bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men
Authors: Olesen Jesper , Gliemann Lasse , Biensø Rasmus , Schmidt Jakob , Hellsten Ylva , Pilegaard Henriette 
Published: February 2014

Key points
Ageing is associated with lifestyle‐related metabolic diseases, and exercise training has been suggested to counteract such metabolic deteriorations.
The natural antioxidant resveratrol has been reported to exert ‘exercise‐like’ health beneficial metabolic and anti‐inflammatory effects in rodents, but little is known about the metabolic effects of resveratrol supplementation alone and in combination with exercise training in humans.
The present findings showed that exercise training markedly improved muscle endurance, increased content and activity of oxidative proteins in skeletal muscle and reduced markers of oxidative stress and inflammation in skeletal muscle of aged men.
Resveratrol alone did not elicit metabolic effects in healthy aged subjects, but even impaired the exercise training‐induced improvements in markers of oxidative stress and inflammation in skeletal muscle.
AbstractThe aim was to investigate the metabolic and anti‐inflammatory effects of resveratrol alone and when combined with exercise training in skeletal muscle of aged human subjects. Healthy, physically inactive men (60–72 years old) were randomized to either 8 weeks of daily intake of 250 mg resveratrol or placebo or to 8 weeks of high‐intensity exercise training with 250 mg resveratrol or placebo. Before and after the interventions, resting blood samples and muscle biopsies were obtained and a one‐legged knee‐extensor endurance exercise test was performed. Exercise training increased skeletal muscle peroxisome proliferator‐activated receptor‐γ co‐activator‐1α mRNA ∼1.5‐fold, cytochrome c protein ∼1.3‐fold, cytochrome c oxidase I protein ∼1.5‐fold, citrate synthase activity ∼1.3‐fold, 3‐hydroxyacyl‐CoA dehydrogenase activity ∼1.3‐fold, inhibitor of κB‐α and inhibitor of κB‐β protein content ∼1.3‐fold and time to exhaustion in the one‐legged knee‐extensor endurance exercise test by ∼1.2‐fold, with no significant additive or adverse effects of resveratrol on these parameters. Despite an overall ∼25% reduction in total acetylation level in skeletal muscle with resveratrol, no exclusive resveratrol‐mediated metabolic effects were observed on the investigated parameters. Notably, however, resveratrol blunted an exercise training‐induced decrease (∼20%) in protein carbonylation and decrease (∼40%) in tumour necrosis factor α mRNA content in skeletal muscle. In conclusion, resveratrol did not elicit metabolic improvements in healthy aged subjects; in fact, resveratrol even impaired the observed exercise training‐induced improvements in markers of oxidative stress and inflammation in skeletal muscle. Collectively, this highlights the metabolic efficacy of exercise training in aged subjects and does not support the contention that resveratrol is a potential exercise mimetic in healthy aged subjects.
Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid
Authors: Boak Lauren M. , Rayner Craig R. , Grayson M. Lindsay , Paterson David L. , Spelman Denis , Khumra Sharmila , Capitano Blair , Forrest Alan , Li Jian , Nation Roger L. , Bulitta Jurgen B. 
Published: February 2014

ABSTRACT

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 ×10
9
/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.
Combination Prophylactic Therapy with Rifampin Increases Efficacy against an Experimental Staphylococcus epidermidis Subcutaneous Implant-Related Infection
Authors: Stavrakis Alexandra I. , Niska Jared A. , Shahbazian Jonathan H. , Loftin Amanda H. , Ramos Romela Irene , Billi Fabrizio , Francis Kevin P. , Otto Michael , Bernthal Nicholas M. , Uslan Daniel Z. , Miller Lloyd S. 
Published: February 2014

ABSTRACT

The incidence of infections related to cardiac devices (such as permanent pacemakers) has been increasing out of proportion to implantation rates. As management of device infections typically requires explantation of the device, optimal prophylactic strategies are needed. Cefazolin and vancomycin are widely used as single agents for surgical prophylaxis against cardiac device-related infections. However, combination antibiotic prophylaxis may further reduce infectious complications. To model a localized subcutaneous implant-related infection, a bioluminescent strain of
Staphylococcus epidermidis
was inoculated onto a medical-procedure-grade titanium disc, which was placed into a subcutaneous pocket in the backs of mice.
In vivo
bioluminescence imaging, quantification of
ex vivo
CFU from the capsules and implants, variable-pressure scanning electron microscopy (VP-SEM), and neutrophil enhanced green fluorescent protein (EGFP) fluorescence in LysEGFP mice were employed to monitor the infection. This model was used to evaluate the efficacies of low- and high-dose cefazolin (50 and 200 mg/kg of body weight) and vancomycin (10 and 110 mg/kg) intravenous prophylaxis with or without rifampin (25 mg/kg). High-dose cefazolin and high-dose vancomycin treatment resulted in almost complete bacterial clearance, whereas both low-dose cefazolin and low-dose vancomycin reduced the
in vivo
and
ex vivo
bacterial burden only moderately. The addition of rifampin to low-dose cefazolin and vancomycin was highly effective in further reducing the CFU harvested from the implants. However, vancomycin-rifampin was more effective than cefazolin-rifampin in further reducing the CFU harvested from the surrounding tissue capsules. Future studies in humans will be required to determine whether the addition of rifampin has improved efficacy in preventing device-related infections in clinical practice.
Mass Balance and Metabolite Profiling of Steady-State Faldaprevir, a Hepatitis C Virus NS3/4 Protease Inhibitor, in Healthy Male Subjects
Authors: Chen Lin-Zhi , Rose Peter , Mao Yanping , Yong Chan-Loi , St. George Roger , Huang Fenglei , Latli Bachir , Mandarino Debra , Li Yongmei 
Published: February 2014

ABSTRACT

The pharmacokinetics, mass balance, and metabolite profiles of faldaprevir, a selective peptide-mimetic hepatitis C virus NS3/NS4 protease inhibitor, were assessed at steady state in 7 healthy male subjects. Subjects received oral doses of 480 mg faldaprevir on day 1, followed by 240 mg faldaprevir on days 2 to 8 and 10 to 15. [
14
C]faldaprevir (240 mg containing 100 μCi) was administered on day 9. Blood, urine, feces, and saliva samples were collected at intervals throughout the study. Metabolite profiling was performed using radiochromatography, and metabolite identification was conducted using liquid chromatography-tandem mass spectrometry. The overall recovery of radioactivity was high (98.8%), with the majority recovered from feces (98.7%). There was minimal radioactivity in urine (0.113%) and saliva. Circulating radioactivity was predominantly confined to plasma with minimal partitioning into red blood cells. The terminal half-life of radioactivity in plasma was approximately 23 h with no evidence of any long-lasting metabolites. Faldaprevir was the predominant circulating form, accounting for 98 to 100% of plasma radioactivity from each subject. Faldaprevir was the only drug-related component detected in urine. Faldaprevir was also the major drug-related component in feces, representing 49.8% of the radioactive dose. The majority of the remainder of radioactivity in feces (41% of the dose) was accounted for in almost equal quantities by 2 hydroxylated metabolites. The most common adverse events were nausea, diarrhea, and constipation, all of which were related to study drug. In conclusion, faldaprevir is predominantly excreted in feces with negligible urinary excretion.
Carbapenemase-Producing Klebsiella pneumoniae Bloodstream Infections: Lowering Mortality by Antibiotic Combination Schemes and the Role of Carbapenems
Authors: Daikos George L. , Tsaousi Sophia , Tzouvelekis Leonidas S. , Anyfantis Ioannis , Psichogiou Mina , Argyropoulou Athina , Stefanou Ioanna , Sypsa Vana , Miriagou Vivi , Nepka Martha , Georgiadou Sarah , Markogiannakis Antonis , Goukos Dimitris , Skoutelis Athanasios 
Published: February 2014

ABSTRACT

Carbapenemase-producing
Klebsiella pneumoniae
strains (CP-Kps) are currently among the most important nosocomial pathogens. An observational study was conducted during 2009 to 2010 in two hospitals located in a high-prevalence area (Athens, Greece). The aims were (i) to evaluate the clinical outcome of patients with CP-Kp bloodstream infections (BSIs), (ii) to identify predictors of mortality, and (iii) to evaluate the various antibiotic schemes employed. A total of 205 patients with CP-Kp BSIs were identified: 163 (79.5%) were infected with KPC or KPC and VIM, and 42 were infected with VIM producers. For definitive treatment, 103 patients received combination therapy (two or more active drugs), 72 received monotherapy (one active drug), and 12 received therapy with no active drug. The remaining 18 patients died within 48 h after the onset of bacteremia. The all-cause 28-day mortality was 40%. A significantly higher mortality rate was observed in patients treated with monotherapy than in those treated with combination therapy (44.4% versus 27.2%;
P
= 0.018). The lowest mortality rate (19.3%) was observed in patients treated with carbapenem-containing combinations. In the Cox proportion hazards model, ultimately fatal disease (hazards ratio [HR], 3.25; 95% confidence interval [CI], 1.51 to 7.03;
P
= 0.003), the presence of rapidly fatal underlying diseases (HR, 4.20; 95% CI, 2.19 to 8.08;
P
< 0.001), and septic shock (HR, 2.15; 95% CI, 1.16 to 3.96;
P
= 0.015) were independent predictors of death. Combination therapy was strongly associated with survival (HR of death for monotherapy versus combination, 2.08; 95% CI, 1.23 to 3.51;
P
= 0.006), mostly due to the effectiveness of the carbapenem-containing regimens.
Metabolism of Cyclopropavir and Ganciclovir in Human Cytomegalovirus-Infected Cells
Authors: Gentry Brian G. , Drach John C. 
Published: February 2014

ABSTRACT

Human cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised patients. The current standard of therapy for the treatment of HCMV infections is ganciclovir (GCV). However, high incidence rates of adverse effects are prevalent and limit the use of this drug. Cyclopropavir (CPV) is 10-fold more effective against HCMV
in vitro
than GCV (50% effective concentrations [EC
50
s] = 0.46 and 4.1 μM, respectively) without any observed increase in cytotoxicity (S. Zhou, J. M. Breitenbach, K. Z. Borysko, J. C. Drach, E. R. Kern, E. Gullen, Y. C. Cheng, and J. Zemlicka, J. Med. Chem. 47:566–575, 2004, doi:10.1021/jm030316s). We have previously determined that the viral protein kinase pUL97 and endogenous cellular kinases are responsible for the conversion of CPV to a triphosphate (TP), the active compound responsible for inhibiting viral DNA synthesis and viral replication. However, this conversion has not been observed in HCMV-infected cells. To that end, we subjected HCMV-infected cells to equivalently effective concentrations (∼5 times the EC
50
) of either CPV or GCV and observed a time-dependent increase in triphosphate levels for both compounds (CPV-TP = 121 ± 11 pmol/10
6
cells; GCV-TP = 43.7 ± 0.4 pmol/10
6
cells). A longer half-life was observed for GCV-TP (48.2 ± 5.7 h) than for CPV-TP (23.8 ± 5.1 h). The area under the curve for CPV-TP produced from incubation with 2.5 μM CPV was 8,680 ± 930 pmol · h/10
6
cells, approximately 2-fold greater than the area under the curve for GCV-TP of 4,520 ± 420 pmol · h/10
6
cells produced from incubation with 25 μM GCV. We therefore conclude that the exposure of HCMV-infected cells to CPV-TP is greater than that of GCV-TP under these experimental conditions.
Outbreak Caused by NDM-1- and RmtB-Producing Escherichia coli in Bulgaria
Authors: Poirel Laurent , Savov Encho , Nazli Arzu , Trifonova Angelina , Todorova Iva , Gergova Ivanka , Nordmann Patrice 
Published: February 2014

ABSTRACT

Twelve consecutive carbapenem-resistant
Escherichia coli
isolates were recovered from patients (infection or colonization) hospitalized between March and September 2012 in different units at a hospital in Bulgaria. They all produced the carbapenemase NDM-1 and the extended-spectrum-β-lactamase CTX-M-15, together with the 16S rRNA methylase RmtB, conferring high-level resistance to all aminoglycosides. All those isolates were clonally related and belonged to the same sequence type, ST101. In addition to being the first to identify NDM-producing isolates in Bulgaria, this is the very first study reporting an outbreak of NDM-1-producing
E. coli
in the world.
Fluoroquinolone-Resistant Pneumococci: Dynamics of Serotypes and Clones in Spain in 2012 Compared with Those from 2002 and 2006
Authors: Domenech Arnau , Tirado-Vélez Jose M. , Fenoll Asunción , Ardanuy Carmen , Yuste Jose , Liñares Josefina , de la Campa Adela G. 
Published: February 2014

ABSTRACT

In Spain, rates of ciprofloxacin resistance in pneumococci were low during the last decade (2.6% in 2002 and 2.3% in 2006). In 2012, the rate remained at 2.3%, equivalent to 83 of 3,621 isolates. Of the 83 resistant isolates, 15 showed a low level (MIC of 4 to 8 μg/ml) and 68 a high level (MIC of 16 to 128 μg/ml) of ciprofloxacin resistance. Thirteen low-level-resistant isolates had single changes in ParC, one had a single ParE change, and one did not present any mutations. High-level-resistant isolates had GyrA changes plus additional ParC and/or ParE changes: 51, 15, and 2 isolates had 2, 3, or 4 mutations, respectively. Although 24 different serotypes were observed, 6 serotypes accounted for 51.8% of ciprofloxacin-resistant isolates: 8 (14.5%), 19A (10.8%), 11A (7.2%), 23A (7.2%), 15A (6.0%), and 6B (6.0%). A decrease in pneumococcal 7-valent conjugate vaccine (PCV7) serotypes was observed from 2006 (35.7%) to 2012 (16.9%), especially of serotype 14 (from 16.3% to 2.4%;
P
< 0.001). In comparison with findings in 2006, multidrug resistance was greater in 2012 (
P
= 0.296), mainly due to the increased presence and/or emergence of clonal complexes associated with non-PCV7 serotypes: CC63 expressing serotypes 8, 15A, and 19A; CC320 (with serotype 19A); and CC42 (with serotype 23A). Although rates of ciprofloxacin resistance remained low and stable throughout the last decade, changes in serotype and genotype distributions were observed in 2012, notably the expansion of a preexisting multidrug-resistant clone, CC63, and the emergence of the CC156 clone expressing serotype 11A.
3′-Nucleotidase/Nuclease Activity Allows Leishmania Parasites To Escape Killing by Neutrophil Extracellular Traps
Authors: Guimarães-Costa Anderson B. , DeSouza-Vieira Thiago S. , Paletta-Silva Rafael , Freitas-Mesquita Anita Leocádio , Meyer-Fernandes José Roberto , Saraiva Elvira M. 
Published: February 2014

ABSTRACT

Leishmaniasis is a widespread neglected tropical disease caused by parasites of the
Leishmania
genus. These parasites express the enzyme 3′-nucleotidase/nuclease (3′NT/NU), which has been described to be involved in parasite nutrition and infection. Bacteria that express nucleases escape the toxic effects of neutrophil extracellular traps (NETs). Hence, we investigated the role of 3′NT/NU in
Leishmania
survival of NET-mediated killing. Promastigotes of
Leishmania infantum
were cultured in high-phosphate (HP) or low-phosphate (LP) medium to modulate nuclease activity. We compared the survival of the two different groups of
Leishmania
during interaction with human neutrophils, assessing the role of neutrophil extracellular traps. As previously reported, we detected higher nuclease activity in parasites cultured in LP medium. Both LP and HP promastigotes were capable of inducing the release of neutrophil extracellular traps from human neutrophils in a dose- and time-dependent manner. LP parasites had 2.4 times more survival than HP promastigotes. NET disruption was prevented by the treatment of the parasites with ammonium tetrathiomolybdate (TTM), a 3′NT/NU inhibitor. Inhibition of 3′NT/NU by 3′-AMP, 5′-GMP, or TTM decreased promastigote survival upon interaction with neutrophils. Our results show that
Leishmania infantum
induces NET release and that promastigotes can escape NET-mediated killing by 3′-nucleotidase/nuclease activity, thus ascribing a new function to this enzyme.
Collapsed scrums and collision tackles: what is the injury risk?
Authors: Roberts Simon P , Trewartha Grant , England Mike , Stokes Keith A 
Published: February 2014

AimTo establish the propensity for specific contact events to cause injury in rugby union.MethodsMedical staff at participating English community-level rugby clubs reported any injury resulting in the absence for one match or more from the day of the injury during the 2009/2010 (n=46), 2010/2011 (n=67) and 2011/2012 (n=76) seasons. Injury severity was defined as the number of matches missed. Thirty community rugby matches were filmed and the number of contact events (tackles, collision tackles, rucks, mauls, lineouts and scrums) recorded.ResultsOf 370 (95% CI 364 to 378) contact events per match, 141 (137 to 145) were tackles, 115 (111 to 119) were rucks and 32 (30 to 33) were scrums. Tackles resulted in the greatest propensity for injury (2.3 (2.2 to 2.4) injuries/1000 events) and the greatest severity (16 (15 to 17) weeks missed/1000 events). Collision tackles (illegal tackles involving a shoulder charge) had a propensity for injury of 15 (12.4 to 18.3) injuries/1000 events and severity was 92 (75 to 112) weeks missed/1000 events, both of which were higher than any other event. Additional scrum analysis showed that only 5% of all scrums collapsed, but the propensity for injury was four times higher (2.9 (1.5 to 5.4) injuries/1000 events) and the severity was six times greater (22 (12 to 42) weeks missed/1000 events) than for non-collapsed scrums.ConclusionsInjury prevention in the tackle should focus on technique with strict enforcement of existing laws for illegal collision tackles. The scrum is a relatively controllable event and further attempts should be made to reduce the frequency of scrum collapse.
Association between population prevalence of smoking and incidence of meningococcal disease in Norway, Sweden, Denmark and the Netherlands between 1975 and 2009: a population-based time series analysis
Authors: Norheim Gunnstein , Sadarangani Manish , Omar Omar , Yu Ly-Mee , Mølbak Kåre , Howitz Michael , Olcén Per , Haglund Margaretha , van der Ende Arie , Pollard Andrew J 
Published: February 2014

ObjectiveTo investigate the relationship between the prevalence of smoking in the population and incidence of invasive meningococcal disease (IMD) among children under 5 years of age.DesignRetrospective, longitudinal, observational study. Poisson regression controlled for confounding factors.SettingNorway, Sweden, Denmark and the Netherlands between 1975 and 2009.PopulationTotal population of approximately 35 million people in these four countries.Data sourcesData were collected from the Ministries of Health, National Statistics Bureaus and other relevant national institutes.ResultsIn Norway, there was a significant positive relationship between the annual prevalence of daily smokers among individuals aged 25–49 years and the incidence of IMD in children under 5 years of age, unadjusted (RR=1.04–1.06, 95% CI 1.02 to 1.07, p<0.001) and after adjustment for time of year (quarter), incidence of influenza-like illness and household crowding (RR=1.05–1.07, 95% CI 1.03 to 1.09, p<0.001). Depending on age group, the risk of IMD increased by 5.2–6.9% per 1% increase in smoking prevalence among individuals aged 25–49 years in adjusted analyses. Using limited datasets from the three other countries, unadjusted analysis showed positive associations between IMD in children related to older smokers in Sweden and the Netherlands and negative associations related to younger smokers in Sweden. However, there were no demonstrable associations between incidence of IMD and prevalence of smoking, after adjustment for the same confounding variables.ConclusionsThe reduced incidence of IMD in Norway between 1975 and 2009 may partly be explained by the reduced prevalence of smoking during this period. High-quality surveillance data are required to confirm this in other countries. Strong efforts to reduce smoking in the whole population including targeted campaigns to reduce smoking among adults may have a role to play in the prevention of IMD in children.