A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations

1998 ◽  
Vol 17 (7) ◽  
pp. 353-364 ◽  
Author(s):  
Edward J Calabrese ◽  
Linda A Baldwin
Keyword(s):  
Dose Response ◽  
A Priori ◽  
Dose Range ◽  
Biological Mechanisms ◽  
Direct Stimulation ◽  
General Classification ◽  
Wide Range ◽  
Temporal Factors ◽  
Relationship Of

The development of a comprehensive database of chemical hormetic responses (i.e., U-or inverted U-shaped dose-response relationships) using objective a priori study design, statistical and study replication criteria has recently been reported.1An assessment of this database reveals the existence of a wide range of hormetic dose-reponse relationships including those demonstrating a direct stimulation or an overcompensation response to a disruption of homeostasis. These two broad types of hormetic responses are affected by temporal factors and display unique patterns of dose-range stimulation, magnitude of stimulatory response and relationship of the maximum stimulatory response to the NOAEL. A general classification of U-shaped dose-response relationships is proposed to provide a more organized framework to evaluate the highly distinctive and diverse hormetic responses within the context of establishing underlying biological mechanisms and exploring risk assessment implications.

The Dose Determines the Stimulation (and Poison): Development of A Chemical Hormesis Database

1997 ◽  
Vol 16 (6) ◽  
pp. 545-559 ◽  
Author(s):  
Edward J. Calabrese ◽  
Linda A. Baldwin
Keyword(s):  
A Priori ◽  
Dose Range ◽  
Evaluation Criteria ◽  
Metabolic Effects ◽  
Growth Responses ◽  
Wide Range ◽  
Order Of Magnitude ◽  
Real Phenomenon ◽  
Effect Level ◽  
Taxonomic Groups

A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer searches utilizing various keyword descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biologic endpoints were assessed, with growth responses the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude with the average low-dose maximum stimulation approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude with the upper end of the hormetic curve approaching the estimated no-observed-effect level (NOEL) for the particular endpoint. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of ≥ doses with <3 doses in the hormetic zone. The present analysis suggests that chem ical hormesis is a reproducible and generalizable biologic phenomenon. Over the last decade advances have been made providing mechanistic insight helpful in explaining the phenomenon of chemical hormesis in multiple biologic systems with various endpoints. The reason for the uncertainty surrounding the existence of hormesis as a “real phenomenon” is believed to be the result of its relatively infrequent observation in the literature due to experimental design considerations, especially with respect to the number of doses, range of doses, and endpoint selection.

In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

1990 ◽  
Vol 8 (6) ◽  
pp. 1070-1082 ◽  
Author(s):  
J M Kirkwood ◽  
M S Ernstoff ◽  
T Trautman ◽  
G Hebert ◽  
Y Nishida ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Dose Response ◽  
Dose Range ◽  
Cell Subset ◽  
Optimal Dosage ◽  
Antitumor Effects ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Wide Range

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.

Maturity and Molt Status of Crustacea: Determining Classification without Prior Criteria

1994 ◽  
Vol 51 (2) ◽  
pp. 408-416 ◽  
Author(s):  
William G. Warren
Keyword(s):  
Iterative Procedure ◽  
A Priori ◽  
Carapace Width ◽  
Snow Crab ◽  
Data Sets ◽  
Chionoecetes Opilio ◽  
Relationship Of ◽  
The Relationship

Existing methodology for estimation is reviewed for the situation where, a priori, the existence of two or more groups can be postulated but, in contrast with discriminant analysis, there is no sample in which the correct categories are known. Such mixture models are applied to two data sets related to the maturity and molt status of snow crab, Chionoecetes opilio, namely (1) the classification of crab as morphometrically mature or immature on the basis of the chela height – carapace width relationship and (2) the determination of the number of molts of crab, during a known period at liberty, from the relationship of size at release and size at recapture of tagged animals, in the latter example, a theoretical constraint is imposed that links the relationships at the different stages. The solution is obtained by "nesting" an iterative procedure within an EM algorithm. The method permits hypotheses concerning the number of groups to be tested, including the hypothesis that the data come from a single homogenous group, and each individual is assigned a probability of belonging to a group.

scholarly journals A systems approach to the characterization and classification of T-cell responses

2017 ◽  
Author(s):  
Shinobu Yamamoto ◽  
Elizabeth Whalen ◽  
Daisuke Chujo ◽  
Durgha Nattamai ◽  
Nicole Baldwin ◽  
...  
Keyword(s):  
T Cell ◽  
Systems Approach ◽  
Meta Analysis ◽  
A Priori ◽  
T Cell Responses ◽  
Cell Responses ◽  
Wide Range

AbstractTypes of T-cell responses are categorized on the basis of a limited number of molecular markers selected usinga prioriknowledge about T-cell immunobiology. We sought to develop a novel systems-based approach for the creation of an unbiased framework enabling assessment of antigenic-peptide specific T-cell responsesin vitro. A meta-analysis of transcriptome data from PBMCs stimulated with a wide range of peptides identified patterns of gene regulation that provided an unbiased classification of types of antigen-specific responses. Further analysis yielded new insight about the molecular processes engaged following antigenic stimulation. This led for instance to the identification of transcription factors not previously studied in the context of T-cell differentiation. Taken together this profiling approach can serve as a basis for the unbiased characterization of antigen-specific responses and as a foundation for the development of novel systems-based immune profiling assays.

Morbidity and Mortality after High-dose Transfusion

2016 ◽  
Vol 124 (2) ◽  
pp. 387-395 ◽  
Author(s):  
Daniel J. Johnson ◽  
Andrew V. Scott ◽  
Viachaslau M. Barodka ◽  
Sunhee Park ◽  
Jack O. Wasey ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Dose Response ◽  
Dose Range ◽  
Adverse Outcomes ◽  
Morbidity And Mortality ◽  
High Dose ◽  
Clinical Predictors ◽  
Response Curves ◽  
Wide Range ◽  
Very High

Abstract Background It is well recognized that increased transfusion volumes are associated with increased morbidity and mortality, but dose–response relations between high- and very-high-dose transfusion and clinical outcomes have not been described previously. In this study, the authors assessed (1) the dose–response relation over a wide range of transfusion volumes for morbidity and mortality and (2) other clinical predictors of adverse outcomes. Methods The authors retrospectively analyzed electronic medical records for 272,592 medical and surgical patients (excluding those with hematologic malignancies), 3,523 of whom received transfusion (10 or greater erythrocyte units throughout the hospital stay), to create dose–response curves for transfusion volumes and in-hospital morbidity and mortality. Prehospital comorbidities were assessed in a risk-adjusted manner to identify the correlation with clinical outcomes. Results For patients receiving high- or very-high-dose transfusion, infections and thrombotic events were four to five times more prevalent than renal, respiratory, and ischemic events. Mortality increased linearly over the entire dose range, with a 10% increase for each 10 units of erythrocytes transfused and 50% mortality after 50 erythrocyte units. Independent predictors of mortality were transfusion dose (odds ratio [OR], 1.037; 95% CI, 1.029 to 1.044), the Charlson comorbidity index (OR, 1.209; 95% CI, 1.141 to 1.276), and a history of congestive heart failure (OR, 1.482; 95% CI, 1.062 to 2.063). Conclusions Patients receiving high- or very-high-dose transfusion are at especially high risk for hospital-acquired infections and thrombotic events. Mortality increased linearly over the entire dose range and exceeded 50% after 50 erythrocyte units.

FUNDAMENTAL NATURE AND CLASSIFICATION OF LABOR MIGRATION

2020 ◽  
Vol 1 (3) ◽  
pp. 14-23
Author(s):  
Tulkin Chulliev ◽  
Keyword(s):  
Labor Migration ◽  
General Classification ◽  
Fundamental Nature

The article explains the fundamental nature of migration by combining the definitions given by other scholars. The issue of labor migration is analyzed. One of the most important problems in contemporary migration processes - the problem of classification- is researched and a general classification is provided

Long-term Effects of Triazol Growth Regulators on Stem Elongation of Rhododendron and Kalmia

HortScience ◽  
1997 ◽  
Vol 32 (3) ◽  
pp. 436E-436
Author(s):  
Martin P.N. Gent
Keyword(s):  
Dose Response ◽  
Growth Regulator ◽  
Stem Elongation ◽  
Spray Application ◽  
Long Term Effects ◽  
Potted Plants ◽  
Response Coefficient ◽  
Wide Range ◽  
Second Year

The persistence of effects of paclobutrazol or uniconazol on stem elongation was determined for several years after large-leaf Rhododendron and Kalmia latifolia were treated with a single-spray application of these triazol growth-regulator chemicals. Potted plants were treated in the second year from propagation, and transplanted into the field in the following spring. The elongation of stems was measured in the year of application and in the following 2 to 4 years. Treatments with a wide range of doses were applied in 1991, 1992, or 1995. For all except the most-dilute applications, stem elongation was retarded in the year following application. At the highest doses, stem growth was inhibited 2 years following application. The results could be explained by a model of growth regulator action that assumed stem elongation was inversely related to amount of growth regulator applied. The dose response coefficient for paclobutrazol was less than that for uniconazol. The dose that inhibited stem elongation one-half as much as a saturating dose was about 0.5 and 0.05 mg/plant, for paclobutrazol and uniconazol, respectively. The dose response coefficient decreased exponentially with time after application, with an exponential time constant of about 2/year. The model predicted a dose of growth regulator that inhibited 0.9 of stem elongation immediately after application would continue to inhibit 0.5 of stem elongation in the following year.

Antineoplastic Activity, Structural Modification, Synthesis and Structure-activity Relationship of Dammarane-type Ginsenosides: An Overview

2019 ◽  
Vol 23 (5) ◽  
pp. 503-516 ◽  
Author(s):  
Qiang Zhang ◽  
Xude Wang ◽  
Liyan Lv ◽  
Guangyue Su ◽  
Yuqing Zhao
Keyword(s):  
Structural Modification ◽  
Gastrointestinal Disease ◽  
Structure Activity Relationship ◽  
Cerebrovascular Diseases ◽  
Activity Relationship ◽  
Cycle Arrest ◽  
Structure Activity ◽  
Wide Range ◽  
Structural Association ◽  
Relationship Of

Dammarane-type ginsenosides are a class of tetracyclic triterpenoids with the same dammarane skeleton. These compounds have a wide range of pharmaceutical applications for neoplasms, diabetes mellitus and other metabolic syndromes, hyperlipidemia, cardiovascular and cerebrovascular diseases, aging, neurodegenerative disease, bone disease, liver disease, kidney disease, gastrointestinal disease and other conditions. In order to develop new antineoplastic drugs, it is necessary to improve the bioactivity, solubility and bioavailability, and illuminate the mechanism of action of these compounds. A large number of ginsenosides and their derivatives have been separated from certain herbs or synthesized, and tested in various experiments, such as anti-proliferation, induction of apoptosis, cell cycle arrest and cancer-involved signaling pathways. In this review, we have summarized the progress in structural modification, shed light on the structure-activity relationship (SAR), and offered insights into biosynthesis-structural association. This review is expected to provide a preliminary guide for the modification and synthesis of ginsenosides.

scholarly journals Modes of Interaction in Naturally Occurring Medical Encounters With General Practitioners: The “One in a Million” Study

2021 ◽  
pp. 104973232199379
Author(s):  
Olaug S. Lian ◽  
Sarah Nettleton ◽  
Åge Wifstad ◽  
Christopher Dowrick
Keyword(s):  
General Practitioners ◽  
Narrative Analysis ◽  
Mode Competition ◽  
General Applicability ◽  
Naturally Occurring ◽  
Wide Range ◽  
The One ◽  
Narrative Mode ◽  
Modes Of Interaction

In this article, we qualitatively explore the manner and style in which medical encounters between patients and general practitioners (GPs) are mutually conducted, as exhibited in situ in 10 consultations sourced from the One in a Million: Primary Care Consultations Archive in England. Our main objectives are to identify interactional modes, to develop a classification of these modes, and to uncover how modes emerge and shift both within and between consultations. Deploying an interactional perspective and a thematic and narrative analysis of consultation transcripts, we identified five distinctive interactional modes: question and answer (Q&A) mode, lecture mode, probabilistic mode, competition mode, and narrative mode. Most modes are GP-led. Mode shifts within consultations generally map on to the chronology of the medical encounter. Patient-led narrative modes are initiated by patients themselves, which demonstrates agency. Our classification of modes derives from complete naturally occurring consultations, covering a wide range of symptoms, and may have general applicability.

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