bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-(
R
)-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium
Authors: Paredes Adriana , de Campos Lourenço Tiago , Marzal Miguel , Rivera Andrea , Dorny Pierre , Mahanty Siddhartha , Guerra-Giraldez Cristina , García Hector H. , Nash Theodore E. , Cass Quezia B. ,   the Cysticercosis Working Group in Peru
Published: December 2012

ABSTRACT

Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with
Taenia solium
cysts. However, drug levels of its active metabolite, albendazole sulfoxide (ABZSO), are erratic, likely resulting in decreased efficacy and suboptimal cure rates in NCC. Racemic albendazole sulfoxide is composed of ABZSO (+)-(
R
)- and (−)-(
S
) enantiomers that have been shown to differ in pharmacokinetics and activity against other helminths. The antiparasitic activities of racemic ABZSO and its (+)-(
R
)- and (−)-(
S
) enantiomers against
T. solium
cysts were evaluated
in vitro
. Parasites were collected from naturally infected pigs, cultured, and exposed to the racemic mixture or to each enantiomer (range, 10 to 500 ng/ml) or to praziquantel as a reference drug. The activity of each compound against cysts was assayed by measuring the ability to evaginate and inhibition of alkaline phosphatase (AP) and parasite antigen release. (+)-(
R
)-ABZSO was significantly more active than (−)-(
S
)-ABZSO in suppressing the release of AP and antigen into the supernatant in a dose- and time-dependent manner, indicating that most of the activity of ABZSO resides in the (+)-(
R
) enantiomer. Use of this enantiomer alone may lead to increased efficacy and/or less toxicity compared to albendazole.
Interactions of Oximino-Substituted Boronic Acids and β-Lactams with the CMY-2-Derived Extended-Spectrum Cephalosporinases CMY-30 and CMY-42
Authors: Kotsakis Stathis D. , Caselli Emilia , Tzouvelekis Leonidas S. , Petinaki Efi , Prati Fabio , Miriagou Vivi 
Published: December 2012

ABSTRACT
CMY-30 and CMY-42 are extended-spectrum (ES) derivatives of CMY-2. ES characteristics are due to substitutions of Gly (CMY-30) and Ser (CMY-42) for Val211 in the Ω-loop. To characterize the effects of 211 substitutions, we studied the interactions of CMY-2, -30, and -42 with boronic acid transition state inhibitors (BATSIs) resembling ceftazidime and cefotaxime, assessed thermal stability of the enzymes in their free forms and in complexes with BATSIs and oximino-β-lactams, and simulated, using molecular dynamics (MD), the CMY-42 apoenzyme and the CMY-42 complexes with ceftazidime and the ceftazidime-like BATSI. Inhibition constants showed that affinities between CMY-30 and CMY-42 and the R1 groups of BATSIs were lower than those of CMY-2. ES variants also exhibited decreased thermal stability either as apoenzymes or in covalent complexes with oximino compounds. MD simulations further supported destabilization of the ES variants. Val211Ser increased thermal factors of the Ω-loop backbone atoms, as previously observed for CMY-30. The similar effects of the two substitutions seemed to be due to a less-constrained Tyr221 likely inducing concerted movement of elements at the edges of the active site (Ω-loop–Q120 loop–R2 loop/H10 helix). This inner-protein movement, along with the wider R1 binding cleft, enabled intense vibrations of the covalently bound ceftazidime and ceftazidime-like BATSIs. Increased flexibility of the ES enzymes may assist the productive adaptation of the active site to the various geometries of the oximino substrates during the reaction (higher frequency of near-attack conformations).
Dissemination of a Carbapenem-Resistant Acinetobacter baumannii Strain Belonging to International Clone II/Sequence Type 2 and Harboring a Novel AbaR4-Like Resistance Island in Latvia
Authors: Saule Mara , Samuelsen Ørjan , Dumpis Uga , Sundsfjord Arnfinn , Karlsone Aija , Balode Arta , Miklasevics Edvins , Karah Nabil 
Published: December 2012

ABSTRACT

An outbreak of hospital-acquired
Acinetobacter baumannii
infections, caused by a
bla
OXA-23
-positive carbapenem-resistant strain belonging to international clone II/ST2, was detected in Latvia. The strain was partially equipped with the
armA
gene and the
intI1-aacA4-catB8-aadA1-qacE
Δ
1
class 1 integron. In addition, the strain carried AbaR25, a novel AbaR4-like resistance island of ∼46,500 bp containing structures similar to the previously described AbaR22 and Tn
6167
islands. AbaR25 was characterized by the occurrence of a second copy of Tn
6022a
interrupted by Tn
2006
carrying the
bla
OXA-23
gene.
Genetic Determinants of Intrinsic Colistin Tolerance in Acinetobacter baumannii
Authors: Hood M. Indriati , Becker Kyle W. , Roux Christelle M. , Dunman Paul M. , Skaar Eric P. 
Published: December 2012

ABSTRACTAcinetobacter baumanniiis a leading cause of multidrug-resistant infections worldwide. This organism poses a particular challenge due to its ability to acquire resistance to new antibiotics through adaptation or mutation. This study was undertaken to determine the mechanisms governing the adaptability ofA. baumanniito the antibiotic colistin. Screening of a transposon mutant library identified over 30 genes involved in inducible colistin resistance inA. baumannii. One of the genes identified waslpsB, which encodes a glycosyltransferase involved in lipopolysaccharide (LPS) synthesis. We demonstrate that loss of LpsB function results in increased sensitivity to both colistin and cationic antimicrobial peptides of the innate immune system. Moreover, LpsB is critical for pathogenesis in a pulmonary model of infection. Taken together, these data define bacterial processes required for intrinsic colistin tolerance inA. baumanniiand underscore the importance of outer membrane structure in both antibiotic resistance and the pathogenesis ofA. baumannii.
Active Escape of Orientia tsutsugamushi from Cellular Autophagy
Authors: Ko Youngho , Choi Ji-Hye , Ha Na-Young , Kim Ik-Sang , Cho Nam-Hyuk , Choi Myung-Sik 
Published: December 2012

ABSTRACT

Orientia tsutsugamushi
, the causative agent of scrub typhus, is an obligate intracellular pathogen. After entry into host cells, the bacterium rapidly escapes from the endosomal pathway and replicates in the cytosol of eukaryotic host cells. Here we show that
O. tsutsugamushi
infection efficiently promotes cellular autophagy, a cell-autonomous defense mechanism of innate immunity. However, most of the internalized bacteria barely colocalized with the induced autophagosomes, even when stimulated with rapamycin, a chemical inducer of autophagy. Treatment of infected cells with tetracycline suppressed bacterial evasion from autophagy and facilitated
O. tsutsugamushi
targeting to autophagosomes, suggesting that the intracellular pathogen may be equipped with a bacterial factor or factors that block autophagic recognition. Finally, we also found that chemical modulators of cellular autophagy or genetic knockout of the
atg3
gene does not significantly affect the intracellular growth of
O. tsutsugamushi
in vitro. These results suggest that
O. tsutsugamushi
has evolved to block autophagic microbicidal defense by evading autophagic recognition even though it activates the autophagy pathway during the early phase of infection.
Transcriptional Regulation of the
nadA
Gene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine
Authors: Fagnocchi Luca , Biolchi Alessia , Ferlicca Francesca , Boccadifuoco Giuseppe , Brunelli Brunella , Brier Sébastien , Norais Nathalie , Chiarot Emiliano , Bensi Giuliano , Kroll J. Simon , Pizza Mariagrazia , Donnelly John , Giuliani Marzia Monica , Delany Isabel 
Published: December 2012

ABSTRACT

The NadA adhesin is a major component of 4CMenB, a novel vaccine to prevent meningococcus serogroup B (MenB) infection. Under
in vitro
growth conditions,
nadA
is repressed by the regulator NadR and poorly expressed, resulting in inefficient killing of MenB strains by anti-NadA antibodies. Interestingly, sera from children infected with strains that express low levels of NadA in laboratory growth nevertheless recognize the NadA antigen, suggesting that NadA expression during infection may be different from that observed
in vitro
. In a strain panel covering a range of NadA levels, repression was relieved through deleting
nadR
. All
nadR
knockout strains expressed high levels of NadA and were efficiently killed by sera from subjects immunized with 4CMenB. A selected MenB strain, NGP165, mismatched for other vaccine antigens, is not killed by sera from immunized infants when the strain is grown
in vitro
. However, in an
in vivo
passive protection model, the same sera effectively protected infant rats from bacteremia with NGP165. Furthermore, we identify a novel hydroxyphenylacetic acid (HPA) derivative, reported by others to be produced during inflammation, which induces expression of NadA
in vitro
, leading to efficient antibody-mediated killing. Finally, using bioluminescent reporters,
nadA
expression in the infant rat model was induced
in vivo
at 3 h postinfection. Our results suggest that during infectious disease, NadR repression is alleviated due to niche-specific signals, resulting in high levels of NadA expression from any
nadA
-positive (
nadA
+
) strain and therefore efficient killing by anti-NadA antibodies elicited by the 4CMenB vaccine.
Carbon Storage Regulator A Contributes to the Virulence of Haemophilus ducreyi in Humans by Multiple Mechanisms
Authors: Gangaiah Dharanesh , Li Wei , Fortney Kate R. , Janowicz Diane M. , Ellinger Sheila , Zwickl Beth , Katz Barry P. , Spinola Stanley M. 
Published: December 2012

ABSTRACT

The carbon storage regulator A (CsrA) controls a wide variety of bacterial processes, including metabolism, adherence, stress responses, and virulence.
Haemophilus ducreyi
, the causative agent of chancroid, harbors a homolog of
csrA
. Here, we generated an unmarked, in-frame deletion mutant of
csrA
to assess its contribution to
H. ducreyi
pathogenesis. In human inoculation experiments, the
csrA
mutant was partially attenuated for pustule formation compared to its parent. Deletion of
csrA
resulted in decreased adherence of
H. ducreyi
to human foreskin fibroblasts (HFF); Flp1 and Flp2, the determinants of
H. ducreyi
adherence to HFF cells, were downregulated in the
csrA
mutant. Compared to its parent, the
csrA
mutant had a significantly reduced ability to tolerate oxidative stress and heat shock. The enhanced sensitivity of the mutant to oxidative stress was more pronounced in bacteria grown to stationary phase compared to that in bacteria grown to mid-log phase. The
csrA
mutant also had a significant survival defect within human macrophages when the bacteria were grown to stationary phase but not to mid-log phase. Complementation in
trans
partially or fully restored the mutant phenotypes. These data suggest that CsrA contributes to virulence by multiple mechanisms and that these contributions may be more profound in bacterial cell populations that are not rapidly dividing in the human host.
Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection
Authors: Kurtz Sherry L. , Foreman Oded , Bosio Catharine M. , Anver Miriam R. , Elkins Karen L. 
Published: December 2012

ABSTRACTWe employedFrancisella tularensislive vaccine strain (LVS) to study mechanisms of protective immunity against intracellular pathogens and, specifically, to understand protective correlates. One potential molecular correlate identified previously was interleukin-6 (IL-6), a cytokine with pleotropic roles in immunity, including influences on T and B cell functions. Given its role as an immune modulator and the correlation with successful anti-LVS vaccination, we examined the role IL-6 plays in the host response to LVS. IL-6-deficient (IL-6 knockout [KO]) mice infected with LVS intradermally or intranasally or anti-IL-6-treated mice, showed greatly reduced 50% lethal doses compared to wild-type (WT) mice. Increased susceptibility was not due to altered splenic immune cell populations during infection or decreased serum antibody production, as IL-6 KO mice had similar compositions of each compared to WT mice. Although LVS-infected IL-6 KO mice produced much less serum amyloid A and haptoglobin (two acute-phase proteins) than WT mice, there were no other obvious pathophysiological differences between LVS-infected WT and IL-6 KO mice. IL-6 KO or WT mice that survived primary LVS infection also survived a high-dose LVS secondary challenge. Using anin vitrooverlay assay that measured T cell activation, cytokine production, and abilities of primed splenocytes to control intracellular LVS growth, we found that IL-6 KO total splenocytes or purified T cells were slightly defective in controlling intracellular LVS growth but were equivalent in cytokine production. Taken together, IL-6 is an integral part of a successful immune response to primary LVS infection, but its exact role in precipitating adaptive immunity remains elusive.
Significant and serious dehydration does not affect skeletal muscle cramp threshold frequency
Authors: Braulick Kyle W , Miller Kevin C , Albrecht Jay M , Tucker Jared M , Deal James E 
Published: December 2012

ObjectiveMany clinicians believe that exercise-associated muscle cramps (EAMC) occur because of dehydration. Experimental research supporting this theory is lacking. Mild hypohydration (3% body mass loss) does not alter threshold frequency (TF), a measure of cramp susceptibility, when fatigue and exercise intensity are controlled. No experimental research has examined TF following significant (3–5% body mass loss) or serious hypohydration (>5% body mass loss). Determine if significant or serious hypohydration, with moderate electrolyte losses, decreases TF.DesignA prepost experimental design was used. Dominant limb flexor hallucis brevis cramp TF, cramp electromyography (EMG) amplitude and cramp intensity were measured in 10 euhydrated, unacclimated men (age=24±4 years, height=184.2±4.8 cm, mass=84.8±11.4 kg). Subjects alternated exercising with their non-dominant limb or upper body on a cycle ergometer every 15 min at a moderate intensity until 5% body mass loss or volitional exhaustion (3.8±0.8 h; 39.1±1.5°C; humidity 18.4±3%). Cramp variables were reassessed posthypohydration.ResultsSubjects were well hydrated at the study's onset (urine specific gravity=1.005±0.002). They lost 4.7±0.5% of their body mass (3.9±0.5 litres of fluid), 4.0±1.5 g of Na+and 0.6±0.1 g K+via exercise-induced sweating. Significant (n=5) or serious hypohydration (n=5) did not alter cramp TF (euhydrated=15±5 Hz, hypohydrated=13±6 Hz; F1,9=3.0, p=0.12), cramp intensity (euhydrated= 94.2±41%, hypohydrated=115.9±73%; F1,9=1.9, p=0.2) or cramp EMG amplitude (euhydrated=0.18±0.06 µV, hypohydrated= 0.18±0.09 µV; F1,9=0.1, p=0.79).ConclusionsSignificant and serious hypohydration with moderate electrolyte losses does not alter cramp susceptibility when fatigue and exercise intensity are controlled. Neuromuscular control may be more important in the onset of muscle cramps than dehydration or electrolyte losses.
Simulation training for improving the quality of care for older people: an independent evaluation of an innovative programme for inter-professional education
Authors: Ross Alastair J , Anderson Janet E , Kodate Naonori , Thomas Libby , Thompson Kellie , Thomas Beth , Key Suzie , Jensen Heidi , Schiff Rebekah , Jaye Peter 
Published: December 2012

IntroductionThis paper describes the evaluation of a 2-day simulation training programme for staff designed to improve teamwork and inpatient care and compassion in an older persons’ unit.ObjectiveThe programme was designed to improve inpatient care for older people by using mixed modality simulation exercises to enhance teamwork and empathetic and compassionate care.MethodsHealthcare professionals took part in: (a) a 1-day human patient simulation course with six scenarios and (b) a 1-day ward-based simulation course involving five 1-h exercises with integrated debriefing. A mixed methods evaluation included observations of the programme, precourse and postcourse confidence rating scales and follow-up interviews with staff at 7–9 weeks post-training.ResultsObservations showed enjoyment of the course but some anxiety and apprehension about the simulation environment. Staff self-confidence improved after human patient simulation (t=9; df=56; p<0.001) and ward-based exercises (t=9.3; df=76; p<0.001). Thematic analysis of interview data showed learning in teamwork and patient care. Participants thought that simulation had been beneficial for team practices such as calling for help and verbalising concerns and for improved interaction with patients.Areas to address in future include widening participation across multi-disciplinary teams, enhancing post-training support and exploring further which aspects of the programme enhance compassion and care of older persons.ConclusionsThe study demonstrated that simulation is an effective method for encouraging dignified care and compassion for older persons by teaching team skills and empathetic and sensitive communication with patients and relatives.
Family witnessed resuscitation: nationwide survey of 337 prehospital emergency teams in France
Authors: Belpomme Vanessa , Adnet Frederic , Mazariegos Ixchel , Beardmore Matt , Duchateau François-Xavier , Mantz Jean , Ricard-Hibon Agnes 
Published: December 2012

ObjectiveTo assess the practices and opinions of prehospital emergency medical services (EMS) with regard to family witnessed resuscitation (FWR) and to analyse the differences between physicians’ and nurses’ responses.DesignAn anonymous questionnaire (30 yes/no questions on demographics and FWR) was sent to all prehospital emergency staff (physicians, nurses and support staff) working for the 377 Mobile Intensive Care Units in France.ResultsOf the 2689 responses received 2664 were analysed. Mean respondent age was 38±8 years, the male to female ratio was 1:2. 87% of respondents had already performed FWR and 38% had offered relatives the option to be present during resuscitation. Most respondents (90%) felt that FWR might cause psychological trauma to the family; 70% thought that FWR might impact on the duration of resuscitation and 68% on EMS team concentration. In the 28% of cases when relatives had asked to be present, 59% of respondents had acquiesced but only 27% were willing to invite relatives to be routinely present.ConclusionsPrehospital EMS teams in France seems to support FWR but are not yet ready to offer it systematically to relatives. Following our survey, written guidelines are currently in development in our department. These guidelines could be the first step of a national strategy for developing FWR in France. We await results from other studies of family members’ opinions to compare prehospital practitioners’ and family members’ views to further develop our practice.
A descriptive analysis of patients with an emergency department diagnosis of acute pericarditis
Authors: Hooper Andrew J , Celenza Antonio 
Published: December 2012

AimTo describe clinical characteristics, assessment and treatment of patients diagnosed in an emergency department (ED) with acute pericarditis.MethodsA medical record review of patients with an ED diagnosis of pericarditis conducted in an adult tertiary hospital over a 5-year period. Variables collected included pain characteristics, associated symptoms, physical examination findings, investigation results, ED treatment and disposition.Results179 presentations were included, with 73.9% men and a mean age of 38.8 years. The majority of patients described pleuritic chest pain worse with inspiration with half characterising the pain as sharp or stabbing, with others describing tightness, dullness or cramping. Radiation to the left shoulder occurred in 2.8% and change of pain with posture occurred in 46.4%. A pericardial rub was documented in 19 presentations. All patients had an ECG recorded with ST segment elevation present in 69.3% and PR segment depression in 49.2%. Nearly 90% of patients had troponin testing but only 6.4% of these were positive. Only 8.1% of cases were treated with colchicine. No patients required pericardiocentesis. Patients with high-risk factors were more likely to have previous pericarditis, dyspnoea, nausea, abnormal investigation results, treatment with colchicine and admission to hospital. However, 16.9% of patients without risk factors were admitted, and 46.9% of patients with at least one risk factor were discharged.ConclusionsPericarditis may not follow the classical clinical description. Admission and discharge decisions appear to relate to individual clinical characteristics rather than known risk factors. Use of colchicine for treatment in ED is infrequent.
Comparison of the costs of care during acute illness by two community children's nursing teams
Authors: Callery Peter , Kyle Richard G , Weatherly Helen , Banks Michele , Ewing Carol , Powell Peter , Kirk Susan 
Published: December 2012

ObjectiveTo compare the costs associated with care by two community children's nursing teams (CCNT).DesignA case study incorporating questionnaire survey, analysis of routinely collected data and analysis of costs in the north-west England.PatientsChildren with acute illness referred for CCNT care.InterventionsTwo CCNT provided care for 273 children during acute illness in order to reduce the number and duration of hospital admissions.Main Outcome MeasuresCosts of CCNT, other services and costs to families.ResultsThe objectives of both CCNT included shortening and avoiding hospitalisations. Most (45 (58%) in case A and 150 (77%) in case B) children were referred for infections. There were differences in the proportion of children who had been hospitalised (45 (57.7%) and 78 (40%)), the mean number of services used before referral to CCNT (1.6 and 2.2) and the staffing profile of the CCNT. There was a statistically significant difference in the overall mean cost to the NHS of CCNT care (£146 and £238, 95% CI for difference of means 7 to 184), associated with higher proportions of children having telephone-only contact (two (3%) and 46 (24%)) and children using almost twice as many other health services during care by one CCNT (means 0.27 and 0.51).ConclusionsCosts of CCNT care can vary widely when all health service use is taken into account. Differences in the way CCNT are integrated with the urgent care system, and the way in which CCNT care is organised, could contribute to variations in costs.