Topical tacrolimus (FK 506) is effective in the treatment of pyoderma gangrenosum.
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Administration, Topical↗
Biomedical subjects
T Ruzicka
Publications and source records attributed to T Ruzicka.
Placebo-controlled evaluation of the irritant potential of tacalcitol (1a,24-dihydroxyvitamin D3) in healthy volunteers.
In the treatment of psoriasis with topical vitamin D3 analogues, lesional and perilesional irritation is the main side-effect. The aim of this study was to investigate whether local side-effects generated by tacalcitol, a vitamin D3 analogue, show concentration dependence. 3 different concentrations of tacalcitol (0.4; 4; 40 microg/g ointment) and the vehicle were applied on normal skin of the back of 25 healthy volunteers under occlusive conditions for 5 days. Assessment of erythema, infiltration and scaling as well as measurement of transepidermal water loss (TEWL) was performed on days 1 to 5. On day 5, additional skin barrier tests (DMSO test, alkali resistance test) were performed. Erythema and slight infiltration, but no scaling, were observed in a number of subjects without significant differences. TEWL also did not show significant differences for the test formulations, though there was a tendency towards lower values in the untreated areas. In the skin barrier tests, a tendency towards higher alkali resistance in the test areas treated with 40 microg tacalcitol/g ointment was detected. Thus, under occlusive conditions, the irritant potential of tacalcitol is very low. There is no convincing evidence of concentration dependence in irritation generated by tacalcitol when applied under occlusive conditions.
Administration, Topical↗
Inhibition of intercellular adhesio nmolecule-1 (ICAM-1) expression in ultraviolet B-irradiated human antigen-presenting cells is restored after repair of cyclobutane pyrimidine dimers.
The present study assessed the molecular mechanism underlying ultraviolet (UV) B radiation-induced inhibition of the expression of the adhesion molecule ICAM-1 in human antigen-presenting cells (APC). UVB radiation-induced inhibition of ICAM-I expression in human peripheral blood monocytes was associated with the generation of cyclobutane pyrimidine dimers (CPD). CPD were reduced by 60% after treatment with liposomal packed photolyase, an enzyme which removes CPD after absorption of photoreactivating light. Although incomplete, reduction of CPD was associated with complete restoration of ICAM-1 expression at the mRNA and protein level. Neither reduction of CPD level nor restoration of ICAM-1 expression were observed, if monocytes were treated with empty liposomes, or if they were irradiated with photoreactivating light prior to application of photolyase. DNA damage might also induce soluble mediators capable of autocrine inhibition of ICAM-1 expression. UVB irradiation of monocytes did not induce IL-10 production, but resulted in release of prostaglandin (PG) E2. Treatment of unirradiated monocytes with PGE2 completely inhibited ICAM-1 expression, thus mimicking the UVB effect. Inhibition of monocytic PGE2 production by indomethacin, however, did not restore ICAM-1 expression. These results suggest that formation of CPD is necessary and sufficient for UVB radiation-induced inhibition of ICAM-1 expression. In contrast, PGE2 might serve a paracrine role in UVB radiation-induced immunosuppression.
Antigen-Presenting Cells↗
Anaphylaxis to polyvinylpyrrolidone in an analgesic preparation.
A 32-year-old patient developed an anaphylactic reaction minutes after oral intake of acetaminophen-containing tablets (Doregrippin)). Scratch testing of the whole preparation was positive in contrast with the negative results obtained with pure acetaminophen. Therefore, scratch tests with the remaining drug components were performed and showed polyvinylpyrrolidone (PVP) to be the aetiological agent. Furthermore, specific IgE antibodies against PVP were demonstrated using a dot blot technique, thus ruling out a pseudo-allergic reaction. This case underlines the necessity to consider not only the active ingredient, but also additives as the causative agent.
Acetaminophen↗
Calgranulin C is overexpressed in lesional psoriasis.
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Humans↗
Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice.
Although T cell dysregulation is thought to underlie the pathogenesis of psoriasis, prominent infiltration and microabscess formation by neutrophils is a distinctive hallmark feature of this common disorder. The exact role of neutrophils in the pathogenesis of psoriasiform alterations in vivo, however, is unknown. Similar to human psoriasis, flaky skin mice (fsn/fsn) revealed a prominent infiltrate of neutrophils, and microabscesses within the hyperproliferative epidermis were associated with de novo expression of intercellular adhesion molecule-1. Intraperitoneal injection with the neutrophil-depleting RB6-8C5 monoclonal antibody (anti-Ly-6G) resulted in a dramatic reduction of the epidermal thickness by 58% compared with isotype-treated animals (p < 0.001). In addition, epidermal microabscesses were conspicuously absent (p < 0.001), and cutaneous neutrophils and T cells, but not mast cells or dendritic cells, were markedly reduced in anti-Ly-6G-treated mice. Proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-1, were also downregulated. Therapeutic effects occurred as early as 4 d after beginning of treatment. Wildtype skin was not affected. When the integrin alphaMbeta2 (CD11b/CD18), which mediates neutrophil localization through binding to intercellular adhesion molecule-1, was blocked in vivo with the M1/70 monoclonal antibody, the epidermal thickness was reduced by 31% (p < 0.002), and neutrophil and T cell accumulation was diminished compared with control animals. Likewise, treatment of fsn/fsn mice with the MP1-22E9 monoclonal antibody neutralizing granulocyte macrophage-colony stimulating factor, a cytokine stimulating neutrophils by upregulating alphaMbeta2, resulted in significant reduction of inflammation and acanthosis by 30% (p < 0.003). These results demonstrate a critical pathogenic role of neutrophils for hyperproliferative inflammatory lesions in fsn/fsn mice, suggesting that blocking neutrophil function may have therapeutic benefit in some human skin disorders.
Abscess↗
Neurotrophin-4 production by human epidermal keratinocytes: increased expression in atopic dermatitis.
Chronic inflammatory conditions of human skin, such as prurigo lesions of atopic dermatitis, are characterized clinically by intense pruritus and histologically by increased innervation. Regulation of skin innervation is thought to depend on neurotrophic factors. In this study, human skin cells were identified as a source of neurotrophins. Cultured keratinocytes expressed neurotrophin-4, whereas dermal fibroblasts expressed neurotrophin-3. In vitro stimulation with interferon-gamma, a marker cytokine for atopic eczema, induced keratinocyte neurotrophin-4 production, which was able to support growth of a neuroglioblastoma-derived cell line. In vivo, immunohistochemistry of human skin for neurotrophins showed neurotrophin-4 staining in the epidermal layer and neurotrophin-3 staining in the dermal compartment. Neurotrophin-4 but not neurotrophin-3 expression was markedly increased in interferon-gamma-injected skin. Prurigo lesions of atopic dermatitis skin were characterized by intense epidermal staining for neurotrophin-4, suggesting a pathophysiologic role for this neurotrophin in the increased innervation characteristic for these skin lesions. This study demonstrates differential expression and regulation of neurotrophins in human skin. It also identifies keratinocyte-derived neurotrophin-4 as a possible link between the immune and the nerve system of human skin.
Antibodies↗
Multiple symmetric lipomatosis: an unusual cause of childhood obesity and mental retardation.
Multiple symmetric lipomatosis (MSL), also known as Launois-Bensaude syndrome or Madelung's disease, is a rare disorder predominantly seen in middle-aged male patients. The disorder is characterized by large subcutaneous fat masses distributed around the neck, shoulders, and other parts of the trunk, often associated with nervous system abnormalities. A close relationship to alcoholism, metabolic disturbances and malignant tumours has been observed. Until now, MSL has only been described in adults. We report on the first two children, a 9-year-old girl and a 13-year-old boy, with the characteristic clinical findings of MSL. The girl presented with severe obesity, developmental delay, mild mental retardation, peripheral neuropathy, and latent hypothyroidism. In addition, she had elevated lactate concentrations in blood and cerebral spinal fluid suggesting mitochondrial dysfunction. Biochemical analyses of muscle showed a respiratory chain complex II deficiency. The boy suffered from severe obesity, mild mental retardation and insulin resistant diabetes mellitus. In both children, analyses of the mitochondrial genome did not reveal major deletions nor the MERRF 8344 point mutation. MSL seems to be a new neurometabolic disorder with heterogeneous clinical expression whose pathogenesis is still unknown.
Adolescent↗
Treatment of nonmelanotic hyperpigmentation with the Q-switched ruby laser.
Hyperpigmentation of the skin is often refractory to conventional therapies, but has significant cosmetic implications if located on visible areas. Because laser systems are capable of removing pigment deposits caused by selective photothermolysis, we addressed the issue of whether the Q-switched ruby laser could be a useful alternative in the treatment of nonmelanotic hyperpigmented skin lesions. We report the successful treatment of a patient with hyperpigmentation caused by iatrogenic human herpesvirus 8-associated Kaposi's sarcoma and a patient with hyperpigmentation caused by long-term antimalarial therapy for cutaneous lupus erythematosus. In both patients, clinical lightening of the darkly pigmented lesions was seen after a single treatment, and a significant improvement was observed after 3 laser applications. The patients tolerated the laser therapy well without any short-term side effects and did not experience either scarring or considerable textural skin changes. Histologic examination was performed before and after laser treatment to confirm the reduction of the pigment deposits. Our data indicate that treatment of nonmelanotic skin hyperpigmentation with the Q-switched ruby laser might be a safe and powerful therapeutic method.
Aged↗
Pyoderma gangrenosum after cesarean delivery.
In this reported case of pyoderma gangrenosum after cesarean delivery, deep ulceration involved the entire lower abdomen before immunosuppressive treatment was started. Initial high doses of prednisolone followed by low doses of cyclosporine A led to complete resolution of the skin lesions. This case report illustrates the importance of early diagnosis and effective systemic immunosuppressive therapy of pyoderma gangrenosum.
Abdomen↗
Topical tacrolimus for recalcitrant leg ulcer in rheumatoid arthritis.
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Administration, Topical↗
Plantar malignant melanoma -- a challenge for early recognition.
The incidence of malignant melanoma has been continuously increasing over the last few decades. Non-plantar melanomas are nowadays usually diagnosed and treated surgically at an early stage. In contrast, melanoma in a plantar location is usually diagnosed at an advanced tumour stage, conferring a poor prognosis. To discover the reasons for this remarkable difference in recognition and prognosis, we analysed our cases of plantar malignant melanoma in a retrospective study. From 1990 to 1997, we treated 925 melanoma patients. Of these, 68 cases (7%) were classified as plantar melanoma. For non-plantar melanoma patients the mean age was 52.6 years, the mean Clark level was 2.8 and the mean tumour depth was 1.22 mm. In contrast, the mean age of patients with plantar melanoma was 63.3 years, the mean Clark level was 3.61 and the mean tumour depth was 2.55 mm. The mean time between the first observation of the plantar skin lesion and the first consultation with a physician (patients' delay) was 4.8 years and, on average, it took an additional 7 months before adequate surgical treatment was performed (physicians' delay). The prognosis of our patients was poor. In 98.5% (n = 67) further metastases were observed on follow-up. Since there is still no cure for advanced plantar malignant melanoma, the early detection and subsequent surgical treatment of plantar melanoma is decisive for the prognosis. Based on our results, the poor survival can be improved by a significant reduction in the time period between the first observation of a plantar skin lesion and surgical treatment. Therefore there is an urgent need for special preventive health care campaigns to reduce significantly both the patients' and the physicians' delay.
Adult↗
Successful treatment of discoid lupus erythematosus with argon laser.
Vascular lesions with telangiectasias on visible areas, such as the face, are common in discoid lupus erythematosus (DLE); however, an efficient management of these skin lesions can sometimes be difficult. Since argon laser light is able to specifically coagulate vascular structures, it has been used in the treatment of various vascular skin malformations. Therefore, we addressed the issue whether argon laser treatment could be a therapeutic alternative for this disease. Here, we report on a patient with DLE, who suffered from long-standing erythematous, telangiectatic plaques on the face refractory to standard regimens of therapy. After 2 laser applications, a significant improvement was observed and after 5 sessions of argon laser therapy the treated skin lesions had completely resolved with an excellent cosmetic result. The patient tolerated the laser treatment well without any short-term side effects. These data indicate that argon laser therapy might be a powerful alternative approach in the treatment of vascular skin lesions of DLE.
Argon↗
UVB-regulated gene expression in human keratinocytes. Analysis by differential display.
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Animals↗
Cloning and characterization of hurpin (protease inhibitor 13): A new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family.
Epidermal keratinocytes are the primary target of the midrange ultraviolet part (UVB, 280-320 nm) of terrestrial sunlight. Analysis of the resulting UV response at the transcriptional level by differential display PCR identified a formerly unrecognized large group of repressed genes. Among those UV-repressible genes, a novel serine proteinase inhibitor (serpin) termed hurpin (HaCaT UV-repressible serpin) has been identified. The isolated full-length cDNAs harbour a 1176 bp open reading frame encoding a potential protein with 391 amino acid residues and a predicted molecular mass of approximately 44 kDa. The novel serpin has nearly 59 % amino acid identity with the squamous cell carcinoma antigen 1 (SCCA1) and squamous cell carcinoma antigen 2 (SCCA2). In addition, it displays all of the structural features unique to the ovalbumin family of serpins (ov-serpins). The amino acid sequence of the hinge region in the reactive site loop suggests that hurpin has the potential for protease inhibition. The putative reactive center P1-P1'residues were identified as Thr356-Ser357 by alignment with other ov-serpins. The physiological target protease is unknown and the in vitro translated hurpin does not form SDS-stable complexes with a variety of known serine proteases. Expression of hurpin is restricted to epidermal cells where two distinct transcripts of 3.0 and 3.4 kb are detectable. Furthermore, expression of hurpin appears to be related to the activation or proliferation state of keratinocytes, since hurpin transcripts are more abundant in immortalized keratinocytes (HaCaT) and in cultured normal human keratinocytes, compared to the expression in normal skin. Moreover, in psoriasis, a skin disease characterized by hyperproliferation of keratinocytes and responsive to therapeutic UV irradiation, overexpression of hurpin is noted in psoriatic skin lesions compared to non-lesional skin.
Amino Acid Sequence↗
Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion.
Mutations of mitochondrial (mt) DNA accumulate during normal aging. The most frequent mutation is a 4,977-base pair deletion also called the common deletion, which is increased in photoaged skin. Oxidative stress may play a major role in the generation of large scale mtDNA deletions, but direct proof for this has been elusive. We therefore assessed whether the common deletion can be generated in vitro through UV irradiation and whether reactive oxygen species are involved in this process. Normal human fibroblasts were repetitively exposed to sublethal doses of UVA radiation and assayed for the common deletion employing a semiquantitative polymerase chain reaction technique. There was a time/dose-dependent generation of the common deletion, attributable to the generation of singlet oxygen, since the common deletion was diminished when irradiating in the presence of singlet oxygen quenchers, but increased when enhancing singlet oxygen half-life by deuterium oxide. The induction of the common deletion by UVA irradiation was mimicked by treatment of unirradiated cells with singlet oxygen produced by the thermodecomposition of an endoperoxide. These studies provide evidence for the involvement of reactive oxygen species in the generation of aging-associated mtDNA lesions in human cells and indicate a previously unrecognized role of singlet oxygen in photoaging of human skin.
Cell Survival↗
Tacrolimus: the drug for the turn of the millennium?
BACKGROUND: Tacrolimus has been shown to be a powerful suppressor of the immune system. It was introduced into clinical use to prevent allograft rejection and is now routinely used in kidney, liver, and heart transplantation. Recently, 2 double-blind multicenter studies demonstrated the therapeutic efficacy of topical and systemic tacrolimus in the inflammatory skin diseases atopic dermatitis and psoriasis. DATA SOURCE: MEDLINE was searched for relevant publications and combined with our own clinical, in vitro, and in vivo studies. STUDY SELECTION: All studies dealing with tacrolimus and dermatology were reviewed. DATA EXTRACTION: Publications with clinically relevant data were included in this review. CONCLUSIONS: Topical tacrolimus is a safe and effective therapeutic agent that may open a new era in the treatment of inflammatory skin diseases, particularly for patients with atopic dermatitis. Before its full potential in dermatology can be assessed, more clinical experience in treating children and comparison with the criterion standard of anti-inflammatory therapy, glucocorticosteroids, are needed.
Dermatitis, Atopic↗
Polymorphisms of the xenobiotic-metabolizing enzymes CYP1A1 and NAT-2 in systemic sclerosis and lupus erythematosus.
The etiology of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several cases, however, xenobiotics (i.e. drugs and occupational agents) were identified as etiologic agents and associations with certain polymorphic alleles of xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1) and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1- and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other chemicals to reactive metabolites. NAT-2 is the most important enzyme in acetylation of aromatic amines, and thus may be responsible for detoxification of many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point mutation in the 3' flanking region of the gene (Msp1) and a mutation in exon 7 leading to an isoleucine-valine-exchange in the heme-binding region of the enzyme, have been described and may lead to a higher basal and inducible enzyme activity. With respect to NAT-2, several alleles which combine for the two phenotypes "fast" and "slow" acetylators have been described. We analyzed the gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed in genomic DNA by PCR, whereas NAT-2 phenotypes were measured by the caffeine method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE group (n = 68) exhibited a significant increase (p < 0.05) in the mutant Val-allele (OR = 2.59) when compared to controls (n = 184). However, no significant differences in allele frequencies for MspI in the SLE group and for both CYP1A1 polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype, patients suffering from SLE (n = 88) 75% and SSc (n = 26) 80.2%, respectively, were slow acetylators compared to 55% slow acetylators in the healthy German population (p < 0.05). The observed increased frequencies of the CYP1A1 mutant Val-allele and the slow actylator phenotype in idiopathic autoimmune disease support our concept that in slow acetylators non-acetylated xenobiotics may accumulate and are subsequently metabolized by other enzymes into reactive intermediates. Thus, enhanced formation of reactive metabolites could alter self-proteins presented to the immune system thus stimulating autoreactive T cells which induce autoimmunity.
Alleles↗