Concentration-response slope
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Jedním z problémů při kloubních náhradách jsou komplikace spojené s pooperačními infekcemi. Infekce způsobené bakteri-emi, které tvoří biofilmy na površích, se nazývají infekce související s biofilmem (biofilm related infections, BRI). V důsledku následné biologické odezvy organismu dochází k silným patofyziologickým změnám vmikroklimatu kolem takto postiženého povrchu (pokles pH, tvorba různých reaktivních forem kyslíku (ROS), vyčerpání iontů železa a zvýšení koncentrace vápenatých iontů). Vytvořili jsme robustní selektivní polymerní potenciometrický senzor ROS a pH senzor pro detekci změn způsobených sterilním zánětem a bakteriálními a plísňovými infekcemi. Senzor ROS se skládá z vodivé polymerní vrstvy na bázi polythiofenu se zabudovaným komplexem porfyrin-kov, který potenciometricky deteguje přítomnost ROS, jak bylo demonstrováno na peroxi-du vodíku. Tento senzor je kovalentně potažen vrstvou odolnou biopasivaci (non-biofouling layer, NBL) tvořenou poly(2-methyl--2-oxazolin)em, která funguje jako biokompatibilizátor.Bylo prokázáno, že potenciometrický senzor vykazuje rychlou odezvu naperoxid vodíku, nezaznamenává interferenci s hovězím sérovým albuminem jako modelovým sérovým proteinem a je schopenplně reverzibilně detegovat ROS s lineární odezvou v širokém rozsahu biologicky relevantních koncentrací (od 0,05μM do10μM). Polymerní pH senzor na bázi polyanilinu a poly(2-methyl-2-oxazolinu) na nosiči z titanové slitiny byl vyvinut pro po-tenciometrickou detekci změn pHv okolí implantátu, aby bylo možné včas detegovat výše uvedené záněty. Vyvinuté elektrody měří změnu pH v rozsahu pH5 až 8, tedy vrozmezí relevantním pro jednotlivé infekce baktériemi a kvasinkami.
One of the problems occurring after the joint replace-ment is connected with the post-surgery infections which are caused by bacteria that form biofilms on surfaces and are referred to as biofilm-related infections (BRI). It is also worth noting that due to the bioresponse, strong path-ophysiologicalchangesinthemicroclimateofanaffectedsurface occur (decrease in pH, formation of various reac-tive oxygen species (ROS), depletion of Fe ions, and in-crease in the concentration of Ca ions). In this work we have prepared a robust selective potentiometric sensorof ROS and pH sensor for the detection of pH changes caused by sterile inflammation and bacterial and fungal infections. The ROS sensor consists of a conductive poly-mer layer based on polythiophene with an incorporated porphyrin-metal complex that potentiometrically detects the presence of ROS (H2O2and ClO–ions). This sensor is connected by the covalent bonds with a non-biofouling layer of poly(2-methyl-2-oxazoline), which works as abio-compa-tibilizer. It was shown that the potentiometric sen-sor shows a rapid response to hydrogen peroxide, does not record any interference with bovine serum albumin as amodel serum protein, and is able to fully reversibly de-tect ROS with a linear response within a wide range of biological relevant concentrations (from 0.05 μM to 10μM). The sensing electrode based on polyaniline and poly(2-methyl-2-oxazoline) on a titanium alloy support was developed for the potentiometric detection of peri-implant pH changes to enable early detection of the afore-mentioned pathologies. The developed electrodes show the changing of pH in the range between 5 and 8 for the individual pathogenic bacteria or pathogenic yeast, with aNernstian slope of −59.6/pH.
- Klíčová slova
- potenciometrický senzor,
- MeSH
- biofilmy MeSH
- klouby chirurgie mikrobiologie MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- potenciometrie * metody přístrojové vybavení MeSH
- protézy kloubů mikrobiologie MeSH
- reaktivní formy kyslíku analýza MeSH
- výzkum MeSH
- zánět diagnóza etiologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Concentration addition as a classic null model for toxicology and pharmacology is based on Loewe's mathematical formulation and the linearity of the isoboles. Novel mathematical models, however, propose curved isoboles in certain conditions. This article aims to test the hypothesis of the curvature of isoboles in experimental measurements. With the assumption of linear isoboles, a partial agonist acts as an antagonist above its maximal effect level. The isoboles automatically convert to a positive slope. For curved isoboles, a partial agonist acts as an antagonist at higher effect levels than its maximal effect alone. The discrepancies between effect levels were studied with an estrogen receptor binding assay (BMAEREluc/ERα) using a mixture of 17β-estradiol and fulvestrant as a partial agonist. A mixture of 17β-estradiol and fulvestrant acts as a partial agonist and causes the diminishing of the effect level of 17β-estradiol at a significantly higher level than the maximal effect of their partial-agonistic dose-response curve. Measured, elevated effect levels were well predicted by the mathematical model. Nonlinear isoboles may change our understanding and definition of synergism or antagonism and prompt further attention in receptor theory.
BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias. METHODS: We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived. RESULTS: On average, an increase of 10 μg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations. CONCLUSIONS: Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.).
- MeSH
- celosvětové zdraví MeSH
- kardiovaskulární nemoci mortalita MeSH
- lidé MeSH
- mortalita * MeSH
- nemoci dýchací soustavy mortalita MeSH
- pevné částice škodlivé účinky analýza MeSH
- příčina smrti MeSH
- riziko MeSH
- velikost částic MeSH
- vystavení vlivu životního prostředí škodlivé účinky analýza zákonodárství a právo MeSH
- znečištění ovzduší škodlivé účinky analýza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
The equilibrium dissociation constant of competitive antagonists represents the affinity of the receptor-ligand interaction, and it is a key characteristic of many therapeutic drugs or toxic compounds. Two commonly used methods by which the affinity of the antagonist can be estimated are Schild analysis and the Cheng-Prusoff method. However, both methods yield different results when applied to systems with slopes not equal to one. The Gaddum equation, which is fundamental for both methods, should be extended to incorporate the slope parameter of the dose-response curves and this extension should diminish the differences between the Schild and Cheng-Prusoff methods. In this study, we derived a novel form of the Gaddum equation with a slope parameter (Hill coefficient) of agonist dose-response curve. We also derived the subsequent equations for Schild and Cheng-Prusoff analysis and we validated the proposed model by the measurement of several known estrogen receptor competitive antagonists. Standardized in vitro yeast reporter gene assay (BMAEREluc/ERα) has been used for the measurements and the range of used antagonist concentrations was 1.37-46.03 μM. By applying our mathematical model, both Schild and Cheng-Prusoff methods provide more similar values of antagonist affinity than the original mathematical approach. The correctness of the model has also been demonstrated by the measurement of a partial agonist with a known receptor affinity. The presented mathematical model significantly reduces the differences in values calculated by the Cheng-Prusoff and Schild methods and yields more accurate estimations of antagonist affinity.
- MeSH
- alfa receptor estrogenů antagonisté a inhibitory metabolismus MeSH
- antagonisté estrogenového receptoru metabolismus farmakologie MeSH
- benzhydrylové sloučeniny metabolismus toxicita MeSH
- biologické modely * MeSH
- endokrinní disruptory metabolismus toxicita MeSH
- estradiol metabolismus farmakologie MeSH
- estrogeny metabolismus farmakologie MeSH
- fenoly metabolismus toxicita MeSH
- kompetitivní vazba MeSH
- lidé MeSH
- ligandy MeSH
- parciální agonismus léků MeSH
- reprodukovatelnost výsledků MeSH
- vazba proteinů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The hypothalamic-pituitary-adrenal (HPA) axis represents an important and evolutionarily ancient biological pathway linking physical and psychological stressors with human health. Despite considerable research exploring the physiological stress response among developed populations, few studies have examined HPA activity in non-industrialized contexts, restricting understanding of variation in human stress reactivity across global socio-ecological diversity. The present study addresses this shortcoming by investigating diurnal cortisol rhythms among Garisakang forager-horticulturalists of remote, lowland Papua New Guinea. Using a large sample of repeated salivary cortisol measurements from 169 participants (age 4-70 years), multilevel growth curve models were constructed to assess Garisakang waking cortisol concentrations and diurnal cortisol slopes. As predicted, results demonstrate identifiable but substantially diminished diurnal cortisol rhythms relative to those of industrialized populations. Sample-wide, Garisakang cortisol concentrations are highest upon waking (mean = 4.86 nmol/L) and decrease throughout the day at a mean rate of only -0.18 nmol/L/h or -6.20%/h. Age and sex significantly predict evaluated cortisol parameters in ways not consistently reported among industrialized populations, suggesting that Garisakang diurnal cortisol rhythms are defined by distinct ontogenetic trajectories across the lifespan. These findings highlight cross-cultural diversity in HPA activity and have important implications for understanding basic mechanisms of the physiological stress response in contexts of chronic physical stressors such as limited nutrition, heavy burden of infectious disease, and high levels of physical activity.
- MeSH
- cirkadiánní rytmus fyziologie MeSH
- cvičení MeSH
- dítě MeSH
- dospělí MeSH
- fyziologický stres fyziologie MeSH
- hydrokortison analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- senioři MeSH
- sliny chemie MeSH
- systém hypofýza - nadledviny fyziologie MeSH
- systém hypotalamus-hypofýza fyziologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Papua Nová Guinea MeSH
BACKGROUND: Malignant hypertension is a life-threatening condition, and its pathophysiology is still poorly understood. The present study was designed to evaluate the role of interaction of the renin-angiotensin system with 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent ω-hydroxylase pathway, in the pathophysiology of angiotensin II (ANG II)-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. METHODS: Malignant hypertension was induced by 12 days׳ dietary administration of 0.3 % indole-3-carbinol (I3C), a natural xenobiotic that activates a mouse renin gene. We hypothesized that chronic administration of fenofibrate, 190mg/kg body weight, a lipid-lowering drug, should increase renal production of 20-HETE, a tubular transport inhibitor; an expected increase in sodium excretion would oppose the development of ANG II-dependent malignant hypertension. Blood pressure was monitored by radiotelemetry, and at the end of the experiment rats were prepared for renal functional studies to evaluate in vivo the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP). RESULTS: In I3C-induced rats, the treatment with fenofibrate significantly attenuated hypertension and improved the slope of the pressure-natriuresis relationship. Although fenofibrate treatment increased kidney gene and protein expression of CYP4A1, a major isoform responsible for 20-HETE formation, it did not increase renal 20-HETE concentration. On the contrary, fenofibrate treatment significantly suppressed renin gene expression, plasma renin activity and plasma and kidney ANG II levels. CONCLUSIONS: Fenofibrate treatment significantly attenuated the course of malignant hypertension in I3C-induced CYP1a1-Ren-2 transgenic rats, and the mechanism responsible for antihypertensive action was fenofibrate-induced suppression of renin-angiotensin system activity.
- MeSH
- aktivace transkripce MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- cytochrom P450 CYP4A metabolismus MeSH
- fenofibrát farmakologie terapeutické užití MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- homeostáza účinky léků MeSH
- hypertenze maligní chemicky indukované farmakoterapie MeSH
- indoly MeSH
- krevní tlak MeSH
- kyseliny hydroxyeikosatetraenové metabolismus MeSH
- ledviny metabolismus MeSH
- natriuréza účinky léků MeSH
- potkani transgenní MeSH
- renální oběh účinky léků MeSH
- renin-angiotensin systém účinky léků MeSH
- renin genetika MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Estrogenic compounds as well as other biologically active substances are commonly present in the form of complex mixtures in the environment. There is still no satisfactory model that would be capable of predicting the toxic effects of mixtures containing partial receptor agonists and compounds with different parameters of their dose-response curves. Therefore, a novel Full Logistic Model (FLM) of prediction using all the parameters of dose-response curves has been suggested and compared with previously published approaches. We tested the receptor-binding activities of selected estrogens including full and partial agonists and their mixtures using yeast reporter gene assays and the human T47D cell line. Combination effects were modeled with FLM and predicted curves were compared with the data obtained experimentally. FLM yielded a good fit to the experimental data from both the receptor-binding assays and gave better predictions than the previously published approaches. FLM also provided satisfactory results regarding final partial agonistic dose-response curves with maximum influenced by the inhibitory effect of the partial agonist. FLM is not limited by any simplification like the toxic equivalency factor approach or generalized concentration addition and therefore it could be employed for mixtures containing chemicals with different parameters of their dose-response curves (maximum, minimum, inflex point or slope).
- MeSH
- benzhydrylové sloučeniny farmakologie MeSH
- biotest MeSH
- buněčné linie MeSH
- chemokin CXCL12 metabolismus MeSH
- estradiol farmakologie MeSH
- estrogeny farmakologie MeSH
- fenoly farmakologie MeSH
- lékové interakce MeSH
- lidé MeSH
- logistické modely * MeSH
- reportérové geny MeSH
- Saccharomyces cerevisiae genetika MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrations. DESIGN: Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-<2.1 ng/mL]; high: 15.0-44.9 pmol/L [2.1-6.3 ng/mL]) trial. SETTING: Seven infertility centers in four countries. PATIENT(S): Two hundred sixty-five women aged ≤37 years. INTERVENTION(S): Controlled ovarian stimulation with either 5.2, 6.9, 8.6, 10.3, or 12.1 μg of rhFSH, or 11 μg (150 IU) of follitropin alfa in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved. RESULT(S): The number of oocytes retrieved increased in an rhFSH dose-dependent manner, from 5.2 ± 3.3 oocytes with 5.2 μg/d to 12.2 ± 5.9 with 12.1 μg/d. The slopes of the rhFSH dose-response curves differed significantly between the two AMH strata, demonstrating that a 10% increase in dose resulted in 0.5 (95% confidence interval 0.2-0.7) and 1.0 (95% confidence interval 0.7-1.3) more oocytes in the low and high AMH stratum, respectively. Fertilization rate and blastocyst/oocyte ratio decreased significantly with increasing rhFSH doses in both AMH strata. No linear relationship was observed between rhFSH dose and number of blastocysts overall or by AMH strata. Five cases of ovarian hyperstimulation syndrome were reported for the three highest rhFSH doses and in the high AMH stratum. CONCLUSION(S): Increasing rhFSH doses results in a linear increase in number of oocytes retrieved in an AMH-dependent manner. The availability of blastocysts is less influenced by the rhFSH dose and AMH level. CLINICAL TRIAL REGISTRATION NUMBER: NCT01426386.
- MeSH
- antimülleriánský hormon aplikace a dávkování MeSH
- dospělí MeSH
- fertilizace in vitro metody MeSH
- folikuly stimulující hormon lidský aplikace a dávkování MeSH
- indukce ovulace metody MeSH
- intracytoplazmatické injekce spermie metody MeSH
- lidé MeSH
- odběr oocytu * MeSH
- rekombinantní proteiny aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
A set of 69 concentration-response curves from 5 acute ecotoxicity assays was fitted with a 2-parameter logistic equation. High correlation between values of regression parameters suggested similar slopes of the curves. This enabled derivation of the empirical single-parameter logistic equation with the sole median effective concentration (EC50) parameter. Such an equation might be useful in the evaluation of lower-quality (preliminary) experimental data and for the reduction of the number of test organisms and of testing costs.
- MeSH
- Aliivibrio fischeri účinky léků MeSH
- Chlorophyta účinky léků MeSH
- Daphnia účinky léků MeSH
- dvojchroman draselný toxicita MeSH
- látky znečišťující životní prostředí toxicita MeSH
- logistické modely * MeSH
- referenční standardy MeSH
- testy akutní toxicity * normy MeSH
- živorodka MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We introduce a new nonlinear electrophoretic model for complex-forming systems with a fully charged analyte and a neutral ligand. The background electrolyte is supposed to be composed of two constituents, which do not interact with the ligand. In order to characterize the electromigration dispersion (EMD) of the analyte zone we define a new parameter, the nonlinear electromigration mobility slope, S(EMD,A). The parameter can be easily utilized for quantitative prediction of the EMD and for comparisons of the model with the simulated and experimental profiles. We implemented the model to the new version of PeakMaster 5.3 Complex that can calculate some characteristic parameters of the electrophoretic system and can plot the dependence of S(EMD,A) on the concentration of the ligand. Besides S(EMD,A), also the relative velocity slope, S(X), can be calculated. It is commonly used as a measure of EMD in electrophoretic systems. PeakMaster 5.3 Complex software can be advantageously used for optimization of the separation conditions to avoid high EMD in complexing systems. Based on the theoretical model we analyze the S(EMD,A) and reveal that this parameter is composed of six terms. We show that the major factor responsible for the electromigration dispersion in complex-forming electrophoretic systems is the complexation equilibrium and particularly its impact on the effective mobility of the analyte. To prove the appropriateness of the model we showed that there is a very good agreement between peak shapes calculated by PeakMaster 5.3 Complex (plotted using the HVLR function) and the profiles simulated by means of Simul 5 Complex. The detailed experimental verification of the new mode of PeakMaster 5.3 Complex is in the next part IV of the series.
