg/ml and against vancomycin-intermediate MRSA (VISA;
n
= 29), heterogeneous vancomycin-intermediate MRSA (hVISA;
n
= 5), and vancomycin-resistant MRSA (
n
= 5) strains, with MICs ranging from 0.12 to 4 μg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method.
Protection against Mycobacterium leprae Infection by the ID83/GLA-SE and ID93/GLA-SE Vaccines Developed for Tuberculosis
Authors: Duthie Malcolm S. , Coler Rhea N. , Laurance John D. , Sampaio Lucas H. , Oliveira Regiane M. , Sousa Ana Lucia M. , Stefani Mariane M. A. , Maeda Yumi , Matsuoka Masanori , Makino Masahiko , Reed Steven G. 
Published: July 2014

ABSTRACT

Despite the dramatic reduction in the number of leprosy cases worldwide in the 1990s, transmission of the causative agent,
Mycobacterium leprae
, is still occurring, and new cases continue to appear. New strategies are required in the pursuit of leprosy elimination. The cross-application of vaccines in development for tuberculosis may lead to tools applicable to elimination of leprosy. In this report, we demonstrate that the chimeric fusion proteins ID83 and ID93, developed as antigens for tuberculosis (TB) vaccine candidates, elicited gamma interferon (IFN-γ) responses from both TB and paucibacillary (PB) leprosy patients and from healthy household contacts of multibacillary (MB) patients (HHC) but not from nonexposed healthy controls. Immunization of mice with either protein formulated with a Toll-like receptor 4 ligand (TLR4L)-containing adjuvant (glucopyranosyl lipid adjuvant in a stable emulsion [GLA-SE]) stimulated antigen-specific IFN-γ secretion from pluripotent Th1 cells. When immunized mice were experimentally infected with
M. leprae
, both cellular infiltration into the local lymph node and bacterial growth at the site were reduced relative to those of unimmunized mice. Thus, the use of the
Mycobacterium tuberculosis
candidate vaccines ID83/GLA-SE and ID93/GLA-SE may confer cross-protection against
M. leprae
infection. Our data suggest these vaccines could potentially be used as an additional control measure for leprosy.
Postnatal epigenetic modification of glucocorticoid receptor gene in preterm infants: a prospective cohort study
Authors: Kantake Masato , Yoshitake Hiroshi , Ishikawa Hitoshi , Araki Yoshihiko , Shimizu Toshiaki 
Published: July 2014

ObjectiveTo examine the environmental effects on cytosine methylation of preterm infant's DNA, because early life experiences are considered to influence the physiological and mental health of an individual through epigenetic modification of DNA.DesignA prospective cohort study, comparison of epigenetic differences in the glucocorticoid receptor (GR) gene between healthy term and preterm infants.SettingNeonatal Intensive Care Unit in a Japanese University Hospital.ParticipantsA cohort of 40 (20 term and 20 preterm) infants was recruited on the day of birth, and peripheral blood was obtained from each infant at birth and on postnatal day 4.Main outcome measuresThe methylation rates in the 1-F promoter region of the GR gene using the Mquant method.ResultsThe methylation rate increased significantly between postnatal days 0 and 4 in preterm infants but remained stable in term infants. Thus, the methylation rate was significantly higher in preterm than in term infants at postnatal day 4. Several perinatal parameters were significantly correlated with this change in the methylation rate. Logistic regression analysis revealed that methylation rates at postnatal day 4 predicted the occurrence of later complications that required glucocorticoid administration during the neonatal period. No gene polymorphism was detected within the GR promoter region analysed.ConclusionsAlthough further large-scale studies are needed to detect the environmental factors that explain the difference in epigenetic modification among infants after birth, our data show that the postnatal environment influences epigenetic programming of GR expression through methylation of the GR gene promoter in premature infants, which may result in relative glucocorticoid insufficiency during the postnatal period.
Economic contraction, alcohol intoxication and suicide: analysis of the National Violent Death Reporting System
Authors: Kaplan M S , Huguet N , Caetano R , Giesbrecht N , Kerr W C , McFarland B H 
Published: July 2014

ObjectivesAlthough there is a large and growing body of evidence concerning the impact of contracting economies on suicide mortality risk, far less is known about the role alcohol consumption plays in the complex relationship between economic conditions and suicide. The aims were to compare the postmortem alcohol intoxication rates among male and female suicide decedents before (2005–2007), during (2008–2009) and after (2010–2011) the economic contraction in the USA.MethodsData from the restricted National Violent Death Reporting System (2005–2011) for male and female suicide decedents aged 20 years and older were analysed by Poisson regression analysis to test whether there was significant change in the fractions of suicide decedents who were acutely intoxicated at the time of death (defined as blood alcohol content ≥0.08 g/dL) prior, during and after the downturn.ResultsThe fraction of all suicide decedents with alcohol intoxication increased by 7% after the onset of the recession from 22.2% in 2005–2007 to 23.9% in 2008–2011. Compared with the years prior to the recession, male suicide decedents showed a 1.09-fold increased risk of alcohol intoxication within the first 2 years of the recession. Surprisingly, there was evidence of a lag effect among female suicide decedents, who had a 1.14-fold (95% CI 1.02 to 1.27) increased risk of intoxication in 2010–2011 compared with 2005–2007.ConclusionsThese findings suggest that acute alcohol intoxication in suicide interacts with economic conditions, becoming more prevalent during contractions.
Biochemical Assays for the Discovery of TDP1 Inhibitors
Authors: Marchand Christophe , Huang Shar-yin N. , Dexheimer Thomas S. , Lea Wendy A. , Mott Bryan T. , Chergui Adel , Naumova Alena , Stephen Andrew G. , Rosenthal Andrew S. , Rai Ganesha , Murai Junko , Gao Rui , Maloney David J. , Jadhav Ajit , Jorgensen William L. , Simeonov Anton , Pommier Yves 
Published: July 2014

Abstract
Drug screening against novel targets is warranted to generate biochemical probes and new therapeutic drug leads. TDP1 and TDP2 are two DNA repair enzymes that have yet to be successfully targeted. TDP1 repairs topoisomerase I–, alkylation-, and chain terminator–induced DNA damage, whereas TDP2 repairs topoisomerase II–induced DNA damage. Here, we report the quantitative high-throughput screening (qHTS) of the NIH Molecular Libraries Small Molecule Repository using recombinant human TDP1. We also developed a secondary screening method using a multiple loading gel-based assay where recombinant TDP1 is replaced by whole cell extract (WCE) from genetically engineered DT40 cells. While developing this assay, we determined the importance of buffer conditions for testing TDP1, and most notably the possible interference of phosphate-based buffers. The high specificity of endogenous TDP1 in WCE allowed the evaluation of a large number of hits with up to 600 samples analyzed per gel via multiple loadings. The increased stringency of the WCE assay eliminated a large fraction of the initial hits collected from the qHTS. Finally, inclusion of a TDP2 counter-screening assay allowed the identification of two novel series of selective TDP1 inhibitors. Mol Cancer Ther; 13(8); 2116–26. ©2014 AACR.
Wave Activity Events and the Variability of the Stratospheric Polar Vortex
Authors: Solomon Abraham 
Published: July 2014

Abstract
During Northern Hemisphere winter, polar stratospheric winds and temperatures exhibit significant variability that is due to the vertical propagation of planetary-scale waves. The most dramatic intraseasonal variations in temperature are associated with sudden stratospheric warmings (SSWs), which are wave-breaking events that occur approximately every other year. This paper will introduce the concept of wave activity events (WAEs), which are periods of enhanced pseudomomentum density in the polar stratosphere that occur every year. It will be demonstrated that all SSWs are associated with WAEs; furthermore, minor warmings and many final warmings in the polar spring are also WAEs, and therefore a better understanding of these more frequent wave events can provide additional insights into stratospheric wave-induced variability. Employing the Interim European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-Interim) for 1979–2011, 119 WAEs are identified and their life cycle is compared with that of the 23 SSWs observed during this period.
Direct Estimate of Lateral Eddy Diffusivity Upstream of Drake Passage
Authors: Tulloch Ross , Ferrari Raffaele , Jahn Oliver , Klocker Andreas , LaCasce Joseph , Ledwell James R. , Marshall John , Messias Marie-Jose , Speer Kevin , Watson Andrew 
Published: July 2014

Abstract
The first direct estimate of the rate at which geostrophic turbulence mixes tracers across the Antarctic Circumpolar Current is presented. The estimate is computed from the spreading of a tracer released upstream of Drake Passage as part of the Diapycnal and Isopycnal Mixing Experiment in the Southern Ocean (DIMES). The meridional eddy diffusivity, a measure of the rate at which the area of the tracer spreads along an isopycnal across the Antarctic Circumpolar Current, is 710 ± 260 m2 s−1 at 1500-m depth. The estimate is based on an extrapolation of the tracer-based diffusivity using output from numerical tracers released in a one-twentieth of a degree model simulation of the circulation and turbulence in the Drake Passage region. The model is shown to reproduce the observed spreading rate of the DIMES tracer and suggests that the meridional eddy diffusivity is weak in the upper kilometer of the water column with values below 500 m2 s−1 and peaks at the steering level, near 2 km, where the eddy phase speed is equal to the mean flow speed. These vertical variations are not captured by ocean models presently used for climate studies, but they significantly affect the ventilation of different water masses.
Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project
Authors: Holding Stephen , Khan Sujoy , Sewell William AC , Jolles Stephen , Dore Philip C 
Published: July 2014

Background Median diagnostic delay of five to six years seen in primary hypogammaglobulinaemia results in morbidity including bronchiectasis. Patients typically have multiple health care encounters and blood tests before the diagnosis is considered. We report outcomes from using the difference between total protein and albumin (globulin fraction) to reduce diagnostic delay in unsuspected hypogammaglobulinaemia. Methods A prospective >5 year programme in the setting of a National Health Services Hospital Blood Sciences pathology service processing serum samples from primary and secondary care. Patients with globulin fraction below the first percentile were reviewed in the context of supplied clinical details. Immunoglobulin measurements were performed in selected patients. Results Of 2,910,850 globulin fractions 27,304 (0.9%) were below the 1st percentile globulin fraction (<18 g/L). After exclusions, 933 (3% of these) had immunoglobulins measured. Of these, 292 had IgG < 5 g/L, 186 < 4 g/L and 80 < 3 g/L, giving respective positive predictive values of 31%, 20% and 8.6%. Positive predictive value for common variable immunodeficiency was 1.3%. We identified 12 new cases of common variable immunodeficiency, 10 new haematological disorders and 20 hypogammaglobulinaemias secondary to medication. Locally derived cut-offs are required as small differences between analysers have a significant effect on screen-positive rates. Conclusions Use of a 1st percentile globulin fraction improved early detection of hypogammaglobulinaemia. This is a useful adjunct to alert clinicians to unsuspected hypogammaglobulinaemia but should not replace immunoglobulin measurement. Patients with globulin fraction below the first percentile should be reviewed for possible hypogammaglobulinaemia.
Healthy Eyes in Schools: An evaluation of a school and community-based intervention to promote eye health in rural Timor-Leste
Authors: Hobday Karen , Ramke Jacqueline , du Toit Rènée , Pereira Sara M 
Published: July 2014

Objective: To assess whether there was an improvement in the knowledge, attitudes and practices of students after the Healthy Eyes in Schools Project intervention and to complete a process evaluation to inform future implementation of health promotion interventions. Design: A descriptive, mixed-methods design was used, including questionnaires and interviews. Setting: Four primary schools in Aileu District, Timor-Leste. Local teachers received training and resources to implement nine lessons about eye health. The intervention was supported in two schools by the concurrent creation of school gardens and improvements to the water and sanitation, where required. Method: Students from classes 5 and 6 participated: 384 students aged 10–17 years (median = 12 years, inter-quartile range = 12–13 years) completed the baseline knowledge, attitudes and practices survey and 237 students participated in a follow-up survey. Interviews with teachers, students and parents informed the process evaluation. Results: The intervention was associated with an improvement in eye health knowledge and some attitudes and practices of students. Attitudes about the capabilities of blind children and adults did not change. The teachers’ attitude and support from principals and an international non-governmental organisation appeared to be key factors in the successful implementation of the Healthy Eyes in Schools Project. The limited eye health in the existing curriculum, limited parent participation and access to healthy food may have influenced the effectiveness of the Healthy Eyes in Schools Project intervention. Conclusion: A number of benefits appeared to be associated with the inclusion of eye health topics in school health and hygiene education in Timor-Leste. Concurrent development of a supportive environment appeared to enable this initiative. The results of this evaluation can be used to advocate to the Ministries of Education and Health and other education stakeholders for the inclusion of eye health in the health and hygiene curriculum.
Radiation dose and mortality risk to children undergoing therapeutic interventional cardiology
Authors: Song Shanjun , Liu Chenzhi , Zhang Menglong 
Published: July 2014

Background Children undergoing interventional cardiology procedures deserve special concern due to the greater radiation sensitivity of their tissues and more remaining years of life during which a radiation-induced cancer may develop. Purpose To determine the patient radiation dose for pediatric therapeutic interventional cardiology and to estimate the patient effective dose and lifetime mortality risk to children associated with five common procedures. Material and Methods Ninety children with congenital heart defects undergoing interventional therapy were enrolled in this study. Data regarding fluoroscopy and radiography time, dose-area product (DAP) and peak skin dose (PSD) for each case were measured. Patients were divided into five groups. The patient effective dose (E) was calculated using a multiplicative model of ICRP 60. The overall lifetime mortality risk was evaluated using appropriate risk coefficients. Results The mean, median, standard deviation, and range of time, PSD, DAP, and E were presented for the five study groups. When these metrics were considered, there were wide variations for different cases within the same group and statistically significant differences between the five groups. The PSD correlated significantly with DAP (Pearson r = 0.70; P < 0.01), but the correlation in individual cases was poor. For all cases, the range of E was found to be between 0.44 and 66.7 mSv. The corresponding risk of lifetime mortality was 1.16 per thousand. Conclusion The current study provides overall data on the time, PSD, E, and lifetime mortality risk for pediatric therapeutic interventional cardiology. Radio frequency ablation showed the highest radiation risk.
New Approaches to Reduce Staphylococcus Aureus Nosocomial Infection Rates: Treating S. Aureus Nasal Carriage
Authors: Perl Trish M , Golub Jonathan E 
Published: July 2014

BACKGROUND: Nosocomial infections cause significant patient morbidity and mortality. The 2.5 million nosocomial infections that occur each year cost the US healthcare system $5 million to $10 million. Staphylococcus aureus has long been recognized as an important pathogen in human disease and is the most common cause of nosocomial infections. OBJECTIVE To describe the epidemiology of S. aureus nosocomial infections that are attributable to patients' endogenous colonization. DATA SOURCES Review of the English-language literature and a MEDLINE search (as of September 1997). DATA SYNTHESIS: The ecologic niche of S. aureus is the anterior nares. The prevalence of S. aureus nasal carriage is approximately 20–25%, but varies among different populations, and is influenced by age, underlying illness, race, certain behaviors, and the environment in which the person lives or works. The link between S. aureus nasal carriage and development of subsequent S. aureus infections has been established in patients on hemodialysis, on continuous ambulatory peritoneal dialysis, and those undergoing surgery. S. aureus nasal carriers have a two- to tenfold increased risk of developing S. aureus surgical site or intravenous catheter infections. Thirty percent to 100% of S. aureus infections are due to endogenous flora and infecting strains were genetically identical to nasal strains. Three treatment strategies may eliminate nasal carriage: locally applied antibiotics or disinfectants, systemic antibiotics, and bacterial interference. Among these strategies, locally applied or systemic antibiotics are most commonly used. Nasal ointments or sprays and oral antibiotics have variable efficacy and their use frequently results in antimicrobial resistance among S. aureus strains. Of the commonly used agents, mupirocin (pseudomonic acid) ointment has been shown to be 97% effective in reducing S. aureus nasal carriage. However, resistance occurs when the ointment has been applied for a prolonged period over large surface areas. CONCLUSIONS Given the importance of S. aureus nosocomial infections and the increased risk of S. aureus nasal carriage in patients with nosocomial infections, investigators need to study cost-effective strategies to prevent certain types of nosocomial infections or nosocomial infections that occur in specific settings. One potential strategy is to decrease S. aureus nasal carriage among certain patient populations.