Current State of Skin Cancer Prevention: A Systematic Review. / Situación actual de la prevención del cáncer de piel: una revisión sistemática.

Skin cancer deaths continue to rise despite the implementation of numerous preventive campaigns and programs. The aim of this systematic review was to evaluate reviews of primary and secondary skin cancer prevention strategies as reported over the past 10 years. We analyzed 63 systematic reviews and meta-analyses: 30 (46.6%) addressing primary interventions and 35 (55.6%) addressing secondary interventions. Two of the reviews covered both. The most widely reported primary prevention approaches were education programs (63.3%), followed by risk modeling to identify individuals at high risk for melanoma (17.6%), and the promotion of sunscreen use (11.8%). The most widely reported secondary prevention measures concerned imaging systems for early skin cancer detection (40%), smartphones and new technologies (22.9%), and visual diagnosis in population-based screening (17.4%). The most effective measures were primary prevention education programs to improve sun protection habits.

Patients' experience during weaning of invasive mechanical ventilation: A review of the literature. / Experiencias del paciente durante la retirada de la ventilación mecánica invasiva: una revisión de la literatura.

OBJECTIVE: Weaning from invasive mechanical ventilation (IMV) is influenced by physiological and psychological factors, the latter being the least studied. The aim was to identify, through the literature, patients' experiences during weaning from IMV and report its influencing factors. METHOD: The literature search was conducted using the Pubmed, CINAHL and PsycINFO databases. The search terms were: "patient", "experience" and "ventilator weaning". The research limits were: age (>19years) and language (English, Spanish and Finnish). RESULTS: Fifteen publications were analysed. The main results were grouped into three main categories according to patient's perceptions, feelings and experiences, influence of professionals' attention and determinants for successful weaning. Patients remember IMV weaning as a stressful process where they experience anxiety, frustration, despair or uncertainty. Nurses have a key role in improving communication with patients and foreseeing their needs. Family support and the care provided by the caregivers were shown as essential during the process. The patient's self-determination, self-motivation and confidence are identified as important factors to achieve successful IMV weaning. CONCLUSIONS: Psychological care, in addition to physical and technical care, is important at providing holistic care. Interventional studies are needed to improve the care during the weaning experience.

Blockade of nociceptive sensory afferent activity of the rat knee joint by the bradykinin B2 receptor antagonist fasitibant.

OBJECTIVE: The aim of this study was to determine in intact and inflamed knee joints of the rat, the effect of the bradykinin (BK) B2 receptor antagonist fasitibant (MEN16132) on nociceptor mechanosensitivity and hyperalgesia. METHODS: Joint afferent sensory fibers of the medial articular nerve of anesthetized animals were electrophysiologically recorded, measuring nerve impulse activity evoked by passive innocuous and noxious movements of the joint, in intact and kaolin and carrageenan-injected joints. Knee joints of rats were also acutely inflamed by intra-articular injection of carrageenan alone. Long term duration of fasitibant antinociceptive effects were behaviorally evaluated using the incapacitance test. RESULTS: BK (100 µM) injected into the saphenous artery, induced excitation and sensitization of multi- and single unit recordings. Fasitibant (300 µM) injected prior to BK, reduced its excitatory effects as well as the overall increase of movement-evoked activity resulting from repeated injections of BK. Fasitibant did not affect movement-evoked activity of sensory fibers of intact, non-inflamed knee joints. Intra-articular fasitibant (100 µg/knee) significantly reduced the carrageenan-induced inflammatory hyperalgesia measured with the incapacitance test up to four days after treatment. This antinociceptive effect was not obtained with systemic endovenous injection of the drug. CONCLUSIONS: Fasitibant prevents B2 receptor-mediated activation and sensitization of peripheral joint afferents and the ensuing inflammatory hyperalgesia, and may be a useful, novel drug for arthritis pain treatment.

Liver transplant with controlled donors after circulatory death with normothermic regional perfusion and brain dead donors: A multicenter cohort study of transfusion, one-year graft survival and mortality.

BACKGROUND: Controlled donation after circulatory death (cDCD) has expanded the donor pool for liver transplantation (LT). However, transfusion requirements and perioperative outcomes should be elucidated. The aim of this multicenter study was to assess red blood cell (RBC) transfusions, one-year graft and patient survival after LT after cDCD with normothermic regional perfusion (NRP) compared with donors after brain death (DBD). METHODS: 591 LT carried out in ten centers during 2019 were reviewed. Thromboelastometry was used to manage coagulation and blood product transfusion in all centers. Normothermic regional perfusion was the standard technique for organ recovery. RESULTS: 447 patients received DBD and 144 cDCD with NRP. Baseline MCF Extem was lower in the cDCD group There were no differences in the percentage of patients (63% vs. 61% p = 0.69), nor in the number of RBC units transfused (4.7 (0.2) vs 5.5 (0.4) in DBD vs cDCD, p = 0.11. Twenty-six patients (6%) died during admission for LT in the DBD group compared with 3 patients (2%) in the cDCD group (p = 0.15). To overcome the bias due to a worse coagulation profile in cDCD recipients, matched samples were compared. No differences in baseline laboratory data, or in intraoperative use of RBC or one-year outcome data were observed between DBD and cDCD recipients. CONCLUSIONS: cDCD with NRP is not associated with increased RBC transfusion. No differences in graft and patient survival between cDCD and DBD were found. Donors after controlled circulatory death with NRP can increasingly be utilized with safety, improving the imbalance between organ donors and the ever-growing demand.

Temperature modulation of slow and fast cortical rhythms.

In the local cortical network, spontaneous emergent activity self-organizes in rhythmic patterns. These rhythms include a slow one (<1 Hz), consisting in alternation of up and down states, and also faster rhythms (10-80 Hz) generated during up states. Varying the temperature in the bath between 26 and 41 degrees C resulted in a strong modulation of the emergent network activity. Up states became shorter for warmer temperatures and longer with cooling, whereas down states were shortest at physiological (36-37 degrees C) temperature. The firing rate during up states was robustly modulated by temperature, increasing with higher temperatures. The sparse firing rate during down states hardly varied with temperature, thus resulting in a progressive merging of up and down states for temperatures around 30 degrees C. Below 30 degrees C and down to 26 degrees C the firing lost rhythmicity, becoming progressively continuous. The slope of the down-to-up transitions, which reflects the speed of recruitment of the local network, was progressively steeper for higher temperatures, whereas wave-propagation speed exhibited only a moderate increase. Fast rhythms were particularly sensitive to temperature. Broadband high-frequency fluctuations in the local field potential were maximal for recordings at 36-38 degrees C. Overall, we found that maintaining cortical slices at physiological temperature is critical for the generated activity to be analogous to that in vivo. We also demonstrate that changes in activity with temperature were not secondary to oxygenation changes. Temperature variation sets the in vitro cortical network at different functional regimes, allowing the exploration of network activity generation and control mechanisms.

Intra-articular injections of hyaluronan solutions of different elastoviscosity reduce nociceptive nerve activity in a model of osteoarthritic knee joint of the guinea pig.

OBJECTIVE: To study in guinea pigs knee joints the effects of intra-articular injection of HYADD 4-G (Fidia-Farmaceutici), a novel hyaluronan (HA)-derived elastoviscous material and of Hyalgan (Fidia-Farmaceutici), a HA product with very low viscoelasticity, on movement-evoked nociceptor impulse activity from normal and inflamed knee joints. DESIGN: Nociceptor impulse activity was recorded from single Adelta and C fibers of the medial articular nerve either under control conditions or after induction of an experimental knee joint osteoarthritis (OA) by partial medial menisectomy and transection of the anterior cruciate ligament (PMM-TACL). The stimuli consisted of standardized innocuous and noxious inward and outward rotations of the tibia against the femur of 50s duration, repeated every 5min for 1.5h. RESULTS: The number of movement-evoked impulses was significantly augmented 1 day and 1 week after PMM-TACL compared with intact knee joint. The enhanced impulse response to joint movements 1 week following surgery was attenuated by repeated intra-articular injection of HYADD 4-G and even more prominently by Hyalgan. CONCLUSIONS: HA products have a reducing action on joint nociceptor discharges that appears to depend predominantly on their role as an elastoviscous filter associated with their rheological properties, but also on a chemical effect on sensitized nociceptive terminals of inflamed joint tissues, possibly linked to the HA concentration.

Repetitive spikes in photoreceptor axons of the scorpion eye. Invertebrate eye structure and tetrodotoxin.

A graded depolarization accompanied by nerve impulses can be recorded from the scorpion lateral and median eyes in response to light. Electron microscopy shows that axons forming the optic nerve arise directly from the photoreceptors. Thus, photoreceptors must respond both by the generation of a slow receptor potential and the initiation of spikes. The latency of the first spike, and the maximal and mean discharge frequencies were a function of light intensity. Spikes were abolished by tetrodotoxin. Repetitive firing to light therefore appears to be a normal response of scorpion photoreceptors and is the result of regenerative Na influx in the cell membrane.

Arginine-rich peptides are blockers of VR-1 channels with analgesic activity.

Vanilloid receptors (VRs) play a fundamental role in the transduction of peripheral tissue injury and/or inflammation responses. Molecules that antagonize VR channel activity may act as selective and potent analgesics. We report that synthetic arginine-rich hexapeptides block heterologously expressed VR-1 channels with submicromolar efficacy in a weak voltage-dependent manner, consistent with a binding site located near/at the entryway of the aqueous pore. Dynorphins, natural arginine-rich peptides, also blocked VR-1 activity with micromolar affinity. Notably, synthetic and natural arginine-rich peptides attenuated the ocular irritation produced by topical capsaicin application onto the eyes of experimental animals. Taken together, our results imply that arginine-rich peptides are VR-1 channel blockers with analgesic activity. These findings may expand the development of novel analgesics by targeting receptor sites distinct from the capsaicin binding site.

Three-dimensional reconstruction of scleral cold thermoreceptors of the cat eye.

Sensory endings that respond to local cooling were identified electrophysiologically in the cat's sclera. Functionally identified scleral thermal fibers were then used to analyze the structural characteristics of cold receptor endings. Four Adelta units sensitive to controlled cooling of their scleral receptive fields were recorded. The receptive areas were mapped, demarcated with pins and examined electron microscopically using extensive three-dimensional reconstructions. The supporting tissue within the receptive areas of cold units consisted of dense collageneous tissue with a small number of blood vessels that were either veins or capillaries. Adelta nerve fibers were found within these tissue blocks presumably corresponding with cold sensitive fibers. Small nerves and single nerve fibers devoid of a perineurium were found in all parts of the tissue, only occasionally passing a blood vessel. The terminal portions showed axonal swellings all along the unmyelinated segment filled with mitochondria, glycogen particles, and some vesicles. About 30% of the terminal axonal membrane is not covered by Schwann cells. In the unmyelinated distal portion, the mitochondrial content ranged from 0.012 to 0.038 microm(3) mitochondrial volume per microm(2) nerve fiber membrane. In comparison with sensory endings in the cat's knee joint, cold receptors in the cat sclera showed many similarities in their three-dimensional structure with polymodal nociceptor endings of the knee joint but contain less mitochondria. This suggests that cold sensory endings do not require specialized cellular processes for the transduction of cold stimuli, as is the case for multimodal transduction and sensitization in the terminal portion of polymodal nociceptors.

Capsaicin and carbon dioxide act by distinct mechanisms on sensory nerve terminals in the cat cornea.

The discharge of single afferent units recorded from filaments of the mixed ciliary nerve of anaesthetised cats was used to study the effects of CO2, capsaicin and the capsaicin antagonist, capsazepine, on sensory nerve terminals in the cornea. Units were selected on the basis of their sensitivity to CO2 (98.5% applied to the cornea for 30 s in a moist gas stream). Of these units, about 50% (18/38) also responded to capsaicin (0.1 microM applied as droplet and washed off after 20 s), with a discharge of similar magnitude to that produced by CO2. The other CO2-sensitive units (20/38) did not respond to capsaicin. Capsaicin-sensitive units responded more rapidly to CO2 (mean latency to first spike 0.7 +/- 0.2 s) than capsaicin-insensitive units (mean latency to first spike 5.1 +/- 1.2 s). On the basis of their conduction velocity, both the capsaicin-sensitive and the capsaicin-insensitive groups included both A- and C-fibres. Application of capsazepine (10 microM for 5-20 min) to the cornea reversibly blocked the response of the units to capsaicin without affecting responses to CO2. Units that were acutely desensitised by exposure to capsaicin (0.1 microM) for 30 s, during which time the discharge evoked by capsaicin declined to zero, still responded to CO2, though the response was reduced by 44% compared with controls. It is concluded that activation of sensory afferents in the cat cornea by capsaicin and by CO2 appear to involve distinct mechanisms, since: (a) many CO2- sensitive units are not excited by capsaicin; (b) capsazepine selectively blocks excitation by capsaicin without affecting responses to CO2; and (c) desensitisation to capsaicin impairs only partially the responsiveness to CO2.

Elastoviscous substances with analgesic effects on joint pain reduce stretch-activated ion channel activity in vitro.

Activation by noxious mechanical stimuli of sensory nerve fibres that signal joint pain takes place through stretch-activated ion channels, which open in response to increased membrane tension. It has been suggested that the analgesic effect of hyaluronan solutions used for intra-articular treatment of joint pain in humans are mediated by a reduction of the sensitivity of mechanosensory ion channels of nociceptive nerve terminals. We have investigated whether cross-linked hyaluronan solutions (hylans) of different elastoviscosities modify the response characteristics of stretch-activated ion channels of Xenopus laevis oocytes. Patch-clamp recordings on intact oocytes and in excised membrane patches (outside-out and inside-out configurations) were performed in Barth's solution (control condition) and after exposure to hylans of different elastoviscosities. For mechanical stimulation, monitored suction was applied through the microelectrode and the activity of stretch-activated channels was recorded. The activity of stretch-activated channels was significantly reduced in the presence of high elastoviscous hylan A (0.8% polymer content, molecular weight 6M) and of a mixture of hylan A (90% by weight) and hylan B (10% by weight), 0.9% total polymer content, a clinically used hylan product. In contrast, solutions of hylan A with the same chemical composition but reduced elastoviscosity (0.8% polymer content, molecular weight 96000) were found ineffective. It is concluded that stretch-activated channels have a decreased mechanical sensitivity in the presence of elastoviscous solutions of hylan, but not in the presence of non-elastoviscous solutions of hylan of the same concentration. These data suggest that the analgesic effects of intra-articular injections of elastoviscous solutions of hylans are due to a reduction of the sensitivity to mechanical forces of stretch-activated channels present in the membrane of joint mechanonociceptors.

Electrophysiological properties of identified trigeminal ganglion neurons innervating the cornea of the mouse.

The cornea is innervated by three functional types of neurons: mechanosensory, polymodal and cold-sensitive neurons, all of which are presumed to be nociceptive. To explore if corneal neurons constitute a heterogeneous population according to their electrophysiological properties, intracellular recordings were made in vitro from trigeminal ganglion neurons innervating the cornea of the mouse. Corneal neurons were labelled with FluoroGold applied after a corneal epithelial wound. Five days later, the trigeminal ganglion attached to the eye by its nerves was removed and placed in a superfusion chamber. FluoroGold-positive cells that also responded to electrical stimulation of the cornea were considered corneal neurons. Non-corneal neurons were also studied. Based on their conduction velocity at room temperature, corneal neurons were classified as myelinated A (>1.5m/s) or non-myelinated C (< or =1.5m/s) neurons. A and C neurons differed significantly in their passive and active electrical properties. Virtually all corneal C neurons and about two-thirds of A neurons exhibited a hump in the falling phase of the action potential (S neurons), while the remaining A neurons (F neurons) showed faster and narrower action potentials without a hump. Among non-corneal neurons, A neurons of the F type were found in a proportion of about 50%. Based on their ability to produce somatic action potentials in tetrodotoxin (0.1 microM), non-corneal neurons were classified as fully or partially tetrodotoxin sensitive, which were mainly of the Adelta type, and tetrodotoxin resistant, which were C neurons. Among the corneal neurons, those with a faster action potential, possibly associated to the expression of tetrodotoxin-sensitive Na(+) channels, may be pure corneal mechanosensory neurons, all of which are known to belong to the Adelta type. Neurons with a slower action potential showing a hump in the repolarization phase are both corneal Adelta and C polymodal nociceptive neurons, a type of cell in which tetrodotoxin-resistant Na(+) channels have been identified. The possibility is raised that the small population of neurons with a very high input resistance are cold-sensitive neurons. From the present results, we suggest that the electrophysiological properties of primary sensory neurons innervating the cornea are attributable not only to their conduction velocities, but also to the functional characteristics of their peripheral nerve terminals.

Intracellular free calcium responses to protons and capsaicin in cultured trigeminal neurons.

Acidic solutions and capsaicin are selective chemical stimuli for nociceptive neurons. The effect of these stimuli on intracellular calcium concentration was analysed in cultured trigeminal neurons of newborn rabbits. Rapid reductions in pH (from 7.4 to 5) evoked a transient rise in intracellular calcium concentration of 270% on average over the basal level (162.5 +/- 3.5 nM; n = 174) in 86% of the neurons. Maximal responses were found at pH 5.5. Proton-induced transients were diminished or abolished by 20 mM CaCl2, by zero CaCl2 and by 1 microM Ruthenium Red. In response to 1 microM capsaicin, 40% of the cells that were sensitive to protons also increased their intracellular calcium concentration to 218% of control. Capsaicin-induced intracellular calcium concentration rises were composed of an initial peak followed by a second, slower intracellular calcium concentration elevation. The capsaicin response was completely blocked by 1 microM Ruthenium Red, and disappeared in zero calcium, but was augmented in high extracellular calcium. Intracellular calcium concentration responses to capsaicin were still observed in neurons whose response to protons was desensitized by sustained exposure to low pH (pH 6.5). Cells surviving a 10-24h capsaicin (10 microM) treatment, still displayed responses to pH reductions. These results suggest that intracellular calcium concentration rises induced by moderate reductions in pH0 and capsaicin occur through different mechanisms.

Reduction by antiinflammatory drugs of the response of corneal sensory nerve fibers to chemical irritation.

PURPOSE: Nonsteroidal antiinflammatory drugs (NSAIDs) have been applied topically to reduce ocular pain caused by corneal injury or anterior segment surgery. The authors investigated whether the analgesic effects of the NSAIDs diclofenac, indomethacin, and flurbiprofen and of the calcium channel antagonist diltiazem on corneal pain are mediated by a reduction of nerve activity in corneal polymodal nociceptive fibers. METHODS: Impulse activity of single A-delta and C corneal nerve fibers was recorded from the ciliary nerves of anesthetized cats. Polymodal units were identified by their response to both touching with the Cochet-Bonnet esthesiometer and to acidic stimulation with 30-second pulses of 80% or 98.5% CO2 or 60 microl of 10 mM acetic acid, applied to the corneal receptive area. Ongoing impulse activity, firing responses to CO2 or acetic acid, and mechanical threshold of single fibers were recorded before and at various times (5 to 90 minutes) after topical application of 0.1% sodium diclofenac, 0.03% sodium flurbiprofen, 0.1% indomethacin, and 0.045% diltiazem hydrochloride or of their vehicles. RESULTS: Indomethacin, diclofenac, and flurbiprofen, in decreasing order of potency, gradually reduced the mean frequency of the impulse response of corneal polymodal nerve fibers evoked by CO2 stimuli. The progressive increase of ongoing activity, observed in vehicle-treated eyes after repeated CO2 stimulation was also prevented by NSAIDs. Diltiazem also attenuated the response to CO2 for a shorter period of time and with a faster time course. The mechanical threshold of corneal polymodal fibers was not affected by treatment with any of these drugs. CONCLUSIONS: Indomethacin, diclofenac, and flurbiprofen, as well as the calcium antagonist diltiazem, diminish the responsiveness of corneal polymodal nociceptors to chemical stimuli. This appears to be caused, in part, by a direct effect of these drugs on the excitability of polymodal nerve endings, but also by an inhibition by NSAIDs of the formation of cyclooxygenase products such as prostaglandins, thus reducing the enhanced responsiveness of nociceptors caused by local release of arachidonic acid metabolites from injured cells.

Chronic stimulation of ocular sympathetic fibers in unanesthetized rabbits.

The goal of this study was to devise a technique to implant permanent electrodes in the cervical sympathetic trunk, to stimulate the ocular adrenergic fibers for periods of hours or days in awake, unrestrained rabbits. Electrodes were made of a silver wire soldered to a multistranded wire and enclosed in silicone. Two of these electrodes were wrapped around the preganglionic sympathetic nerve, their leads emerging through a hole in the back of the neck. Success of the procedure was confirmed by the mydriasis elicited by electrical stimulation of the nerve following surgery; threshold voltages for the pupillary response varied between 5-10 volts. In eight rabbits, suprathreshold sympathetic stimulation was performed on the following days by means of a portable stimulator using increasing frequencies (1, 3, 5, 8, and 10 Hz) during a 20-hr period. Dilation of the ipsilateral pupil and vasoconstriction in the ear, measured by the fall in temperature of the ear's surface, was observed as long as stimulation was maintained. Both effects were proportional to the frequency of stimulation. Maximal mydriasis was obtained at 8 Hz, whereas full vasoconstriction was elicited with 5 Hz. Intraocular pressure, measured in 10 rabbits with a Perkins tonometer at the end of a 24-hr stimulation period, did not differ from pre-stimulation values. It was concluded that chronic stimulation of the sympathetic nerve allows to maintain known levels of adrenergic activity in the eye, and may be a useful method to study the actions of the adrenergic system on various ocular functions in unanesthetized animals.

Effects of chronic sympathetic stimulation on corneal wound healing.

To explore the possibility that adrenergic fibers influence epithelial wound healing in the rabbit cornea, chronic electrodes were implanted in the left cervical sympathetic nerve, and symmetrical wounds were produced on the corneal epithelium of both eyes by means of n-heptanol. Continuous sympathetic stimulation was applied to awake, unrestrained animals during the wound-healing process (2-3 days) by use of a portable stimulator that delivered 1 ms, 3-Hz electric pulses at an amplitude necessary to evoke mydriasis. Migration rates of epithelial cells surrounding the wound and estimated wound closure times were calculated by measuring the reduction in wound size. In stimulated corneas, the epithelial migration rate was smaller (36.9 +/- 6.2 microns/hr) than in control corneas (49.4 +/- 5.4 microns/hr), the differences being significant (P < 0.05). Significant differences in wound closure times between stimulated (53.2 +/- 6.8 hr) and control (41.3 +/- 5.5 hr) corneas were also observed. These results suggest a modulatory influence of corneal adrenergic fibers on the processes that follow epithelial injury of the cornea.

Effects of stimulation of the ocular sympathetic nerves on IOP and aqueous humor flow.

Ocular sympathetic nerves were stimulated chronically in awake rabbits using electrodes unilaterally implanted on the cervical sympathetic trunk. IOP was measured by pneumatonometry and aqueous inflow was measured by fluorophotometry. In each animal, continuous trains of 1 msec pulses were delivered by means of a portable electrical stimulator. Experiments were spaced by 1 week recovery periods. Stimulation was varied over a range of amplitudes (5-15 V) and frequencies (3-12 Hz). Continuous sympathetic stimulation produced an immediate sharp decrease in IOP followed by a gradual rise to pre-stimulation values which were attained 60-90 min after onset. A rebound increase in IOP occurred when stimulation was terminated. The magnitude of the initial IOP drop, the delay in the return to pre-stimulation IOP, and the rebound rise in IOP subsequent to termination of electrical stimulation were proportional to the stimulation frequency. Maximal effects were observed at 12 Hz, and stimulation with 8-10 Hz for 180 min caused a sustained reduction in anterior chamber aqueous humor flow. Topical 2% phentolamine 1 hr before stimulation markedly reduced IOP and abolished the acute IOP changes observed in untreated stimulated animals. Topical 1% timolol did not affect either the initial IOP drop or the rebound; however, the IOP recovered during stimulation to values greater than pre-stimulation IOP. We conclude that in rabbits the beta-adrenergic effect of prolonged sympathetic nerve stimulation is to decrease aqueous flow. Chronic electrical stimulation in awake animals provides an experimental model for studying the role of the ocular sympathetic nerves.

Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer.

PURPOSE: To develop an instrument to measure corneal sensitivity. Mechanical stimulation was performed with increasing air flow. Chemical stimulation consisted of local pH decreases induced by a mixture of air and CO2 at different concentrations. METHODS: Air and 98.5% CO2 were mixed with an electronic, proportional-direction control valve to obtain gas mixtures from 0% to 80% CO2. The regulated outflow of gas was carried to a probe mounted on a slit lamp holder, where it was warmed and its CO2 concentration monitored. An electronic valve directed gas pulses of controlled duration to the cornea. Corneal stimulation was performed in 17 young human subjects. The intensity of the experienced sensation was recorded in a continuous visual analog scale (VAS). To obtain threshold values and intensity-response curves, 3-second pulses were applied. For mechanical stimulation, air pulses of increasing flow were used. For chemical stimulation, gas mixtures of increasing CO2 concentration at subthreshold flow and CO2 in stepped increases of 5% was applied. RESULTS: Mechanical and chemical stimulation of the cornea evoked a brief sensation of irritation. Mechanical threshold (flow values) varied among subjects but were reproducible within each subject and were higher with warmed air. The magnitude of the sensation increased proportionally to the flow of air. The mean chemical stimulation threshold (CO2 concentration) was 25% +/- 3%. Increases in CO2 concentration from 10% to 80% augmented proportionally the intensity of the evoked sensation. CONCLUSIONS: The gas esthesiometer, which combines variable air flow and CO2 concentrations, permits application to the cornea of mechanical stimuli of controlled force and pH reductions of increasing magnitude. This instrument may be useful in a separate exploration of mechanical and chemical sensitivity of the cornea in human subjects.

Sensations evoked by selective mechanical, chemical, and thermal stimulation of the conjunctiva and cornea.

PURPOSE: To study the sensations evoked by selective mechanical, chemical, and thermal stimulation of the conjunctiva and compare them with those elicited by similar stimulation of the cornea. METHODS: Six young subjects participated in the study. Using a gas esthesiometer, selective mechanical (air puffs at flows from 0 to 264 ml/min), chemical (0--80% CO(2) in air), and thermal (air at temperatures from -10 degrees C to +80 degrees C) stimulation was performed on the center of the cornea and on the temporal conjunctiva. The intensity, degree of irritation, stinging and burning pain components, and thermal characteristics of the evoked sensation were evaluated after each stimulus in separate, 10-cm continuous visual analogue scales (VASs). The ability of the subjects to identify the quality of the stimulus applied to the cornea and the conjunctiva was also studied. RESULTS: The subjective intensity and thermal components (cooling or warming) of the sensation reported after mechanical, chemical, and heat stimulation were similar in the conjunctiva and cornea, although lower VAS scores were always reported in the conjunctiva for the irritation and the stinging and burning pain components. In the cornea, stimulation with low temperatures was perceived as a cooling sensation with an irritative component. In the conjunctiva, cooling was perceived as a purely cold sensation. Subjects showed similar discrimination capability in the cornea and the conjunctiva for the various types of stimuli. CONCLUSIONS: Sensations evoked in the cornea by selective mechanical, chemical, and heat and cold stimulation always presented an irritation component. In the conjunctiva, stimuli of the same intensity are always perceived as less irritating than in the cornea. Cold and other non-noxious subqualities of sensation can be evoked in the conjunctiva.

Effects of capsaicin on corneal wound healing.

This study examined whether the depletion of neuropeptides from sensory nerve terminals induced by capsaicin modifies the healing rate of experimental corneal wounds in adult rabbits. Capsaicin (33 or 3.3 mM solutions) was administered topically and/or by a single retrobulbar injection to one eye while the fellow eye, treated with the vehicle, served as a control. After 1-3 weeks of treatment, an epithelial wound was made in the center of the cornea of both eyes with n-heptanol. Migration rates of epithelial cells surrounding the wound and estimated wound closure times were calculated by measuring the reduction in wound size. Combined treatment with 33 mM retrobulbar and 3.3 mM topical capsaicin for 3 weeks induced a significant delay in epithelial migration rates and in wound closure times (P less than 0.05). Topical or retrobulbar capsaicin alone for 3 weeks and combined treatment lasting only 1 week were not sufficient to modify wound healing times. The substance P antagonist, spantide (3 mM), applied topically for 1-3 weeks before or immediately after corneal wounding was also ineffective in changing wound closure rates. These findings suggest that the delayed wound healing observed after prolonged treatment with capsaicin could be due to a sustained depletion of neuropeptides from corneal sensory endings, supporting the hypothesis that trophic effects of sensory nerves on corneal epithelium are, at least in part, mediated by neuropeptides contained in peripheral nerve terminals.