Graded responses

There have been a number of attempts, by the introduction of a further parameter into the Hammett equation, to quantify this graded response—via through-conjugation—on the part of a p-substituent. Among the best known of these is the Yukawa-Tsuno equation, [7], which, in the form shown here, is... 

Bass DA, Parce JW, Dechatelet LR et al. (1983) Flow cytometric studies of oxidative product formation by neutrophils a graded response to membrane stimulation. J Immunol. 130 1910-1918. 

In graded response one can resort to using surrogates, and the classic Hill model (or sigmoid model as described in Equation 18.16 above) is used to correlate observed effect (E(t)) with the concentration modified by an exponent that is called Hill coefficient in classic sigmoidal model, the Hill coefficient h) would be equal to 1 ... 

Analyze the samples on the flow cytometer. (See Chapter 36, Fig. 2, for normal light-scatter profiles.) When the fluorescence gain is properly adjusted, the unstimulated control cells (shaded curve. Fig. 2) should be visible on scale with the PMA-stimulated cells (open curves. Fig. 2). PMA (1-100 ng/mL) should stimulate a dose-dependent (graded) response. All normal granulocytes should exhibit an oxidative metabolic response to PMA (see Note 2). 

Anticonvulsants can be suitably studied by use of quantal dose-response curves. For example, to assess the potential of new anticonvulsants to control epileptic seizures in humans, these drugs are initially tested for their ability to protect animals against experimentally induced seizures. In the presence of a given dose of the drug, the animal either has the seizure or does not that is, it either is or is not protected. Thus, in the design of this experiment, the effect of the drug (protection) is all or none. This type of response, in contrast to a graded response, must be described in a noncontinuous manner. 

Dose-response curves illustrating the graded responses of five guinea pigs (a-e) to increasing doses of levarterenol. The responses are increases in heart rate above the rate measured before the administration of the drug. Broken lines indicate 50% of maximum response (horizontal) and individual ED50 values (vertical). 

If the risk of the disease in question increases with the amount of exposure, this is considered to be a strong indication of causality, although absence of a graded response is not necessarily evidence against a causal relationship. Demonstration of a decline in risk after cessation of or reduction in exposure in individuals or in whole populations also supports a causal interpretation of the findings. 

Toxic responses may be detected in a variety of ways in animals, and some of these have already been alluded to in previous chapters. Toxic responses may be the all-or-none type such as the death of the organism or they may be graded responses. Thus, the main means of detection are as follows ... 

The term response can take a number of different forms. In a biochemical assay, the response may be determined by changes in something quantitative, such as changes in ion concentration, absorbance, or fluorescence. Quantifiable examples of in vivo response include changes in body temperature and blood pressure. With this type of data (graded response), the range of responses collected in the study will determine what defines a... 

Deterministic responses are those for which the severity varies with dose and for which a threshold usually exists. In some toxicology texts, this type of response is called a graded response, to reflect both the increase in incidence of the response and the increase in its severity that usually are observed as the dose increases above the threshold. If the dose does not exceed a certain threshold, the probability of occurrence of a particular response is presumed to be zero. Deterministic responses often occur soon after exposure, and a causal relationship between dose and response in such cases is easily established if the dose is sufficiently high. Deterministic responses resulting from exposure to chemical toxicants include, for example, increased protein in the urine, birth defects and sterility,... 

Figure 6.2 Concentration-response curve for graded response (A) arithmetic scale (B) log concentration scale. Kd(app) is arbitrarily taken to be 4.5 nM.

Nilsson M, Engstrom G, Ericson LE (1986) Graded response in the individual thyroid follicle cell to increasing doses of TSH. Mol Cell Endocrinol 44 165-9 O Connor JC, Frame SR, Davis LG, Cook JC (1999) Detection of thyroid toxicants in a tier I screening battery and alterations in thyroid endpoints over 28 days of exposure. Toxicol Sci 51 54-70... 

Raivich G, Bohatschek M, Kloss CUA, Werner A, Jones LL, Kreutzberg GW (1999) Neuroglial activation repertoire in the injured brain graded response, molecular mechanisms and cues to physiological function, Brain Res Rev 30 77-105. 

Since the persistent depolarization of end plates is associated with an ef ux of K+ ions, hyperkalemia can result (risk of cardiac arrhythmias). Only in a few muscle types (e. g., extraocular muscle) are muscle fibers supplied with multiple end plates and therefore capable of a graded response. Here succinylcholine causes depolarization distributed over the entire fiber, which responds with a contracture. Intraocular pressure rises, which must be taken into account during eye surgery. 

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