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Lower Limit (lower + limit)
Selected AbstractsYouden Index and Optimal Cut-Point Estimated from Observations Affected by a Lower Limit of DetectionBIOMETRICAL JOURNAL, Issue 3 2008Marcus D. Ruopp Abstract The receiver operating characteristic (ROC) curve is used to evaluate a biomarker's ability for classifying disease status. The Youden Index (J), the maximum potential effectiveness of a biomarker, is a common summary measure of the ROC curve. In biomarker development, levels may be unquantifiable below a limit of detection (LOD) and missing from the overall dataset. Disregarding these observations may negatively bias the ROC curve and thus J. Several correction methods have been suggested for mean estimation and testing; however, little has been written about the ROC curve or its summary measures. We adapt non-parametric (empirical) and semi-parametric (ROC-GLM [generalized linear model]) methods and propose parametric methods (maximum likelihood (ML)) to estimate J and the optimal cut-point (c *) for a biomarker affected by a LOD. We develop unbiased estimators of J and c * via ML for normally and gamma distributed biomarkers. Alpha level confidence intervals are proposed using delta and bootstrap methods for the ML, semi-parametric, and non-parametric approaches respectively. Simulation studies are conducted over a range of distributional scenarios and sample sizes evaluating estimators' bias, root-mean square error, and coverage probability; the average bias was less than one percent for ML and GLM methods across scenarios and decreases with increased sample size. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods. We address the limitations and usefulness of each method in order to give researchers guidance in constructing appropriate estimates of biomarkers' true discriminating capabilities. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointmentPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 2p1 2010N. Doss Doss N, Kamoun M-R, Dubertret L, Cambazard F, Remitz A, Lahfa M, de Prost Y. Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointment. Pediatr Allergy Immunol 2010: 21: 321,329. © 2009 John Wiley & Sons A/S Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2,15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of ,60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was ,11.8%, exceeding the non-inferiority limit of ,15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 ± 5.0 and 8.6 ± 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep. [source] Screening for the calstabin-ryanodine receptor complex stabilizers JTV-519 and S-107 in doping control analysisDRUG TESTING AND ANALYSIS, Issue 1 2009Mario Thevis Abstract Recent studies outlined the influence of exercise on the stability of the skeletal muscle calstabin1-ryanodine receptor1-complex, which represents a major Ca2+ release channel. The progressive modification of the type-1 skeletal muscle ryanodine receptor (RyR1) combined with reduced levels of calstabin1 and phosphodiesterase PDE4D3 resulted in a Ca2+ leak that has been a suggested cause of muscle damage and impaired exercise capacity. The use of 1,4-benzothiazepine derivatives such as the drug candidates JTV-519 and S-107 enhanced rebinding of calstabin1 to RyR1 and resulted in significantly improved skeletal muscle function and exercise performance in rodents. Due to the fact that the mechanism of RyR1 remodelling under exercise conditions were proven to be similar in mice and humans, a comparable effect of JTV-519 and S-107 on trained athletes is expected, making the compounds relevant for doping controls. After synthesis of JTV-519, S-107, and a putative desmethylated metabolite of S-107, target compounds were characterized using nuclear magnetic resonance spectroscopy and electrospray ionization (ESI),high-resolution/high-accuracy Orbitrap mass spectrometry. Collision-induced dissociation pathways were suggested based on the determination of elemental compositions of product ions and H/D-exchange experiments. The most diagnostic product ion of JTV-519 was found at m/z 188 (representing the 4-benzyl-1-methyl piperidine residue), and S-107 as well as its desmethylated analog yielded characteristic fragments at m/z 153 and 138 (accounting for 1-methoxy-4-methylsulfanyl-benzene and 4-methoxy-benzenethiol residues, respectively). The analytes were implemented in existing doping control screening procedures based on liquid chromatography, multiple reaction monitoring and simultaneous precursor ion scanning modes using a triple quadrupole mass spectrometer. Validation items such as specificity, recovery (68,92%), lower limit of detection (0.1,0.2 ng/mL), intraday (5.2,18.5%) and interday (8.7,18.8%) precision as well as ion suppression/enhancement effects were determined. Copyright © 2009 John Wiley & Sons, Ltd. [source] Processes and mechanisms of dynamic channel adjustment to delta progradation: the case of the mouth channel of the Yellow River, ChinaEARTH SURFACE PROCESSES AND LANDFORMS, Issue 6 2003Changxing Shi Abstract This paper analyses the processes and mechanisms of a three-stage channel adjustment over a cycle of the Yellow River mouth channel extension based on data comprising hydrologic measurements and channel geometric surveys. Rapid siltation in the mouth channel takes place in the young stage when the channel is being built by deposits and in the old stage when the channel cannot further adjust itself to keep sediment transport in equilibrium. It is disclosed that the bankfull width,depth ratio, bed material size and slope decrease in the young and mature stages but do not change in the old stage. The reduction of bankfull width,depth ratio and bed material size during the young and mature stages is found to be able to offset the effect of the slope reduction on sediment transport due to continuous mouth progradation. They reach their limits in old stage, and a constant slope is kept by unceasing sediment accumulation. The grain size composition of incoming sediment and the fining mechanism are responsible for the occurrence of lower limit of bed material size. The reason for the existence of a limit of bankfull cross-sectional shape is that the large flows can fully transport the sediment load they are carrying, and siltation in the channel in the old stage takes place mainly in the low flows. It is suggested that the bankfull discharge plays an important role in shaping the channel but that the entire channel form is the product of both the large and low flows plus the effects of interaction between them. Channel pattern change shows a process from a braided pattern in the young stage to a straight pattern in the mature and old stages, and the straight channel becomes gradually sinuous. The occurrence and transformation of the channel patterns are supported by two planform predictors, but are also facilitated by some other conditions. Copyright © 2003 John Wiley & Sons, Ltd. [source] Lead(II) Potentiometric Sensor Based on 1,4,8,11-Tetrathiacyclotetradecane Neutral Carrier and Lipophilic AdditivesELECTROANALYSIS, Issue 11 2008Mohamed Abstract A potentiometric sensor for lead(II) ions based on the use of 1,4,8,11-tetrathiacyclotetradecane (TTCTD) as a neutral ionophore and potassium tetrakis-(p -chlorophenyl)borate as a lipophilic additive in plasticized PVC membranes is developed. The sensor exhibits linear potentiometric response towards lead(II) ions over the concentration range of 1.0×10,5,1.0×10,2,mol L,1 with a Nernstian slope of 29.9,mV decade,1 and a lower limit of detection of 2.2×10,6,mol L,1 Pb(II) ions over the pH range of 3,6.5. Sensor membrane without a lipophilic additive displays poor response. The sensor shows high selectivity for Pb(II) over a wide variety of alkali, alkaline earth and transition metal ions. The sensor shows long life span, high reproducibility, fast response and long term stability. Validation of the method by measuring the lower limit of detection, lower limit of linear range, accuracy, precision and sensitivity reveals good performance characteristics of the proposed sensor. The developed sensor is successfully applied to direct determination of lead(II) in real samples. The sensor is also used as an indicator electrode for the potentiometric titration of Pb(II) with EDTA and potassium chromate. The results obtained agree fairly well with data obtained by AAS. [source] Investigation of the Effect of Different Glassy Carbon Materials on the Performance of Prussian Blue Based Sensors for Hydrogen PeroxideELECTROANALYSIS, Issue 3 2003Francesco Ricci Abstract Three different kinds of glassy carbon (GC-R, GC-K, GC-G) were equally pretreated, further modified with electrochemically deposited Prussian Blue and used as sensors for hydrogen peroxide at an applied potential of ,50,mV (vs. Ag|AgCl). Their performance was evaluated with respect to the following parameters: the coverage and electrochemistry of the electrodeposited Prussian Blue, the sensitivity and the lower limit of detection for hydrogen peroxide, and the operational stability of the sensors. GC-R showed the best behavior concerning the surface coverage and the operational stability of the electrodeposited Prussian Blue. For this electrode the sensitivity for hydrogen peroxide (10,,M) was 0.25,A/M cm2 and the detection limit was 0.1,,M. Scanning electron microscopy was used to study the surfaces of the three electrodes before and after the electrodeposition of Prussian Blue and to search for the reason for the three different behaviors between the different glassy carbon materials. The Prussian Blue modified GC-R was also used for the construction of a glucose biosensor based on immobilizing glucose oxidase in Nafion membranes on top of electrodeposited Prussian Blue layer. The operational stability of the glucose biosensors was studied in the flow injection mode at an applied potential of ,50,mV (vs. Ag|AgCl) and alternatively injecting standard solutions of hydrogen peroxide (10,,M) and glucose (1,mM) for 3,h. For the GC-R based biosensor a 2.8% decrease of the initial glucose response was observed. [source] Ethyl glucuronide in hair.ADDICTION, Issue 6 2009A sensitive, specific marker of chronic heavy drinking ABSTRACT Aims This study aims to define a cut-off concentration for ethyl glucuronide in hair to determine if there was a history of heavy drinking. Settings Pavia, Italy. Participants We analysed hair samples from 98 volunteers among teetotallers, social drinkers and heavy drinkers, whose ethanol daily intake (EDI) was estimated by means of a written questionnaire. Measurements Ethyl glucuronide hair concentration (HEtG) was measured by liquid chromatography-tandem mass spectrometry (lower limit of quantification: 3 pg/mg) using a fully validated method. Findings The HEtG level providing the best compromise between sensitivity (0.92) and specificity (0.96) at detecting an EDI of 60 g or higher during the last 3 months was 27 pg/mg. None of the factors examined among those known to affect ethanol metabolism and/or the diagnostic power of other markers of ethanol use or hair analyses, including age, gender, body mass index, tobacco smoke, prevalent beverage, hair colour, cosmetic treatments and hygienic habits was found to influence marker performance significantly. However, the slight differences in HEtG performance observed for some factors (e.g. body mass index, smoke and hair treatments) require further studies on larger groups of individuals in order to assess their influence more precisely. Conclusions Our results confirm further that HEtG is a sensitive and specific marker of chronic heavy drinking. [source] Thyroid Function in Girls with Epilepsy with Carbamazepine, Oxcarbazepine, or Valproate Monotherapy and after Withdrawal of MedicationEPILEPSIA, Issue 3 2004Leena K. Vainionpää Summary: Purpose: Antiepileptic drugs may affect the serum thyroid hormone concentrations. The aim of this study was to evaluate thyroid function in 78 girls taking carbamazepine (CBZ), oxcarbazepine (OXC), or valproate (VPA) monotherapy for epilepsy and after withdrawal of the treatment. Methods: Forty-one girls taking VPA, 19 taking CBZ, and 18 taking OXC for epilepsy, as well as 54 healthy age-matched controls, aged 8 to 18 years, participated in the study. All the girls were examined clinically, and their pubertal stage was assessed. Blood samples were obtained for thyroid hormone and antibody assays. These examinations were repeated after a mean follow-up of 5.8 years to assess thyroid function, and 64 (82%) of 78 patients and 42 (78%) of 54 controls agreed to participate in the second evaluation. Results: In the first evaluation, the mean serum thyroid hormone concentrations were lower in the girls taking CBZ [thyroxine (T4), 70.2; SD, 10.9 nM; and free thyroxine (FT4), 11.5; SD, 1.8 pM] or OXC (T4, 74.9; SD, 16.4 nM; and FT4, 11.3; SD, 1.8 pM) than in the control girls (T4, 96.6; SD, 15.1 nM, and FT4, 14.4; SD, 1.5 pM; p < 0.001, all comparisons). However, thyrotropin (TSH) concentrations were normal in the girls taking CBZ or OXC. Sixty-three% of the girls taking CBZ and 67% of the girls taking OXC had serum T4 and/or FT4 levels below the lower limit of the reference range. The VPA-treated girls with epilepsy had normal serum T4 and FT4 concentrations, but slightly increased TSH levels (3.3; SD, 1.5 mU/L; p < 0.01) compared with the control girls (2.5; SD, 1.0 mU/L). Normal serum hormone concentrations were restored in the patients who discontinued the medication. Conclusions: Both CBZ and OXC reduce serum thyroid hormone concentrations in girls with epilepsy. Conversely, VPA is associated with normal serum thyroid hormone and increased thyrotropin levels. However, our results suggest that the changes in serum thyroid hormone and thyrotropin levels are reversible after withdrawal of the medication. [source] Deslipping of Ester Rotaxanes: A Cooperative Interplay of Hydrogen Bonding with Rotational BarriersEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 24 2003Petra Linnartz Abstract A series of rotaxanes has been synthesized which contain two ester groups in their axles. All rotaxanes bear the same tetralactam wheel. The kinetics of the de-slipping reaction of these rotaxanes were monitored in tetrachloroethane (TCE) and dimethyl sulfoxide (DMSO) resulting in the observation of a significant solvent effect. In TCE, two isomeric rotaxanes that differ merely with respect to the orientation of the ester groups show a remarkable difference in their deslipping behavior. When the ester carbonyl group is directly attached to the axle center piece, the rotaxane decomposes with a half life of ca. 10 h at 100 °C. The reverse orientation with the carbonyl group attached to the stopper blocks deslipping almost completely and a lower limit for the half life at 100 °C of 25,000 h was obtained. These results can be interpreted by inferring a cooperative action of hydrogen bonding between wheel and axle and differences in rotational barriers. Molecular modeling and AM1 calculations support this interpretation. The implications of these results for the determination of steric size and the optimization of molecular machines are discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] A new role for MSY in single-species and ecosystem approaches to fisheries stock assessment and managementFISH AND FISHERIES, Issue 1 2001In 1977, Peter Larkin published his now-famous paper, ,An epitaph for the concept of maximum sustained yield'. Larkin criticized the concept of single-species maximum sustained yield (MSY) for many reasons, including the possibility that it may not guard against recruitment failure, and the impossibility of maximising sustainable yields for all species simultaneously. However, in recent years, there has been a fundamental change in the perception of the fishing mortality associated with MSY (FMSY) as a limit to be avoided rather than a target that can routinely be exceeded. The concept of FMSY as a limit is embodied in several United Nations Food and Agriculture Organization (FAO) agreements and guidelines, and has now been incorporated into the US Magnuson,Stevens Fishery Conservation and Management Act. As a result, the United States now requires the development of overfishing definitions based on biological reference points that treat the FMSY as a limit reference point and must also define a lower limit on biomass below which rebuilding plans with strict time horizons must be developed. This represents a major paradigm shift from the previously mandated (but often unachieved) objective to simply maintain fishing mortalities at levels below those associated with recruitment overfishing. In many cases, it requires substantial reductions in current fishing mortality levels. Therefore, the necessity of the new paradigm is continually questioned. This paper draws on examples from several fisheries, but specifically focuses on the recent US experience illustrating the practical difficulties of reducing fishing mortality to levels below those corresponding to MSY. However, several studies suggest that even more substantial reductions in fishing mortality may be necessary if ecosystem considerations, such as multispecies interactions, maintenance of biodiversity and genetic diversity, and reduction of bycatch and waste, are taken into account. The pros and cons of moving beyond single-species assessment and management are discussed. A US plan for improving stock assessments indicates that even a ,basic' objective such as ,adequate baseline monitoring of all managed species' may be extremely costly. Thus, the suggestion of Larkin (1983, 1997) that the costs of research and management should not exceed 10,20% of the landed value of the catch may preclude comprehensive ecosystem management. More importantly, neither single-species nor ecosystem-based fisheries management is likely to improve appreciably unless levels of fishing capacity are aligned with resource productivity, as is currently being promoted by FAO and several individual nations. [source] Thermal habitat of striped bass (Morone saxatilis) in coastal waters of northern Massachusetts, USA, during summerFISHERIES OCEANOGRAPHY, Issue 5 2010GARY A. NELSON Abstract Striped bass, Morone saxatilis, were captured and released with temperature-measuring data storage tags in Salem Sound, Massachusetts, to collect data on their thermal preferences in coastal and marine waters and to identify environmental factors that may influence temperatures experienced during their summer residence. Striped bass recaptured during summer of 2006 (21 of 151 releases) experienced a wide range of temperatures (6.5,28.0°C) while at-large for 1,53 days. Overall mean temperature and standard deviation selected by striped bass recaptured in Salem Sound during the longest commonly-shared duration of time (3,12 July) were 17.8 and 3.57°C, respectively. Comparison of temperature data between fish and 13 vertical arrays in Salem Sound revealed that striped bass experienced higher and more variable temperatures, and that daily changes in temperature actually experienced were unrelated to daily changes in surrounding ambient temperature. Regular cyclical changes in temperature of all striped bass and vertical arrays were identified as influences of the local tide, which contributed about a 2°C change in temperature, on average, over the complete cycle. Most striped bass appeared to limit their activities to depths shallower than the lower limit of the thermocline, above which temperatures generally exceed 9.0°C in Salem Sound. Therefore, it is likely that the vertical distribution of striped bass is restricted by the low temperatures below this depth. An implication of this finding is that the spatial distribution of striped bass may be defined coarsely by knowledge of the distribution of temperature in coastal areas. [source] New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humansFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2004M. Trellu Abstract Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax = 1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax = 0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1. [source] Rapid climate change-related growth decline at the southern range edge of Fagus sylvaticaGLOBAL CHANGE BIOLOGY, Issue 11 2006ALISTAIR S. JUMP Abstract Studies on Fagus sylvatica show that growth in populations toward the southern limit of this species' distribution is limited strongly by drought. Warming temperatures in the Mediterranean region are expected to exacerbate drought where they are not accompanied by increases in precipitation. We studied levels of annual growth in mature F. sylvatica trees over the last half-century in the Montseny Mountains in Catalonia (northeast Spain). Our results show significantly lower growth of mature trees at the lower limit of this species' distribution when compared with trees at higher altitudes. Growth at the lower Fagus limit is characterized by a rapid recent decline starting in approximately 1975. By 2003, growth of mature trees had fallen by 49% when compared with predecline levels. This is not an age-related phenomenon, nor is it seen in comparable populations at higher altitudes. Analysis of climate-growth relationships suggests that the observed decline in growth is a result of warming temperatures and that, as precipitation in the region has not increased, precipitation is now insufficient to ameliorate the negative effects of increased temperatures on tree growth. As the climate-response of the studied forest is comparable with that of F. sylvatica forests in other southern European regions, it is possible that this growth decline is a more widespread phenomenon. Warming temperatures may lead to a rapid decline in the growth of range-edge populations and a consequent retreat of the species distribution in southern Europe. Assessment of long-term growth trends across the southern range edge of F. sylvatica therefore merits further attention. [source] Process Considerations for Trolling Borehole Flow LogsGROUND WATER MONITORING & REMEDIATION, Issue 3 2006Phil L. Oberlander Horizontal hydraulic conductivity with depth is often understood only as a depth-integrated property based on pumping tests or estimated from geophysical logs and the lithology. A more explicit method exists for determining hydraulic conductivity over small vertical intervals by collecting borehole flow measurements while the well is being pumped. Borehole flow rates were collected from 15 deep monitoring wells on the Nevada Test Site and the Nevada Test and Training Range while continuously raising and lowering a high-precision impeller borehole flowmeter. Repeated logging passes at different logging speeds and pumping rates typically provided nine unique flow logs for each well. Over 60 km of borehole flow logs were collected at a 6.1-cm vertical resolution. Processing these data necessitated developing a methodology to delete anomalous values, smooth small-scale flow variations, combine multiple borehole flow logs, characterize measurement uncertainty, and determine the interval-specific lower limit to flow rate quantification. There are decision points in the data processing where judgment and ancillary analyses are needed to extract subtle hydrogeologic information. The analysis methodology indicates that processed measurements from a high-precision trolling impeller flowmeter in a screened well can confidently detect changes in borehole flow rate of ,0.7% of the combined trolling and borehole flow rate. An advantage of trolling the flowmeter is that the impeller is nearly always spinning as it is raised and lowered in the well and borehole flow rates can be measured at lower values than if measurements were taken while the flowmeter was held at a fixed depth. [source] Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor EffectHEADACHE, Issue 2 2010Anthony W. Fox (Headache 2010;50:249-255) Background., The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after Tmax = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life. Objective., The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. Methods., Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at Tmax, 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). Results., The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of Cmax). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC0-10h was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A. Conclusions., There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan. [source] Film boiling heat transfer around a vertical finite-length cylinder with a convex hemispherical bottomHEAT TRANSFER - ASIAN RESEARCH (FORMERLY HEAT TRANSFER-JAPANESE RESEARCH), Issue 3 2010Takashi Yamada Abstract The film boiling heat transfer around a vertical silver cylinder with a convex hemispherical bottom was investigated experimentally in quiescent water at atmospheric pressure. The experiments have been carried out using a quenching method. The diameter and length of the test cylinder are 32 mm and 48 mm, respectively. The test cylinder was heated to about 600 °C in an electric furnace and then cooled in saturated or subcooled water with an immersion depth of about 100 mm. The degree of liquid subcooling was varied from 0 K to 30 K. The analytical solutions for saturated and subcooled boiling are obtained by applying a two-phase boundary layer theory for vapor film with a smooth interface. The experimental data correlates within ±15% based on the proposed prediction method. Also, the lower limit of film boiling was examined in terms of wall heat flux and degree of superheating. © 2010 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/htj.20289 [source] Interleukin-17 as a new marker of severity of acute hepatic injuryHEPATOLOGY RESEARCH, Issue 4 2007Yuki Yasumi Aim:, To determine cytokines associated with the progression of acute hepatic injury (AHI), we comprehensively evaluated the serum levels of 17 cytokines. Methods:, We simultaneously measured serum levels of 17 cytokines on admission using a newly developed suspension array protein assay system in 51 patients with AHI, including 15 conventional AHI (CAHI), 15 severe AHI (SAHI) and 21 fulminant hepatic failure (FHF). Results:, Interleukin (IL)-6, IL-8 and IL-17 levels were significantly different among the three disease types as determined by one-way analysis of variance, and only the IL-17 level showed a significant elevation in SAHI and FHF than in CAHI. Namely, the IL-17 levels in SAHI and FHF patients were 4.4 (2.0,11.0) (mean [1 .s.d. range]) and 5.6 (2.0,18.5) pg/mL, respectively, whereas all CAHI patients showed levels lower than the lower limit of detection (2.0 pg/mL). In multiple regression analysis for each factor of model for end-stage liver disease (MELD) score, only IL-10 level was selected as the significant independent variable for total bilirubin level, only IL-17 level for prothrombin time, and TNF-, and IL-1, levels for creatinine level. Conclusion:, These data suggest the usefulness of serum IL-17 level in evaluating the severity of AHI, thus emphasizing the necessity for the basic investigation of the pathological role of IL-17 in acute hepatitis. [source] Mesalazine 4 g daily given as prolonged-release granules twice daily and four times daily is at least as effective as prolonged-release tablets four times daily in patients with ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 3 2001Dr. Per G. Farup Abstract Background High doses of mesalazine usually result in an inconvenient dosage schedule and reduced compliance. The goal of this trial was to compare the effects of mesalazine 4 g daily given as prolonged-release granules in packets of 1 g with that of prolonged-release tablets of 0.5 g. Methods Two hundred twenty-seven patients with mild-to-moderate ulcerative colitis were randomized to treatment with two packets twice daily (Gr-b.i.d.), 1 packet four times daily (Gr-q.i.d.) or 2 tablets four times daily (Ta-q.i.d.) for 8 weeks. A disease activity index (ulcerative colitis disease activity index; UC-DAI) was calculated, and the granules were defined as noninferior to the tablets if the lower limit of the 95% CI for the differences was more than ,1 UC-DAI score unit. Results Noninferiority of the granules compared with the tablets was demonstrated. The mean improvement in the UC-DAI in the treatment groups Gr-b.i.d., Gr-q.i.d., and Ta-q.i.d. were 3.2, 2.9, and 2.4, respectively; the proportion of complete responders in the three groups 39%, 37%, and 31%, respectively. There were no differences in side effects. Conclusion Mesalazine 4 g daily given as prolonged-release granules twice and four times daily is at least as effective as prolonged-release tablets four times daily in patients with mild to moderate ulcerative colitis. The patients preferred the twice daily dosing. [source] Linearity analysis in pipeline A/D convertersINTERNATIONAL JOURNAL OF CIRCUIT THEORY AND APPLICATIONS, Issue 6 2009Behnam Sedighi Abstract A method for estimating integral nonlinearity (INL) in pipeline analog-to-digital converters is presented. In this method, errors in each stage are modeled by an equivalent input-referred gain error and an input-referred nonlinearity. For a switched capacitor implementation, the proposed model predicts the maximum statistical INL in terms of capacitor mismatch and also provides an exact formula for INL in terms of finite gain of operational amplifiers. Using this model, it is proved that a high per-stage resolution reduces the power consumption in low-speed converters, whereas in high-speed circuits 1.5-bit or 2.5-bit stage is more advantageous. It is also shown that when voltage swing is below 1,V, the lower limit for the size of the capacitors is mainly determined by thermal noise rather than by INL. Copyright © 2008 John Wiley & Sons, Ltd. [source] Estimating age by tooth wear of prehistoric human remains in Brazilian archaeological sitesINTERNATIONAL JOURNAL OF OSTEOARCHAEOLOGY, Issue 5 2006R. N. Oliveira Abstract The occlusal surfaces of 298 permanent maxillary and mandibular molar teeth of prehistoric shellfish-gatherer subjects from the Piaēaguera and Tenorio sites (4930 to 1875 BP), near the central-northern coastline of Sćo Paulo, Brazil, were examined for classification of macro-wear stages. Molar tooth wear is an indication of masticatory activity and can be used in the estimation of age at death. The examination of visual and schematic aspects of occlusal macro-wear used a visual chart proposed by Brothwell, which includes the three superior and inferior, left and right, permanent molars. Three examiners performed the macroscopic observations twice under the same conditions. The resulting age estimates were compared with previous information of age estimated by skeletal examination. A reduced intra- and inter-observer variation was observed; all re-examinations indicated discrepancies of less than two years for the upper and lower limit of the age range estimates. The procedure was also considered consistent with the skeletal method used for age estimation of human remains excavated in Brazilian archaeological shell mounds, with a discrepancy of less than 8.22 years between the upper and lower limits of estimates by both methods. Age classification by the occlusal molar wear may be a useful tool for the classification of archaeological findings, mainly when only fragmentary skeletal remains are excavated. The current results indicate that the application of the Brothwell chart for Brazilian archaeological series presented satisfactory results of consistency, and its expanded use may represent a relevant adjunct for research. Copyright © 2006 John Wiley & Sons, Ltd. [source] Evaluation of the nano-oligosaccharide factor lipido-colloid matrix in the local management of venous leg ulcers: results of a randomised, controlled trialINTERNATIONAL WOUND JOURNAL, Issue 2 2008Jean-Luc Schmutz Abstract The nano-oligosaccharide factor (NOSF) is a new compound aiming to promote wound closure mainly through inhibition of matrix metalloproteinase (MMP) activity. This factor is incorporated within a lipido-colloid matrix (Techonology Lipido-Colloid-NOSF matrix) and locally released in the wound. The objective of this study was to document the performance (non inferiority or superiority) of the NOSF relative to the Promogran® matrix (oxidised regenerated cellulose, ORC) effect in the local management of venous leg ulcers (VLUs). This was a 12-week, open, two-arm, multicentre, randomised study. Patients were selected if the area of their VLU [ankle brachial pressure index ,0·80] ranged from 5 to 25 cm2 with a duration ,3 months. Ulcers had to be free from necrotic tissue. In addition to receiving compression bandage therapy, patients were randomly allocated to either NOSF matrix or ORC treatment for 12 weeks. The VLUs were assessed on a weekly basis and wound tracings were recorded. Percentage wound relative reduction (%RR) was the primary efficacy criterion. Secondary objectives were wound absolute reduction (AR), healing rate (HR) and % of wounds with ,40% reduction compared with baseline. A total of 117 patients were included (57 NOSF matrix and 60 ORC). Mean population age was 71·3 ± 13·5 years, body mass index was ,30 kg/m2 in 39·3% and 15·4% were diabetics. Fifty-six per cent of the VLUs were present for >6 months, 61% were recurrent and 68% were stagnating despite appropriate care. Mean wound area at baseline was 11·2 ± 7·4 cm2. At the last evaluation, mean difference between the groups for %RR was 33·6 ± 15·0% in favour of NOSF matrix with a unilateral 95% confidence interval (CI) lower limit of 8·6% not including the null value. Therefore, a superiority of NOSF matrix effect compared with ORC was concluded (P = 0·0059 for superiority test). The median of the wound area reduction was 61·1% and 7·7% in the NOSF matrix and control groups, respectively (per-protocol analysis), or 54·4% versus 12·9% in intent-to-treat analysis (p = 0·0286). Median AR was 4·2 cm2 in the NOSF group and 1·0 cm2 with ORC (P = 0·01). Median HR was ,0·056 and ,0·015 cm2/day in NOSF and ORC groups, respectively (P = 0·029). By logistic regression, the NOSF versus control odds ratio to reach 40% area reduction was 2·4 (95% CI: 1·1,5·3; P = 0·026). In the oldest and largest VLUs, a strong promotion of healing effect was particularly observed in the NOSF matrix group compared with the control group. NOSF matrix is a very promising option for the local management of chronic wounds, especially for VLUs with poor healing prognosis. [source] Accuracy of Spirometry in Diagnosing Pulmonary Restriction in Elderly PeopleJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 11 2009Simone Scarlata MD OBJECTIVES: To compare the accuracy of a diagnosis of pulmonary restriction made using forced vital capacity (FVC) less than the lower limit of normal (LLN) with the criterion standard diagnosis made using total lung capacity (TLC) less than the LLN in an elderly population. DESIGN: Retrospective analysis. SETTING: A teaching hospital. PARTICIPANTS: Five hundred sixty-four ambulatory and acute care hospital patients aged 65 to 96 underwent complete pulmonary function evaluation. MEASUREMENTS: Sensitivity, specificity, positive and negative predictive values (PPV, NPV) of diagnosis of pulmonary restriction defined as FVC less than the LLN were calculated in the overall sample and after stratification according to bronchial obstruction. Expected PPV and NPV at different background prevalence of true pulmonary restriction (5% and 15%) were calculated using the Bayes theorem. RESULTS: Low sensitivity (0.32) and high specificity (0.95) were found, with an area under the receiver operating characteristic curve (AUC) of 0.89. In participants without bronchial obstruction, specificity was even higher, although sensitivity decreased to 0.28 (AUC=0.92). The PPV was good (0.81), whereas with a low to moderate a priori probability (prevalence from 5% to 15%) the NPV was fair (,0.89). CONCLUSION: A reduction in FVC below LLN cannot reliably identify true pulmonary restriction in elderly people, confirming previous findings in the adult population. Normal FVC, instead, can effectively exclude pulmonary restriction regardless of the presence of bronchial obstruction when the a priori probability is low or moderately high. [source] Tunable transport of glucose through ionically-crosslinked alginate gels: Effect of alginate and calcium concentrationJOURNAL OF APPLIED POLYMER SCIENCE, Issue 5 2008Mari-Kate E. McEntee Abstract Alginate beads have numerous biomedical applications, ranging from cell encapsulation to drug release. The present study focuses on the controlled release of glucose from calcium-alginate beads. The effects of alginate concentrations (1,6 wt %) and calcium chloride concentrations (0.1,1.0M) on glucose release from beads were examined. It was found that the time required for complete glucose release from beads could be tuned from 15 min to over 2 h, simply by varying alginate and calcium chloride concentrations in beads. For calcium-alginate beads with sodium alginate concentrations of 1,4 wt %, higher sodium alginate concentrations lead to more prolonged release of glucose and thus a smaller value of a rate constant k, a parameter shown to be proportional to the diffusion coefficient of glucose in the alginate gel. For beads with sodium alginate concentrations of 4,6 wt %, there was no statistically significant difference in k values, indicating a lower limit for glucose release from calcium-alginate beads. Similarly, higher calcium chloride concentrations appear to extend glucose release, however, no conclusive trend can be drawn from the data. In a 50 : 50 mixture of calcium-alginate beads of two different alginate concentrations (1 and 4 wt %), glucose release showed a two-step profile over the time range of 20,50 min, indicating that the pattern and time of glucose release from beads can be tuned by making combinations of beads with varying alginate and/or calcium chloride concentrations. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source] High-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry for the determination of flocoumafen and brodifacoum in whole bloodJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2007Mi-cong Jin Abstract A high-performance liquid chromatographic,tandem mass spectrometric (HPLC,MS,MS) assay was developed and validated to determine quantitatively flocoumafen and brodifacoum in whole blood using warfarin as an internal standard (IS). Liquid,liquid extraction, using ethyl acetate, was used to isolate flocoumafen, brodifacoum and the IS from the biological matrix. Detection was performed on a mass spectrometer by negative electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The calibration curves were linear (r2 > 0.998) in the concentration range of 0.1,100.0 ng ml,1 with a lower limit of quantification of 0.05 ng ml,1 for flocoumafen, and 0.1 ng ml,1 for brodifacoum in whole blood. Intra-day and inter-day relative standard deviations (RSDs) were less than 8.0% and 10.8%, respectively. Recoveries of flocoumafen and brodifacoum ranged from 78.0% to 83.7%. This assay can be used to determine trace flocoumafen and brodifacoum in whole blood to investigate suspected poisoning of human and animals. Copyright © 2006 John Wiley & Sons, Ltd. [source] Validation of an LC,MS Method for the Detection and Quantification of BZP and TFMPP and their Hydroxylated Metabolites in Human Plasma and its Application to the Pharmacokinetic Study of TFMPP in Humans,JOURNAL OF FORENSIC SCIENCES, Issue 5 2010Ushtana Antia M.Sc. Abstract:, An LC,MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of "party pills" or "legal herbal highs," and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibration curves were linear from 1 to 50 ng/mL (R2 > 0.99); the lower limit of quantification (LLOQ) was 5 ng/mL; the accuracy was >90%; the intra- and interday relative standard deviations (R.S.D) were <5% and <10%, respectively. Human plasma concentrations of TFMPP were measured in blood samples taken from healthy adults (n = 6) over 24 h following a 60-mg oral dose of TFMPP: these peaked at 24.10 ng/mL (±1.8 ng/mL) (Cmax) after 90 min (Tmax). Plasma concentrations of 1-(3-trifluoromethyl-4-hydroxyphenyl) piperazine peaked at 20.2 ng/mL (±4.6 ng/mL) after 90 min. TFMPP had two disposition phases (t½ = 2.04 h (±0.19 h) and 5.95 h (±1.63 h). Apparent clearance (Cl/F) was 384 L/h (±45 L/h). [source] Differentiating Human Bone from Animal Bone: A Review of Histological MethodsJOURNAL OF FORENSIC SCIENCES, Issue 2 2007Maria L. Hillier M.Sc. ABSTRACT: This review brings together a complex and extensive literature to address the question of whether it is possible to distinguish human from nonhuman bone using the histological appearance of cortical bone. The mammalian species included are rat, hare, badger, racoon dog, cat, dog, pig, cow, goat, sheep, deer, horse, water buffalo, bear, nonhuman primates, and human and are therefore not exhaustive, but cover those mammals that may contribute to a North American or Eurasian forensic assemblage. The review has demonstrated that differentiation of human from certain nonhuman species is possible, including small mammals exhibiting Haversian bone tissue and large mammals exhibiting plexiform bone tissue. Pig, cow, goat, sheep, horse, and water buffalo exhibit both plexiform and Haversian bone tissue and where only Haversian bone tissue exists in bone fragments, differentiation of these species from humans is not possible. Other primate Haversian bone tissue is also not distinguishable from humans. Where differentiation using Haversian bone tissue is undertaken, both the general microstructural appearance and measurements of histological structures should be applied. Haversian system diameter and Haversian canal diameter are the most optimal and diagnostic measurements to use. Haversian system density may be usefully applied to provide an upper and lower limit for humans. [source] Quantification of fudosteine in human plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry employing precolumn derivatization with 9-fluorenylmethyl chloroformateJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 5 2006Fengguo Xu Abstract This paper describes a novel method for the sensitive and selective determination of fudosteine in human plasma. The method involves a derivatization step with 9-fluorenylmethyl chloroformate (FMOC-Cl) in borate buffer and detection based on high-performance liquid chromatography-electrospray ionization mass spectrometry (LC/ESI/MS). After acetonitrile-induced protein precipitation of plasma samples, fudosteine was derivatized with FMOC-Cl, then extracted by ethyl acetate, evaporated, reconstituted and injected using an LC/ESI/MS instrument. Separation was achieved using an ODS column and isocratic elution. Excellent linearity was obtained for the entire calibration range from 0.05 to 20 µg/ml. Validation assays of the lower limit of quantification (LLOQ) as well as for the intra- and inter-batch precision and accuracy met the international acceptance criteria for bioanalytical method validation. Using the developed analytical method, fudosteine could be detected for the first time in human plasma with a low limit of detection (LLOD) of 0.03 µg/ml. The proposed method has been successfully applied to study the pharmacokinetics of fudosteine in healthy Chinese volunteers after single and multiple oral administration. Copyright © 2006 John Wiley & Sons, Ltd. [source] Simple, sensitive and rapid liquid chromatographic/electrospray ionization tandem mass spectrometric method for the quantification of lacidipine in human plasmaJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 7 2004N. V. S. Ramakrishna Abstract A simple, sensitive and rapid liquid chromatographic/electrospray ionization tandem mass spectrometric method was developed and validated for the quantification of lacidipine in human plasma using its structural analogue, amlodipine, as internal standard (IS). The method involves a simple single-step liquid,liquid extraction with tert -butyl methyl ether. The analyte was chromatographed on an Xterra MS C18 reversed-phase chromatographic column by isocratic elution with 20 mM ammonium acetate buffer,acetonitrile (10 : 90, v/v; pH 6) and analyzed by mass spectrometry in the multiple reaction monitoring mode. The precursor to product ion transitions of m/z 456.4 , 354.4 and m/z 409.3 , 238.3 were used to measure the analyte and the I.S., respectively. The chromatographic run time was 1.5 min and the weighted (1/x2) calibration curves were linear over the range 0.1,25 ng ml,1. Lacidipine was sensitive to temperature in addition to light. The method was validated in terms of accuracy, precision, absolute recovery, freeze,thaw stability, bench-top stability and re-injection reproducibility. The limit of detection and lower limit of quantification in human plasma were 50 and 100 pg ml,1, respectively. The within- and between-batch accuracy and precision were found to be well within acceptable limits (<15%). The analyte was stable after three freeze,thaw cycles (deviation <15%). The average absolute recoveries of lacidipine and amlodipine (IS) from spiked plasma samples were 51.1 ± 1.3 and 50.3 ± 4.9%, respectively. The assay method described here could be applied to study the pharmacokinetics of lacidipine. Copyright © 2004 John Wiley & Sons, Ltd. [source] Dynamics of lamivudine-resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapyJOURNAL OF MEDICAL VIROLOGY, Issue 7 2008Samreen Ijaz Abstract Adefovir dipivoxil has been used alone or together with lamivudine to suppress lamivudine-resistant hepatitis B virus (HBV). However, the dynamics of HBV populations under different selection pressures and their impact on treatment outcome are poorly understood. Pyrosequencing® was applied to quantify longitudinally the evolution of wild type and lamivudine/ adefovir-resistant HBV. Eight patients, with lamivudine-resistant HBV, were randomized to receive adefovir monotherapy or adefovir/lamivudine combination therapy for a median of 79 and 71 weeks, respectively. Pyrosequencing® proved highly sensitive with a lower limit of quantitation of minor HBV populations of 2% irrespective of viraemia levels. Adefovir/lamivudine treatment resulted in greater viraemia reduction than adefovir monotherapy. During combination therapy, lamivudine-resistant HBV populations (codons 180 and 204) remained dominant (>90%) and no adefovir-resistance developed. During adefovir monotherapy, reversion to wild-type HBV was detected in two patients with one patient accumulating rapidly adefovir-resistant HBV along with increased viraemia. In conclusion, the dynamics of drug-resistant HBV strains vary under different selection pressures which have a significant impact on the success of rescue therapy, as well as for the selection of new mutations. The use of techniques such as Pyrosequencing provides an evidence-based approach for successful management of drug-resistant HBV. J. Med. Virol. 80: 1160,1170, 2008. © 2008 Wiley-Liss, Inc. [source] Limitation in obtainable surface roughness of hardened cement paste: ,virtual' topographic experiment based on focussed ion beam nanotomography datasetsJOURNAL OF MICROSCOPY, Issue 2 2008P. TRTIK Summary Surface roughness affects the results of nanomechanical tests. The surface roughness values to be measured on a surface of a porous material are dependent on the properties of the naturally occurring pore space. In order to assess the surface roughness of hardened cement paste (HCP) without the actual influence of the usual sample preparation for nanomechanical testing (i.e. grinding and polishing), focussed ion beam nanotomography datasets were utilized for reconstruction of 3D (nanoscale resolution) surface profiles of hardened cement pastes. ,Virtual topographic experiments' were performed and root mean square surface roughness was then calculated for a large number of such 3D surface profiles. The resulting root mean square (between 115 and 494 nm) is considerably higher than some roughness values (as low as 10 nm) reported in the literature. We suggest that thus-analysed root mean square values provide an estimate of a ,hard' lower limit that can be achieved by ,artefact-free' sample preparation of realistic samples of hardened cement paste. To the best of our knowledge, this ,hard' lower limit was quantified for a porous material based on hydraulic cement for the first time. We suggest that the values of RMS below such a limit may indicate sample preparation artefacts. Consequently, for reliable nanomechanical testing of disordered porous materials, such as hardened cement paste, the preparation methods may require further improvement. [source] | ||||||||||||||||||||||||||||||||||||||||||||||