Refractory state

A condition in which a receptor is unresponsive despite the presence of agonist also referred to as a refractory state . Typically this state is the consequence of prolonged exposure to agonist, and occurs after receptor activation it is a built in mechanism to limit a receptor s effects. Mechanistically the desensitised state differs from the resting, closed state of a receptor because in the latter state, a receptor can respond to agonist. This difference predicts that these states are structurally distinct. The desensitised state may also be stabilised by very low concentrations of agonist, such that no measurable activation of the receptor precedes it. Desensitisation is an intrinsic property of many receptors but can also be influenced by other interactions or modifications, such as phosphorylation. 

Desensitization can be defined as the tendency of a response to wane, despite the presence of a stimulus of constant intensity (e.g., constant agonist concentration). In the case of the nicotinic ACh receptor, good evidence suggests that desensitization results from a change in receptor conformation to an inactive refractory state (Rang and Ritter, 1970). To describe this in terms of the AChR activation mechanism, we could add a desensitized state to the scheme shown in Eq. (6.2) to give ... 

Acute lesions show reduced expression of IL-12, a key cytokine of Th-1 polarization which was shown on the mRNA level by in situ hybridization in acute skin lesions. The reason for the relative lack in the expression of lL-12 is not completely understood yet. Skin-infiltrating CD40L+ T cells may contribute to the relative inability of IL-12 upregulation in acute eczema leading to a refractory state of constitutive APC via an intracellular ERK-dependent signaling pathway [20]. 

Down-regulation and the accompanying receptor changes may explain the tolerant or refractory state seen in severe asthmatics who no longer respond to P-adrenoceptor agonists. 

One such phenomenon is endotoxin tolerance. It is known that LPS stimulation is associated with a prompt response (NF-/cB translocation to the nucleus and cytokine production) followed by a refractory state, wherein a second challenge is far less effective at provoking such a response (97,98). Cross-tolerance has been observed when a primary stimulus with lipopeptides is used in place of LPS (99). Although some have attributed tolerance to the production of antiinflammatory cytokines such as TGF/3 and/or IL-10 (100), it is more widely held that tolerance reflects the activation of a feedback pathway within cells, causing paralysis of the LPS response. One example of tolerance at the cellular level involves the production of NF-kB p50 homodimers, which can bind to diverse promoters within the cell and prevent activation by p50/p65 heterodimers (101). Other levels of blockade are also possible and are currently under investigation. 

Fig. 1.1. Response (right) of an excitable system to different stimuli (left). The system has a stable fixed point. Panel a) A sub-threshold perturbation generates a small system response. Panel b) A super-threshold perturbation initiates an excitation loop. Panel c) The system can not be excited by a super-threshold perturbation applied during the refractory state. Panel d) Two successive super-threshold perturbations generate excitations only if both are applied to the system in the rest state.

The spent sorbent from FBC may be taken directly to disposal and is much easier than the disposal salts produced by wet limestone scrubbing. These latter species are contained in wet sludge having a high volume and a high content of salt-laden water. The mineral products of FBC, however, are quite dry and in a chemically refractory state and, therefore, disposal is much easier and less likely to result in pollution. 

Administration of ASA can lead to a refractory state lasting several days, in which further provocations produce no reaction and in which there is some degree of cross-tolerance (Pleskow et ai, 1982). Daily ASA administration therefore has been used as therapy, but although many patients are improved, some deteriorate (Chiu, 1983). Dietary avoidance regimes are reportedly successful in the control of chronic urticaria, but their place in the routine treatment of chronic asthma is not established (Doeglas, 1975 Ros et al., 1976 Tarlo and Broder, 1982). 

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