Local and systemic expression of basic fibroblast growth factor in a patient with familial glomangioma.

Glomangiomas are rare cutaneous tumours composed of glomus cells, which are modified smooth muscle cells. The aetiology of this condition is thought to involve a mutation in a novel gene acting to regulate angiogenesis. We report a patient from a large family with three generations affected by familial multiple glomangiomas. We hypothesized that the growth factors basic fibroblast growth factor and vascular endothelial growth factor, which stimulate/regulate angiogenesis could be involved in the pathogenesis of these lesions. Therefore, using enzyme-linked immunosorbent assays and immunohistochemistry, respectively, we measured systemic and tissue levels of these growth factors in a patient with familial glomangiomas. In addition, we investigated endothelial mitogenicity of the patient's serum as a functional assay of systemic growth factor activity.

Panniculitis in association with apomorphine infusion.

This study was undertaken to ascertain the histopathology and aetiology of cutaneous nodules observed in Parkinson's patients treated with continuous subcutaneous apomorphine. Ten patients were recruited, answered questionnaires, and underwent skin biopsies and full blood count, and nine were patch tested to apomorphine and its preservative. Six had serum IgE levels measured. A florid panniculitis was seen in all biopsies; five were predominantly eosinophilic, three lymphocytic and two neutrophilic; in seven cases the panniculitis was mixed and in three it was septal. Patch testing was universally negative and the IgE levels were normal.

Cutaneous responses to endothelin-1 and histamine in patients with vibration white finger.

Vibration white finger (VWF) is the episodic blanching of the fingers that occurs in response to cold in those who work with hand-held vibrating tools. Clinically the condition differs from primary Raynaud's phenomenon as persistent pain and paresthesia are common in the hands and arms and occur independently of the "white attacks." We have previously reported a decrease in protein gene product 9.5 and calcitonin gene-related peptide-immunoreactive nerve fibers in the digital skin of individuals with VWF. In this study, we have sought to determine whether this deficit of immunoreactive sensory-motor nerves has a functional counterpart in vivo. Histamine produces a rapid wheal and flare response following intradermal injection, whereas endothelin-1 (ET-1) produces a central area of pallor with a surrounding neurogenic flare. In contrast, calcitonin gene-related peptide produces a non-neurogenic erythema. In this study, histamine and ET-1 were injected into the dorsum of the middle phalanx and the local neurovascular response was assessed by measuring the area of the visible flare or pallor. Basal finger blood flow was also measured by laser Doppler flowmetry in each of the digits prior to intradermal injection. The experiments were performed at 21 degrees C and 4 degrees C. Patients with VWF and asymptomatic vibration-exposed workers had significantly lower resting skin blood flow at both 21 degrees C and 4 degrees C than heavy manual workers with no vibration exposure. The size of the histamine- and ET-1-induced flares at both 21 degrees C and 4 degrees C was significantly smaller in patients with VWF when compared with the asymptomatic vibration-exposed workers and heavy manual workers. The size of the ET-1-induced pallor was smaller in patients with VWF when compared with the heavy manual workers at both 21 degrees C and 4 degrees C. In contrast, the area of erythema induced by intradermal injection of calcitonin gene-related peptide at both 21 degrees C and 4 degrees C was of a similar size in patients with VWF and in heavy manual workers. These results indicate that the neuroneal deficit identified by immunohistochemistry in the digital skin of patients with VWF has a functional counterpart in vivo and is evident as a reduced ability to propagate an axon-reflex vasodilator response when challenged with histamine and ET-1. Furthermore, these results enable patients with VWF to be differentiated from both asymptomatic vibration-exposed workers, in whom the histamine- and ET-1-induced flares are normal, and those with primary Raynaud's disease, in whom the ET-1 flare is reduced and the histamine-induced flare is normal.

Expression of nerve growth factor receptors in cutaneous inflammation.

Evidence indicates that the neurotrophin nerve growth factor (NGF) is a mediator of cutaneous inflammatory responses. Cellular responses to NGF are facilitated by two receptors called trk A and p75 neurotrophin receptor (p75NTR). In the current study we have investigated the expression of these receptors in lesional and non-lesional skin from patients with plaque psoriasis and in normal skin exposed to three times the minimal erythema dose of ultraviolet (UV) B radiation. Trk A immunostaining was confined to the basal keratinocytes in normal skin. There was a significant reduction in trk A immunostaining in both non-lesional and lesional psoriatic skin compared with control skin. In UVB-irradiated normal skin, there was a significant reduction in trk A immunostaining at 4 h after irradiation, which was still evident at 48 h. In normal skin, p75NTR immunopositive fine nerve fibres were present throughout the dermis and occasionally seen in the epidermis. Thick nerve fibres were evident in the deep dermis and in the middle region of the dermis. p75NTR immunopositive basal keratinocytes were occasionally seen. There was a statistically significant loss of p75NTR immunopositive fine nerve fibres in the epidermis of lesional psoriatic skin and a statistically significant loss of p75NTR immunopositive fine nerve fibres in the dermis in both non-lesional and lesional psoriatic skin. p75NTR immunopositive thick nerve fibres were reduced in lesional psoriatic skin compared with normal skin. UVB irradiation of normal skin led to a statistically significant decrease in the p75NTR immunopositive fine nerve fibres in the epidermis at 48 h after irradiation. There was no significant reduction in the dermal p75NTR immunoreactivity. These results demonstrated that expression of both NGF receptors is decreased following an acute inflammatory stimulus and also in association with a chronic inflammatory dermatosis.

Treatment of psoriasis with intermittent short course cyclosporin (Neoral). A multicentre study.

A 1 year, prospective multicentre study was performed to investigate the efficacy and safety of intermittent treatment with cyclosporin in psoriasis vulgaris. Subjects received cyclosporin (Neoral) 5 mg/kg per day until achieving 90% reduction in area affected, or for a maximum of 12 weeks. Those failing to demonstrate a satisfactory response were withdrawn. When further treatment was required, cyclosporin was recommenced. This cycle was repeated up to three times. Psoriasis activity was recorded using the area affected and sign scores for erythema, scaling and infiltration. Overall assessments of response and tolerability were recorded. Forty-one subjects, mean age 36, mean PASI 12.8, entered the first treatment period. Thirty-three received a second period of treatment and 16 a third. Eighteen failed to complete the study as planned: five were withdrawn due to adverse events, four due to treatment failure and nine due to protocol violations. At the end of each treatment period, significant improvements were seen in all efficacy parameters. Overall response was graded as 'considerable improvement' or 'minimal or no symptoms', by over 80% of subjects and investigators. Median intervals to relapse for subjects remaining in the study were 72 days (range 28-329) and 53 days (range 14-141) after periods 1 and 2, respectively. There were significant increases in mean serum creatinine and blood pressure during each treatment period. However, there were no significant differences in either parameter between baseline and the final follow-up visit. At the end of each treatment period, overall tolerability of the treatment was considered 'good' or 'very good' by over 80% of subjects and investigators.

Hypersensitivity in aseptic loosening of total hip replacements. The role of constituents of bone cement.

Aseptic loosening is seen in a significant proportion of cemented total hip replacements (THR). In a small subgroup of patients who suffer early loosening polyethylene debris is unlikely to be responsible. We recently reported one case of allergic contact dermatitis to N,N-dimethylparatoluidine (DMT), an accelerator used in bone cement. We have therefore investigated this using skin-patch tests to a variety of substances including metals, polyethylene and the separated individual components of Simplex cement. We studied 70 patients, 15 with aseptic loosening less than two years after THR, 25 with satisfactory long-term cemented fixation, five with infected loosening of cemented THRs and 25 awaiting hip arthroplasty. We found seven positive reactions to DMT, all of them in patients with the rapid onset of aseptic loosening. Allergy to DMT is recognized in the dental profession in respect of the 'denture sore mouth' syndrome, and could also be an occupational hazard since some industrial glues contain DMT. Our results suggest the need for awareness of possible previous dental or occupational exposure of the constituents of bone cement. We recommend the use of skin-patch testing in high-risk cases.

Systemic sclerosis associated with right ventricular cardiomyopathy.

Systemic sclerosis is an uncommon multisystem disorder of unknown aetiology which predominantly affects the skin. Cardiac involvement, which is far more common than was originally realized, may affect any part of the heart but most frequently affects the left ventricular myocardium. Right ventricular dysfunction is usually associated with pulmonary vascular disease. We report a case of systemic sclerosis associated with right ventricular cardiomyopathy in whom pulmonary artery pressures were normal.

Neuropeptides induce release of nitric oxide from human dermal microvascular endothelial cells.

Nitric oxide is a potent mediator of endothelium-dependent vasodilation, the synthesis of which is catalyzed by the constitutively expressed enzyme endothelial nitric oxide synthase. In this study we have investigated whether human dermal microvascular endothelial cells express endothelial oxide synthase and whether the vasodilator neuropeptides, calcitonin gene-related peptide and substance P, stimulate the release of nitric oxide from these cells. Endothelial nitric oxide synthase was identified by immunohistochemistry in the blood vessels in both the papillary and deep dermis of normal skin, and also in monolayers of human dermal microvascular extracts prepared from both the dermis of normal human skin and human dermal microvascular endothelial cells, a 135-kDa band corresponding to endothelial nitric oxide synthase was identified. Nitric oxide was released from unstimulated human dermal microvascular endothelial cells as assessed by inhibition of platelet aggregation and nitrate formation. Endothelial cell-mediated inhibition of platelet aggregation was blocked by hemoglobin. Calcitonin gene-related peptide, (100 pM to 100 nM) directly inhibited platelet aggregation, and this direct effect was not modulated by microvascular endothelial cells. Substance P (10 nM to 1 muM) and calcitonin gene-related peptide (100 pM to 10 nM) significantly (p<0.05) increased nitrite formation, and this increase was blocked by the competitive nitric oxide synthase antagonist, NG-monomethyl-L-arginine. These results demonstrate that endothelial nitric oxide synthase is expressed in the microvascular endothelium of normal human skin and that human dermal microvascular endothelial cells release nitric oxide constitutively and in response to vasodilator neuropeptides.

Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon.

It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynaud's phenomenon (RP). Both endothelin-1 (ET-1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature, and calcitonin gene-related peptide (CGRP), a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET-1 levels are raised, and there is a diminution of CGRP-containing perivascular nerves in finger skin in RP. We undertook a pharmacological study to investigate the sensitivity of the digital cutaneous microvasculature to intradermal ET-1 and CGRP. Differences were found in RP compared with normal digital skin, supporting the idea that the digital cutaneous microvasculature is actively involved in the pathogenesis of RP. In RP, the erythematous response to ET-1 was diminished at both 20 and 5 degrees C (a low temperature at which RP classically occurs) providing pharmacological support for the morphological evidence that in RP there is a deficiency of CGRP-containing nerves in the distal digital skin.

Inhibitors of nitric oxide synthase in human skin.

The aim of this study was to investigate in human skin in vivo the role of nitric oxide in maintaining resting vascular tone, in the vasodilatation caused by local warming and by ultraviolet B light exposure, and in the response to exogenous calcitonin gene-related peptide (CGRP). Cutaneous blood flow was assessed by planimetry of the visible erythema or pallor and by laser Doppler flowmetry. Intradermal injection of the inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester (L-NAME; 25 nmol), into forearm skin produced a visible pallor and a reduction of blood flow at a controlled ambient temperature of 21 degrees C. The control, NG-nitro-D-arginine methyl ester (D-NAME; 25 nmol) or NG-monomethyl-L-arginine (L-NMMA; 25 nmol) did not cause pallor or reduce blood flow. L-NAME and L-NMMA caused dose- and time-dependent increases in pallor, and reductions in cutaneous blood flow in skin that had been locally warmed by immersion in water at 45 degrees C and in skin that had been exposed to ultraviolet B light. D-NAME and D-NMMA at comparable concentrations did not have the effects on skin blood flow observed with the L forms. L-NAME and L-NMMA both inhibited the increased blood flow in human skin caused by the intradermal injection of CGRP (12.5 or 25 pmol). The reduction of CGRP-induced increase of blood flow by L-NAME was reversed by L-arginine. Neither D-NAME nor D-NMMA inhibited the increase in blood flow caused by CGRP. Neither L-NAME nor L-NMMA inhibited the increase in blood flow in human skin caused by the intradermal injection of prostaglandin E2 (63 pmol). The data show that nitric oxide is involved in the maintenance of resting blood flow in human skin and also in the cutaneous vasodilator responses to local warming, ultraviolet B irradiation, or injection of CGRP.

The effect of topical steroid on the actions of vasoconstrictor and vasodilator peptides in human skin.

The effect of topical application of clobetasol propionate ointment (0.05% w/v) on the vascular changes induced by intradermal injections of histamine, calcitonin gene-related peptide, substance P, endothelin-1 and compound 48/80 was studied. Clobetasol propionate ointment was applied topically under occlusion to the forearm skin of healthy volunteers and vehicle base was applied to the contralateral forearm. The intradermal injections were made 4 h or, in a separate study, 72 h after topical steroid application. Responses were measured by planimetry and laser Doppler flowmetry. Four hours application of steroid did not significantly alter the responses to any of the vasoactive substances. After 72 hours application, clobetasol propionate significantly increased the size of the endothelin-1-induced area of vasoconstriction (p < 0.02) and significantly reduced the size of the flares induced by endothelin-1 (p < 0.02), substance P (p < 0.009) and compound 48/80 (p < 0.05). We conclude that the most likely explanation of our data is an inhibition by the steroid of cutaneous mast cell function.

Nerve growth factor contributes to the up-regulation of growth-associated protein 43 and preprotachykinin A messenger RNAs in primary sensory neurons following peripheral inflammation.

Peripheral inflammation induced in adult rats by an intraplantar injection of complete Freund's adjuvant results in a rapid (6 h) increase in the expression of the messenger RNAs for the neuronal growth-associated protein 43 and for preprotachykinin A, the precursor for substance P, in dorsal root ganglion sensory neurons innervating the inflamed area. This increase peaks at 48 h and then declines by five days. The changes are present in the dorsal root ganglion cells innervating the inflamed skin (lumbar 4 or 5) but no elevation was found in the third lumbar dorsal root ganglion which innervates neighbouring non-inflamed skin. The increased growth-associated protein 43 messenger RNA in the dorsal root ganglion is followed by a marked increase in growth-associated protein 43-like immunoreactive fibres in the epidermis of the inflamed skin. Systemic administration of neutralizing anti-nerve growth factor antibodies immediately prior to the inflammation prevents the increase in growth-associated protein 43 and preprotachykinin A messenger RNAs in the sensory neurons. A subcutaneous injection of nerve growth factor (200 ng) into the hindpaw elevates preprotachykinin A but not growth-associated protein 43 messenger RNA in the fourth lumbar dorsal root ganglion 48 h post-injection and this could be prevented by co-administration of the anti-nerve growth factor serum. The production of nerve growth factor in inflamed target tissues leads to alterations in the phenotype of responsive adult primary sensory neurons which include a change in the levels of a growth-related protein and a peptide neuromodulator.(ABSTRACT TRUNCATED AT 250 WORDS)

Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells.

Src-related cytoplasmic PTKs are physically and functionally associated with cell surface receptors and are involved in signal transduction. In this paper we report the identification of src-related proteins p59fyn, pp60c-src and p62yes in human microvascular endothelial cells cultured from normal human skin and their physical association with the thrombospondin receptor CD36. Such an association represents a potential signalling pathway by which thrombospondin may regulate angiogenesis.

Cutaneous nerve fibre depletion in vibration white finger.

Vibration white finger or hand-arm vibration syndrome is the episodic blanching of the fingers in response to cold occurring in those who work with hand held vibrating tools. Clinically the condition differs from primary Raynaud's phenomenon as persistent paraesthesiae and pain are common in the hands and arms and these occur independently from the 'white attacks'. Symptoms can become severe enough to warrant a change of occupation. Industrial compensation may be awarded for vibration white finger but, at present, no simple or reliable objective diagnostic test is available. Calcitonin gene-related peptide (CGRP) is a neuropeptide with powerful vasodilator properties. A deficiency of immunoreactive CGRP nerve fibres has been previously demonstrated in the digital cutaneous microvasculature of patients with primary and secondary Raynaud's phenomenon with the distribution and quantity of other types of nerve fibres not being significantly altered. To determine if the innervation of the cutaneous microvasculature in vibration white finger was also abnormal skin biopsy samples from the fingers of 15 patients with vibration white finger, six healthy age matched controls who worked with vibrating machinery and 26 healthy age matched controls who were heavy manual workers without exposure to vibrating machinery were examined by immunohistochemistry. To try to correlate any histological abnormalities with clinical neurological deficit sensory nerve conduction studies have so far been performed in six patients with vibration white finger.(ABSTRACT TRUNCATED AT 250 WORDS)