bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells
Authors: Girard Richard M. B. M. , Crispim Marcell , Stolić Ivana , Damasceno Flávia Silva , Santos da Silva Marcelo , Pral Eizabeth Mieko Furusho , Elias Maria Carolina , Bajić Miroslav , Silber Ariel Mariano 
Published: July 2016

ABSTRACT

Trypanosoma cruzi
is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti-
T. cruzi
activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC
50
) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K
1
cells, exhibiting a 50% cytotoxic concentration (CC
50
) of 13.47 ± 0.37 μM and an IC
50
of 0.14 ± 0.12 μM against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 μM. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (<90). These data suggest that MB17 could be an interesting lead compound against
T. cruzi
.
Personalized Therapeutic Cocktail of Wild Environmental Phages Rescues Mice from Acinetobacter baumannii Wound Infections
Authors: Regeimbal James M. , Jacobs Anna C. , Corey Brendan W. , Henry Matthew S. , Thompson Mitchell G. , Pavlicek Rebecca L. , Quinones Javier , Hannah Ryan M. , Ghebremedhin Meron , Crane Nicole J. , Zurawski Daniel V. , Teneza-Mora Nimfa C. , Biswas Biswajit , Hall Eric R. 
Published: July 2016

ABSTRACT

Multidrug-resistant bacterial pathogens are an increasing threat to public health, and lytic bacteriophages have reemerged as a potential therapeutic option. In this work, we isolated and assembled a five-member cocktail of wild phages against
Acinetobacter baumannii
and demonstrated therapeutic efficacy in a mouse full-thickness dorsal infected wound model. The cocktail lowers the bioburden in the wound, prevents the spread of infection and necrosis to surrounding tissue, and decreases infection-associated morbidity. Interestingly, this effective cocktail is composed of four phages that do not kill the parent strain of the infection and one phage that simply delays bacterial growth
in vitro
via a strong but incomplete selection event. The cocktail here appears to function in a combinatorial manner, as one constituent phage targets capsulated
A. baumannii
bacteria and selects for loss of receptor, shifting the population to an uncapsulated state that is then sensitized to the remaining four phages in the cocktail. Additionally, capsule is a known virulence factor for
A. baumannii
, and we demonstrated that the emergent uncapsulated bacteria are avirulent in a
Galleria mellonella
model. These results highlight the importance of anticipating population changes during phage therapy and designing intelligent cocktails to control emergent strains, as well as the benefits of using phages that target virulence factors. Because of the efficacy of this cocktail isolated from a limited environmental pool, we have established a pipeline for developing new phage therapeutics against additional clinically relevant multidrug-resistant pathogens by using environmental phages sourced from around the globe.
Replacement of GroEL in Escherichia coli by the Group II Chaperonin from the Archaeon Methanococcus maripaludis
Authors: Shah Riddhi , Large Andrew T. , Ursinus Astrid , Lin Bevan , Gowrinathan Preethy , Martin Jörg , Lund Peter A. 
Published: July 2016

ABSTRACT

Chaperonins are required for correct folding of many proteins. They exist in two phylogenetic groups: group I, found in bacteria and eukaryotic organelles, and group II, found in archaea and eukaryotic cytoplasm. The two groups, while homologous, differ significantly in structure and mechanism. The evolution of group II chaperonins has been proposed to have been crucial in enabling the expansion of the proteome required for eukaryotic evolution. In an archaeal species that expresses both groups of chaperonins, client selection is determined by structural and biochemical properties rather than phylogenetic origin. It is thus predicted that group II chaperonins will be poor at replacing group I chaperonins. We have tested this hypothesis and report here that the group II chaperonin from
Methanococcus maripaludis
(Mm-cpn) can partially functionally replace GroEL, the group I chaperonin of
Escherichia coli
. Furthermore, we identify and characterize two single point mutations in Mm-cpn that have an enhanced ability to replace GroEL function, including one that allows
E. coli
growth after deletion of the
groEL
gene. The biochemical properties of the wild-type and mutant Mm-cpn proteins are reported. These data show that the two groups are not as functionally diverse as has been thought and provide a novel platform for genetic dissection of group II chaperonins.

IMPORTANCE
The two phylogenetic groups of the essential and ubiquitous chaperonins diverged approximately 3.7 billion years ago. They have similar structures, with two rings of multiple subunits, and their major role is to assist protein folding. However, they differ with regard to the details of their structure, their cofactor requirements, and their reaction cycles. Despite this, we show here that a group II chaperonin from a methanogenic archaeon can partially substitute for the essential group I chaperonin GroEL in
E. coli
and that we can easily isolate mutant forms of this chaperonin with further improved functionality. This is the first demonstration that these two groups, despite the long time since they diverged, still overlap significantly in their functional properties.
Characterization of Key Helicobacter pylori Regulators Identifies a Role for ArsRS in Biofilm Formation
Authors: Servetas Stephanie L. , Carpenter Beth M. , Haley Kathryn P. , Gilbreath Jeremy J. , Gaddy Jennifer A. , Merrell D. Scott 
Published: July 2016

ABSTRACTHelicobacter pylorimust be able to rapidly respond to fluctuating conditions within the stomach. Despite this need for constant adaptation,H. pyloriencodes few regulatory proteins. Of the identified regulators, the ferric uptake regulator (Fur), the nickel response regulator (NikR), and the two-component acid response system (ArsRS) are each paramount to the success of this pathogen. While numerous studies have individually examined these regulatory proteins, little is known about their combined effect. Therefore, we constructed a series of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS. A growth curve analysis revealed minor variation in growth kinetics across the strains; these were most pronounced in the triple mutant and in strains lacking ArsS. Visual analysis showed that strains lacking ArsS formed large aggregates and a biofilm-like matrix at the air-liquid interface. Biofilm quantification using crystal violet assays and visualization via scanning electron microscopy (SEM) showed that all strains lacking ArsS or containing a nonphosphorylatable form of ArsR (ArsR-D52N mutant) formed significantly more biofilm than the wild-type strain. Molecular characterization of biofilm formation showed that strains containing mutations in the ArsRS pathway displayed increased levels of cell aggregation and adherence, both of which are key to biofilm development. Furthermore, SEM analysis revealed prevalent coccoid cells and extracellular matrix formation in the ArsR-D52N, ΔnikRΔarsS, and ΔfurΔnikRΔarsSmutant strains, suggesting that these strains may have an exacerbated stress response that further contributes to biofilm formation. Thus,H. pyloriArsRS has a previously unrecognized role in biofilm formation.IMPORTANCEDespite a paucity of regulatory proteins, adaptation is key to the survival ofH. pyloriwithin the stomach. While prior studies have focused on individual regulatory proteins, such as Fur, NikR, and ArsRS, few studies have examined the combined effect of these factors. Analysis of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS revealed a previously unrecognized role for the acid-responsive two-component system ArsRS in biofilm formation.
Does well-child care education improve consultations and medication management for childhood fever and common infections? A systematic review
Authors: Peetoom Kirsten K B , Smits Jacqueline J M , Ploum Luc J L , Verbakel Jan Y , Dinant Geert-Jan , Cals Jochen W L 
Published: July 2016

BackgroundFever is common in preschool children and is often caused by benign self-limiting infections. Parents' lack of knowledge and fever phobia leads to high healthcare consumption.ObjectiveTo systematically review the effect of providing educational interventions about childhood fever and common infections in well-child clinics (WCCs), prior to illness episodes, on parental practices: healthcare-seeking behaviour (frequency of physician consultations, appropriateness of consultations) and medication management.DesignMedline, Embase, CINAHL, PsycINFO, Cochrane Library, Web of Science were searched. We included randomised controlled trials evaluating interventions in WCC settings focusing on educating parents prior to new illness episodes to improve parental practices during episodes of childhood fever and common infections. Data were extracted on study design, sample characteristics, type of intervention, outcome measures and results.ResultsEight studies were eligible for data extraction. Educating parents, in WCCs, prior to new episodes of childhood fever and common infections reduces daytime physician consultations of parents, home visits and telephone consultations, and enhances medication management. However, single and multicomponent interventions vary in effectiveness in reducing the frequency of daytime physician consultations and differ in their potential to reduce the number of home visits and general practitioner out-of-hours contacts. Only multicomponent interventions achieved a reduction in telephone consultations and improved medication management.ConclusionsEducating parents in WCCs prior to episodes of childhood fever and common infections showed potential to improve parental practices in terms of healthcare-seeking behaviour and medication management.
Medication usage, treatment intensification, and medical cost in patients with type 2 diabetes: a retrospective database study
Authors: Bonafede Machaon , Chandran Arthi , DiMario Stefan , Saltiel-Berzin Rita , Saliu Drilon 
Published: July 2016

ObjectiveThe goal of this study was to describe medication usage patterns in patients with type 2 diabetes mellitus (T2DM) initiating treatment with non-insulin antidiabetic drugs (NIADs), basal insulin, or prandial/mixed insulin using real-world data.Research design and methodsA retrospective analysis using the Truven Health MarketScan Research Databases was conducted to identify adults (≥18 years) with T2DM from 2006 to 2012. Patients were categorized into four cohorts based on diabetes treatment. Cohort 1 (n=597 664) consisted of newly diagnosed patients who did not receive any treatment, cohort 2 (n=342 511) included NIAD initiators, cohort 3 (n=99 578) included basal insulin initiators, and cohort 4 (n=62 876) included prandial/mixed insulin initiators. Patients transitioned out of a cohort once they met the criteria for the next one.ResultsPatients in cohort 2 were younger (56.2 years, SD±12.1) than patients in cohorts 1, 3, and 4 (58 years, SD±0.75). Metformin was the most commonly prescribed drug in cohort 2 patients. Basal insulin usage decreased from 71% in year 1 to 47% in year 4, in cohort 3 patients. Approximately one-third of these patients switched to prandial/mixed insulin each year. In cohort 4, the usage of prandial/mixed insulin decreased to 61% by year 4. Use of basal insulin and NIAD remained common in this group. Mean glycosylated hemoglobin (HbA1c) values decreased by ∼1% for each of the treatment cohorts following treatment initiation and remained stable during follow-up. All-cause and diabetes-related medical costs were highest for patients in cohorts 3 and 4.ConclusionsOverall, our findings demonstrate that treatment intensification was low in all study cohorts despite elevated HbA1c levels during preindex and follow-up period.
Prevalence of disability in Manikganj district of Bangladesh: results from a large-scale cross-sectional survey
Authors: Moniruzzaman Mohammad , Zaman M Mostafa , Mashreky Saidur Rahman , Rahman A K M Fazlur 
Published: July 2016

ObjectiveTo conduct a comprehensive survey on disability to determine the prevalence and distribution of cause-specific disability among residents of the Manikganj district in Bangladesh.MethodsThe survey was conducted in Manikganj, a typical district in Bangladesh, in 2009. Data were collected from 37 030 individuals of all ages. Samples were drawn from 8905 households from urban and rural areas proportionate to population size. Three sets of interviewer-administered questionnaires were used separately for age groups 0–1 years, 2–10 years and 11 years and above to collect data. For the age groups 0–1 years and 2–10 years, the parents or the head of the household were interviewed to obtain the responses. Impairments, activity limitations and restriction of participation were considered in defining disability consistent with the International Classification of Functioning, Disability and Health framework.ResultsOverall, age-standardised prevalence of disability per 1000 was 46.5 (95% CI 44.4 to 48.6). Prevalence was significantly higher among respondents living in rural areas (50.2; 95% CI 47.7 to 52.7) than in urban areas (31.0; 95% CI 27.0 to 35.0). Overall, female respondents had more disability (50.0; 95% CI 46.9 to 53.1) than male respondents (43.4; 95% CI 40.5 to 46.3). Educational deprivation was closely linked to higher prevalence of disability. Commonly reported prevalences (per 1000) for underlying causes of disability were 20.2 for illness, followed by 9.4 for congenital causes and 6.8 for injury, and these were consistent in males and females.ConclusionsDisability is a common problem in this typical district of Bangladesh, which is largely generalisable. Interventions at community level with special attention to the socioeconomically deprived are warranted.
Invasiveness of pharmacokinetic studies in children: a systematic review
Authors: Altamimi Mohammed I , Choonara Imti , Sammons Helen 
Published: July 2016

ObjectivesTo explore whether pharmacokinetic (PK) studies in paediatric patients are becoming less invasive. This will be evaluated by analysing the number of samples and volume of blood collected for each study within four different decades.MethodsA systematic literature review was performed to identify PK papers describing number of samples and volume of blood collected in studies of children aged 0–18 years. The following databases were searched: MEDLINE (1946 to December 2015), EMBASE (1974 to December 2015), International Pharmaceutical Abstracts (1970 to December 2015), CINAHL and Cochrane Library.ResultsA total of 549 studies were identified between 1974 and 2015. There were 52 studies between 1976 and 1985, 105 between 1986 and 1995, 201 between 1996 and 2005 and 191 between 2006 and 2015. The number of blood samples collected per participant increased between the first two decades (p=0.013), but there was a decrease in the number of samples in the subsequent two decades (p=0.044 and p<0.001, respectively). Comparing the first and last decades, there has been no change in the number of blood samples collected. There were no significant differences in volume collected per sample or total volume per child in any of the age groups. There was however a significant difference in the frequency of blood sampling between population PK studies (median 5 (IQR 3–7)) and non-population PK studies (median 8 (IQR 6–10); p=<0.001).ConclusionsThe number of blood samples collected for PK studies in children rose in 1985–1995 and subsequently declined. There was no overall change in the volume of blood collected over the 4 decades. The usage of population PK methods reduces the frequency of blood sampling in children.
Crew resource management training in the intensive care unit. A multisite controlled before–after study
Authors: Kemper Peter F , de Bruijne Martine , van Dyck Cathy , So Ralph L , Tangkau Peter , Wagner Cordula 
Published: July 2016

IntroductionThere is a growing awareness today that adverse events in the intensive care unit (ICU) are more often caused by problems related to non-technical skills than by a lack of technical, or clinical, expertise. Team training, such as crew resource management (CRM), aims to improve these non-technical skills. The present study evaluated the effectiveness of CRM in the ICU.MethodsSix ICUs participated in a paired controlled trial, with one pretest and two post-test measurements (after 3 and 12 months). Three ICUs received CRM training and were compared with a matched control unit. The 2-day classroom-based training was delivered to multidisciplinary groups (ie, ICU physicians, nurses, managers). All levels of Kirkpatrick's evaluation framework were assessed using a mixed method design, including questionnaires, observations and routinely administered patient outcome data.ResultsLevel I—reaction: participants were very positive directly after the training. Level II—learning: attitudes towards behaviour aimed at optimising situational awareness were relatively high at baseline and remained stable. Level III—behaviour: self-reported behaviour aimed at optimising situational awareness improved in the intervention group. No changes were found in observed explicit professional oral communication. Level IV—organisation: patient outcomes were unaffected. Error management culture and job satisfaction improved in the intervention group. Patient safety culture improved in both control and intervention units.ConclusionsWe can conclude that CRM, as delivered in the present study, does not change behaviour or patient outcomes by itself, yet changes how participants think about errors and risks. This indicates that CRM requires a combination with other initiatives in order to improve clinical outcomes.
Secular trends in physical fitness and body size in Lithuanian children and adolescents between 1992 and 2012
Authors: Venckunas Tomas , Emeljanovas Arunas , Mieziene Brigita , Volbekiene Vida 
Published: July 2016

Background and methodsThere is a paucity of data on contemporary secular trends on the different aspects of physical fitness in school-aged children and adolescents. This study presents the largest ever data set on changes in fitness between 1992, 2002 and 2012 for both genders of schoolchildren aged 11–18 years (n=16 199). Eurofit test battery was used to assess the balance, flexibility, muscular strength and power, agility and cardiorespiratory fitness. Anthropometrics were also measured and body mass index (BMI) was calculated.ResultsThe study has shown loss of flexibility, leg muscle power, upper body strength and cardiorespiratory fitness between 1992 and 2012, although there was an improvement in abdominal muscle strength in girls, agility in boys and balance in both genders during the same period. At large, negative trends in aspects of fitness seen between 1992 and 2002 have not slowed down between 2002 and 2012. Positive trends in agility and abdominal muscle strength seen before 2002 have regressed or were reversed between 2002 and 2012, while balance continued to improve at increased pace. While the BMI continued to increase in all groups, analysis of covariance has shown that it was not the main cause of changes in fitness.ConclusionsThe general decline in physical fitness in Lithuanian schoolchildren observed between 1992 and 2002 continued between 2002 and 2012, although some aspects of fitness showed a positive trend. If this general negative trend continues, it will compromise the well-being of future adults and create a serious economic burden on the society.
Effects of 12 Weeks of Atorvastatin Therapy on Myocardial Fibrosis and Circulating Fibrosis Biomarkers in Statin-NaïVe Patients with Hypertension with Atherosclerosis
Authors: Chang Yi-Yao , Wu Yen-Wen , Lee Jen-Kuang , Lin Yu-Min , Lin Yen-Ting , Kao Hsian-Li , Hung Chi-Sheng , Lin Hung-Ju , Lin Yen-Hung 
Published: July 2016

The purpose of this study was to assess the effects of 12 weeks of atorvastatin treatment on myocardial fibrosis in patients with hypertension with atherosclerosis. 15 statin-naïve participants (11 males; mean age 67±10 years) with atherosclerosis were given atorvastatin (40 mg/day) for 12 weeks and underwent echocardiography including ultrasonic tissue characterization by cyclic variation of integrated backscatter (CVIBS). Serum galectin-3 and fibrosis markers including aminoterminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-2, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also analyzed. After 12 weeks of atorvastatin (40 mg/day) treatment, serum total cholesterol and low-density lipoprotein cholesterol decreased significantly (204±31 to 140±24 mg/dL and 133±26 to 69±17 ng/mL, respectively, both p<0.001). In myocardial fibrosis analysis, CVIBS increased significantly (6.6±1.9 to 8.5±2.7 dB, p=0.024). In addition, the circulating fibrosis markers serum PIIINP and TIMP-1 decreased significantly (9.5±2.7 to 6.4±1.4 ng/mL, p=0.012 and 299±65 to 250±45 ng/mL, p=0.024, respectively). 12 weeks of medium dose atorvastatin treatment resulted in a significant reduction in myocardial fibrosis as evaluated by morphofunctional parameters and plasma markers of tissue fibrosis. Trial registration number NTC00172419; results.