bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of H
2
Blockade and Food on Single-Dose Pharmacokinetics of GSK1322322, a Peptide Deformylase Inhibitor Antibacterial
Authors: Naderer Odin J. , Dumont Etienne , Zhu John , Kurtinecz Milena , Jones Lori S. 
Published: March 2013

ABSTRACT

GSK1322322 is first in a new class of antibiotics, peptide deformylase inhibitors, and is active against multidrug-resistant respiratory and skin pathogens. Part 1 of this phase 1, randomized, single-dose (1,000 mg) study in 20 healthy volunteers compared the relative bioavailability of three different tablet formulations of GSK1322322 (fast release, intermediate release, and slow release) to that of the previously studied powder-in-bottle formulation to assess the optimal formulation for progression into clinical trials. Part 2 assessed the effect of a high-fat meal and drug interaction with an H
2
blocker and an H
2
blocker plus vitamin C on the pharmacokinetic profile of GSK1322322. Of the three tablet formulations, fast-release GSK1322322 provided pharmacokinetic profiles similar to those of the powder-in-bottle reference formulation (∼93% relative bioavailability) and was selected for progression in part 2. When GSK1322322 was administered with a high-fat meal, the maximum observed plasma concentration (
C
max
) was reduced by 20%, and the time to maximum plasma concentration (
T
max
) was delayed by 1.9 h. The exposure (area under the concentration-time curve [AUC]) increased by ∼20% compared to that in volunteers in the fasted state. Coadministration of GSK1322322 with an H
2
blocker resulted in a slight delay in absorption (
T
max
∼0.75 h later) and 58 and 38% decreases in the
C
max
and AUC
0–∞
values, respectively, compared to GSK1322322 alone. This effect was reversed with vitamin C intake (i.e., no delay in
T
max
and the
C
max
and AUC
0–∞
values decreased by only 21 and 12%, respectively). GSK1322322 was generally well tolerated, and most adverse events were mild in intensity during both parts of the study.
Flagellar Motility Is a Key Determinant of the Magnitude of the Inflammasome Response to Pseudomonas aeruginosa
Authors: Patankar Yash R. , Lovewell Rustin R. , Poynter Matthew E. , Jyot Jeevan , Kazmierczak Barbara I. , Berwin Brent 
Published: March 2013

ABSTRACT

We previously demonstrated that bacterial flagellar motility is a fundamental mechanism by which host phagocytes bind and ingest bacteria. Correspondingly, loss of bacterial motility, consistently observed in clinical isolates from chronic
Pseudomonas aeruginosa
infections, enables bacteria to evade association and ingestion of
P. aeruginosa
by phagocytes both
in vitro
and
in vivo
. Since bacterial interactions with the phagocyte cell surface are required for type three secretion system-dependent NLRC4 inflammasome activation by
P. aeruginosa
, we hypothesized that reduced bacterial association with phagocytes due to loss of bacterial motility, independent of flagellar expression, will lead to reduced inflammasome activation. Here we report that inflammasome activation is reduced in response to nonmotile
P. aeruginosa
. Nonmotile
P. aeruginosa
elicits reduced IL-1β production as well as caspase-1 activation by peritoneal macrophages and bone marrow-derived dendritic cells
in vitro
. Importantly, nonmotile
P. aeruginosa
also elicits reduced IL-1β levels
in vivo
in comparison to those elicited by wild-type
P. aeruginosa
. This is the first demonstration that loss of bacterial motility results in reduced inflammasome activation and antibacterial IL-1β host response. These results provide a critical insight into how the innate immune system responds to bacterial motility and, correspondingly, how pathogens have evolved mechanisms to evade the innate immune system.
RegA, the Regulator of the Two-Component System RegB/RegA of Brucella suis, Is a Controller of Both Oxidative Respiration and Denitrification Required for Chronic Infection in Mice
Authors: Abdou Elias , Deredjian Amélie , Jiménez de Bagüés María Pilar , Köhler Stephan , Jubier-Maurin Véronique 
Published: March 2013

ABSTRACT

Adaptation to oxygen deficiency is essential for virulence and persistence of
Brucella
inside the host. The flexibility of this bacterium with respect to oxygen depletion is remarkable, since
Brucella suis
can use an oxygen-dependent transcriptional regulator of the FnrN family, two high-oxygen-affinity terminal oxidases, and a complete denitrification pathway to resist various conditions of oxygen deficiency. Moreover, our previous results suggested that oxidative respiration and denitrification can be simultaneously used by
B. suis
under microaerobiosis. The requirement of a functional cytochrome
bd
ubiquinol oxidase for nitrite reductase expression evidenced the linkage of these two pathways, and the central role of the two-component system RegB/RegA in the coordinated control of both respiratory systems was demonstrated. We propose a scheme for global regulation of
B. suis
respiratory pathways by the transcriptional regulator RegA, which postulates a role for the cytochrome
bd
ubiquinol oxidase in redox signal transmission to the histidine sensor kinase RegB. More importantly, RegA was found to be essential for
B. suis
persistence
in vivo
within oxygen-limited target organs. It is conceivable that RegA acts as a controller of numerous systems involved in the establishment of the persistent state, characteristic of chronic infections by
Brucella
.
Granzyme D Is a Novel Murine Mast Cell Protease That Is Highly Induced by Multiple Pathways of Mast Cell Activation
Authors: Rönnberg Elin , Calounova Gabriela , Guss Bengt , Lundequist Anders , Pejler Gunnar 
Published: March 2013

ABSTRACTGranzymes are serine proteases known mostly for their role in the induction of apoptosis. Granzymes A and B have been extensively studied, but relatively little is known about granzymes C to G and K to M. T cells, lymphohematopoietic stromal cells, and granulated metrial gland cells express granzyme D, but the function of granzyme D is unknown. Here we show that granzyme D is expressed by murine mast cells and that its level of expression correlates positively with the extent of mast cell maturation. Coculture of mast cells with live, Gram-positive bacteria caused a profound, Toll-like receptor 2 (TLR2)-dependent induction of granzyme D expression. Granzyme D expression was also induced by isolated bacterial cell wall components, including lipopolysaccharide (LPS) and peptidoglycan, and by stem cell factor, IgE receptor cross-linking, and calcium ionophore stimulation. Granzyme D was released into the medium in response to mast cell activation. Granzyme D induction was dependent on protein kinase C and nuclear factor of activated T cells (NFAT). Together, these findings identify granzyme D as a novel murine mast cell protease and implicate granzyme D in settings where mast cells are activated, such as bacterial infection and allergy.
Integrated magnetobiostratigraphy of the middle Eocene–lower Oligocene interval from the Monte Cagnero section, central Italy
Authors: Jovane Luigi , Savian Jairo F. , Coccioni Rodolfo , Frontalini Fabrizio , Bancalà Giuseppe , Catanzariti Rita , Luciani Valeria , Bohaty Steven M. , Wilson Paul A. , Florindo Fabio 
Published: March 2013

Abstract

The Monte Cagnero sedimentary section, which crops out in the northeastern Apennines near Urbania in the Umbria–Marche Basin (Italy), contains well-exposed strata spanning the middle Eocene to lower Oligocene interval. We use an integrated magnetobiostratigraphic approach to generate a high-resolution age model for the Monte Cagnero section, with the goal of obtaining a reliable chronostratigraphic framework for studying Eocene–Oligocene palaeoceanographic changes during the switch from greenhouse to icehouse conditions. The studied sediments consist of alternating reddish and greenish limestones and marlstones. A new integrated age model for the section is based on high-resolution palaeomagnetic analyses, combined with detailed planktonic foraminiferal and calcareous nannofossil biostratigraphic results. Rock magnetic measurements show that the magnetic mineralogy is dominated by a mixture of high- and low-coercivity minerals, probably representing a combination of hematite and magnetite. A robust magnetostratigraphic signal, together with the identification of key planktonic foraminiferal and nannofossil biostratigraphic events, allows construction of a detailed age model for the section. Based on these results, we infer that the section spans a continuous interval (within magnetochron resolution) from the middle Eocene to lower Oligocene (
c
. 41–27 Ma; Chrons C18r–C12r). The Monte Cagnero section, therefore, represents a sequence that is suitable for studying the impact of the Neo-Tethyan gateway closure on subtropical Eocene circulation and determining the nature and timing of palaeoceanographic changes in the Tethys through the late middle Eocene to early Oligocene interval.
Middle Eocene to early Oligocene magnetostratigraphy of ODP Hole 711A (Leg 115), western equatorial Indian Ocean
Authors: Savian Jairo F. , Jovane Luigi , Bohaty Steven M. , Wilson Paul A. 
Published: March 2013

Abstract
Ocean Drilling Program (ODP) Site 711, located in the western equatorial Indian Ocean near the Seychelles Archipelago on Madingley Rise, is an important site for studying middle Eocene to early Oligocene climatic evolution. This site is ideal for studying the impact of Neo-Tethyan gateway closure on Indian Ocean currents and circulation to further understand global climate changes through the greenhouse to icehouse transition. Middle Eocene-to-lower Oligocene strata recovered within Hole 711A (Cores 711A-14X to 21X) primarily consist of clay-bearing nannofossil oozes/chalks, with layers rich in radiolarians. Here, we report a high-resolution magnetostratigraphic record and a new integrated age model for the middle Eocene-to-lower Oligocene section of Hole 711A. Correlation of the polarity pattern to the geomagnetic polarity timescale provides a record from Chron C19r (middle Eocene) to C12r (early Oligocene). Our results extend the existing polarity record down into the middle Eocene and confirm published results from the lower Oligocene section of the hole. Overall, these new results from Hole 711A have important implications for identifying and dating global climate change events, and for reconstructing calcite compensation depth history at this site.

Supplementary material:

Magnetostratigraphic data used for construction of age models for Hole 711A included in this study are available at:
www.geolsoc.org.uk/SUP18595
Phytochemical and nutrient/antinutrient interactions in cherry tomato (Lycopersicon esculentum) fruits
Authors: Oyetayo Folake Lucy , Ibitoye Muyiwa Femi 
Published: March 2013

The fruit of the cherry tomato ( Lycopersicon esculentum (Solanaceae)) was analysed for mineral and antinutrient composition. Phosphorus (33.04 ± 0.21 mg/100g) was the most abundant mineral in the fruit, followed by calcium (32.04 ± 0.06 mg/100g), and potassium (11.9 ± 0.1 mg/100g) and manganese (9.55 ± 0.28 mg/100g) were also present in appreciable quantities. Antinutrients, including phytate, glycoside, saponin and tannin, were screened and quantified. Phytate (112.82 ± 0.1 mg/100g), glycoside (2.33 ± 0.00 mg/100g), saponin (1.31 ± 0.00 mg/100g) and tannin (0.21 ± 0.00 mg/100g) were present in the fruit but phlobatanin and glycosides with steroidal rings were not found. The calculated calcium:phytate ratio of the fruits was below the critical value and the calculated [calcium] [phytate]:[zinc] molar ratio was less than the critical value. The calcium:phosphorus ratio (0.97 mg/100g) shows the fruit to be a good source of food nutrients, while the sodium:potassium value was less than 1. Ca/P ratio below 0.5 indicates deficiency of these minerals while Na/K ratio above 1 is detrimental because of excessive sodium levels. The results of the study generally revealed the fruit to be rich in minerals but containing insufficient quantities of antinutrients to result in poor mineral bioavailability.
Evaluation of Hepatic Steatosis in Dogs With Congenital Portosystemic Shunts Using Oil Red O Staining
Authors: Hunt G. B. , Luff J. A. , Daniel L. , Bergh R. Van den 
Published: March 2013

The aims of this prospective study were to quantify steatosis in dogs with congenital portosystemic shunts (CPS) using a fat-specific stain, to compare the amount of steatosis in different lobes of the liver, and to evaluate intra- and interobserver variability in lipid point counting. Computer-assisted point counting of lipid droplets was undertaken following Oil Red O staining in 21 dogs with congenital portosystemic shunts and 9 control dogs. Dogs with congenital portosystemic shunts had significantly more small lipid droplets (<6 μ) than control dogs ( P = .0013 and .0002, respectively). There was no significant difference in steatosis between liver lobes for either control dogs and CPS dogs. Significant differences were seen between observers for the number of large lipid droplets (>9 μ) and lipogranulomas per tissue point ( P = .023 and .01, respectively). In conclusion, computer-assisted counting of lipid droplets following Oil Red O staining of liver biopsy samples allows objective measurement and detection of significant differences between dogs with CPS and normal dogs. This method will allow future evaluation of the relationship between different presentations of CPS (anatomy, age, breed) and lipidosis, as well as the impact of hepatic lipidosis on outcomes following surgical shunt attenuation.
Randomly amplified polymorphic-DNA analysis for detecting genotoxic effects of Boron on maize (Zea mays L.)
Authors: Sakcali M Serdal , Kekec Guzin , Uzonur Irem , Alpsoy Lokman , Tombuloglu Huseyin 
Published: March 2013

This study was carried out to investigate the genotoxic effect of boron (B) on maize using randomly amplified polymorphic DNA (RAPD) method. Experimental design was conducted under 0, 5, 10, 25, 50, 100, 125, and 150 ppm B exposures, and physiological changes have revealed a sharp decrease in root growth rates from 28% to 85%, starting from 25 ppm to 150 ppm, respectively. RAPD-polymerase chain reaction (PCR) analysis shows that DNA alterations are clearly observed from beginning to 100 ppm. B-induced inhibition in root growth had a positive correlation with DNA alterations. Total soluble protein, root and stem lengths, and B content analysis in root and leaves encourage these results as a consequence. These preliminary findings reveal that B causes chromosomal aberration and genotoxic effects on maize. Meanwhile, usage of RAPD-PCR technique is a suitable biomarker to detect genotoxic effect of B on maize and other crops for the future.
Function of the liver and bile ducts in humans exposed to lead
Authors: Kasperczyk A , Dziwisz M , Ostałowska A , Świętochowska E , Birkner E 
Published: March 2013

Lead is very common in the environment, and it is therefore important to characterize its possible adverse health effects. The aim of this study was to evaluate the impact of lead exposure on selected functions of the liver and bile ducts in people who are chronically exposed to the metal because of their occupations. To provide this information, the activity of specific enzymes and the bilirubin concentration were determined in blood serum, and morphological parameters of the liver and bile ducts were evaluated using the ultrasonic imaging method. Healthy male employees of a lead–zinc processing facility ( n = 145) who were occupationally exposed to lead were divided into two subgroups as a function of the lead concentrations in blood (PbB): low lead exposure (PbB = 20–35 μg/dl; n = 57) and high lead exposure (PbB = 35–60 μg/dl; n = 88). Human exposure to lead compounds was found to cause liver enlargement and to activate inflammatory reactions with the characteristics of moderate cholestasis within the bile ducts, while no characteristics of necrotic damage of hepatic cells were noted. It seems that lipid peroxidation can be one of the toxic mechanisms of lead which induce moderate cholestasis. The effects depend on the extent of the lead exposure and were greater in subjects with higher exposure levels, particularly subjects with PbB values greater than 35 μg/dl.
The many faces of social time: A sociological approach
Authors: Cipriani Roberto 
Published: March 2013

Do all clocks and calendars refer to the same time? EE Evans-Pritchard reported that the Nuer culture divided time into ‘ecological’ and structural temporal categories. Alheit made a distinction between everyday, routinized, cyclical time and life-experience time. Time is capable of devouring everything; it can reach beyond what has already been; it can sunder itself from the past, without turning back. Social time has many facets: it may be very short, short, long or very long. Immobility within life space, as time passes, is tantamount to continuous change in space and time. Finally, a categorization of time might be founded on four modalities: micro-time, meso-time, macro-time, mega-time.
Assessing possible selection bias in a national voluntary MS longitudinal study in Australia
Authors: Taylor Bruce V , Palmer Andrew , Simpson Steve , Lucas Robyn ,   NZMSPS study group, Simmons Rex D , Mason Deborah , Pearson John , Clarke Glynnis , Sabel Clive , Willoughby Ernie , Richardson Anne , Abernethy David 
Published: March 2013

Background: Surveying volunteer members of a multiple sclerosis registry is a very cost-effective way of assessing the impact of the disease on life outcomes. However, whether the data from such a study can be generalised to the whole population of persons living with MS in a country or region is unclear. Methods: Here we compare the demographic and disease characteristics of participants in one such study, the Australian Multiple Sclerosis Longitudinal Study (AMSLS), with two well-characterised MS prevalence studies with near-complete ascertainment of MS in their study regions. Results: Although some differences were found, these largely represented the effects of geography (sex ratios) and local factors (national immunomodulatory therapy prescribing requirements), and the cohorts were otherwise comparable. Overall, despite comprising only 12–16% of MS cases in Australia, the AMSLS is highly representative of the MS population. Conclusions: Therefore with some minor caveats, the AMSLS data can be generalised to the whole Australasian MS population. Volunteer disease registries such as this can be highly representative and provide an excellent convenience sample when studying rare conditions such as MS.
Pharmacoepidemiology and the Australian regional prevalence of multiple sclerosis
Authors: Hollingworth Samantha , Walker Kimitra , Page Andrew , Eadie Mervyn 
Published: March 2013

Background: Over some 50 years, field surveys have shown that the prevalence of multiple sclerosis (MS) increases with increasing distance from the equator in both the northern and the southern hemispheres. Such a latitudinal gradient has been found in field surveys of MS prevalence carried out at different times in various local regions of Australia. Objective: The objective of this paper is to use a pharmacoepidemiological approach to obtain whole of population estimates of the prevalence of MS in the various Australian states and territories from the use of MS disease-modifying drugs used to treat relapsing–remitting MS (RRMS). Methods: We analysed the dispensed use of subsidised RRMS drugs by jurisdiction. Results: In the 2005–2008 period, the calculated mean treated RRMS prevalence in Australia ranged from 7.5 per 100,000 in the far north to 53.2 per 100,000 in the extreme south and was linearly related to increasing southerly latitude. Public domain Australian data suggested that multiplying this prevalence by a factor of 2.2 (to account for untreated RRMS and other types of MS) may provide a measure of the prevalence of all varieties of the disease. Conclusion: These findings provide contemporary and more comprehensive evidence for the gradient of MS prevalence with latitude in Australia than has previously been available.
A comparative study of CSF neurofilament light and heavy chain protein in MS
Authors: Kuhle Jens , Plattner Kim , Bestwick Jonathan P , Lindberg Raija L , Ramagopalan Sreeram V , Norgren Niklas , Nissim Ahuva , Malaspina Andrea , Leppert David , Giovannoni Gavin , Kappos Ludwig 
Published: March 2013

Background: There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)). Methods: We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light® enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfHSMI35 assay. Results: Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls ( p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in patients with relapsing disease ( rs = 0.31; p = 0.002), spinal cord relapses and with CSF markers of acute inflammation. The ability of NfL to distinguish patients from controls was greater than that of NfHSMI35 in both CIS patients ( p = 0.001) and all MS stages grouped together ( p = 0.035). Conclusions: NfL proved to be a stable protein, an important prerequisite for a reliable biomarker, and the NF-light® ELISA performed better in discriminating patients from controls, compared with the ECL-NfHSMI35 immunoassay. We confirmed and expanded upon previous findings regarding neurofilaments as quantitative markers of neurodegeneration. Our results further support the role of neurofilaments as a potential surrogate measure for neuroprotective treatment in MS studies.
Surgical castration for androgen-deprivation therapy of prostate cancer – relevance in current practice
Authors: Rajasundaram Ramanan , Gunendran Thiru , George Nicholas 
Published: March 2013

Objective: Rapid control of the disease is essential in the management of patients with critical and symptomatic metastatic prostate cancer. Pharmacological castration has become the main form of androgen-deprivation therapy (ADT) for prostate cancer, with luteinising hormone-releasing hormone (LHRH) agonists being used in more than 90% of cases. Surgical castration has become the less preferred modality. This article aims to explore the clinical and economic advantages of bilateral sub-capsular orchidectomy (BSCO). Method: Pre- and post-operative serial testosterone levels were taken from patients who had BSCO for adenocarcinoma of the prostate. The half-life of testosterone was calculated. The cost of surgical castration on the National Health Service (NHS) was compared to the cost of LHRH agonists. Results: Ten patients with a median prostate-specific antigen (PSA) level of 93 ng/ml (range 26 to 4557 ng/ml) were included. Their mean random pre-operative testosterone level was 13.8 ng/ml (range 6.8 to 21.8 ng/ml). The mean half-life of testosterone was 61.7 minutes when calculated from the first two hours, and 67 minutes when calculated from the total drop with no significant variation ( p = 0.464). Four patients reached castrate levels of testosterone within four to six hours. The total cost of an inpatient BSCO in the NHS was £850 to £1154. This was more or less equivalent to one year’s worth of the commonly used LHRH agonists without including the cost of medical services. Conclusions: Testosterone has a short half-life and reaches castrate levels within hours of the BSCO procedure. Rapid castration by BSCO would benefit patients with critical metastatic disease. BSCO on the NHS in patients with more than one year of life expectancy is also economically beneficial.