scholarly journals Transmission and dose–response experiments for social animals: a reappraisal of the colonization biology of Campylobacter jejuni in chickens

2011 ◽  
Vol 8 (65) ◽  
pp. 1720-1735 ◽  
Author(s):  
Andrew J. K. Conlan ◽  
John E. Line ◽  
Kelli Hiett ◽  
Chris Coward ◽  
Pauline M. Van Diemen ◽  
...  
Keyword(s):  
Dose Response ◽  
Standard Dose ◽  
Experimental Studies ◽  
Infectious Agent ◽  
Lag Phase ◽  
Infectious Agents ◽  
Infectious Dose ◽  
Response Data ◽  
Social Animals

Dose–response experiments characterize the relationship between infectious agents and their hosts. These experiments are routinely used to estimate the minimum effective infectious dose for an infectious agent, which is most commonly characterized by the dose at which 50 per cent of challenged hosts become infected—the ID 50 . In turn, the ID 50 is often used to compare between different agents and quantify the effect of treatment regimes. The statistical analysis of dose–response data typically makes the assumption that hosts within a given dose group are independent. For social animals, in particular avian species, hosts are routinely housed together in groups during experimental studies. For experiments with non-infectious agents, this poses no practical or theoretical problems. However, transmission of infectious agents between co-housed animals will modify the observed dose–response relationship with implications for the estimation of the ID 50 and the comparison between different agents and treatments. We derive a simple correction to the likelihood for standard dose–response models that allows us to estimate dose–response and transmission parameters simultaneously. We use this model to show that: transmission between co-housed animals reduces the apparent value of the ID 50 and increases the variability between replicates leading to a distinctive all-or-nothing response; in terms of the total number of animals used, individual housing is always the most efficient experimental design for ascertaining dose–response relationships; estimates of transmission from previously published experimental data for Campylobacter spp. in chickens suggest that considerable transmission occurred, greatly increasing the uncertainty in the estimates of dose–response parameters reported in the literature. Furthermore, we demonstrate that accounting for transmission in the analysis of dose–response data for Campylobacter spp. challenges our current understanding of the differing response of chickens with respect to host-age and in vivo passage of bacteria. Our findings suggest that the age-dependence of transmissibility between hosts—rather than their susceptibility to colonization—is the mechanism behind the ‘lag-phase’ reported in commercial flocks, which are typically found to be Campylobacter free for the first 14–21 days of life.

scholarly journals A method for incorporating a time-dose-response model into a Giardia lamblia outbreak

2017 ◽  
Vol 15 (4) ◽  
pp. 490-504
Author(s):  
Bidya Prasad ◽  
Michael O. Ryan ◽  
Charles N. Haas
Keyword(s):  
Dose Response ◽  
Giardia Lamblia ◽  
Probability Model ◽  
Infectious Agent ◽  
Likelihood Estimation ◽  
Dependency Model ◽  
Using Data ◽  
Best Fit ◽  
Time Dose

Experimental time-to-infection data is a useful, but often underutilized, material for examining the mechanics of in vivo pathogen growth. In this paper, the authors attempt to incorporate a time-dose-response (TDR) equation into a model which predicts the number of ill persons per day in a Giardia lamblia epidemic using data collected from a Pittsfield, Massachusetts outbreak. To this end, dose-response and TDR models were generated for Giardia exposure to beaver and human volunteers, and a maximum likelihood estimation approach was used to ensure that the models provided acceptable fits. The TDR equation that best-fit the human data was the beta-Poisson with exponential-reciprocal dependency model, and this was chosen to be incorporated into the outbreak model. The outbreak model is an expanded probability model that convolutes an assumed incubation distribution of the infectious agent with an exposure distribution. Since the beta-Poisson with exponential-reciprocal dependency models the time-to-infection density distribution, it is input as the incubation distribution. Several density functions, including the Weibull, lognormal, gamma, and uniform functions served as exposure distributions. The convolution of the time-dependent probability distribution with the lognormal distribution yielded the best-fit for the outbreak model.

scholarly journals Prediction of dose-dependent in vivo acetylcholinesterase inhibition by profenofos in rats and humans using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry

2021 ◽  
Vol 95 (4) ◽  
pp. 1287-1301
Author(s):  
Isaac Omwenga ◽  
Shensheng Zhao ◽  
Laetitia Kanja ◽  
Hans Mol ◽  
Ivonne M. C. M. Rietjens ◽  
...  
Keyword(s):  
Dose Response ◽  
In Silico ◽  
Acetylcholinesterase Inhibition ◽  
Ache Inhibition ◽  
Response Data ◽  
Physiologically Based ◽  
Parameter Values ◽  
Dose Dependent

AbstractOrganophosphate pesticides (OPs) are known to inhibit acetylcholine esterase (AChE), a critical effect used to establish health-based guidance values. This study developed a combined in vitro–in silico approach to predict AChE inhibition by the OP profenofos in rats and humans. A physiologically based kinetic (PBK) model was developed for both species. Parameter values for profenofos conversion to 4-bromo-2-chlorophenol (BCP) were derived from in vitro incubations with liver microsomes, liver cytosol, and plasma from rats (catalytic efficiencies of 1.1, 2.8, and 0.19 ml/min/mg protein, respectively) and humans (catalytic efficiencies of 0.17, 0.79, and 0.063 ml/min/mg protein, respectively), whereas other chemical-related parameter values were derived using in silico calculations. The rat PBK model was evaluated against literature data on urinary excretion of conjugated BCP. Concentration-dependent inhibition of rat and human AChE was determined in vitro and these data were translated with the PBK models to predicted dose-dependent AChE inhibition in rats and humans in vivo. Comparing predicted dose-dependent AChE inhibition in rats to literature data on profenofos-induced AChE inhibition revealed an accurate prediction of in vivo effect levels. Comparison of rat predictions (BMDL10 of predicted dose–response data of 0.45 mg/kg bw) and human predictions (BMDL10 of predicted dose–response data of 0.01 mg/kg bw) suggests that humans are more sensitive than rats, being mainly due to differences in kinetics. Altogether, the results demonstrate that in vivo AChE inhibition upon acute exposure to profenofos was closely predicted in rats, indicating the potential of this novel approach method in chemical hazard assessment.

Development of a Generic Physiologically Based Kinetic Model to Predict In Vivo Uterotrophic Responses Induced by Estrogenic Chemicals in Rats Based on In Vitro Bioassays

2019 ◽  
Author(s):  
Mengying Zhang ◽  
Bennard van Ravenzwaay ◽  
Ivonne M C M Rietjens
Keyword(s):  
Dose Response ◽  
In Vitro Toxicity ◽  
Proliferation Assay ◽  
Screening Assay ◽  
Response Data ◽  
Physiologically Based ◽  
Estrogenic Chemicals ◽  
Mcf 7

Abstract The present study assessed the potential of a generic physiologically based kinetic (PBK) model to convert in vitro data for estrogenicity to predict the in vivo uterotrophic response in rats for diethylstibestrol (DES), ethinylestradiol (EE2), genistein (GEN), coumestrol (COU), and methoxychlor (MXC). PBK models were developed using a generic approach and in vitro concentration-response data from the MCF-7 proliferation assay and the yeast estrogen screening assay were translated into in vivo dose-response data. Benchmark dose analysis was performed on the predicted data and available in vivo uterotrophic data to evaluate the model predictions. The results reveal that the developed generic PBK model adequate defines the in vivo kinetics of the estrogens. The predicted dose-response data of DES, EE2, GEN, COU, and MXC matched the reported in vivo uterus weight response in a qualitative way, whereas the quantitative comparison was somewhat hampered by the variability in both in vitro and in vivo data. From a safety perspective, the predictions based on the MCF-7 proliferation assay would best guarantee a safe point of departure for further risk assessment although it may be conservative. The current study indicates the feasibility of using a combination of in vitro toxicity data and a generic PBK model to predict the relative in vivo uterotrophic response for estrogenic chemicals.

Synergism between Tissue-Type Plasminogen Activator and a Genetically Engineered Variant Lacking the Finger Domain, the Growth Factor Domain and the First Kringle Domain

1991 ◽  
Vol 65 (03) ◽  
pp. 286-290 ◽  
Author(s):  
C Mattson ◽  
K Wikström ◽  
C Sterky ◽  
G Pohl
Keyword(s):  
Synergistic Effect ◽  
Dose Response ◽  
Response Curve ◽  
Tissue Type ◽  
Lag Phase ◽  
Individual Dose ◽  
Response Curves ◽  
Type Plasminogen Activator

SummaryA modified variant of human tissue-type plasminogen activator (t-PA) lacking the finger domain (F), the growth factor domain (G) and the first kringle domain (K1), has an extended plasma half-life in vivo, compared to that of t-PA. When the variant (denoted K2P) was tested in vitro for its ability to lyse human plasma clots we found that the activity was characterized by a time lag phase and a sigmoidal dose-response curve. However, an attenuation of the lag phase in vitro was observed both when K2P was mixed with t-PA in a w/w ratio of 4 : 1 and when K2P was allowed to lyse a clot that had been pre-exposed to t-PA i.e. submitted to a limited plasmic digestion. Dosis that in vitro caused 50% lysis within 6 h were calculated from individual dose-response curves and were for K2P, t-PA and K2P/t-PA (4 : 1 w/w) 540 ng/ml, 360 ng/ml and 310 ng/ml, respectively. These results indicated a synergistic effect between K2P and t-PA. However, the data from individual dose-response curves showed that the effect of the K2P/t-PA mixture never was better than that of t-PA alone, and the synergistic effect in vitro is therefore considered to be of limited use. The thrombolytic activity in vivo was evaluated in a rabbit jugular vein thrombus model. Despite the lag phase observed in vitro, K2P was approximately 3 times as effective as t-PA in vivo (bolus injection). The thrombolytic effect of K2P was further potentiated when it was administred together with a small amount of t-PA (4 : 1 w/w). This potentiation in vivo was, in contrast to the effect in vitro, a useful synergistic effect as the dose-response curve for the K2P/t-PA mixture was steeper than that of t-PA and K2P alone. Doses that caused 50% lysis within 3 h were for t-PA, K2P and K2P/t-PA 1.28 mg/kg, 0.56 mg/kg and 0.35 mg/kg, respectively.

Dose-Response Aggregometry in Maternal/Neonatal Platelets

1988 ◽  
Vol 60 (02) ◽  
pp. 314-318 ◽  
Author(s):  
A M A Gader ◽  
H Bahakim ◽  
F A Jabbar ◽  
A L Lambourne ◽  
T H Gaafar ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Dose Response ◽  
Lag Phase ◽  
Phase Slope ◽  
Multiple Doses ◽  
Nonpregnant Adult ◽  
Aggregation Of Platelets

SummaryThe aggregation of platelets collected from maternal/neonatal pairs (n = 240) at the time of childbirth, was studied in response to multiple doses of ADP, collagen, arachidonic acid and ristocetin. Similar responses were obtained from healthy nonpregnant adult controls for comparison. The lag phase, slope of the aggregation curves as well as maximum aggregation (MA%) were recorded and analysed. Neonatal and adult platelets exhibited more enhanced responses to decreasing doses of ADP, arachidonic acid and ristocetin, than maternal platelets. These enhanced responses were exhibited more consistantly in the slopes of the aggregation curves than in MA%. Although neonatal platelets have shown longer lag phase in their responses to collagen, the rate of the aggregation reaction was significantly faster than maternal platelets, with no differences in MA%. These results contradict many previous reports suggesting impaired aggregation responses of neonatal platelets to these agonist. The possible reasons for these contradictions were discussed.

Development and Evaluation of Floating Pulsatile Drug Delivery System Using Meloxicam

2017 ◽  
Vol 7 (04) ◽  
Author(s):  
ShirishaG. Suddala ◽  
S. K. Sahoo ◽  
M. R. Yamsani
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Delivery ◽  
Drug Release ◽  
Drug Delivery System ◽  
Delivery System ◽  
Lag Time ◽  
Oral Dosage ◽  
Lag Phase ◽  
Pulsatile Drug Delivery

Objective: The objective of this research work was to develop and evaluate the floating– pulsatile drug delivery system (FPDDS) of meloxicam intended for Chrono pharmacotherapy of rheumatoid arthritis. Methods: The system consisting of drug containing core, coated with hydrophilic erodible polymer, which is responsible for a lag phase for pulsatile release, top cover buoyant layer was prepared with HPMC K4M and sodium bicarbonate, provides buoyancy to increase retention of the oral dosage form in the stomach. Meloxicam is a COX-2 inhibitor used to treat joint diseases such as osteoarthritis and rheumatoid arthritis. For rheumatoid arthritis Chrono pharmacotherapy has been recommended to ensure that the highest blood levels of the drug coincide with peak pain and stiffness. Result and discussion: The prepared tablets were characterized and found to exhibit satisfactory physico-chemical characteristics. Hence, the main objective of present work is to formulate FPDDS of meloxicam in order to achieve drug release after pre-determined lag phase. Developed formulations were evaluated for in vitro drug release studies, water uptake and erosion studies, floating behaviour and in vivo radiology studies. Results showed that a certain lag time before drug release which was due to the erosion of the hydrophilic erodible polymer. The lag time clearly depends on the type and amount of hydrophilic polymer which was applied on the inner cores. Floating time and floating lag time was controlled by quantity and composition of buoyant layer. In vivo radiology studies point out the capability of the system of longer residence time of the tablets in the gastric region and releasing the drug after a programmed lag time. Conclusion: The optimized formulation of the developed system provided a lag phase while showing the gastroretension followed by pulsatile drug release that would be beneficial for chronotherapy of rheumatoid arthritis and osteoarthritis.

scholarly journals Predicting chromosome damage in astronauts participating in international space station missions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alan Feiveson ◽  
Kerry George ◽  
Mark Shavers ◽  
Maria Moreno-Villanueva ◽  
Ye Zhang ◽  
...  
Keyword(s):  
International Space Station ◽  
Dose Response ◽  
Ex Vivo ◽  
Space Station ◽  
Space Radiation ◽  
Blood Samples ◽  
International Space ◽  
Significant Difference ◽  
Subject Specific

AbstractSpace radiation consists of energetic protons and other heavier ions. During the International Space Station program, chromosome aberrations in lymphocytes of astronauts have been analyzed to estimate received biological doses of space radiation. More specifically, pre-flight blood samples were exposed ex vivo to varying doses of gamma rays, while post-flight blood samples were collected shortly and several months after landing. Here, in a study of 43 crew-missions, we investigated whether individual radiosensitivity, as determined by the ex vivo dose–response of the pre-flight chromosome aberration rate (CAR), contributes to the prediction of the post-flight CAR incurred from the radiation exposure during missions. Random-effects Poisson regression was used to estimate subject-specific radiosensitivities from the preflight dose–response data, which were in turn used to predict post-flight CAR and subject-specific relative biological effectiveness (RBEs) between space radiation and gamma radiation. Covariates age, gender were also considered. Results indicate that there is predictive value in background CAR as well as radiosensitivity determined preflight for explaining individual differences in post-flight CAR over and above that which could be explained by BFO dose alone. The in vivo RBE for space radiation was estimated to be approximately 3 relative to the ex vivo dose response to gamma irradiation. In addition, pre-flight radiosensitivity tended to be higher for individuals having a higher background CAR, suggesting that individuals with greater radiosensitivity can be more sensitive to other environmental stressors encountered in daily life. We also noted that both background CAR and radiosensitivity tend to increase with age, although both are highly variable. Finally, we observed no significant difference between the observed CAR shortly after mission and at > 6 months post-mission.

scholarly journals A Review on the Medicinal and Pharmacological Properties of Traditional Ethnomedicinal Plant Sonapatha, Oroxylum indicum

Sinusitis ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 71-89
Author(s):  
Ganesh Chandra Jagetia
Keyword(s):  
Glucose Transporter ◽  
Skin Diseases ◽  
Regulatory Element ◽  
Experimental Studies ◽  
Fatty Acid Synthetase ◽  
Preclinical Models ◽  
Oroxylin A ◽  
Oroxylum Indicum

Oroxylum indicum, Sonapatha is traditionally used to treat asthma, biliousness, bronchitis, diarrhea, dysentery, fevers, vomiting, inflammation, leukoderma, skin diseases, rheumatoid arthritis, wound injury, and deworm intestine. This review has been written by collecting the relevant information from published material on various ethnomedicinal and pharmacological aspects of Sonapatha by making an internet, PubMed, SciFinder, Science direct, and Google Scholar search. Various experimental studies have shown that Sonapatha scavenges different free radicals and possesses alkaloids, flavonoids, cardio glycosides, tannins, sterols, phenols, saponins, and other phytochemicals. Numerous active principles including oroxylin A, chrysin, scutellarin, baicalein, and many more have been isolated from the different parts of Sonapatha. Sonapatha acts against microbial infection, cancer, hepatic, gastrointestinal, cardiac, and diabetic disorders. It is useful in the treatment of obesity and wound healing in in vitro and in vivo preclinical models. Sonapatha elevates glutathione, glutathione-s-transferase, glutathione peroxidase, catalase, and superoxide dismutase levels and reduces aspartate transaminase alanine aminotransaminase, alkaline phosphatase, lactate dehydrogenase, and lipid peroxidation levels in various tissues. Sonapatha activates the expression of p53, pRb, Fas, FasL, IL-12, and caspases and inhibited nuclear factor kappa (NF-κB), cyclooxygenase (COX-2), tumor necrosis factor (TNFα), interleukin (IL6), P38 activated mitogen-activated protein kinases (MAPK), fatty acid synthetase (FAS), sterol regulatory element-binding proteins 1c (SREBP-1c), proliferator-activated receptor γ2 (PPARγ2), glucose transporter (GLUT4), leptin, and HPV18 oncoproteins E6 and E7 at the molecular level, which may be responsible for its medicinal properties. The phytoconstituents of Sonapatha including oroxylin A, chrysin, and baicalein inhibit the replication of SARS-CoV-2 (COVID-19) in in vitro and in vivo experimental models, indicating its potential to contain COVID-19 infection in humans. The experimental studies in various preclinical models validate the use of Sonapatha in ethnomedicine and Ayurveda.

scholarly journals Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2506
Author(s):  
Wamidh H. Talib ◽  
Ahmad Riyad Alsayed ◽  
Alaa Abuawad ◽  
Safa Daoud ◽  
Asma Ismail Mahmod
Keyword(s):  
Clinical Trials ◽  
Current Knowledge ◽  
Biological Activities ◽  
Experimental Studies ◽  
Therapeutic Effects ◽  
Cell Proliferation Inhibition ◽  
Different Types ◽  
Solid Foundation

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

scholarly journals Weighted mixed-effects dose–response models for tables of correlated contrasts

2021 ◽  
Vol 21 (2) ◽  
pp. 320-347
Author(s):  
Nicola Orsini
Keyword(s):  
Dose Response ◽  
Response Pattern ◽  
Mixed Effects ◽  
Data Generation ◽  
Measures Of Association ◽  
Response Models ◽  
Response Data ◽  
Hazard Ratios ◽  
Health Related ◽  
Generation Mechanisms

Recognizing a dose–response pattern based on heterogeneous tables of contrasts is hard. Specification of a statistical model that can consider the possible dose–response data-generating mechanism, including its variation across studies, is crucial for statistical inference. The aim of this article is to increase the understanding of mixed-effects dose–response models suitable for tables of correlated estimates. One can use the command drmeta with additive (mean difference) and multiplicative (odds ratios, hazard ratios) measures of association. The postestimation command drmeta_graph greatly facilitates the visualization of predicted average and study-specific dose–response relationships. I illustrate applications of the drmeta command with regression splines in experimental and observational data based on nonlinear and random-effects data-generation mechanisms that can be encountered in health-related sciences.

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