[Cutaneous manifestations of sarcoidosis]. / Kutane Manifestationen bei Sarkoidose.

Skin manifestations of sarcoidosis occur in up to 30% of cases. This review summarizes and illustrates in detail the differences between specific and unspecific skin manifestations of sarcoidosis. Important differential diagnoses, such as tuberculosis, cutaneous lymphoma and syphilis have to be excluded. The indications for systemic treatment are primarily determined by the extent of organ involvement and also by the cosmetic impairment.

General anaesthesia-induced anaphylaxis: impact of allergy testing on subsequent anaesthesia.

BACKGROUND: Immunoglobulin E-mediated allergy to drugs and substances used during general anaesthesia as well as non-allergic drug hypersensitivity reactions may account for anaesthesia-induced anaphylaxis. As IgE-mediated anaphylaxis is a potentially life-threatening reaction, identification of the culprit allergen is essential to avoid anaphylaxis recurrence during subsequent general anaesthesia. OBJECTIVE: To study whether preventive recommendations derived from allergy testing after intraoperative anaphylaxis were followed in subsequent general anaesthesia. METHODS: Results of standardized allergy testing after anaesthesia-induced anaphylaxis and outcome of subsequent general anaesthesia were analysed retrospectively. RESULTS: Fifty-three of 107 patients were diagnosed with IgE-mediated allergy to a drug or substance used during general anaesthesia, and 54 patients were test negative. Twenty-eight of 29 allergy patients tolerated subsequent general anaesthesia uneventfully. One patient with cefazolin allergy suffered from anaphylaxis recurrence due to accidental reapplication of cefazolin. Twenty-two of 24 test-negative patients tolerated subsequent general anaesthesia, whereas two patients again developed anaphylaxis despite pre-medication regimens. CONCLUSION AND CLINICAL RELEVANCE: Our results confirm the practical impact of allergy testing in general anaesthesia-induced anaphylaxis. By identification of the allergen, it is possible to avoid allergic anaphylaxis during subsequent anaesthesia. In most cases, recommended pre-medication seems to prevent the recurrence of non-allergic drug hypersensitivity reactions.

Aminopenicillin-associated exanthem: lymphocyte transformation testing revisited.

BACKGROUND: The lymphocyte transformation test (LTT) has been promoted as in-vitro test for diagnosis of drug hypersensitivity. For determination of statistical LTT sensitivity, series of patients with clinically uniform reactions followed by complete drug hypersensitivity work-up are mandatory. Assessment of LTT specificity requires control patients who tolerated exposure to the drug studied. OBJECTIVE: To prospectively determine the diagnostic value of the LTT in a clinically and diagnostically well-defined series of patients. METHODS: Patients with exanthematous skin eruptions after ampicillin (AMP) intake were included in this study. After exclusion or confirmation of delayed-onset allergic AMP hypersensitivity by skin and provocation testing, two independent LTTs were performed: one standard LTT and a modified LTT with additional anti-CD3/anti-CD28 monoclonal antibody stimulation. RESULTS: By testing, delayed-onset allergic AMP hypersensitivity was diagnosed in 11 patients and definitely ruled out in 26. The standard LTT reached a diagnostic sensitivity of 54.5% while the modified LTT yielded 72.7%. However, the methodical test modification resulted in a decline of specificity from 92.3% (standard LTT) to 76.9%. CONCLUSIONS AND CLINICAL RELEVANCE: In cases of AMP-associated exanthems, the diagnostic value of the LTT compared with routine allergy testing is limited. When evaluating such exanthems, provocation testing remains the gold standard. Delayed reading of intradermal skin tests remains most useful to avoid positive provocation reactions.

[Serious complications following gluteal injection of silicone]. / Schwere Komplikationen nach glutealer Silikoninjektion.

Silicone has a broad range of medical applications and plays an important role, for example, in plastic reconstruction. The use of silicone, however, may result in unpredictable consequences for the patient. These range from swelling and erythema at the site of injection and regional lymphadenopathy to the development of disseminated granulomas distant from the administration site. We report a woman who developed extensive distally-spreading ulcerations in both buttocks several years after gluteal silicone injection. Potential systemic reactions of silicone include intrapulmonary granulomas, embolism and related pneumonitis. Moreover, an association with the development of autoimmune diseases and neoplasias has been discussed. Therapeutic options include surgically removing the silicone and topical or systemic anti-inflammatory drug therapy. However, due to the diffuse dissemination of silicone, the former is often not completely possible and for the latter empirical data are limited and follow-up studies are missing. Liquid silicone is no longer authorized in Europe or in the U.S.A. When silicone implants are used, the decision should be weighed carefully and the patient adequately counseled. In addition, follow-up care on a regular basis is mandatory for both those with implants and those who obtained injections of liquid silicone in the past.

[Uncommon cutaneous ulcerative and systemic sarcoidosis. Successful treatment with hydroxychloroquine and compression therapy]. / Seltene ulzerierende kutane und systemische Sarkoidose. Erfolgreiche Therapie mit Hydroxychloroquin und medizinischer Kompressionstherapie.

Sarcoidosis is a granulomatous multisystemic disease of unclear etiology, which can affect any organ. The cutaneous manifestations are variable, but ulcerative cutaneous sarcoidosis is very rare. One must rule out other granulomatous skin diseases, especially necrobiosis lipoidica. There is no standarized therapy; usually an interdisciplinary approach over years taking multiple side effects into consideration is needed. A 58-year-old woman with a long history of cutaneous, nodal and pulmonary sarcoidosis suddenly developed ulcerations within the disseminated skin lesions on her legs. The combination of systemic hydroxychloroquine and modern wound management lead to complete healing of the ulcers and a significant improvement in the remaining skin lesions.

Diagnostic testing in suspected fluoroquinolone hypersensitivity.

BACKGROUND: Because of their broad antibacterial activity in the gram-negative and gram-positive spectrum, high oral bioavailability, and good tissue penetration, fluoroquinolone antibiotics are widely used. Besides direct drug-related side-effects, fluoroquinolones may cause hypersensitivity reactions. OBJECTIVE: The aim of this retrospective analysis was to present the results of diagnostic testing in cases of clinically suspected fluoroquinolone-induced immediate or delayed hypersensitivity. METHODS: We studied 101 patients with a history of immediate or delayed hypersensitivity symptoms in temporal relation to treatment with a fluoroquinolone antibiotic using standardized skin testing, followed by oral challenges. Patients with anaphylaxis symptoms were further evaluated with in vitro tests. RESULTS: Fluoroquinolone hypersensitivity was excluded in 71 patients by tolerated oral challenge tests. During positive challenge tests, six patients (three out of these had positive and three had negative skin prick tests) developed anaphylaxis symptoms but the presumed IgE-mediated mechanism could not be confirmed by in vitro tests. Patch testing was constantly negative; however, in two patients a rash was induced by the challenge tests. CONCLUSION: History alone leads clearly to a considerable over-estimation of fluoroquinolone hypersensitivity. Moreover, skin or in vitro tests do not seem to be very useful in identifying hypersensitive patients. Challenge tests appear to be necessary for definitely confirming or ruling out fluoroquinolone hypersensitivity.

Superimposed linear psoriasis: differential therapeutic response of linear and nonlinear lesions.

Linear psoriasis is a very unusual clinical variation of psoriasis. Typical clinical features include early onset of erythematosquamous lesions along Blaschko's lines, ability to elicit psoriatic features, absence of pruritus and positive family history for psoriasis. Recently, the term 'superimposed linear psoriasis' was coined for cases with development of nonlinear psoriatic lesions at predilection sites in later life. We report a 19-year-old woman meeting all criteria for the diagnosis of superimposed linear psoriasis including typical histological features. Remarkably, treatment with topical steroids and dithranol cleared the psoriatic lesions on predilection sites whereas the linear lesions were resistant to topical therapy. Linear psoriatic lesions are believed to be caused by genetic alterations in early embryogenesis leading to loss of heterozygosity at a gene locus involved in the pathogenesis of psoriasis. Comparison of mosaic keratinocytes derived from linear lesions with wild-type keratinocytes from the same person may therefore allow identification of key regulatory genes.

A high school gym-induced disease.

Physical exercise may induce upper and lower airway symptoms such as rhinitis and asthma. Rhinitis symptoms are often neglected although runny nose and nasal congestion may interfere with performance of the affected individual. A detailed history regarding locality and time of symptoms is of most significance for taking the appropriate diagnostic measures and identifying, as in this case, an uncommon form of allergic rhinitis to airborne spores from moulds.

NF-kappaB determines localization and features of cell death in epidermis.

Specialized forms of physiologic cell death lacking certain characteristic morphologic features of apoptosis occur in terminally differentiating tissues, such as in the outer cell layers of epidermis. In these cell layers, NF-kappaB translocates from the cytoplasm to the nucleus and induces target gene expression. In light of its potent role in regulating apoptotic cell death in other tissues, NF-kappaB activation in these cells suggests that this transcription factor regulates cell death during terminal differentiation. Here, we show that NF-kappaB protects normal epithelial cells from apoptosis induced by both TNFalpha and Fas, whereas NF-kappaB blockade enhances susceptibility to death via both pathways. Expression of IkappaBalphaM under control of keratin promoter in transgenic mice caused a blockade of NF-kappaB function in the epidermis and provoked premature spontaneous cell death with apoptotic features. In normal tissue, expression of the known NF-kappaB-regulated antiapoptotic factors, TRAF1, TRAF2, c-IAP1, and c-IAP2, is most pronounced in outer epidermis. In transgenic mice, NF-kappaB blockade suppressed this expression, whereas NF-kappaB activation augmented it, consistent with regulation of cell death by these NF-kappaB effector proteins. These data identify a new role for NF-kappaB in preventing premature apoptosis in cells committed to undergoing physiologic cell death and indicate that, in stratified epithelium, such cell death normally proceeds via a distinct pathway that is resistant to NF-kappaB and its antiapoptotic target effector genes.

Nuclear factor kappaB subunits induce epithelial cell growth arrest.

Nuclear factor kappaB (NF-kappaB) gene-regulatory proteins play important roles in inflammation, neoplasia, and programmed cell death. Recently, blockade of NF-kappaB function has been shown to result in epithelial hyperplasia, suggesting a potential role for NF-kappaB in negative growth regulation. We expressed active NF-kappaB subunits in normal epithelial cells and found that NF-kappaB profoundly inhibits cell cycle progression. This growth inhibition is resistant to mitogenic stimuli and is accompanied by other features of irreversible growth arrest. NF-kappaB-triggered cell cycle arrest is also associated with selective induction of the cyclin-dependent kinase inhibitor p21CiP1, with overexpression of p21(Cip1) alone inducing findings similar to those seen with NF-kappaB in vitro. An active NF-kappaB subunit expressed in the epidermis of p21(CiP1-/- mice, however, displays only partial growth-inhibitory effects, suggesting that full NF-kappaB growth inhibition is only partially p21(Cip1) dependent in this setting. These data indicate that NF-kappaB can trigger cell cycle arrest in epithelial cells in association with selective induction of a cell cycle inhibitor.

Trichorhinophalangeal syndrome type I: clinical and molecular characterization of 3 members of a family and 1 sporadic case.

BACKGROUND: Trichorhinophalangeal syndrome type I (TRPS I) is a rare autosomal dominant disorder clinically characterized by sparse and slow-growing hair, pear-shaped nose, elongated philtrum, thin upper lip, and bone deformities, in particular, cone-shaped epiphyses of the phalanges. Very recently, the responsible gene TRPS1 has been cloned on human chromosome 8q24. OBSERVATION: We describe a mother and her 2 daughters and a female patient with a sporadic case of TRPS I. In the familial case, mutation analysis showed an insertional mutation at position 2480 of the TRPS1 gene leading to a premature translational stop. Careful clinical examination showed craniofacial and radiologic features typical of TRPS I, including short stature, in all 3 affected individuals. Additionally, they presented with a receded triangular medio-occipital hairline, which has not been described in TRPS I so far. In the sporadic case, we identified a single base deletion at position 2110 of the TRPS1 gene leading to frameshift and premature translational stop at codon 766. The patient presented with the typical TRPS I phenotype but was of normal stature. CONCLUSIONS: The TRPS I is characterized by variable clinical expression of the triad of hair, craniofacial, and skeletal abnormalities. New genetic approaches, including mutation analysis, now allow identification of carriers of the TRPS1 gene mutations.

[Successful treatment of angiosarcoma with liposomal-encapsulated doxorubicin]. / Erfolgreiche Therapie eines Angiosarkoms mit liposomal verkapseltem Doxorubizin.

Cutaneous angiosarcoma is a rare tumor of endothelial origin, often difficult to diagnose and with an unfavorable prognosis. A 85-year-old woman presented with an extensive angiosarcoma involving her right leg. The tumor was not clinically typical but the diagnosis was confirmed histologically. Because of her age and the extent of the tumor, we elected to treat primarily with cobalt-60 irradiation. The tumor unfortunately progressed during radiation therapy, so we decided to begin palliative chemotherapy with liposome-encapsulated doxorubicin. The patient received six cycles of doxorubicin (Caelyx, 15 mg/m(2) i.v. in four-week intervals) which was well-tolerated and led to complete regression of angiosarcoma which has lasted for 6 months. Chemotherapy with liposome-encapsulated doxorubicin may represent a well-tolerable therapeutic option in cases where surgery and irradiation are not possible or fail. Further studies are necessary to prove the efficacy of doxorubicin therapy in angiosarcoma.

Linear variant of chronic cutaneous lupus erythematosus: a clue for the pathogenesis of chronic cutaneous lupus erythematosus?

Lesions of chronic cutaneous lupus erythematosus usually occur in a discoid pattern as erythematous, well-defined, scaly patches affecting face and scalp. The linear variant of chronic cutaneous lupus erythematosus is an exceptional clinical variation with band-like arranged lesions along the lines of Blaschko which represent the developmental growth pattern of embryonic ectodermal cells. Therefore, this unusual clinical observation may provide additional clues for the pathogenesis of chronic cutaneous lupus erythematosus. It is intriguing to hypothesize that linear lesions of chronic cutaneous lupus erythematosus may be caused by increased susceptibility of resident skin cells due to mutations of genes in early embryogenesis.

Rituximab in autoimmune bullous diseases: mixed responses and adverse effects.

BACKGROUND: Intolerably high doses of systemic corticosteroids and additional immunosuppressants may be required to control disease activity in autoimmune bullous skin diseases. New therapeutic options are needed for such patients. OBJECTIVES: To determine the efficacy and adverse effects of adjuvant rituximab. METHODS: Seven patients with refractory autoimmune blistering diseases (pemphigus vulgaris, PV, n = 4; bullous pemphigoid, BP, n = 2; mucous membrane pemphigoid, MMP, n = 1) were treated four times with rituximab at an individual dose of 375 mg m(-2) at weekly intervals. RESULTS: All lesions cleared in three patients (two PV, one BP), while they were reduced by more than 50% in three others (two PV, one BP). The concomitant immunosuppressive medication was reduced in five patients (four PV, one BP). The patient with MMP developed bilateral blindness while nasopharyngeal lesions resolved. Three patients (two BP, one PV) experienced severe adverse events including fatal pneumonia. CONCLUSIONS: Adjuvant B-cell depletion by rituximab is effective in otherwise therapy-resistant bullous autoimmune disorders but may be associated with substantial adverse effects including fatal outcomes.

Congenital brachydactyly and nail hypoplasia: clue to bone-dependent nail formation.

Congenital hyponychia and anonychia are rare malformations which may form part of syndromes such as nail-patella syndrome, ectodermal dysplasias and brachydactylies, or may occur as an isolated finding. Congenital hyponychia and anonychia are frequently accompanied by underlying skeletal abnormalities. A 20-year-old woman showed congenital bilateral hypoplasia or aplasia of the second, third and fourth toenails with corresponding phalanx dysplasia or aplasia of the affected toes. Malformations of the hands or other congenital defects were absent. The findings in this patient do not exactly fit any known entities. Our clinical observation prompted us to review the literature on congenital hyponychia/anonychia and to summarize recent advances in understanding molecular events in nail development. In conclusion, the association of nail anomalies with aplasia and/or hypoplasia of corresponding middle and/or distal phalanges supports the hypothesis of bone-dependent nail formation.

Coexpression of heat-shock protein 60 and intercellular-adhesion molecule-1 is related to increased adhesion of monocytes and T cells to aortic endothelium of rats in response to endotoxin.

Bacterial cell-wall lipopolysaccharide (LPS) is the main endotoxin contributing to local inflammation and systemic toxicity during Gram-negative infections and induces aortic endothelial injury with or without cell death and replication followed by increased leukocyte adhesion. Heat-shock protein (hsp) 60 is under study in our laboratory as a potential antigen inducing immunologic attack to endothelial cells in atherogenesis. To investigate the mechanism of LPS-induced endothelial injury and the phenotypes of adhering cells, Lewis rats were treated in vivo or, in aortic organ cultures, with LPS to determine the expression of intercellular-adhesion molecule-1 (ICAM-1) and hsp60 on aortic endothelium and to characterize phenotypes of adhering leukocytes. Increased ICAM-1 expression by aortic endothelium was observed as early as 3 hr after LPS injection and persisted up to 72 hr, whereas elevated levels of hsp60 were found between 6 and 48 hr. In vitro application of various types of stress, such as LPS, H2O2, and high temperature, not only stimulated endothelial expression of hsp60 but, concomitantly, that of ICAM-1. The number of adhering leukocytes was significantly increased on aortic endothelium 6 hr after LPS administration, and the predominant leukocytes adhering to stressed endothelium were monocytes (80%) and T lymphocytes (8 to 20%). In organ cultures of rat aortic intimal, LPS, and H2O2 evoked increased leukocyte adhesion, which proved to be selective, because adherent leukocytes were mostly Ia+ monocytes and T cells, i.e., activated. Adhering T cells were gamma/delta antigen-receptor positive in 8 to 16% after LPS stress, whereas these cells amount to only 2 to 4% of peripheral blood T cells. Blocking of adhesion molecules ICAM-1, LFA-1 alpha, and/or LFA-1 beta reduced adhesion up to 34%. Increased coordinated LPS-dependent expression of hsp60 and ICAM-1 correlates with monocyte and T-cell adhesion to aortic endothelium. These observations may be significant for elucidating the mechanism of the initiating events in the development of atherosclerosis.

Surface staining and cytotoxic activity of heat-shock protein 60 antibody in stressed aortic endothelial cells.

Heat-shock protein (hsp) expression can be induced by high temperature, exposure to cytokines or oxygen radicals, ischemia, hemodynamic overload, or viral infections. To determine whether surface expression of hsp60 occurs in aortic endothelial cells stressed by high temperature or cytokines, cells from rat aortas were cultivated and stained with several types of monoclonal antibodies against hsp60. Other antibodies, eg, those against intercellular adhesion molecule-1 (ICAM-1), or immune response-associated antigens were also used as controls. Positive staining of endothelial cells on the surface and in the cytoplasm was observed after pretreatment of the cells with cytokine-containing medium, tumor necrosis factor-alpha (TNF-alpha), or interleukin-1 alpha and labeling with a specific monoclonal antibody against hsp60 (II-13). Fluorescence-activated cell sorter analyses showed that over 80% of living endothelial cells stressed by cytokine-containing medium, by TNF-alpha, or at 42 degrees C, but not by interleukin-1 alpha, were positively surface stained with this antibody. Increased intensity of immunostaining with antibodies to ICAM-1 and immune response-associated antigen was also seen on the cytokine-stressed endothelial cells. Furthermore, when TNF-alpha stimulated endothelial cells labeled with 51Cr were incubated with antibody II-13 in the presence of complement, significant lysis occurred. In summary, endothelial cells stressed by high temperature or certain cytokines, eg, TNF-alpha, express hsp60 in the cytoplasm and on their surfaces, and these cells were susceptible to complement-dependent lysis by hsp60-specific antibody. These observations may be significant for elucidating the mechanisms of the involvement of immune reactions to hsp65/60 in initiating atherosclerosis.