bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of T‐Cell‐Stimulating Activity of Mycobacteria‐Infected Macrophages
Authors: Kimura H. , Maeda Y. , Takeshita F. , Takaoka L. E. , Matsuoka M. , Makino M. 
Published: August 2004

AbstractMacrophages are one of the most abundant host cells to come in contact with mycobacteria. However, the infected macrophages less efficiently stimulate autologous T cells in vitro. We investigated the effect of the induction of phenotypic change of macrophages on the host cell activities by using Mycobacterium leprae as a pathogen. The treatment of macrophages with interferon‐γ (IFN‐γ), GM‐CSF and interleukin‐4 deprived macrophages of CD14 antigen expression but instead provided them with CD1a, CD83 and enhanced CD86 antigen expression. These phenotypic features resembled those of monocyte‐derived dendritic cells (DC). These macrophage‐derived DC‐like cells (MACDC) stimulated autologous CD4+ and CD8+ T cells when infected with M. leprae. Further enhancement of the antigen‐presenting function and CD1a expression of macrophages was observed when treated with IFN‐γ. The M. leprae‐infected and ‐treated macrophages expressed bacterial cell membrane‐derived antigens on the surface and were efficiently cytolysed by the cell membrane antigen‐specific CD8+ cytotoxic T lymphocytes (CTL). These results suggest that the induction of phenotypic changes in macrophages can lead to the upregulation of host defence activity against M. leprae.
Evidence for a Type 1 Diabetes Susceptibility Locus (IDDM10) on Chromosome 10p11‐q11 in a Russian Population
Authors: Chistiakov D. A. , Seryogin Y. , Savost'anov K. V. , Zilberman L. I. , Titovich E. V. , Kuraeva T. L. , Dedov I. I. , Nosikov V. V. 
Published: August 2004

AbstractAround 20 susceptibility loci for type 1 diabetes mellitus (T1DM) have been mapped. One of these loci, IDDM10, was found on chromosome 10p11‐q11. Here, we investigated whether the IDDM10 locus contributes in the susceptibility to T1DM in a Russian family dataset. One hundred and fourteen simplex Russian families, each containing two siblings (one affected with T1DM diagnosed and one nondiabetic sibling), and 97 multiplex families, containing 106 affected full sibling pairs, were studied. Genomic DNA from the venous blood of the patients was genotyped by PCR using 12 microsatellites (D10S193, D10S548, D10S565, D10S586, D10S588, D10S675, D10S1243, D10S1426, D10S1733, D10S1772, D10S1780 and D10S1783) located on chromosome 10p11‐q11. Using the multipoint linkage analysis, the region of suggestive linkage, with a multipoint logarithm of odds (LOD) ratio (MLS) value of more than 2.2, was found between markers D10S1733 and D10S1780, an area of 9.0 cM on the genetic map. The maximum linkage peak (MLS = 2.85 and nonparametric logarithm = 2.68) was observed between markers D11S565 and D11S1243. Using the transmission disequilibrium test, an association of these markers, D10S565 (P overall = 0.0082) and D10S1243 (P overall = 0.017), with T1DM was shown. These results suggest the evidence for the IDDM10 susceptibility locus on chromosome 10p11‐q11.
A Simplified Cytokine Immunoassay Using Magnetic Polymer Particles
Authors: McNeill A. , Kastrup J. , Bäckström B. T. 
Published: August 2004

AbstractAccurate detection of cytokines is essential for understanding their biological role in the immune system. Various methods to detect cytokines have been developed, including sandwich enzyme‐linked immunosorbent assay (ELISA) and flow cytometry‐based methods. All of the currently available methods have limitations, however. These limitations include time and extensive handling in standard sandwich ELISAs and the need for specialized equipment in flow cytometry‐based assays. We have developed a magnetic polymer cytokine immunoassay and demonstrate that this assay is rapid and simple, needs less handling and offers better dynamic range, compared to standard sandwich ELISA. Furthermore, it does not require flow cytometry equipment, which is often used in microparticle‐based polymer immunoassays. The magnetic polymer cytokine immunoassay described in this study is as sensitive as a standard sandwich ELISA. Because the method is not limited to the use of magnetic polymer particles, it is versatile and compatible with a number of different solid matrixes.
The Marinoan glaciation (Neoproterozoic) in northeast Svalbard
Authors: Halverson Galen P. , Maloof Adam C. , Hoffman Paul F. 
Published: August 2004

AbstractTwo separate and distinct diamictite‐rich units occur in the mixed carbonate‐siliciclastic Polarisbreen Group, which comprises the top kilometer of >7 km of Neoproterozoic strata in the northeast of the Svalbard archipelago. The platformal succession accumulated on the windward, tropical to subtropical margin of Laurentia. The older Petrovbreen Member is a thin glacimarine diamictite that lacks a cap carbonate. It contains locally derived clasts and overlies a regional karstic disconformity that was directly preceded by a large (>10‰) negativeδ13C anomaly in the underlying shallow‐marine carbonates. This anomaly is homologous to anomalies in Australia, Canada and Namibia that precede the Marinoan glaciation. The younger and thicker Wilsonbreen Formation comprises terrestrial ice‐contact deposits. It contains abundant extrabasinal clasts and is draped by a transgressive cap dolostone 3–18 m thick. The cap dolostone is replete with sedimentary features strongly associated with post‐Marinoan caps globally, and its isotopic profile is virtually identical to that of other Marinoan cap dolostones. From the inter‐regional perspective, the two diamictite‐rich units in the Polarisbreen Group should represent the first and final phases of the Marinoan glaciation. Above the Petrovbreen diamictite are ∼200 m of finely laminated, dark olive‐coloured rhythmites (MacDonaldryggen Member) interpreted here to represent suspension deposits beneath shorefast, multi‐annual sea ice (sikussak). Above the suspension deposits and below the Wilsonbreen diamictites is a <30‐m‐thick regressive sequence (Slangen Member) composed of dolomite grainstone and evaporitic supratidal microbialaminite. We interpret this sabkha‐like lagoonal sequence as an oasis deposit that precipitated when local marine ice melted away under greenhouse forcing, but while the tropical ocean remained covered due to inflow of sea glaciers from higher latitudes. It appears that the Polarisbreen Group presents an unusually complete record of the Marinoan snowball glaciation.
Depositional wedge tops: interaction between low basal friction external orogenic wedges and flexural foreland basins
Authors: Ford Mary 
Published: August 2004

AbstractGrowth structures develop mainly across depositional wedge tops where the top of the distal orogenic wedge lies below local base level within the flexural foreland basin. Documented examples indicate that optimum conditions for the development of a depositional wedge top occur when the dip of the upper surface of the outer orogenic wedge (α) is low (0–1°), regardless of the taper angle (α+β), where β is the inclination of the base of the wedge. Low α angles are associated with the presence of low friction décollements, usually salt. Therefore, depositional wedge tops develop most commonly on low basal friction wedges. In natural examples such as the northern Apennines, the South Central Pyrenees and the Zagros, it is shown that whereas α is consistently low, β can vary considerably (1–9°), being principally controlled by flexure of the lower plate. In addition, the distribution of deformation in the wedge is complex. The applicability of the critical wedge model to low basal friction external orogenic zones is examined. Neither taper angles, nor the complex distribution of internal deformation nor the often associated forward slip of the whole wedge, can be satisfactorily explained by the established critical wedge model. As weak detachments such as salt cannot support any significant topography, it follows that low basal friction wedges cannot attain a critical state and, therefore, the critical wedge model cannot be satisfactorily applied to these external orogenic systems. This model, however, explains well the behaviour of external orogenic wedges with high basal friction. In the analysis of orogenic wedges, separate analysis of the angles α and β proves more useful than the critical taper angle α+β.
Role of crustal anisotropy in modifying the structural and sedimentological evolution of extensional basins: the Gamtoos Basin, South Africa
Authors: Paton Douglas A. , Underhill John R. 
Published: August 2004

AbstractThrough the investigation of crustal heterogeneities, sedimentary basin architecture and seismic stratigraphy, we demonstrate how a crust‐scale anisotropy controls the initiation of rifting and the subsequent structural and sedimentological evolution of the Mesozoic Gamtoos Basin, southern South Africa. The results demonstrate that the >90‐km‐long Gamtoos Fault established its length very early in its syn‐rift phase (within ∼5 Ma of rift initiation) before accruing over 6 s (two‐way‐travel time (TWT)), or >12 km, of displacement without any significant subsequent increase in length. In addition, there is no evidence at the resolution of the data of fault segmentation, isolated depocentres nor of intra‐basin faults progressively coalescing during the syn‐rift interval. The early establishment of length resulted in a rapid transition from a terrestrial depositional environment to anoxic, deep marine conditions. The Gamtoos Fault has a 90° bend in the fault trace that we propose is inherited from the underlying structure. Immediately adjacent to the bend the basin‐fill is significantly deformed and a high‐amplitude (>1.7s TWT) monoclinal fold is observed. Previous workers proposed that the fold was a consequence of a complex interplay between compression and extension. Through a restoration of the basin‐fill deformation we produce a model that suggests that the fold is a consequence of the accommodation of extension by the unusual plan‐view trace of the fault. The evolution of the basin does not conform to current fault growth models and it is proposed that its unusual and complex development can be attributed to the underlying crustal‐scale anisotropy, a fact that is likely to be important in other areas in which crustal stretching is superimposed on heterogeneous continental crust.
Detrital thermochronology – a new perspective on hinterland tectonics, an example from the Andean Amazon Basin, Ecuador
Authors: Ruiz G. M. H. , Seward D. , Winkler W. 
Published: August 2004

AbstractIn order to understand the significance of detrital grain ages in sedimentary basins, a new approach is presented. Five characteristic paths, identified by the change in age of detrital grain populations combined with the change in lagtime over time, can be related to different geodynamic settings in the source regions. When lagtime and grain age increase over time, a change in source must be invoked – this is usually a direct response to a geological event. A constant cooling age, a vertical path, associated implicitly with increasing lagtime, implies erosion of materials that had passed through the closure temperature rapidly – exhuming sufficient rock to supply detritus over the time of the path. Constant lagtimes, regardless of the lagtime itself, are indicative of thermochronological stability in the source region. This can involve fast or slow cooling. Finally, decreasing lagtimes support the notion of increasing cooling rates in the source regions over time. A test study is presented from sediments of the northern Ecuadorian Sub‐Andean Zone where geological events had previously been identified using alternative methods. The addition of heavy‐mineral studies increased the precision in the interpretation. At 90 Ma, rapidly decreasing lagtimes point to a phase of tectonic activity. From about 85 Ma until about 60 Ma the lagtimes were approximately zero. This represents a phase of rapid exhumation of the source regions correlating with the previously identified Pallatanga event. An associated increase of metamorphic minerals occurs over this time span, pointing to increased erosion from deeper horizons. At about 70 Ma, the oldest source region, the shield to the east, was switched off. This timing correlates with a change from marine to continental conditions in the basin, a change in palaeocurrent directions from the east to the west, as well as an associated influx of material from the growing Cordillera Real. At about 55 Ma, a change in source is identified by a change in slope of the lagtime curve together with a change in heavy minerals. From 50 to 35 Ma a renewed period of tectonism in the source region is correlated with the docking of the Macuchi terrane which clearly had an effect of increased erosion in the Cordillera Real bringing in higher grade metamorphic minerals. From about 32 Ma onwards the lagtime has been somewhat constant at about 30 Myr. This does not imply, however, a steady‐state environment as it is well known from other geological evidence that there have been other events within this time frame. One must be cautious about over‐interpreting the lagtime as a method to determine steady state in any region. It is a matter of scale.
First‐trimester exposure to amoxycillin/clavulanic acid: a prospective, controlled study
Authors: Berkovitch Matitiahu , Diav‐Citrin Orna , Greenberg Revital , Cohen Michal , Bulkowstein Mordechai , Shechtman Svetlana , Bortnik Oxana , Arnon Judy , Ornoy Asher 
Published: August 2004

AimsThe number of published studies on the use of amoxycillin/clavulanic acid during pregnancy is small and so is the number of pregnancies investigated in those studies. In this study we wished to investigate prospectively the safety of intrauterine exposure to amoxycillin/clavulanic acid in a relatively large cohort of women.MethodsWomen treated (n = 191) with amoxycillin/clavulanic acid during the first trimester of pregnancy were recruited from two teratogen information centres in Israel. Exposed women were matched for age, smoking habits and alcohol consumption with 191 controls exposed to amoxycillin only for similar medical indications.ResultsMaternal age, birth weight, gestational age at delivery, rates of live births and abortions were comparable between the two groups. Rates of major malformations in the amoxycillin/clavulanic acid group (3/158, 1.9%) did not differ significantly from controls (5/163, 3%) (P = 0.49, relative risk = 0.62, 95% confidence interval 0.15, 2.55), and were within the expected baseline risk for the general population.ConclusionThese data suggest that exposure to amoxycillin/clavulanic acid during pregnancy is unlikely to be associated with an increased risk of malformations.
Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study
Authors: Smyth J. M. , Collier P. S. , Darwish M. , Millership J. S. , Halliday H. L. , Petersen S. , McElnay J. C. 
Published: August 2004

AimsTo characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment.MethodsData were collected from 35 infants (gestational age 25–34 weeks; postnatal age 1–77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1–0.2 mg kg−1) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared.ResultsThe concentration‐time course of indometacin was best described by a one‐compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h−1 and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l−1. Closure occurred in 75% of infants with a plasma concentration ≥ 0.4 mg l−1 24 h after the last dose.ConclusionsDosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration ≥ 0.4 mg l−1. Although the pharmacokinetic estimates will be affected by both interindividual and within‐individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.
Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study
Authors: Grach Michael , Massalha Wattan , Pud Dorit , Adler Rivka , Eisenberg Elon 
Published: August 2004

AimsThe coadministration of subantinociceptive doses of oxycodone with morphine has recently been shown to result in a synergistic antinociceptive effect in rats. The present study was aimed to investigate the possibility that coadministration of morphine and oxycodone can produce a similar synergistic effect in humans exposed to an experimental model of cold pressor test (CPT).MethodsThe enriched enrolment design was used to exclude ‘stoic’ and ‘placebo responders’ in a single‐blind fashion. ‘Nonstoic’, placebo ‘nonresponder’ female volunteers (n = 30) were randomly assigned to receive 0.5 mg kg−1 oral morphine sulphate, 0.5 mg kg−1 oral oxycodone hydrochloride, and the combination of 0.25 mg kg−1 morphine sulphate with 0.25 mg kg−1 oxycodone hydrochloride, 1 week apart from each other, in a double‐blind crossover design. Latency to pain onset (threshold), pain intensity (VAS), and pain tolerance (time until removal of the hand from the water) were measured six times over a 3‐h period, subsequent to the administration of each medication, and were used to assess their antinociceptive effect.ResultsThe combination produced a significantly higher effect on latency to pain onset than that of morphine alone [difference in mean postbaseline value 2.2; 95% confidence interval (CI) 0.48, 3.9; P = 0.01] but the effect was nonsignificantly smaller that that of oxycodone alone. Similarly, the effect of the combination on pain tolerance was significantly larger than that of morphine alone (combination difference 8.4; 95% CI 2.5, 14.3; P = 0.007), whereas oxycodone alone caused a nonsignificantly larger effect than that of the combination treatment. Comparisons of pain magnitude failed to show any significant differences between the three treatments.ConclusionsThese results indicate that at the doses tested, morphine and oxycodone do not produce synergistic antinociceptive effects in healthy humans exposed to the CPT.
Venetian treacle and the foundation of medicines regulation
Authors: Griffin J. P. 
Published: August 2004

Mithridatium and the related product Theriac were both regarded from the time of their original formulations in the 2nd Century BC and the 1st Century AD respectively, until the mid 18th Century as universal panaceas. Any failure of these products to achieve the desired therapeutic result was attributed to defective composition or manufacture. As a result measures were introduced to ensure the quality of ingredients used in these products composition, the establishment of standard formulations and assurance of the competence of the manufacturer. Manufacture frequently was required to take place in public.Doubts about the efficacy of these panaceas arose in the mid 18th century and concerns of the adverse nature of interactions between the numerous ingredients surfaced in Heberden's treatise of 1745, as result of which these products disappeared from Editions of The London Pharmacopoeia after 1746. Subsequently, arising from these concerns for safety and efficacy, a call was made in 1799 for the establishment of a Public Committee of eminent physicians to scrutinise all new products prior to their launch to an gullible public. The concepts developed in the history of Mithridatium form the basis of modern medicines regulation.
Characterization of human cytochrome P450 enzymes catalyzing domperidone N‐dealkylation and hydroxylation in vitro
Authors: Ward Bryan A. , Morocho Alan , Kandil Abdullah , Galinsky Raymond E. , Flockhart David A. , Desta Zeruesenay 
Published: August 2004

AimsTo confirm the identity of the major metabolites of domperidone and to characterize the cytochrome P450s (CYPs) involved in their formation.MethodsHuman liver microsomes (HLMs) were used to characterize the kinetics of domperidone metabolism and liquid chromatography‐mass spectrometry to identify the products. Isoform‐specific chemical inhibitors, correlation analysis and expressed human CYP genes were used to identify the CYPs involved in domperidone oxidation.ResultsIn HLMs, domperidone underwent hydroxylation to form 5‐hydroxydomperidone (MIII) and N‐dealkylation to form 2,3‐dihydro‐2‐oxo‐1H‐benzimidazole‐1‐propionic acid (MI) and 5‐chloro‐4‐piperidinyl‐1,3‐dihydro‐benzimidazol‐2‐one (MII). The formation of all three metabolites (n = 4 HLMs) followed apparent Michaelis‐Menten kinetics. The mean Km values for MI, MII and MIII formation were 12.4, 11.9, and 12.6 µm, respectively. In a panel of HLMs (n = 10), the rate of domperidone (5 µm and 50 µm) metabolism correlated with the activity of CYP3A (r > 0.94; P < 0.0001). Only ketoconazole (1 µm) (by 87%) and troleandomycin (50 µm) (by 64%) inhibited domperidone (5 µm) metabolism in HLMs. Domperidone (5 and 50 µm) hydroxylation and N‐dealkylation was catalyzed by expressed CYP3A4 at a higher rate than the other CYPs. CYP1A2, 2B6, 2C8 and 2D6 also hydroxylated domperidoneConclusionsCYP3A‐catalyzed N‐dealkylation and aromatic hydroxylation are the major routes for domperidone metabolism. The drug would be expected to demonstrate highly variable bioavailability due to hepatic, and possibly intestinal first‐pass metabolism after oral administration. Increased risk of adverse effects might be anticipated during concomitant administration with CYP3A inhibitors, as well as decreased efficacy with inducers of this enzyme.
Stress levels experienced by the parents of enterally fed children
Authors: Pedersen S. D. , Parsons H. G. , Dewey D. 
Published: August 2004

AbstractBackground  The stress levels of parents of children with chronic illness/disability who were also involved in an enteral feeding programme were examined and compared to the stress levels of parents of healthy children and parents of children with other chronic illnesses reported in previous research.Methods  Sixty‐four parents who had a child with an enteral feeding tube completed the Parenting Stress Index (PSI).Results  Based on criteria developed by Abidin (1995), 42.18% (n = 29) of these parents displayed high stress levels. T‐tests revealed that Total Stress scores on the PSI of the parents of children involved in the enteral feeding programme were significantly higher than those reported in the sample of parents used to norm the PSI (P < 0.001), and comparison samples of parents of children with growth deficiencies (P < 0.001) and parents of children with insulin‐dependent diabetes mellitus (P < 0.01). Compared to a sample of parents of children with Rett syndrome, the parents of children involved in the enteral feeding programme reported similar levels of stress on the Parent Domain of the PSI and significantly less stress on the Child Domain (P < 0.001).Conclusions  Factors associated with the stress reported by parents of children with an enteral feeding tube were severity of their child's illness/disability, the constant caretaking demands placed on the parent, and the level of support provided by the parents’ social network.