bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug development for liver diseases: focus on picroliv, ellagic acid and curcumin
Authors: Girish C. , Pradhan Suresh Chandra 
Published: November 2008

AbstractThe use of herbal drugs for the treatment of liver diseases has a long tradition in many eastern countries. The easy accessibility without the need for laborious pharmaceutical synthesis has drawn increased attention towards herbal medicines. Few herbal preparations exist as standardized extracts with major known ingredients or even as pure compounds. Some of the herbals, which show promising activity, are ellagic acid for antifibrotic treatment, phyllanthin for treating chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis and picroliv for liver regeneration. These compounds, which have proven antioxidant, antiviral or anticarcinogenic properties, can serve as primary compounds for further development as hepatoprotective drugs. This review provides the chemistry, pharmacology and future aspects of picroliv, ellagic acid and curcumin with focus on hepatoprotective properties. These phytochemicals may prove to be very useful in the treatment of hepatotoxicity induced by viral agents, toxic drugs and plant poisons. The high safety profile may be an added advantage. However, poor bioavailability and temperature and light sensitivity can reduce the efficacy of drugs like curcumin. In future, the derivatives or new combinations of these drugs may prove to be useful.
In vitro effects of the cyclooxygenase inhibitor indomethacin and of the phospholipase‐C inhibitor U‐73122 on carbachol‐induced contractions of porcine detrusor muscle
Authors: Badawi Jasmin Katrin , Seja Tobias , Bross Stephan 
Published: November 2008

AbstractProstaglandin synthetase inhibitors belong to one substance class additionally used in the treatment of bladder dysfunctions associated with involuntary bladder contractions. However, the mechanism of action of non‐steroidal anti‐inflammatory drugs (NSAIDs) on the detrusor muscle is not clear. In this study, it was examined in vitro whether the NSAID indomethacin exhibited an inhibitory effect on carbachol‐induced contractions of the porcine detrusor muscle. Additionally, the inhibitory effect of the phospholipase‐C inhibitor U‐73122 on carbachol‐induced contractions of the porcine detrusor muscle was investigated. Experiments were performed on the muscle strips of the porcine detrusor muscle suspended in a tissue bath. Effects of indomethacin at 10−6and 10−5 mon the maximum carbachol‐induced contraction and on the carbachol–response curve were investigated. Additionally, the inhibitory influence of U‐73122 at a concentration of 10−5.5 mon the carbachol–response curve was investigated. Pretreatment with indomethacin at both concentrations did not result in a significant reduction in the maximum contraction compared with the control. In the experiments in which carbachol concentration‐response curves were generated, indomethacin exhibited at both concentrations a very small but significant change at carbachol concentrations of 10−8and 10−7.5 m. In the experiments with U‐73122, a significant change was found in the concentration–response curve of carbachol at all concentrations of carbachol from 10−6.5to 10−4 m. The mean maximum carbachol‐induced contraction was 141.8 ± 6.8% after incubation with U‐73122 and 166.0 ± 6.4% in the control group (P < 0.05). Indomethacin did not inhibit the carbachol‐induced contractions of the porcine detrusor muscle. The cyclooxygenase does not play a significant role in the carbachol‐induced bladder contraction of the porcine detrusor muscle. The inhibitory action of the phospholipase‐C inhibitor U‐73122 on the carbachol‐induced contraction was significant, but small. The results point to an inferior role of this pathway.
Role of endogenous endothelin in endothelial dysfunction in murine model of systemic sclerosis: tight skin mice 1
Authors: Richard Vincent , Solans Violaine , Favre Julie , Henry Jean‐Paul , Lallemand Françoise , Thuillez Christian , Marie Isabelle 
Published: November 2008

AbstractSystemic sclerosis (SSc) is a systemic inflammatory disorder, resulting in severe vascular dysfunction. The endothelin (ET) system has vasoconstrictor and profibrotic properties and has been shown to be activated in SSc. ET antagonists are currently used in SSc‐related pulmonary arterial hypertension, but the endothelial impact of ET antagonists remains less known in SSc. We thus assessed the effects of the dual ETA–ETB antagonist, bosentan, on endothelial dysfunction in a murine model of SSc, the heterozygous tight‐skin mice 1 (TSK1+). Six‐week‐old TSK1+ were either untreated or treated for 6 weeks with bosentan (100 mg/kg/day), and compared with controls. Endothelial function was evaluated in isolated mesenteric resistance arteries, using a small vessel myograph. TSK1+ displayed endothelial dysfunction, as shown by a decreased response of mesenteric arteries to acetylcholine, especially in the presence of l‐nitro‐arginine methyl ester (l‐NAME), corresponding to NO‐independent, prostaglandin‐mediated relaxation. The NO‐independent relaxation was partially restored in bosentan‐treated TSK1+, and this was abolished by a cyclo‐oxygenase inhibitor. Therefore, the murine model of SSc, TSK1+ exhibits severe endothelial dysfunction of peripheral resistance arteries. The ET antagonist bosentan prevents endothelial alterations, suggesting a major role of ET in the adverse vascular effects of SSc.
Pharmacokinetic predictions in children by using the physiologically based pharmacokinetic modelling
Authors: Bouzom F. , Walther B. 
Published: November 2008

AbstractNowadays, 50–90% of drugs used in children have never been actually studied in this population. Consequently, either our children are often exposed to the risk of adverse drug events or to lack of efficacy, or they are unable to benefit from a number of therapeutic advances offered to adults, as no clinical study has been properly performed in children. Actually the main methods used to calculate the dose for a child are based on allometric methods taking into account different categories of age, the body weight and/or the body surface area. Unfortunately, these calculation methods consider the children as small adults, which is not the case. Physiologically based pharmacokinetics is one way to integrate the physiological changes occurring in the childhood and to anticipate their impact on the pharmacokinetic processes: absorption, distribution, metabolism and excretion/elimination. From different examples, the application of this modelling approach is discussed as a possible and valuable method to minimize the ethical and technical difficulties of conducting research in children.
Evaluation of drugs in pediatrics using K‐PD models: perspectives
Authors: Tod M. 
Published: November 2008

AbstractSome pharmacodynamic (PD) models, called K‐PD models, have been developed for the description of drug action kinetics in the absence of drug concentration measurements. Because blood samples for drug measurements are not needed, these models may be very useful in pediatric studies, by reducing their invasiveness. In addition, a number of PD measurements are also non‐invasive and specific devices exist for measures in children. Therefore, the kinetics of drug action may be characterized with minimal invasiveness. A brief description of the key features of these models is given, and a number of examples of application are presented. K‐PD models are expected to be most useful when the drug kinetics is simple (i.e. when the one‐compartment model is a reasonable description), or when the response kinetics is slow compared with drug kinetics. K‐PD models have already demonstrated their usefulness in animal and adult studies. They are very attractive for pediatric studies and they should facilitate the assessment of drug efficacy and safety.
Integration of modelling and simulation into the development of intravenous busulfan in paediatrics: an industrial experience
Authors: Nguyen L. 
Published: November 2008

AbstractBusulfan (Bu) is commonly used in preparative conditioning regimen prior to bone marrow transplantation in infants (< 1 year old), children and adolescents (up to 17 years old). The clinical development of an intravenous form of busulfan (Busilvex®) was based on pharmacokinetic (PK) modeling and simulation techniques. A retrospective population PK analysis was initially performed from a first study in 24 pediatric patients (0.45–16.7 years old) and a log‐linear relationship between body weight and Busilvex® clearance was demonstrated with no age‐dependency. For an optimal area under the curve (AUC) targeting, a new Bu dosing regimen [i.e. 5 dose levels (0.80 to 1.20 mg/kg) adjusted to 5 discrete weight categories] was developed and assessed through population PK‐based simulations. The benefit from this new dosing strategy was validated in a second trial including 55 children (0.30–17.2 years old). This prospective trial confirmed the previous simulations: an efficient therapeutic targeting whatever the patient's age or body weight. Over 80% of the children were within the desired plasma exposure window, and the initial PK model was validated on the confirmatory dataset.
The use of pharmacokinetic models in paediatric onco‐haematology: effects on clinical outcome through the examples of busulfan and cyclosporine
Authors: Bleyzac N. 
Published: November 2008

AbstractOverall survival after allogeneic haematopoietic stem cell transplantation (HSCT) is reduced by the high rate of transplantation‐related mortality (TRM), especially because of liver veno‐occlusive disease (VOD) or acute graft‐vs.‐host disease (GVHD) because of the toxicity or inefficacy of busulfan and cyclosporine (CsA), respectively. Results of clinical outcome of previous studies performed to optimize busulfan and CsA therapy by controlling their pharmacokinetic variability by means of maximum a posteriori (MAP) Bayesian individualization of both drugs are presented. The 90‐day VOD‐free survival was significantly higher in patients with individualized busulfan doses: 97% vs. 76%. Monitoring CsA trough blood concentrations allowed us to obtain a successful GVHD outcome (mild or moderate GVHD and graft vs. leukaemia effect (GVL) in malignant diseases and no GVHD (in non‐malignant ones) in the majority of our patients. Severe GVHD occurred in <5% of patients. TRM in children can be significantly decreased by using population pharmacokinetic models and MAP Bayesian individualization of dose regimens for drugs such as CsA and busulfan.
Plasticity of death rates in stationary phase in Saccharomyces cerevisiae
Authors: Minois Nadège , Lagona Francesco , Frajnt Magdalena , Vaupel James W. 
Published: November 2008

SummaryFor the species that have been most carefully studied, mortality rises with age and then plateaus or declines at advanced ages, except for yeast. Remarkably, mortality for yeast can rise, fall and rise again. In the present study we investigated (i) if this complicated shape could be modulated by environmental conditions by measuring mortality with different food media and temperature; (ii) if it is triggered by biological heterogeneity by measuring mortality in stationary phase in populations fractionated into subpopulations of young, virgin cells, and replicatively older, non‐virgin cells. We also discussed the results of a staining method to measure viability instead of measuring the number of cells able to exit stationary phase and form a colony. We showed that different shapes of age‐specific death rates were observed and that their appearance depended on the environmental conditions. Furthermore, biological heterogeneity explained the shapes of mortality with homogeneous populations of young, virgin cells exhibiting a simple shape of mortality in conditions under which more heterogeneous populations of older cells or unfractionated populations displayed complicated death rates. Finally, the staining method suggested that cells lost the capacity to exit stationary phase and to divide long before they died in stationary phase. These results explain a phenomenon that was puzzling because it appeared to reflect a radical departure from mortality patterns observed for other species.
Predicting Admissions for Childhood Asthma Based on Proximity to Major Roadways
Authors: Newcomb Patricia , Li Jianling 
Published: November 2008

Purpose: This retrospective study is an investigation of the relationship between traffic exposure and childhood asthma exacerbations in a previously unstudied geographic area. We hypothesized that, controlling for selected demographic and social factors, exposure to traffic emissions would allow the prediction of hospital utilization for children with asthma.
Design: Using hospital and emergency department (ED) records, we investigated the relationship between proximity to major roadways and admissions for asthma exacerbations in the Fort Worth metropolitan area, designated as not attaining federal air health standards. The sample included 2,357 children from 1 to 12 years of age admitted for emergency or inpatient treatment in a 288‐bed, nonprofit children's medical center in Fort Worth, Texas from January 1, 2004 to December 31, 2005. Data were analyzed using GIS mapping and logistic regression.
Methods: Deidentification data were collected from hospital databases after IRB approval and waiver of parental permission or patient consent. Student's t test was used to compare groups with and without primary asthma diagnosis on admission in respect to distance from major roadways. Logistic regression was used to model relationships between asthma admission and patients' characteristics, exposure to traffic, and social environment.
Findings: Controlling for several demographic factors, asthma occurrences were positively related to traffic exposures. On average, patients with asthma lived closer to major roadways than did patients who did not have asthma. Patients with asthma also tended to live in neighborhoods with more roads than did those who did not have asthma; 3/4 of the children admitted for asthma during the study period and less than 1/3 of the children admitted for nonasthma diagnoses lived within 1,500 meters of a major roadway (p=.0001). Controlling for other factors, every meter increase in proximity to major roadways produced 0.1% increase in likelihood of admission.
Clinical Relevance: Knowledge of risk factors and their relative magnitudes enable nurses to better tailor symptom management for individual patients.
Neurofibromatosis 2 leads to higher incidence of strabismological and neuro‐ophthalmological disorders
Authors: Feucht Matthias , Griffiths Birgit , Niemüller Ilka , Haase Wolfgang , Richard Gisbert , Mautner Victor‐Felix 
Published: November 2008

Abstract.Purpose:  Ophthalmic features of neurofibromatosis 2 (NF2) include juvenile cataract, retinal hamartomas and tumours of the cranial nerves. We hypothesize that these tumours lead to strabismological and neuro‐ophthalmological symptoms, including palsies of cranial nerves III, IV and VI, nystagmus and gaze palsies.Methods:  We carried out a retrospective review of 73 patients with known genotype. They underwent ophthalmic, neuro‐ophthalmological and strabismological examination. Statistical analysis was performed by calculating odds ratios and their 95% confidence intervals.Results:  Mean best corrected visual acuity was 0.85. Strabismus was found in 38 of 73 patients (52%). A deviation based on a cranial nerve palsy was found in 16 patients (22%) and three had supranuclear palsies. Eleven of 73 patients had a nystagmus, mostly caused by peripheral–vestibular disturbance. Binocular single vision was normal in 41 (58%), subnormal in six (8%) and not present in 24 (34%) patients. The average refractive error was − 0.57 D. Myopia of ≥ 0.5 D was present in 47 (33%) eyes and hyperopia of ≥ 2.0 D was measured in 11 (8%) eyes. In the subgroup analysis of NF2 mutation types, the relative risk for cranial nerve palsies and negative stereopsis was statistically significantly increased for the nonsense mutation group. The mosaicism group had a statistically significant decreased relative risk for concomitant squint, as did patients with unfound mutations for strabismus and poor stereopsis.Conclusions:  The present study is, to our knowledge, the first to examine a larger collection of NF2 patients for strabismological and neuro‐ophthalmological lesions. Compared with the normal population, our sample showed a higher amount of strabismus, refractive errors and an increased incidence of vestibular nystagmus.
Exploring the mast cell enigma: a personal reflection of what remains to be done
Authors: Henz Beate M. 
Published: November 2008

Abstract: Mast cells are traditionally viewed as effector cells of allergic reactions and parasitic diseases, but their importance in host defense against bacteria, in tissue remodelling, their bone marrow and stem cell origin and a central role of the stem cell factor (SCF) as mast cell growth and chemotactic factor has been worked out only in recent years. Despite this, major aspects about the nature of the cells and their role in disease remain unclear. This holds in particular for the identification of mast cell precursors and the role of growth factors that stimulate specific mast cell commitment from stem cells, such as nerve growth factor, neutrotrophin‐3 and certain interleukins, alone and during interaction with SCF. Early data suggesting also an involvement of specific transcription factors need to be expanded in this process. Furthermore, although mast cell proliferative disease (mastocytosis) has been shown to be often associated with SCF receptor c‐kit mutations, reasons for the development of this disease remain unclear. This holds also for mast cell release mechanisms in many types of mast cell‐dependent urticaria. Exciting new insights are emerging regarding the role of mast cells in bacterial infections, in defense against tumors, in wound healing and in the interplay with the nervous system, with hormones, and in the neurohormonal network. The aim of this reflection is to delineate the many known and unknown aspects of mast cells, with a special focus on their development, and to discuss in detail two mast cell‐related diseases, namely mastocytosis and urticaria.
The evolution of a pre-heated intergalactic medium
Authors: Borgani S. , Viel M. 
Published: November 2008

Abstract
We analyse the evolution of the intergalactic medium by means of an extended set of large box size hydrodynamical simulations which include pre-heating. We focus on the properties of the z∼ 2 Lyman α forest and the population of clusters and groups of galaxies at z= 0. We investigate the distribution of voids in the Lyman α flux and the entropy–temperature relation of galaxy groups, comparing the simulation results to recent data from high-resolution quasar spectra and X-ray observations. Pre-heating is included through a simple phenomenological prescription, in which at z= 4 the entropy of all gas particles, whose overdensity exceeds a threshold value δh, is increased to a minimum value Kfl. While the entropy level observed in the central regions of galaxy groups requires a fairly strong pre-heating, with Kfl &gt; 100 keV cm2, the void statistics of the Lyman α forest impose that this pre-heating should take place only in relatively high-density regions, δh≳ 30, in order not to destroy the cold filaments that give rise to the forest. We conclude that any injection of non-gravitational energy in the diffuse baryons should avoid low-density regions at high redshift and/or take place at relatively low redshift z≲ 1.
A Strategic Framework for Monitoring Coastal Change in Australia's Wet‐dry Tropics – Concepts and Progress
Authors: MAX FINLAYSON C. , ELIOT IAN , ELIOT MATTHEW 
Published: November 2008

AbstractA strategic framework for monitoring natural and human‐induced change in the coastal plains of the Alligator Rivers Region in the wet‐dry tropics of northern Australia is presented. The framework also supports refinement of methods used to monitor the vulnerability of coastal areas to change, including human‐induced climate change and sea‐level rise. The information derived through the framework can be used to assess scenarios, highlight the potential significance and implications of changes, and assist land managers formulate management responses.The framework incorporates several large‐scale studies for monitoring atmospheric and hydrodynamic processes as well as mapping and monitoring projects specific to environmental change in the freshwater wetlands and the floodplains of the Region. Monitoring is proposed to address processes influencing the stability and rate of change of the floodplain environments. These include large‐scale processes, such as inter‐annual variability in weather conditions affecting the morphology of the coastal plains, shoreline and riverbank stabilisation, headward expansion of tidal creeks, and salinisation of freshwater basins.Information management is also addressed, and a Geographic Information System structure proposed for effective data collation, analysis and management. The information management system will facilitate data sharing and participation of multiple agencies and organisations interested in coastal change, especially where a landscape perspective or whole ecosystem approach is advocated.
Planning to Reduce Risk: The Wildfire Management Overlay in Victoria, Australia
Authors: HUGHES RACHEL , MERCER DAVID 
Published: November 2008

AbstractIn a world where climate change is a ‘given’, the concepts of vulnerability, resilience and risk are now pivotal in public policy debates in many countries. Within this context, planning controls are designed to facilitate safe, sustainable and prosperous communities. In line withMarch's (2007, 11) observation that ‘one important “reason to plan” is the reduction of risk’, Victoria's Wildfire Management Overlay (WMO) was developed with the aim of mitigating wildfire risk through the identification of high risk areas and ensuring that minimum fire protection measures are implemented. The need for such an Overlay is becoming increasingly apparent as climate change contributes to the growing frequency and intensity of bushfires in Australia. Empirical research has found that, by following WMO prescriptions, the risk of a dwelling igniting from direct flame or radiant heat generated in a one in 50‐year fire event can be greatly minimised. Yet not all local Councils in Victoria have built the WMO into their land use planning processes and schemes. Barriers to adoption include: lack of political will, a distrust of ‘over‐regulation’, lack of training and mentoring of planning staff, and potential conflicts with vegetation conservation objectives.