Keloid disease: Review with clinical atlas. Part I: Definitions, history, epidemiology, clinics and diagnosis.

Keloids are chronic progressive dermal pseudo-tumors that can grow considerably in volume and surface area but do not invade other tissues. They are usually triggered by dermal injury or inflammation, but they are not scars in the normal sense of the word, since they enlarge and progress over decades. The phenomenon usually referred to as "hypertrophic scars" represents a kind of keloidal process that does not extend beyond the initial site of injury and spontaneously regresses in 12-24 months. The multiplication of keloids and hypertrophic scars in a single patient is known as keloid disease. Keloid disease is due to a familial predisposition (autosomal dominant) that preferentially affects people of non-European ancestry, especially those of sub-Saharan African descent. Keloid disease has a deep impact on quality of life, not only because of disfiguring lesions, but also because of the frequency of associated intense neurogenic pruritus and pain, as well as recurrent bouts of suppuration. Diagnosis relies primarily on a good knowledge of the clinical characteristics of keloids, thus warranting the inclusion of a clinical atlas in the first part of the review. The second part will deal with the pathology, pathophysiology and treatment of keloid disease.

Neutrophilic dermatoses.

Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND are classified based upon the localization of neutrophils within the skin and clinical features. Recent findings suggest that ND are due to two main mechanisms: i) a polyclonal hereditary activation of the innate immune system (polygenic or monogenic); or ii) a clonal somatic activation of myeloid cells such as encountered in myelodysplastic syndrome or VEXAS syndrome. ND belong to internal medicine as a great number of patients with ND suffer from an underlying condition (such as hematological malignancy, inflammatory bowel disease, auto-immune and auto-inflammatory diseases). ND are diagnoses of exclusion and physicians should always consider differential diagnoses, particularly skin infections. Here, we review the pathophysiology and classification of the main ND (i.e., subcorneal pustular dermatosis (Sneddon-Wilkinson Disease) and Intercellular IgA dermatoses, aseptic pustulosis of the folds, Sweet syndrome, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, erythema elevatum diutinum, neutrophilic urticarial dermatosis and neutrophilic panniculitis), their clinical and histopathological features, and we highlight the investigations that are useful to identify ND-associated diseases and to exclude the differential diagnoses.

[Tumor necrosis receptor associated periodic syndrome (TRAPS): State of the art]. / La fièvre récurrente liée au récepteur 1 du TNF (TNF receptor associated periodic syndrome ­ TRAPS).

Tumour necrosis receptor associated periodic syndrome (TRAPS) is a rare cosmopolitan dominant autosomal disease that belongs to the group of recurrent autoinflammatory syndromes. TRAPS is characterized by recurrent bouts of fever lasting more than 7 days, with arthralgia, myalgia, abdominal pain, erythematous rash and sometimes ocular symptoms. During flares, raised inflammatory markers are constant. The age of onset may occur during childhood but also during adulthood. TRAPS is caused by mutations in the TNF receptor 1 (TNFRSF1A) gene that may occur in most of the populations over the world. In the majority of patients, history shows affected relatives, even if sporadic cases do exist. Management of TRAPS usually involves corticosteroid therapy during inflammatory flares. The most severe cases require a treatment with biological agents (mainly interleukin 1 inhibitors). The prognosis of TRAPS is overall good; the main risk is represented by the development of secondary inflammatory amyloidosis. This risk is greatest in patients with structural mutations leading to conformation abnormalities of the TNFRSF1A receptor. Regular clinical and biological monitoring is essential in the follow-up of TRAPS patients.

Taurine action on mitral cell activity in the frog olfactory bulb in vivo.

Taurine (TAU) is a free amino acid that is particularly abundant in the olfactory bulb. In the frog, TAU is located in the terminations of the primary olfactory axons and in the granular cell layer. TAU action seems to be associated with gamma amino butyric acid (GABA), the main inhibitory neurotransmitter involved in the processing of the sensory signal. The present study was designed to assess the action of TAU in vivo during the olfactory network's stimulation by odors. It was performed by recording the single-unit activity of mitral cells, the main bulbar output neurons. TAU effects were tested on both their spontaneous and odor-induced firing activity. Interactions between TAU and GABA were examined by analyzing TAU effects under the selective blocking action of GABAA or GABAB antagonists. TAU was found to suppress the spontaneous firing of mitral cells, mainly without altering their odor response properties. By testing GABA antagonists, we further show that TAU action is associated with GABAergic inhibitory mechanisms mainly via GABAB receptors. Thus, TAU action clearly reduces background activity in favor of the emergence of the odor-induced activity in the same manner as GABA action does via GABAB receptors. As a conclusion, we propose that, in the frog olfactory bulb, the joint actions of TAU and GABA may favor the processing of the primary sensory information by increasing the signal to noise ratio.

GABA(B)-mediated action in the frog olfactory bulb makes odor responses more salient.

In the olfactory bulb, GABA(B) receptors are selectively located in the glomerular layer. A current hypothesis is that GABAergic inhibition mediated through these receptors would be, at least partly, presynaptic and would exerted by decreasing the release of the olfactory receptor neuron excitatory neurotransmitter. Here, we assessed, in the frog, the in vivo action of baclofen, a GABA(B) agonist, on single-unit mitral cell activity in response to odors. Local application of baclofen in the glomerular region of the olfactory bulb was shown to drastically affect mitral cell spontaneous activity, since they became totally silent. Moreover, under baclofen, mitral cells still responded to odors and still specified odor concentration increases through their temporal response patterns. The pharmacological specificity of the GABA(B) agonist action was confirmed by showing that saclofen, a GABA(B) antagonist, partly prevented the inhibitory action of baclofen and restored the initial rate of mitral cell spontaneous activity. The results show that GABA(B)-mimicked inhibition suppressed mitral cell spontaneous activity while odor responses were maintained. This suggests that olfactory receptor neurons partly drive spontaneous mitral cell activity. Moreover, the effect of GABA(B)-mediated inhibition was seen to be very close to that described previously for dopamine D(2) receptor-mediated inhibition. In conclusion, we propose that these two inhibitory mechanisms would offer the possibility to reduce or suppress mitral cell spontaneous activity so as to make their responses to odor especially salient.

Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding-electrophysiological study.

Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D2 type in mammals. The present study assessed, in the frog, both the anatomical localization of D2-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [125I]iodosulpride-labelled D2 binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D2 antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity. In the frog olfactory bulb, both anatomical localization of D2-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio.

Physiological and histological recovery of the olfactory mucosa of the frog after a dichlobenil injection.

Four days after a single systemic injection of 50 mg/kg of dichlobenil (2,6-dichlorobenzonitrile), the olfactory neuroepithelium of the frog is extensively damaged. At the same time, electrophysiological responses to odorant stimulations (2-heptanone, D-limonene, amyl acetate, camphor) are largely reduced. Pretreatment of the animals with metyrapone, an inhibitor of cytochrome P-450 enzymatic systems, inhibits the histological and physiological toxic effects of the dichlobenil injection. The olfactory tissue recovered 3 months after the dichlobenil injections and responses to odorant stimulations returned. The same dichlobenil injections did not induce lesions in the vomeronasal neuroepithelium.

The activity of olfactory receptor cells is affected by acetylcholine and substance P.

The effects of acetylcholine (ACh) and substance P (SP) on the unit activity of receptor cells recorded from the superfused frog olfactory mucosa were studied. Single neurones were excited or, more rarely, depressed by the application of chemicals. Cholinergic antagonists were used to investigate the involvement of nicotinic and muscarinic receptors in the recorded responses. The ACh-evoked firing was antagonized by D-tubocurarine (D-TC), atropine (ATR) and SP. Responses to SP appeared to be D-TC resistant, but activation by the peptide was moderately antagonized by ATR. The results suggest that ACh and SP could affect the functioning of the olfactory receptor cells.

Olfactory receptor cell function is affected by trigeminal nerve activity.

In the frog, antidromic electrical stimulation of the ophthalmic branch of the trigeminal nerve (NV-ob) evokes a slow potential in the olfactory mucosa, modifies the activity of receptor cells and modulates the responses to odour. Substance P (SP) application evokes similar electrical responses. These results imply that the functioning of the olfactory system might be controlled at the receptor cell level. It is suggested that the trigeminal system could modulate the activity of the olfactory receptor cells via a local axon reflex which may result in the release of SP.

[Electrical responses of frog olfactory mucosa to the administration of acetylcholine and substance P]. / Réponses électriques de la muqueuse olfactive de Grenouille à l'application d'acétylcholine et de substance P.

The effects of acetylcholine and substance P were studied on the Frog's olfactory mucosa. Stimulation with these chemicals elicited low-threshold slow electrical potentials. Moreover, prior application of substance P strongly depressed the electrical response of the mucosa to acetylcholine. These results are discussed in relation to the possibility that acetylcholine and substance P could act on the functioning of the olfactory neuroreceptors.

Investigations of the discriminative properties of the frog's olfactory mucosa using a photoactivable odorant.

The photoactivable compound phenylazide interacts reversibly with the frog's olfactory epithelium when delivered as an olfactory stimulus. Its application together with UV irradiation resulted in a differential reduction of the responses (electro-olfactogram) to several odorants. It was found that this chemical modification of the sensory membrane affected the responses in relative ratios which could be predicted from a classification of the odorants based upon independent studies of receptor cell odor sensitivity. The responses to chemicals representative of the 'aromatic group' were clearly more reduced than those to compounds of the 'camphoraceous group'. It is suggested that the olfactory discrimination mechanisms can be approached by the use of this method.

Olfactory receptor cell activity under electrical polarization of the nasal mucosa in the frog. I. Spontaneous activity.

The electrical activity of single olfactory receptor cells was studied under electrical polarization of the olfactory epithelium in the frog. 1. The spontaneous discharge frequency varied as a linear function of the polarizing current in the range 1--20 X 10(--6)A. 2. Surface positive polarizations caused the spike activity to increase; surface-negative polarizations suppressed the activity. 3. Partial accommodation to the current was observed. 4. After-effects of short duration occurred: Rebound suppression after positive polarization, rebound excitation after negative polarization. 5. A high percentage of receptor units found in the frog's mucosa displayed no spontaneous activity.

Evidence for a synaptically mediated decrease in conductance in a crustacean myocardium.

1. In the neurogenic heart of the isopod Porcellio dilatatus, electrical stimulation of the cardio-regulatory nerves at rates greater than 20-25 pulses/s elicited inhibitory junctional potentials (IJPs) in the myocardium. Its cessation was followed by a long lasting hyperpolarization of myocardial membrane (post-stimulus hyperpolarization = PSH). 2. During the PSH the membrane resistance of the heart muscle increased. The PSH was enhanced by myocardium hyperpolarization, decreased by depolarization and reversed around -50 mV. 3. Picrotoxin inhibited the summated IJPs elicited by the stimulation and thus caused the membrane to maximally hyperpolarize during inhibitory train, thus suggesting a composite nature of the inhibitory processes. 4. The PSH was reversibly reduced in K+-free saline or in ouabain containing saline but partial restoration was obtained by injection of inward current to the myocardium. 5. The PSH was abolished in lithium saline and reduced in Na+-deficient (choline) solution. Cl-deficient solution that markedly affected the summated IJPs shortly after its introduction did not affect the PSH. 6. It is proposed that the PSH results from a decrease in conductance, presumably to both Na+ and K+. The implication of such a mechanism as a component of the inhibitory regulation of this crustacean heart is discussed.

Neural regulation of the heart muscle in an isopod crustacean: acceleration and peripheral inhibition.

1. In the neurogenic heart of the isopod crustacean Porcellio dilatatus, repetitive electrical stimulation of the cardiac nerves elicted either cardio-acceleratory or cardio-inhibitory effects depending on the stimulation parameters. 2. Acceleratory effects were accompanied by a decrease of membrane potential and by changes in the contour of the spontaneous electrical responses: increase in the speed of the rising phase and enhancement of the plateau phase. 3. Inhibitory stimulation acted on rhytjmicity and/or contour of spontaneous responses. At stimulation pulse frequencies beyond 25/s a hyperpolarization appeared after the cessation of the inhibitory train. 4. Inhibitory stimulation elicted IJPs in the myocardium. Their reversal potential was found to be close to the value of the resting membrane potential. During inhibitory stimulation, the membrane resistance of the heart muscle was frequently decreased. 5. The effects of changing the external chloride content, and of adding GABA and picrotoxin support the hypothesis that the inhibitory impulses increased the myocardium permeability to CL-. 6. On the basis of these findings it is assumed that cardio-inhibitory fibres act on both cardiac ganglion and myocardium. 7. Comparisons are established between the wood-louse's heart and the skeletal or heart muscle of some arthropods. The functional significance of peripheral inhibition is further discussed in relation to the nature of the spontaneous electrical responses and to contraction.

Contribution of an electrogenic pump to the resting membrane polarization in a crustacean heart.

1. In the neurogenic heart of the isopod crustacean Porcellio dilatatus, external K+ removal depolarized the membrane (K0 effect) whereas subsequent restoration of K+ resulted in a rapid hyperpolarization (K1 effect). 2. The amplitude of the K1 effect depended on the duration of the prior K+ deprivation and on the subsequent K+ concentration. 3. The membrane resistance slightly increased during the K0 effect; during the K1 effect, it only returned to its control value. 4. Ouabain, cooling and replacement of external Na+ by Li+ also produced depolarization. 5. The K1 effect was suppressed by ouabain and markedly depressed by lowering the temperature to 4-6 degrees C. It was abolished if Li+ replaced Na+ during the prior privation of K+; moreover Li+ was unable to act as a substitute for external K+ in generating the K1 effect if used at equivalent concentration, but enhanced the effect at high concentration. 6. The findings are consistent with the presence of an electrogenic sodium pump in the myocardium of Porcellio contributing to the resting membrane potential. 7. Changes in the spontaneous rhythm observed during K0 and K1 are further suggestive of the presence of an electrogenic Na+ pump in the pacemaker neurons of the cardiac ganglion. Another explanation is also proposed. 8. The magnitude of the spontaneous contractions of the heart was increased during the K0 effect and markedly decreased during the K1 effect. An indirect effect of the changes in internal Na+ concentration on the contractile processes is suggested.