bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum levels of desacyl ghrelin in patients with schizophrenia on clozapine monotherapy
Authors: Wysokiński Adam , Kowalski Marek L. , Kłoszewska Iwona 
Published: April 2014

AimDesacyl ghrelin is a hormone that might be a functional inhibitor of ghrelin, a potent hunger‐stimulating peptide.MethodsWe determined fasting serum desacyl ghrelin levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age‐ and sex‐matched controls. Biochemical and anthropometric measurements were combined with body composition determined using bioelectric impedance analysis.ResultsThere were no differences in desacyl ghrelin levels between patients taking clozapine and the control group (272.09 ± 137.96 vs 259.62 ± 140.91 pg/mL, z = 0.17, P = 0.87). In the clozapine group, there were no differences between men and women for ghrelin levels (246.66 ± 123.17 vs 295.39 ± 151.77 pg/mL, z = −0.98, P = 0.32). In the clozapine group, fasting serum levels of ghrelin negatively correlated with waist‐to‐hip ratio (WHR) (r = −0.45, P = 0.03) and ionized calcium (r = −0.45, P = 0.03). Levels of ghrelin were lower in patients with WHR above World Health Organization‐defined cut‐off points (246.84 ± 114.34 [Q1 = 152.18, Q2 = 220.92, Q3 = 327.85] vs 400.30 ± 123.36 [Q1 = 283.73, Q2 = 414.03, Q3 = 485.8] pg/mL, z = 2.52, P = 0.01). In the clozapine group, there were no correlation with age, height, weight, body mass index, abdominal circumference, waist circumference, hip circumference, WHR, blood pressure, total cholesterol, high‐density lipoproteins, low‐density lipoproteins, triglycerides, uric acid, homocysteine, glucose, insulin, clozapine dose, duration of treatment with antipsychotics, duration of treatment with clozapine, total fat, target fat, basal metabolic rate, target weight, lean weight, body water, homoeostasis model assessment of insulin resistance (HOMA) 1‐IR, HOMA2‐IR and quantitative insulin sensitivity check index.ConclusionBased on our results, we cannot conclude that treatment with clozapine affects levels of desacyl ghrelin. Also, in our study population we did not confirm previously described associations between desacyl ghrelin and various metabolic parameters.
Photooxidation of Tetrahydrobiopterin under UV Irradiation: Possible Pathways and Mechanisms
Authors: Buglak Andrey A. , Telegina Taisiya A. , Lyudnikova Tamara A. , Vechtomova Yulia L. , Kritsky Mikhail S. 
Published: April 2014

AbstractTetrahydrobiopterin (H4Bip) is a cofactor for several key enzymes, including NO synthases and aromatic amino acid hydroxylases (AAHs). Normal functioning of the H4Bip regeneration cycle is extremely important for the work of AAHs. Oxidized pterins may accumulate if the H4Bip regeneration cycle is disrupted or if H4Bip autoxidation occurs. These oxidized pterins can photosensitize the production of singlet molecular oxygen 1O2 and thus cause oxidative stress. In this context, we studied the photooxidation of H4Bip in phosphate buffer at pH 7.2. We found that UV irradiation of H4Bip affected its oxidation rate (quantum yield Φ300 = (2.7 ± 0.4) × 10−3). The effect of UV irradiation at λ = 350 nm on H4Bip oxidation was stronger, especially in the presence of biopterin (Bip) (Φ350 = (9.7 ± 1.5) × 10−3). We showed that the rate of H4Bip oxidation linearly depends on Bip concentration. Experiments with KI, a selective quencher of triplet pterins at micromolar concentrations, demonstrated that the oxidation is sensitized by the triplet state biopterin 3Bip. Apparently, electron transfer sensitization (Type‐I mechanism) is dominant. Energy transfer (Type‐II mechanism) and singlet oxygen generation play only a secondary role. The mechanisms of H4Bip photooxidation and their biological meaning are discussed.
The Lifeworlds of Organic and Conventional Farmers in Central‐southern England: A Phenomenological Enquiry
Authors: Kings David , Ilbery Brian 
Published: April 2014

AbstractLittle comparative research has investigated the ‘lifeworlds’ of organic and conventional farmers. Using phenomenology, this article explores and describes the ‘lifeworlds’ of farmers in central‐southern England with the aim of identifying their understandings and experiences in relation to their choice of farming system. On‐farm ‘lifeworld’ interviews and observations (examined in terms of movement, rest and encounter) showed that, in contrast to conventional farmers, organic farmers often have less tidy farms, perceive the farm and ‘natural’ environment as one and the same, place more importance on their dwelling and experience greater feelings of isolation. Most of the organic respondents' understandings of farming were more closely linked to the ‘natural’ environment, biodiversity and agricultural sustainability than the conventional farmers, whose agricultural understandings were often concerned with creating pheasant cover and providing ‘good environments’ for foxes.
Regulation of Personal Social Services – TheIsraeli Experience
Authors: Lahat Lihi , Talit Gal 
Published: April 2014

AbstractThe current article explores the aspects of regulatory policy in the field of personal social services. InIsrael, the government sets standards, and finances and oversees personal social services, while the services themselves are provided primarily by non‐governmental organizations. Based on a qualitative study we examined two questions. First, what characterizes the implementation of regulatory mechanisms in the field of personal social services inIsrael? Second, how can we explain the outcomes of regulation in the personal social services inIsrael? In a unique approach, we used the institutional analysis and development (IAD) framework to explore the regulatory practices implemented in community residences and hostels for people with intellectual disabilities and in after school programmes. The findings revealed that although there were implementation gaps in both cases, theIADmight improve our understanding of the nature and magnitude of these gaps. Furthermore, the insights gained may have implications for policymakers in their development of regulatory policy.
Soil dispersion tests combined with topographical information can describe field‐scale sediment and phosphorus losses
Authors: Villa A. , Djodjic F. , Bergström L. 
Published: April 2014

AbstractMethods for estimating sediment and phosphorus (P) transfer from agricultural land to surface waters are needed to mitigate their adverse impact on water quality. This study quantified sediment and P losses from five agricultural fields and evaluated the patterns observed based on the intrinsic risk of sediment and P mobilization from the soil, together with field topographical and hydrological data. The mobilization risk was estimated using the environmental soil dispersion test DESPRAL. High‐resolution LiDAR elevation data and crop management data were used to describe transport and delivery of the material mobilized. Annual flow‐weighted suspended solids (SS) concentration in drainage water ranged from 48 to 374 mg/L, total P (TP) from 0.12 to 0.39 mg/L and unreactive P (UP) from 0.08 to 0.33 mg/L. The mobilization risk, measured as turbidity in the aliquot recovered from the dispersion test, varied from 781 to 2310 nephelometric turbidity units (NTU). The method proved to be efficient in describing and differentiating sediment and P mobilization potential between fields. The topographical data also showed large differences between fields, with the length–slope (LS) parameter varying from 0.037 to 0.999. Based on assessments of source (mobilization risk) and transport factors (LS, crop management data), it was possible to characterize fields as favoured or limited in terms of source and transport and to explain the long‐term SS and P losses observed at field scale.
Phasevarions Mediate Epigenetic Regulation of Antimicrobial Susceptibility in Neisseria meningitidis
Authors: Jen Freda E.-C. , Seib Kate L. , Jennings Michael P. 
Published: April 2014

ABSTRACT

Phase variation is a common feature of host-adapted bacterial pathogens such as
Neisseria meningitidis
. Recently, we reported that this rapid on/off switching of gene expression occurs in DNA methyltransferases, altering expression in multiple genes via changes in global methylation. In the current study, we compared MIC values of strains with ModA11, ModA12, and ModD1 phasevarions, revealing MIC differences due to ModA11 and ModA12 switching, with a ModA11_OFF strain showing 4-fold reduced susceptibilities to ceftazidime and ciprofloxacin.
The Broad-Spectrum Antiviral Compound ST-669 Restricts Chlamydial Inclusion Development and Bacterial Growth and Localizes to Host Cell Lipid Droplets within Treated Cells
Authors: Sandoz Kelsi M. , Valiant William G. , Eriksen Steven G. , Hruby Dennis E. , Allen Robert D. , Rockey Daniel D. 
Published: April 2014

ABSTRACT

Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium
Coxiella burnetii
in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-
C. burnetii
activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process.
Benefits of a Pharmacology Antimalarial Reference Standard and Proficiency Testing Program Provided by the Worldwide Antimalarial Resistance Network (WWARN)
Authors: Lourens Chris , Lindegardh Niklas , Barnes Karen I. , Guerin Philippe J. , Sibley Carol H. , White Nicholas J. , Tarning Joel 
Published: April 2014

ABSTRACT

Comprehensive assessment of antimalarial drug resistance should include measurements of antimalarial blood or plasma concentrations in clinical trials and in individual assessments of treatment failure so that true resistance can be differentiated from inadequate drug exposure. Pharmacometric modeling is necessary to assess pharmacokinetic-pharmacodynamic relationships in different populations to optimize dosing. To accomplish both effectively and to allow comparison of data from different laboratories, it is essential that drug concentration measurement is accurate. Proficiency testing (PT) of laboratory procedures is necessary for verification of assay results. Within the Worldwide Antimalarial Resistance Network (WWARN), the goal of the quality assurance/quality control (QA/QC) program is to facilitate and sustain high-quality antimalarial assays. The QA/QC program consists of an international PT program for pharmacology laboratories and a reference material (RM) program for the provision of antimalarial drug standards, metabolites, and internal standards for laboratory use. The RM program currently distributes accurately weighed quantities of antimalarial drug standards, metabolites, and internal standards to 44 pharmacology,
in vitro
, and drug quality testing laboratories. The pharmacology PT program has sent samples to eight laboratories in four rounds of testing. WWARN technical experts have provided advice for correcting identified problems to improve performance of subsequent analysis and ultimately improved the quality of data. Many participants have demonstrated substantial improvements over subsequent rounds of PT. The WWARN QA/QC program has improved the quality and value of antimalarial drug measurement in laboratories globally. It is a model that has potential to be applied to strengthening laboratories more widely and improving the therapeutics of other infectious diseases.
Ceftobiprole Activity against over 60,000 Clinical Bacterial Pathogens Isolated in Europe, Turkey, and Israel from 2005 to 2010
Authors: Farrell David J. , Flamm Robert K. , Sader Helio S. , Jones Ronald N. 
Published: April 2014

ABSTRACT

Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the
in vitro
antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible
Staphylococcus aureus
(MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and
Streptococcus pneumoniae
(99.3% susceptible), with MIC
90
values of 0.25, 0.12, ≤0.06, and 0.5 μg/ml, respectively. Ceftobiprole was active against methicillin-resistant
S. aureus
(MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC
90
of 2 μg/ml. Ceftobiprole was active against
Enterococcus faecalis
(MIC
50/90
, 0.5/4 μg/ml) but not against most
Enterococcus faecium
isolates. Ceftobiprole was very potent against the majority of
Enterobacteriaceae
(87.3% susceptible), with >80% inhibited at ≤0.12 μg/ml. The potency of ceftobiprole against
Pseudomonas aeruginosa
(MIC
50/90
, 2/>8 μg/ml; 64.6% at MIC values of ≤4 μg/ml) was similar to that of ceftazidime (MIC
50/90
, 2/>16 μg/ml; 75.4% susceptible), but limited activity was observed against
Acinetobacter
spp. and
Stenotrophomonas maltophilia
. High activity was also observed against all
Haemophilus influenzae
(MIC
90
, ≤0.06 μg/ml) and
Moraxella catarrhalis
(MIC
50/90
, ≤0.06/0.25 μg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens.
Validation of Antibiotic Susceptibility Testing Guidelines in a Routine Clinical Microbiology Laboratory Exemplifies General Key Challenges in Setting Clinical Breakpoints
Authors: Hombach Michael , Courvalin Patrice , Böttger Erik C. 
Published: April 2014

ABSTRACT
This study critically evaluated the new European Committee for Antimicrobial Susceptibility Testing (EUCAST) antibiotic susceptibility testing guidelines on the basis of a large set of disk diffusion diameters determined for clinical isolates. We report several paradigmatic problems that illustrate key issues in the selection of clinical susceptibility breakpoints, which are of general importance not only for EUCAST but for all guidelines systems, i.e., (i) the need for species-specific determinations of clinical breakpoints/epidemiological cutoffs (ECOFFs), (ii) problems arising from pooling data from various sources, and (iii) the importance of the antibiotic disk content for separating non-wild-type and wild-type populations.
Pharmacological Study of Cefoxitin as an Alternative Antibiotic Therapy to Carbapenems in Treatment of Urinary Tract Infections Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli
Authors: Guet-Revillet H. , Emirian A. , Groh M. , Nebbad-Lechani B. , Weiss E. , Join-Lambert O. , Bille E. , Jullien V. , Zahar J. R. 
Published: April 2014

ABSTRACT

Cefoxitin could be an alternative to carbapenems in extended-spectrum-beta-lactamase-producing
Escherichia coli
(ESBL-EC) infections. However, pharmacological and clinical data regarding cefoxitin are limited. Using a recent pharmacological model and the MICs of ESBL-EC collected from pyelonephritis, we determined the probabilities to reach four pharmacological targets: free cefoxitin concentrations above the MIC during 50% and 100% of the administration interval (T>MIC = 50% and T>MIC = 100%, respectively) and free cefoxitin concentrations above 4× MIC during 50% and 100% of the administration interval (T>4MIC = 50% and T>4MIC = 100%, respectively). Cefoxitin could be used to treat ESBL-EC pyelonephritis, but administration modalities should be optimized according to MICs in order to reach pharmacological targets.
Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics
Authors: North Thomas W. , Villalobos Andradi , Hurwitz Selwyn J. , Deere Jesse D. , Higgins Joanne , Chatterjee Payel , Tao Sijia , Kauffman Robert C. , Luciw Paul A. , Kohler James J. , Schinazi Raymond F. 
Published: April 2014

ABSTRACTUsing an established nonhuman primate model, rhesus macaques were infected intravenously with a chimeric simian immunodeficiency virus (SIV) consisting of SIVmac239with the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase from clone HXBc2 (RT-SHIV). The impacts of two enhanced (four- and five-drug) highly active antiretroviral therapies (HAART) on early viral decay and rebound were determined. The four-drug combination consisted of an integrase inhibitor, L-870-812 (L-812), together with a three-drug regimen comprising emtricitabine [(−)-FTC], tenofovir (TFV), and efavirenz (EFV). The five-drug combination consisted of one analog for each of the four DNA precursors {using TFV, (−)-FTC, (−)-β-d-(2R,4R)-1,3-dioxolane-2,6-diaminopurine (amdoxovir [DAPD]), and zidovudine (AZT)}, together with EFV. A cohort treated with a three-drug combination of (−)-FTC, TFV, and EFV served as treated controls. Daily administration of a three-, four-, or five-drug combination of antiretroviral agents was initiated at week 6 or 8 after inoculation and continued up to week 50, followed by a rebound period. Plasma samples were collected routinely, and drug levels were monitored using liquid chromatography-tandem mass spectrometry (LC–MS-MS). Viral loads were monitored with a standard TaqMan quantitative reverse transcriptase PCR (qRT-PCR) assay. Comprehensive analyses of replication dynamics were performed. RT-SHIV infection in rhesus macaques produced typical viral infection kinetics, with untreated controls establishing persistent viral loads of >104copies of RNA/ml. RT-SHIV loads at the start of treatment (V0) were similar in all treated cohorts (P> 0.5). All antiretroviral drug levels were measureable in plasma. The four-drug and five-drug combination regimens (enhanced HAART) improved suppression of the viral load (within 1 week;P< 0.01) and had overall greater potency (P< 0.02) than the three-drug regimen (HAART). Moreover, rebound viremia occurred rapidly following cessation of any treatment. The enhanced HAART (four- or five-drug combination) showed significant improvement in viral suppression compared to the three-drug combination, but no combination was sufficient to eliminate viral reservoirs.
Characterization of a Respiratory Syncytial Virus L Protein Inhibitor
Authors: Tiong-Yip Choi-Lai , Aschenbrenner Lisa , Johnson Kenneth D. , McLaughlin Robert E. , Fan Jun , Challa SreeRupa , Xiong Hui , Yu Qin 
Published: April 2014

ABSTRACT
The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function.
A Low-Affinity Penicillin-Binding Protein 2x Variant Is Required for Heteroresistance in Streptococcus pneumoniae
Authors: Engel Hansjürg , Mika Moana , Denapaite Dalia , Hakenbeck Regine , Mühlemann Kathrin , Heller Manfred , Hathaway Lucy J. , Hilty Markus 
Published: April 2014

ABSTRACT

Heteroresistance to penicillin in
Streptococcus pneumoniae
is the ability of subpopulations to grow at a higher antibiotic concentration than expected from the MIC. This may render conventional resistance testing unreliable and lead to therapeutic failure. We investigated the role of the primary β-lactam resistance determinants, penicillin-binding protein 2b (PBP2b) and PBP2x, and the secondary resistance determinant PBP1a in heteroresistance to penicillin. Transformants containing PBP genes from the heteroresistant strain Spain
23F
2349
in the nonheteroresistant strain R6 background were tested for heteroresistance by population analysis profiling (PAP). We found that
pbp2x
, but not
pbp2b
or
pbp1a
alone, conferred heteroresistance to R6. However, a change of
pbp2x
expression was not observed, and therefore, expression does not correlate with an increased proportion of resistant subpopulations. In addition, the influence of the CiaRH system, mediating PBP-independent β-lactam resistance, was assessed by PAP on
ciaR
disruption mutants but revealed no heteroresistant phenotype. We also showed that the highly resistant subpopulations (HOM*) of transformants containing low-affinity
pbp2x
undergo an increase in resistance upon selection on penicillin plates that partially reverts after passaging on selection-free medium. Shotgun proteomic analysis showed an upregulation of phosphate ABC transporter subunit proteins encoded by
pstS
,
phoU
,
pstB
, and
pstC
in these highly resistant subpopulations. In conclusion, the presence of low-affinity
pbp2x
enables certain pneumococcal colonies to survive in the presence of β-lactams. Upregulation of phosphate ABC transporter genes may represent a reversible adaptation to antibiotic stress.