Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate.

Langerhans cell histiocytosis (LCH) can be a difficult therapeutic problem. We present a 40-year-old woman with a 4-year history of LCH who was successfully treated with low-dose methotrexate (20 mg weekly).

Papular palmoplantar hyperkeratosis following chronic medical exposure to arsenic: human papillomavirus as a co-factor in the pathogenesis of arsenical keratosis?

This study presents the case of a 38-year-old patient from Pakistan with vitiligo, who developed multiple verrucous papules on the palms and soles several years after receiving "herbal treatment" from a travelling Indian doctor for a period of 12 months. Histopathological examination showed changes consistent with the diagnosis of arsenical keratosis. Molecularbiological examination of a skin biopsy detected an atypical human papillomavirus. This observation supports the concept of human papillomavirus as a co-factor in the pathogenesis of premalignant arsenic-induced skin tumours.

Plasma levels after peroral and topical ibuprofen and effects upon low pH-induced cutaneous and muscle pain.

Cutaneous applications are gaining popularity in the treatment of cutaneous pain and of painful disorders in joints and muscle. The low pH-pain model in human skin has previously been able to demonstrate the effects of NSAIDs in dose-dependent manner and to establish time-effect relationships. We examined the analgesic action of ibuprofen after cutaneous application and compared the effects with oral administration. The two studies (with n = 12 subjects each) were performed in a double-blind, randomized fashion with a 1-week cross-over interval. In study 1 volunteers received intradermal infusions with phosphate buffered saline solution of pH 5.2 and received either 800 mg ibuprofen per os and topical placebo, or 4 g of a 5% commercial ibuprofen gel topically applied and oral placebo capsules, respectively. In study 2 the same protocol was applied with painful intramuscular infusion of stronger, isotonic phosphate buffer (pH 5.2). The flow rate of the pH-infusion was individually adjusted to induce pain with a magnitude of 20% on a visual analogue scale (ranging from 'no' (0%) to 'unbearable pain' (100%)). Ibuprofen (S-, R-) plasma levels after oral administrations were measured with HPLC, and after topical applications, by gas chromatography combined with mass spectroscopy to determine plasma levels in the range of ng/ml. In the cutaneous model pain ratings decreased to zero after topical verum gel within 45 min of the observation period of 55 min. Pain reduction after peroral ibuprofen was of the same magnitude, but was achieved within only 30 min. In the muscle model, the commercial ibuprofen gel did not reduce the pain in the acidic muscle. The peroral ibuprofen was less effective in the muscle compared to the skin pain model, although there was a significant progressive pain reduction within 55 min. Reasons for the differential susceptibility of cutaneous vs muscular acidosis pain to ibuprofen remain to be established.

The pH response of rat cutaneous nociceptors correlates with extracellular [Na+] and is increased under amiloride.

Excess hydrogen ions induce sustained nociceptor excitation as well as pain, and this has been suggested, with evidence from sensory ganglion cells, to result from gating a slowly inactivating sodium/calcium inward current. In the rat skin-nerve preparation, isolated receptive fields of pH-sensitive C-fibre terminals were exposed to low-pH solutions of various sodium concentrations. The pH responses showed a good correlation with log [Na+]e, which supports the above model. Amiloride has previously been shown to block a pH-induced Na+ current involved in sensory transduction in hamster taste cells; however, it has been shown to act differently in cutaneous nociceptors. Amiloride induced a dose-dependent increase in and prolongation of the nociceptive pH responses, with a prominent acceleration of the onset. The latter could be mimicked by replacing external sodium with sucrose, thus impeding sodium-proton antiport. Together, the findings indicate functional expression of amiloride-sensitive Na+/H+-antiporters, which enable the nociceptive nerve endings to extrude invading H+. Intracellular acidification may thus compete with Na+/H+ exchange, and pHi may be decisive in the transduction of nociception and pain from tissue acidosis.

Unilateral linear lichen planus with mucous membrane involvement.

Linear lichen planus is a rare distinctive variant of lichen planus (LP) characterized by a pruritic eruption of lichenoid, violaceous papules in a linear distribution that sometimes assume a Blaschko line pattern. We describe a 33-year-old woman who presented with a 4-month history of a slightly pruritic unilateral linear array of papular lesions on the left side of her neck that were clinically and histologically consistent with linear LP. Two months after the onset of her skin disease she developed typical lesions with a lacy white pattern on the left lateral aspect of her tongue and the left buccal mucosa with a striking predominance for the left side. Clinically the lesions on the patient's neck were similar to lichen striatus or lichenoid epidermal naevus, a variant of linear verrucous epidermal naevus. However, the histological features and the fact that later in the course of her disease the patient developed typical LP of the oral mucosa suggest that this patient has the rare condition of linear LP with unilateral restriction.

Inflammatory mediators potentiate pain induced by experimental tissue acidosis.

Electrophysiological evidence from cutaneous nociceptors suggested a synergism between excitatory actions of inflammatory mediators (IM) and low pH. In human skin it is possible to induce constant ongoing pain with continuous infusion of acid buffer. This method was used to study the interaction with mediators of inflammation psychophysiologically. A skin area on the palmar forearm of 6 subjects (either gender, age 22-35 years) was continuously infiltrated with a phosphate buffered electrolyte solution (pH 5.2) using a motorized syringe pump that was adjusted so as to produce constant pain of about 20% on a visual analog scale (VAS; extending from 'no' to 'unbearable pain'). Pain was assessed on the VAS at 10-sec intervals; the rating was called up by means of an acoustic signal. An additional cannula was placed in the skin before the infusion of acidic buffer started. Injections of an acidic combination of IM (BK, 5-HT, HIS, PGE2) 0.2 ml were then given through the cannula at intervals of 10 min in a randomized double blind order of concentrations. The other arm was used for negative control, i.e. IM in neutral solution were injected into normal skin continuously infiltrated with a buffer solution at pH 7.4. The IM induced dose-dependent, transient burning pain on both arms-markedly more intense and prolonged, however, in the acidotic skin (P < 0.004, U-test). The difference corresponded to a 10-fold increase in algogenic potency with 10(-7) M IM, being smaller with 10(-6) and 10(-5) M concentration. The interaction between low pH and IM was mutual: additional injections of plain phosphate buffer (pH 5.2) into the acidotic skin were significantly more painful (20-fold) after application of IM than under control conditions. Thus, we tend to conclude that it is the inflammatory mediators that potentiate the algogenic effect of low pH rather than vice versa. Tissue acidosis appears as a dominant factor in inflammatory pain.

Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia?

To study the role of protons in ischemic muscle pain we employed the "submaximal effort tourniquet technique' and, in a second attempt, an intramuscular pressure infusion of acid phosphate buffer. The pH measured in the forearm skin covering the muscles at work during the tourniquet test continuously dropped to a mean value of pH 7.00 +/- 0.26, starting 1 min after the contractions, while the pain increased in direct correlation with the hydrogen ion concentration (r = 0.96). After restoring the blood supply, the intradermal proton concentration decreased more slowly than the muscular pain. The same subjective quality of deep muscular pain was achieved with pressure infusion of acid phosphate buffer (pH 5.2) into the forearm muscles. Constant flow rates evoked constant, apparently non-adapting magnitudes of pain with a log-linear stimulus-response relationship (r = 0.93). Changes in flow rate were followed by changes in pain ratings with a certain phase lag. We conclude that muscular pain induced by infusion of acidic phosphate buffer and pain from ischemic contractions are generated through the same mechanisms based on the algogenic action of protons.

Diltiazem blocks the PH-induced excitation of rat nociceptors together with their mechanical and electrical excitability in vitro.

1. The effect of the calcium channel antagonist diltiazem on pH-induced sustained nociceptor excitation was investigated in a rat skin-saphenous nerve preparation, in vitro, where receptive fields of identified and isolated single fibers were superfused at the corium side with controlled solutions to assess their chemosensitivity. 2. Unmyelinated mechano-heat sensitive ("polymodal") C fiber terminals (n = 78) were superfused with a CO2-saturated synthetic interstitial fluid (CO2-SIF, pH 6.1). Fibers responding to this acid pH condition (n = 60; 77%) were further stimulated for > or = 30 min and additionally treated with diltiazem in various concentrations (10(-6)-10(-3) M) during the middle 10-min period. Usually only one concentration of diltiazem was applied per fiber, although in some cases diltiazem was applied repeatedly and in increasing concentrations. 3. Diltiazem dose-dependently and reversibly reduced the pH-induced sustained nociceptor discharge to a significant degree or completely abolished it. With higher concentrations, both the relative number of units affected and the average amount of suppression were enhanced. The half-maximal blocking concentration (IC50) was estimated to 1.1.10(-4) M diltiazem, the half-maximal concentration for gradual suppression of the pH response was 2.10(-5) M diltiazem. 4. Also, the delay of onset of the suppressive effect decreased with higher diltiazem concentrations. After diltiazem, a partial recovery of the pH-induced discharge was achieved within 10 min depending on the degree of suppression. 5. Before, after, and sometimes during the superfusion, the mechanical (von Frey) thresholds were determined and found to be significantly increased after partial wash out of diltiazem (10(-4) and 10(-3) M; P < 0.006 and P < 0.008, respectively). After 10(-3) M diltiazem superfusion (and 10 min of wash-out), the responsiveness to mechanical stimulation of the majority of the fibers was still totally lost. 6. Heat thresholds were still found to be significantly increased after treatment with diltiazem at 10(-3) and 10(-4) M concentrations (and 10 min of wash out), but appeared unchanged after wash out of lower concentrations. 7. In five mechano-heat-sensitive C fibers, electrical stimulation via a microelectrode placed in the receptive field was used to demonstrate a diltiazem-dose-dependent (10(-5), 10(-4), 10(-3) M) progressive retardation of the nerve conduction velocity and an increase of the electrical threshold. Superfusion for 6 min of diltiazem 10(-5) M was sufficient to block axonal conduction as well as mechanosensitivity, which both recovered synchronously during wash out. 8. It can be concluded from the results that the suppressive effect of diltiazem on pH-induced nociceptor excitation can be explained by a use-dependent axonal block, comparable with the action of local anesthetics and affecting all modalities of sensory responsiveness. 9. The findings provide no indication that a transformed calcium channel specifically sensitive to diltiazem is involved in pH-induced sustained nociceptor excitation.

Pain due to experimental acidosis in human skin: evidence for non-adapting nociceptor excitation.

The mechanisms of acid pain induction by superfusion of a human blister base and by intradermal infusion of acid phosphate buffer are compared in this study. Superfusion of a freshly opened blister base with CO2-saturated 'synthetic interstitial fluid' (pH 6.1) led to pain that linearly faded away during 15 min. In contrast, the protein content of the blister effluate approached a very low basal level within the first 5 min of superfusion, irrespective of the pH applied, which suggests a progressive sealing of the blister base impeding macromolecular permeation first, and invasion of protons and CO2 later. In contrast, pressure infusion of an acidic buffer into the skin induced constant pain for as long as a flow rate was maintained. The time course and distribution of the intracutaneous pH changes induced were monitored at different distances to the infusion point using a pH-sensitive needle electrode. The continuous infusion produced a restricted area of cutaneous tissue acidosis where pH values were sufficiently low presumably to excite nociceptors. This area had relatively sharp borders, and in the border zone a steady-state of the local pH was reached within about 20 min (at an infusion rate of 40 ml/h) suggesting a balance between acidifying and neutralizing forces. The acid pain increased during the first minutes of infusion closely in parallel to the pH near the infusion point, remained constant at constant pH and flow rate and declined more rapidly than the pH was able to recover after discontinuation of the infusion. In conclusion, the results suggest that the pain from the experimental tissue acidosis is due to non-adapting excitation of a relatively constant population of nociceptors terminating in a spatially restricted volume of tissue.

[Sclerotic fibroma]. / Das sklerotische Fibrom.

The clinical and histological diagnosis of sclerotic fibroma is important because of its potential association with Cowden's syndrome. Despite its distinctive histological appearance the lesion is often mis-diagnosed. We therefore present five of our own cases (2F, 3M) in which the tumor was located on the head (n = 2), arm (n = 2) and leg (n = 1), respectively. Clinically, the lesions were white to flesh-colored firm nodules ranging in size from 0.5 to 1.2 cm. None of our patients revealed any clinical evidence of Cowden's disease. Simple surgical excision seems to be curative. Histologically, they were well-circumscribed but not encapsulated dermal nodules composed of stori-form-arranged sclerosing collagen bundles and vimentin-positive fibroblastlike cells interspersed in three cases by a number of alpha-smooth-muscle actin-positive myofibroblasts. Approximately 50% of cells (dermal dendritic cells (DD)) also reacted for factor XIIIa evenly scattered throughout the lesion in contrast to the very few (< 5%) CD34+ DD found predominantly at the lower border, thus possibly reflecting the distribution of these cells in normal skin. Sclerotic fibroma expands the spectrum of fibrous lesions that may express alpha-smooth-muscle actin.

A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro.

A major role of local acidosis in long lasting excitation and sensitization of cutaneous nociceptors has recently been demonstrated. In inflamed tissue, acid pH meets with a mixture of inflammatory mediators which, by themselves, stimulate nociceptors though being subject to profound tachyphylaxis. We have mimicked this condition in a rat skin-saphenous nerve preparation in vitro which allows direct application of chemicals to the isolated receptive fields at the corium side. Stimulant solutions used were CO2-saturated "synthetic interstitial fluid" (CO2-SIF, pH 6.1), and "inflammatory soup" (IS) in submaximal concentration containing bradykinin, 5-HT, histamine, prostaglandin E2 (all 10(-6) M in SIF at 38.5 degrees C and pH 7.0), and a combination made of CO2-saturated IS (CO2-IS, pH 6.1). Identified mechano-heat sensitive ("polymodal") C-fiber terminals (n = 36) were treated with these solutions for 5 min at 10 min intervals or for 30 min of sustained stimulation: 20 units responded to CO2-SIF, 12 to IS, whereas 27 units (75%) were excited by CO2-IS. Thus, 6 out of 15 units insensitive to either of the two basic solutions were stimulated by their combination. This enhanced effect of CO2-IS was also expressed in shorter latencies (than with CO2-SIF) and in a significantly larger mean response magnitude of the fiber population: 152 spikes with the combination versus 45 spikes evoked by IS and 93 spikes by CO2-SIF (n = 25; p < 0.002 and < 0.02, respectively, Wilcoxon test).(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of cholinergic agonists and antagonists on sensory nerve endings in rat skin, in vitro.

1. Cholinergic effects on primary sensory afferents were investigated in a superfused skin-saphenous nerve preparation of the rat that allows the application of chemicals topically to the corium side of identified receptive fields. 2. The acetylcholine analogue carbachol (carbamoylcholine) selectively excited cutaneous C-fibers of nociceptive character; in proportion, almost half of the mechanoheat sensitive ("polymodal," C-MH, n = 27), and a third of the mechanocold sensitive (C-MC, n = 10), and high-threshold mechanosensitive (C-HTM, n = 6) C-fibers were activated. 3. None of slowly and rapidly adapting A beta fibers, low and high threshold mechanoreceptive A delta fibers (n = 19) gave a response to high concentrations (< or = 10(-4) M) of carbachol. 4. The carbachol threshold concentrations of C-nociceptors ranged between 10(-7) and 10(-4) M; 10(-6) M was most frequently encountered. 5. The carbachol-induced discharges showed a dose-response relationship without obvious "ceiling" from 10(-6) to 10(-4) M. Tachyphylaxis was not prominent; the fibers mostly developed ongoing activity after exposure to carbachol. 6. Repeated carbachol treatment of C-MH units left with a marked and sustained desensitization to mechanical (von Frey) stimulation, while the heat responsiveness remained unchanged. 7. In a group of carbachol-sensitive C-nociceptors (n = 4), two units could also be excited with muscarine (10(-6) M), one with nicotine (10(-6) M), and one unit with both substances.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin.

The present study was performed to decide whether tissue acidosis can induce sustained pain and, by that, possibly contribute to the pain in inflammation or ischaemia. A motorized syringe pump was used to infuse an isotonic phosphate buffer solution (pH 5.2) via sterile filter and cannula into the palmar forearm skin of human subjects (n = 6). This resulted in a localized burning pain sensation (edema and flare response) that was sustained as long as a constant flow was maintained. Flow rates between 1.2 and 12 ml/h were needed to reach individual pain ratings around 20% of a visual analogue scale (VAS). Increasing the flow in multiples of this basic rate led to approximately log-linear increases in individual pain ratings with reasonable congruence of the slopes. Stopping the pump or cooling the skin close to the cannula caused an abrupt pain relief. Prolonged infusion at flow rates producing pain ratings around 20% VAS led to localized changes in mechanical sensitivity: The touch threshold increased--as it did with control infusion of phosphate buffer at pH 7.4. However, the punctate force producing a threshold sensation of pain dropped from 64 to 5.7 mN (median values); the final level was usually reached within 15 min. In conclusion, experimental tissue acidosis provides a controllable and harmless method to produce sustained, graded and spatially restricted pain and hyperalgesia to mechanical stimulation.

Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro.

In ischemic and in inflamed tissues, pH levels down to 5.4 have been measured, and this local acidosis may contribute to pain and hyperalgesia in disease states. To evaluate the role of acid pH in nociception, we have studied identified primary afferents in a rat skin-saphenous nerve preparation in vitro where the receptive fields can be superfused at the highly permeable corium side with controlled solutions. The nerve endings were exposed to CO2-saturated synthetic interstitial fluid (SIF;pH 6.1) and to carbogen-gassed SIF phosphate buffered to different acid pH levels (5 min duration, 10 min intervals). Mechanical thresholds were repeatedly tested in a "blind" fashion by von Frey hair stimulation. Low-threshold mechanosensitive A beta- (n = 12) and A delta-fibers (n = 11) were not excited or sensitized by acid pH levels. In 24 of 96 nociceptor type C- and A delta-fibers, irregular low-frequency discharge with poor response characteristics was induced. However, a distinct subpopulation of mechanoheat sensitive, "polymodal" C-units (n = 25; 38%) showed stimulus-related responses increasing with proton concentration and encoding the time course of the pH change. Threshold levels were found to range from pH 6.9 to 6.1; mean maximum discharge was at pH 5.2. All such fibers responded to CO2 as well as to phosphate-buffered solution at the same pH 6.1. The CO2 responses, however, displayed significantly shorter latencies and more pronounced dynamic phases. The carboanhydrase blocker acetazolamide markedly delayed and reduced the CO2 responses. Prolonged application of acid pH (30 min) evoked nonadapting activity irrespective of oxygen supply. Many, but certainly not all, fibers sensitive to protons were also driven by capsaicin (10(-6) M, 10(-5) M) and vice versa. Repeated or prolonged treatment with low pH induced a significant and lasting decrease of the mechanical (von Frey) thresholds in almost all C-fibers tested (from 35 to 16 mN, on average), and this occurred whether or not a fiber was excited by protons. The sensitizing effect was more pronounced the higher the initial von Frey thresholds (0.75 rank correlation). This sensitization to mechanical stimulation was in contrast to the combined action of other inflammatory mediators, bradykinin, 5-HT, histamine and prostaglandin E2. In conclusion, we suggest that pH sensitivity of nociceptors may be an important source of pain and hyperalgesia.

[X-ray signs of foreign body aspiration in children]. / Röntgenzeichen der Fremdkörperaspiration bei Kindern.

Preoperative chest X-rays were taken in both postanterior and partially lateral views of 94 children with foreign-body aspiration. Additional fluoroscopy was employed in 70 patients. In 7% of the cases, the foreign body was radiopaque; in an equal amount of cases, there were no radiological findings. In the remaining results we observed: emphysema as an indirect radiological sign in two-thirds of the cases; in less than one-third, poststenotic atelectasis; pneumonia in 10%; bronchitis in 9%; pneumothorax in 2%.