Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E(2) and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10(-9) M. Substance P-induced (10(-8)-10(-6) M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 microg per ml). Only the highest concentration of substance P (10(-5) M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10(-11) M), but too low to induce protein extravasation (10(-8) M) or even mast cell degranulation (10(-5) M). J Invest Dermatol 115:1015-1020 2000

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In contrast to the well-defined and evidence-based limits of the ABI, the diagnostic criteria for a pathologic TBI remain ambiguous. Although several guidelines and reviews of PAD diagnostics recommend a TBI <0.70 as cutoff, it is not strictly evidence-based. The current literature is not sufficient to conclude a specific cutoff as diagnostic for PAD. The current studies in normal populations and the correlation with angiography are sparse, and additional trials are needed to further validate the limits. Large-scale trials are needed to establish the risk of morbidity and mortality for the various diagnostic limits of the TBI.

Conclusion. These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.

Summary Background The mediator mechanisms of the cutaneous wheal and flare response, which underlies allergic skin and urticarial conditions, are controversial. The wheal results primarily from a direct effect of histamine on the local vascular bed, but to what extent does histamine diffuse within the wheal? The flare is neurogenic in origin, being disseminated within the dermis by axon reflexes, but do the neuropeptides released from the nerve endings cause the vasodilatation directly or do they induce the further release of histamine which then transduces the fiare? Objective We have addressed these questions by inserting 216 μm diameter microdialysis fibres into the dermis within the different areas of the wheal and flare to monitor changes in histamine levels provoked by intradermal injections of histamine, allergen, codeine and substance P. Twenty‐one subjects participated in the investigations. Results The histamine concentration in unprovoked skin was 10.5 ± 0.6 nM. As the dialysis efficacy was 50%, this equates to tissue concentrations of 20 nM. All provicants released large amounts of histamine at the injection site, maximum histamine levels being 337–1293 nM. Diffusion of histamine within the wheai was poor, levels at 2.3 mm and 3.7 mm from the site of injection being 4–22% and 0.2–3.7% respectively of those 1 mm from the injection site. No increased histamine levels were detected in the flare with any provicant. Atraumatic delivery to the skin of histamine in infusion concentrations of 30–10000 nM caused concentration‐related effects, at least 100 nM being necessary to induce a significant increase in skin blood flow, a threshold of 300–1000 being required to stimulate a visible flare and a measurable erythema, and 3000–10000 nM being the minimum for induction of a wheal. Thus the skin blood vessels and nerves are responsive to histamine, but at relatively high concentrations Conclusions These data support the theory that the flare reaction to local histamine injection or release is a neurogenic reflex not involving histamine release at its effector end.