Facial flushing in rosacea is often induced by trigger events. However, trigger causation mechanisms are currently unclear. This study tested the central hypothesis that rosacea causes sympathetic and axon reflex-mediated alterations resulting in trigger-induced symptomatology. Twenty rosacea patients and age/sex-matched controls participated in one or a combination of symptom triggering stressors. In protocol 1, forehead skin sympathetic nerve activity (SSNA; supraorbital microneurography) was measured during sympathoexcitatory mental (2-min serial subtraction of novel numbers) and physical (2-min isometric handgrip) stress. In protocol 2, forehead skin blood flow (laser-Doppler flowmetry) and transepithelial water loss/sweat rate (capacitance hygrometry) were measured during sympathoexcitatory heat stress (whole body heating by perfusing 50°C water through a tube-lined suit). In protocol 3, cheek, forehead, forearm, and palm skin blood flow were measured during nonpainful local heating to induce axon reflex vasodilation. Heart rate (HR) and mean arterial pressure (MAP) were recorded via finger photoplethysmography to calculate cutaneous vascular conductance (CVC; flux·100/MAP). Higher patient transepithelial water loss was observed (rosacea 0.20 ± 0.02 vs. control 0.10 ± 0.01 mg·cm(-2)·min(-1), P < 0.05). HR and MAP changes were not different between groups during sympathoexcitatory stressors or local heating. SSNA during early mental (32 ± 9 and 9 ± 4% increase) and physical (25 ± 4 and 5 ± 1% increase, rosacea and controls, respectively) stress was augmented in rosacea (both P < 0.05). Heat stress induced more rapid sweating and cutaneous vasodilation onset in rosacea compared with controls. No axon reflex vasodilation differences were observed between groups. These data indicate that rosacea affects SSNA and that hyperresponsiveness to trigger events appears to have a sympathetic component.

New Findings r What is the central question of this study?Calcium is an important second messenger in eccrine sweating; however, whether modulation of extracellular Ca 2+ and Ca 2+ entry has the capacity to modulate sweat rate in non-glabrous human skin has not been explored. r What is the main finding and its importance?Acetylcholine to sweat rate dose-response relationships identify that local in vivo Ca 2+ chelation and L-type Ca 2+ channel antagonism have the capacity to attenuate the cholinergic sensitivity of eccrine sweat glands. Importantly, these data translate previous glabrous in vitro animal studies into non-glabrous in vivo human skin.Calcium is an important second messenger in eccrine sweating, with both internal and external sources being identified in vitro. It is unclear whether in vivo modulation of extracellular Ca 2+ levels or influx has the capacity to modulate sweat rate in non-glabrous human skin. To test the hypothesis that lowering interstitial Ca 2+ levels would decrease the sensitivity of the ACh to sweat rate (via capacitance hygrometry) dose-response relationship, nine healthy subjects received six ACh doses (1 × 10 −5 to 1 × 10 0 m in 10-fold increments) with and without a Ca 2+ chelator (12.5 mg ml −1 EDTA) via forearm intradermal microdialysis (protocol 1). To test the hypothesis that attenuating Ca 2+ influx via L-type Ca 2+ channels would also decrease the sensitivity of the ACh to sweat rate dose-response relationship, 10 healthy subjects received similar ACh doses with and without a phenylalkylamine Ca 2+ channel blocker (1 mm verapamil; protocol 2). Non-linear regression curve fitting identified a right-shifted ED 50 in EDTA-treated sites compared with ACh alone (−1.0 ± 0.1 and −1.5 ± 0.1 logm, respectively; P < 0.05), but unchanged maximal sweat rate (0.60 ± 0.07 and 0.58 ± 0.11 mg cm −2 min −1 , respectively; P > 0.05) in protocol 1. Protocol 2 also resulted in a right-shifted ED 50 (verapamil, −0.9 ± 0.1 logm; ACh alone, −1.6 ± 0.2 logm; P < 0.05), with unchanged maximal sweat rate (verapamil, 0.45 ± 0.08 mg cm −2 min −1 ; ACh alone, 0.35 ± 0.06 mg cm −2 min −1 ; P > 0.05). Thus, local in vivo Ca 2+ chelation and L-type

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These data indicate that facial skin initial CVC peaks to local heating are similar to non-glabrous skin. In contrast to forearm responses, facial topical sensory blockade does not abate axon reflex responses to local heating. Palm skin data indicate that maximal skin blood flow is not obtained during local heating as it is in non-glabrous skin.

Our study indicates that approximately 50% or more of BCC and SCC patients with positive margins found on biopsies did not have cancer cells present at the time of wide excisions.