Showing papers by "University of Queensland published in 2004"
TL;DR: The current understanding of IFN‐γ ligand, receptor, ignal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophages function during infection are reviewed.
Abstract: Interferon-gamma (IFN-gamma) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-gamma ligand, receptor, signal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-gamma signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-gamma are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-alpha, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.
3,589 citations
TL;DR: A new way of exploring packing modes and intermolecular interactions in molecular crystals is described, using Hirshfeld surfaces to partition crystal space, using identifiable patterns of interaction between small molecules to rationalize the often complex mix of interactions displayed by large molecules.
Abstract: A new way of exploring packing modes and intermolecular interactions in molecular crystals is described, using Hirshfeld surfaces to partition crystal space. These molecular Hirshfeld surfaces, so named because they derive from Hirshfeld's stockholder partitioning, divide the crystal into regions where the electron distribution of a sum of spherical atoms for the molecule (the promolecule) dominates the corresponding sum over the crystal (the procrystal). These surfaces reflect intermolecular interactions in a novel visual manner, offering a previously unseen picture of molecular shape in a crystalline environment. Surface features characteristic of different types of intermolecular interactions can be identified, and such features can be revealed by colour coding distances from the surface to the nearest atom exterior or interior to the surface, or by functions of the principal surface curvatures. These simple devices provide a striking and immediate picture of the types of interactions present, and even reflect their relative strengths from molecule to molecule. A complementary two-dimensional mapping is also presented, which summarizes quantitatively the types of intermolecular contacts experienced by molecules in the bulk and presents this information in a convenient colour plot. This paper describes the use of these tools in the compilation of a pictorial glossary of intermolecular interactions, using identifiable patterns of interaction between small molecules to rationalize the often complex mix of interactions displayed by large molecules.
2,049 citations
TL;DR: There are 481 segments longer than 200 base pairs that are absolutely conserved between orthologous regions of the human, rat, and mouse genomes, which represent a class of genetic elements whose functions and evolutionary origins are yet to be determined, but which are more highly conserving between these species than are proteins.
Abstract: There are 481 segments longer than 200 base pairs (bp) that are absolutely conserved (100% identity with no insertions or deletions) between orthologous regions of the human, rat, and mouse genomes. Nearly all of these segments are also conserved in the chicken and dog genomes, with an average of 95 and 99% identity, respectively. Many are also significantly conserved in fish. These ultraconserved elements of the human genome are most often located either overlapping exons in genes involved in RNA processing or in introns or nearby genes involved in the regulation of transcription and development. Along with more than 5000 sequences of over 100 bp that are absolutely conserved among the three sequenced mammals, these represent a class of genetic elements whose functions and evolutionary origins are yet to be determined, but which are more highly conserved between these species than are proteins and appear to be essential for the ontogeny of mammals and other vertebrates.
1,690 citations
TL;DR: Bellerophon was specifically developed to detect 16S rRNA gene chimeras in PCR-clone libraries of environmental samples but can be applied to other nucleotide sequence alignments.
Abstract: Summary: Bellerophon is a program for detecting chimeric sequences in multiple sequence datasets by an adaption of partial treeing analysis. Bellerophon was specifically developed to detect 16S rRNA gene chimeras in PCR-clone libraries of environmental samples but can be applied to other nucleotide sequence alignments.
Availability: Bellerophon is available as an interactive web server at http://foo.maths.uq.edu.au/~huber/bellerophon.pl
1,595 citations
TL;DR: In this article, a review on the science of the t-m transformation in ZrO2 and its application in the modeling of transformation-toughhening behavior, while also summarizing the microstructural control needed to use the benefits in ZRO2-toughened ceramics.
Abstract: The recognition of the potential for enhanced fracture toughness that can be derived from controlled, stress-activated tetragonal (t) to monoclinic (m) transformation in ZrO2-based ceramics ushered in a new era in the development of the mechanical properties of engineering ceramics and provided a major impetus for broader-ranging research into the toughening mechanisms available to enhance the fracture properties of brittle-matrix materials. ZrO2-based systems have remained a major focal point for research as developments in understanding of the crystallography of the t→m transformation have led to more-complete descriptions of the origins of transformation toughening and definition of the features required of a transformation-toughening system. In parallel, there have been significant advances in the design and control of microstructure required to optimize mechanical properties in materials developed commercially. This review concentrates on the science of the t→m transformation in ZrO2 and its application in the modeling of transformation-toughening behavior, while also summarizing the microstructural control needed to use the benefits in ZrO2-toughened ceramics.
1,552 citations
TL;DR: Regression to the mean is a ubiquitous phenomenon in repeated data and should always be considered as a possible cause of an observed change and can be alleviated through better study design and use of suitable statistical methods.
Abstract: Background Regression to the mean (RTM) is a statistical phenomenon that can make natural variation in repeated data look like real change. It happens when unusually large or small measurements tend to be followed by measurements that are closer to the mean. Methods We give some examples of the phenomenon, and discuss methods to overcome it at the design and analysis stages of a study. Results The effect of RTM in a sample becomes more noticeable with increasing measurement error and when follow-up measurements are only examined on a sub-sample selected using a baseline value. Conclusions RTM is a ubiquitous phenomenon in repeated data and should always be considered as a possible cause of an observed change. Its effect can be alleviated through better study design and use of suitable statistical methods.
1,500 citations
TL;DR: Simulated data sets were used to test the power and accuracy of Monte Carlo resampling methods in generating statistical thresholds for identifying F0 immigrants in populations with ongoing gene flow, and hence for providing direct, real‐time estimates of migration rates.
Abstract: Genetic assignment methods use genotype likelihoods to draw inference about where individuals were or were not born, potentially allowing direct, real-time estimates of dispersal. We used simulated data sets to test the power and accuracy of Monte Carlo resampling methods in generating statistical thresholds for identifying F0 immigrants in populations with ongoing gene flow, and hence for providing direct, real-time estimates of migration rates. The identification of accurate critical values required that resampling methods preserved the linkage disequilibrium deriving from recent generations of immigrants and reflected the sampling variance present in the data set being analysed. A novel Monte Carlo resampling method taking into account these aspects was proposed and its efficiency was evaluated. Power and error were relatively insensitive to the frequency assumed for missing alleles. Power to identify F0 immigrants was improved by using large sample size (up to about 50 individuals) and by sampling all populations from which migrants may have originated. A combination of plotting genotype likelihoods and calculating mean genotype likelihood ratios (DLR) appeared to be an effective way to predict whether F0 immigrants could be identified for a particular pair of populations using a given set of markers.
1,481 citations
TL;DR: The current advances in flavonoids in food is reviewed, with emphasis on health aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.
Abstract: There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids through epidemiological studies. As occurrence of flavonoids is directly associated with human daily dietary intake of antioxidants, it is important to evaluate flavonoid sources in food. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. However, there is still difficulty in accurately measuring the daily intake of flavonoids because of the complexity of existence of flavonoids from various food sources, the diversity of dietary culture, and the occurrence of a large amount of flavonoids itself in nature. Nevertheless, research on the health aspects of flavonoids for humans is expanding rapidly. Many flavonoids are shown to have antioxidative activity, free-radical scavenging capacity, coronary heart disease prevention, and anticancer activity, while some flavonoids exhibit potential for anti-human immunodeficiency virus functions. As such research progresses. further achievements will undoubtedly lead to a new era of flavonoids in either foods or pharmaceutical supplements. Accordingly, an appropriate model for a precise assessment of intake of flavonoids needs to be developed. Most recent research has focused on the health aspects of flavonoids from food sources for humans. This paper reviews the current advances in flavonoids in food, with emphasis on health aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.
1,345 citations
TL;DR: Aesthetic attributes, convenience of facilities for walking, accessibility of destinations, and perceptions about traffic and busy roads were found to be associated with walking for particular purposes, and early evidence is promising.
1,301 citations
TL;DR: In this paper, a metafrontier production function model for firms in different groups having different technologies is presented, which enables the calculation of comparable technical efficiencies for firms operating under different technologies.
Abstract: This paper presents a metafrontier production function model for firms in different groups having different technologies. The metafrontier model enables the calculation of comparable technical efficiencies for firms operating under different technologies. The model also enables the technology gaps to be estimated for firms under different technologies relative to the potential technology available to the industry as a whole. The metafrontier model is applied in the analysis of panel data on garment firms in five different regions of Indonesia, assuming that the regional stochastic frontier production function models have technical inefficiency effects with the time-varying structure proposed by Battese and Coelli ( 1992).
1,133 citations
TL;DR: Patients with LV dyssynchrony >/=65 ms respond to CRT and have an excellent prognosis after CRT, and Receiver-operator characteristic curve analysis demonstrated that an optimal cutoff value of 65 ms for LV dySSynchrony yielded a sensitivity and specificity of 80% to predict clinical improvement and of 92% to Predict LV reverse remodeling.
TL;DR: The results indicate that the antagonistic interactions between multiple components of ABA and the JA-ethylene signaling pathways modulate defense and stress responsive gene expression in response to biotic and abiotic stresses.
Abstract: The plant hormones abscisic acid (ABA), jasmonic acid (JA), and ethylene are involved in diverse plant processes, including the regulation of gene expression during adaptive responses to abiotic and biotic stresses. Previously, ABA has been implicated in enhancing disease susceptibility in various plant species, but currently very little is known about the molecular mechanisms underlying this phenomenon. In this study, we obtained evidence that a complex interplay between ABA and JA-ethylene signaling pathways regulate plant defense gene expression and disease resistance. First, we showed that exogenous ABA suppressed both basal and JA-ethylene–activated transcription from defense genes. By contrast, ABA deficiency as conditioned by the mutations in the ABA1 and ABA2 genes, which encode enzymes involved in ABA biosynthesis, resulted in upregulation of basal and induced transcription from JA-ethylene responsive defense genes. Second, we found that disruption of AtMYC2 (allelic to JASMONATE INSENSITIVE1 [JIN1]), encoding a basic helix-loop-helix Leu zipper transcription factor, which is a positive regulator of ABA signaling, results in elevated levels of basal and activated transcription from JA-ethylene responsive defense genes. Furthermore, the jin1/myc2 and aba2-1 mutants showed increased resistance to the necrotrophic fungal pathogen Fusarium oxysporum. Finally, using ethylene and ABA signaling mutants, we showed that interaction between ABA and ethylene signaling is mutually antagonistic in vegetative tissues. Collectively, our results indicate that the antagonistic interactions between multiple components of ABA and the JA-ethylene signaling pathways modulate defense and stress responsive gene expression in response to biotic and abiotic stresses.
TL;DR: The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia.
Abstract: Understanding variations in the incidence of schizophrenia is a crucial step in unravelling the aetiology of this group of disorders. The aims of this review are to systematically identify studies related to the incidence of schizophrenia, to describe the key features of these studies, and to explore the distribution of rates derived from these studies. Studies with original data related to the incidence of schizophrenia (published 1965–2001) were identified via searching electronic databases, reviewing citations and writing to authors. These studies were divided into core studies, migrant studies, cohort studies and studies based on Other Special Groups. Between- and within-study filters were applied in order to identify discrete rates. Cumulative plots of these rates were made and these distributions were compared when the underlying rates were sorted according to sex, urbanicity, migrant status and various methodological features. We identified 100 core studies, 24 migrant studies, 23 cohort studies and 14 studies based on Other Special Groups. These studies, which were drawn from 33 countries, generated a total of 1,458 rates. Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4). Those studies conducted in urban versus mixed urban-rural catchment areas generated significantly higher rate distributions. The distribution of rates in migrants was significantly higher compared to native-born; the migrant/native-born rate ratio median (10%–90% quantile) was 4.6 (1.0–12.8). Apart from the finding that older studies reported higher rates, other study features were not associated with significantly different rate distributions (e.g. overall quality, methods related to case finding, diagnostic confirmation and criteria, the use of age-standardization and age range). There is a wealth of data available on the incidence of schizophrenia. The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia.
TL;DR: In this paper, the authors proposed an alternative topology of nonisolated per-panel dc-dc converters connected in series to create a high voltage string connected to a simplified dc-ac inverter.
Abstract: New residential scale photovoltaic (PV) arrays are commonly connected to the grid by a single dc-ac inverter connected to a series string of pv panels, or many small dc-ac inverters which connect one or two panels directly to the ac grid. This paper proposes an alternative topology of nonisolated per-panel dc-dc converters connected in series to create a high voltage string connected to a simplified dc-ac inverter. This offers the advantages of a "converter-per-panel" approach without the cost or efficiency penalties of individual dc-ac grid connected inverters. Buck, boost, buck-boost, and Cu/spl acute/k converters are considered as possible dc-dc converters that can be cascaded. Matlab simulations are used to compare the efficiency of each topology as well as evaluating the benefits of increasing cost and complexity. The buck and then boost converters are shown to be the most efficient topologies for a given cost, with the buck best suited for long strings and the boost for short strings. While flexible in voltage ranges, buck-boost, and Cu/spl acute/k converters are always at an efficiency or alternatively cost disadvantage.
TL;DR: In this paper, the authors proposed a tripartite model for social identity, which can be represented in terms of three factors: centrality, ingroup affect, and ingroup ties, and examined the efficacy of this model in five studies involving a total of 1078 respondents, one nonstudent sample, and three group memberships.
Abstract: Despite the importance of the social identification construct in research and theory on group processes and intergroup relations, the issue of its dimensionality remains unresolved. It is proposed that social identity can be represented in terms of three factors: centrality; ingroup affect; and ingroup ties. I examined the efficacy of this model in five studies involving a total of 1078 respondents, one nonstudent sample, and three group memberships (university, gender, and nationality). Results of confirmatory factor analyses support the acceptability of the tripartite model, which fits the data significantly better than one- or two-dimensional (cognition/affect) alternatives. Correlations with theoretically relevant variables provide support for the convergent and discriminant validity of the three factors. Advantages and implications of the three-factor model are considered, with particular reference to social identity theory.
TL;DR: Evidence is presented that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.
Abstract: The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity) This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease
TL;DR: The wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of primary aldosteronism, which was previously believed to account for less than 1% of hypertensives.
Abstract: Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.
TL;DR: Mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD are discussed andNMDA receptor antagonists have potential for the therapeutic amelioration of AD.
TL;DR: Genetic analysis of the wMel genome further supports the hypothesis that mitochondria share a common ancestor with the α-Proteobacteria, but shows little support for the grouping of mitochondria with species in the order Rickettsiales.
Abstract: The complete sequence of the 1,267,782 bp genome of Wolbachia pipientis wMel, an obligate intracellular bacteria of Drosophila melanogaster, has been determined. Wolbachia, which are found in a variety of invertebrate species, are of great interest due to their diverse interactions with different hosts, which range from many forms of reproductive parasitism to mutualistic symbioses. Analysis of the wMel genome, in particular phylogenomic comparisons with other intracellular bacteria, has revealed many insights into the biology and evolution of wMel and Wolbachia in general. For example, the wMel genome is unique among sequenced obligate intracellular species in both being highly streamlined and containing very high levels of repetitive DNA and mobile DNA elements. This observation, coupled with multiple evolutionary reconstructions, suggests that natural selection is somewhat inefficient in wMel, most likely owing to the occurrence of repeated population bottlenecks. Genome analysis predicts many metabolic differences with the closely related Rickettsia species, including the presence of intact glycolysis and purine synthesis, which may compensate for an inability to obtain ATP directly from its host, as Rickettsia can. Other discoveries include the apparent inability of wMel to synthesize lipopolysaccharide and the presence of the most genes encoding proteins with ankyrin repeat domains of any prokaryotic genome yet sequenced. Despite the ability of wMel to infect the germline of its host, we find no evidence for either recent lateral gene transfer between wMel and D. melanogaster or older transfers between Wolbachia and any host. Evolutionary analysis further supports the hypothesis that mitochondria share a common ancestor with the alpha-Proteobacteria, but shows little support for the grouping of mitochondria with species in the order Rickettsiales. With the availability of the complete genomes of both species and excellent genetic tools for the host, the wMel-D. melanogaster symbiosis is now an ideal system for studying the biology and evolution of Wolbachia infections.
TL;DR: The capacity of MNV-1 to replicate in a STAT-1-regulated fashion and the unexpected tropism of a norovirus for cells of the hematopoietic lineage provide important insights into Norovirus biology.
Abstract: Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine norovirus 1 (MNV-1) infects macrophage-like cells in vivo and replicates in cultured primary dendritic cells and macrophages. MNV-1 growth was inhibited by the interferon-alphabeta receptor and STAT-1, and was associated with extensive rearrangements of intracellular membranes. An amino acid substitution in the capsid protein of serially passaged MNV-1 was associated with virulence attenuation in vivo. This is the first report of replication of a norovirus in cell culture. The capacity of MNV-1 to replicate in a STAT-1-regulated fashion and the unexpected tropism of a norovirus for cells of the hematopoietic lineage provide important insights into norovirus biology.
TL;DR: Evidence linking Cd-related kidney dysfunction and decreases in bone mineral density in nonoccupationally exposed populations who showed no signs of nutritional deficiency points to the much-needed revision of the current provisional tolerable weekly intake (PTWI) for Cd.
Abstract: Cadmium is a cumulative nephrotoxicant that is absorbed into the body from dietary sources and cigarette smoking The levels of Cd in organs such as liver and kidney cortex increase with age because of the lack of an active biochemical process for its elimination coupled with renal reabsorption Recent research has provided evidence linking Cd-related kidney dysfunction and decreases in bone mineral density in nonoccupationally exposed populations who showed no signs of nutritional deficiency This challenges the previous view that the concurrent kidney and bone damage seen in Japanese itai-itai disease patients was the result of Cd toxicity in combination with nutritional deficiencies, notably, of zinc and calcium Further, such Cd-linked bone and kidney toxicities were observed in people whose dietary Cd intakes were well within the provisional tolerable weekly intake (PTWI) set by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives of 1 μg/kg body weight/day or 70 μg/day This evidence points to the much-needed revision of the current PTWI for Cd Also, evidence for the carcinogenic risk of chronic Cd exposure is accumulating and Cd effects on reproductive outcomes have begun to emerge
TL;DR: The role of follower self-conception in leader-ship effectiveness is discussed in this paper, where it is shown that self-construal, selfefficacy, self-esteem, and self-consistency may be affected by leadership and may mediate the effects of leadership on follower behavior.
Abstract: This article reviews empirical research on the role of follower self-conception in leader-ship effectiveness. and specifies an agenda for future research in this area. The review shows that several aspects of follower self-conception (i.e., self-construal, self-efficacy, self-esteem, and self-consistency) may be affected by leadership. and may mediate the effects of leadership on follower behavior. There also is consistent evidence that follower self-construal moderates the impact of leadership on follower attitudes and behavior. Two key themes for future research are defined. First, future research should focus on the development of theory about the role of relational self-construal in the leadership process. Second, it seems particularly valuable to develop theory about the interplay of different aspects of follower self-conception in leadership effectiveness. including the interactive effects of these aspects of self Working backwards from these theoretical models of follower self-conception, specific leader behavior relevant to these aspects of self should then be identified. (C) 2004 Elsevier Inc. All rights reserved.
TL;DR: In this article, a review suggests that this technology has immense potential for research in basic and applied animal ecology and that efforts to incorporate biotelemetry into broader ecological research programs should yield novel information that has been challenging to collect historically from free-ranging animals in their natural environments.
Abstract: Remote measurement of the physiology, behaviour and energetic status of free-living animals is made possible by a variety of techniques that we refer to collectively as 'biotelemetry'. This set of tools ranges from transmitters that send their signals to receivers up to a few kilometers away to those that send data to orbiting satellites and, more frequently, to devices that log data. They enable researchers to document, for long uninterrupted periods, how undisturbed organisms interact with each other and their environment in real time. In spite of advances enabling the monitoring of many physiological and behavioural variables across a range of taxa of various sizes, these devices have yet to be embraced widely by the ecological community. Our review suggests that this technology has immense potential for research in basic and applied animal ecology. Efforts to incorporate biotelemetry into broader ecological research programs should yield novel information that has been challenging to collect historically from free-ranging animals in their natural environments. Examples of research that would benefit from biotelemetry include the assessment of animal responses to different anthropogenic perturbations and the development of life-time energy budgets.
TL;DR: Critics have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within ‘acceptable’ ranges, and controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring.
Abstract: The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.
TL;DR: This data driven and experts' opinion approach is the basis for proposing an optimal simplified set of responder criteria for OA clinical trials.
TL;DR: Since GlyRs are involved in motor reflex circuits of the spinal cord and provide inhibitory synapses onto pain sensory neurons, these agents may provide lead compounds for the development of muscle relaxant and peripheral analgesic drugs.
Abstract: The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ion channels. Functional receptors of this family comprise five subunits and ...
TL;DR: Do non-coding RNAs that are derived from the introns and exons of protein- coding and non-protein-c coding genes represent a fundamental advance in the genetic operating system of higher organisms?
Abstract: Do non-coding RNAs that are derived from the introns and exons of protein-coding and non-protein-coding genes represent a fundamental advance in the genetic operating system of higher organisms? Recent evidence from comparative genomics and molecular genetics indicates that this might be the case. If so, there will be profound consequences for our understanding of the genetics of these organisms, and in particular how the trajectories of differentiation and development and the differences among individuals and species are genomically programmed. But how might this hypothesis be tested?
TL;DR: The SCAS-P is recommended as a screening instrument for normal children and as a diagnostic instrument in clinical settings and for both convergent and divergent validity: the measure correlated well with the parent report for internalizing symptoms, and lower with externalizing symptoms.
TL;DR: This paper reviews data from a variety of sources that have some bearing on questions of the origins of social fears and concludes with an initial model that draws together some of the current findings and aims to provide a platform for future research directions.
TL;DR: The literature dealing with the electrochemical corrosion characteristics of unalloyed copper in aqueous chloride media is examined in this paper, where a wide range of electrode geometries, the importance of the chloride ion and the mass transport of anodic corrosion products on the corrosion behaviour of copper are made clear for both freshly polished and ‘filmed’ surfaces.