[ANCA-positive vasculitis of the skin and kidneys associated with acne conglobata]. / cANCA-positive Vaskulitis der Haut und Nieren im Verlauf einer Acne vulgaris conglobata.

A 19 year old man with severe acne conglobata and ulcerated pyoderma gangraenosum-like skin lesions on the face was first treated with isotretinoin (Roaccutan((R))), then immunosuppressively with prednisolone, diaminodiphenylsulfone (Dapson-Fatol((R))) and mycophenolate mofetil (Cellcept((R))). Under a daily maintenance dose of immunosuppressive treatment with 2.5 mg prednisolone and 1 g mycophenolate mofetil, weakness, muscle and joint aches appeared. Due to proteinuria, haematuria and an elevated antineutrophil cytoplasmic antibody (cANCA) and the histological detection of a leukocytoclastic vasculitis, the diagnosis of cANCA positive vasculitis of the skin and kidneys was established. Therapy with cyclophosphamide (Endoxan((R))) along with prednisolone was effective. An exact classification of this disease process was not possible.

Systemic sclerosis-related Raynaud's phenomenon: effects of iloprost infusion therapy on serum cytokine, growth factor and soluble adhesion molecule levels.

Microvascular damage occurs in systemic sclerosis and is associated with increased serum levels of endothelial adhesion molecules and endothelium-associated cytokines, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, endothelin-1 and vascular endothelial growth factor (VEGF). Iloprost, a prostacyclin analogue, induces clinical benefit in patients suffering from scleroderma-related Raynaud's phenomenon. This study was performed to investigate the effect of iloprost infusions on endothelium activation. Serum samples from 12 patients with systemic sclerosis were examined using specific enzyme-linked immunoassays. The serum levels of sICAM-1, sVCAM-1 and soluble E-selectin were initially elevated and significantly reduced after iloprost infusions. The serum concentrations of VEGF and endothelin-1 revealed decreased levels after therapy too. These results indicate that the well-known clinical benefit of iloprost infusions on Raynaud's phenomenon is serologically detectable by a reduction of serum levels of endothelium-associated adhesion molecules, cytokines and growth factors reflecting an improvement in endothelial function.

Cutaneous breast angiosarcoma after conserving treatment of breast cancer.

Cutaneous angiosarcoma is a rare malignancy that sometimes occurs as a late sequela of breast conservation therapy. We report on a 79-year-old female who developed well-differentiated angiosarcoma in a lymphedematous left breast 5.5 years after surgery and radiotherapy for early invasive ductal breast cancer. The initial appearance was very similar to late radiation dermatitis, and histologically interpreted as scar tissue with atypical vascular lesion. The lesion progressed further, and was clinically suspicious for angiosarcoma. Thus, a second biopsy was taken which confirmed the diagnosis. A complete mastectomy removed all the tumor with clear margins. However, within a period of 16 months she presented four local recurrences which were treated by wide local excision. At present, the patient is free of locally recurrent tumour for 7 months. The few cases of breast angiosarcoma after breast conservation therapy reported so far demonstrate that these lesions are difficult to diagnose due to their rarity and their highly variable and benign appearance, which sometimes may mimic radiation-induced cutaneous changes. Since chronic lymphedema possibly contributes to the development of angiosarcoma, long-term clinical surveillance of these patients is recommended. Biopsies should be taken if new skin lesions occur.

Circadian rhythms in microalgae.

Circadian rhythms have been described in a variety of microalgae. In each group, some model organisms arose and most detailed studies have been done with them. They include the cyanobacterium ("blue-green alga") Synechococcus and eukaryotic microalgae Gonyaulax polyedra (Dinophyta), Chlamydomonas reinhardtii (Chlorophyta), and Euglena gracilis (Euglenophyta). This review focuses on recent approaches to depict molecular components of the circadian system and the mechanisms of regulation in these organisms. In Synechococcus, the identification of the kailocus, which represents a central part of its oscillatory system, is discussed, as well as diverse approaches based on a luminescent reporter gene, which is driven by a clock-controlled cyanobacterial promoter. In eukaryotic microalgae, the diversity of genes/proteins that are controlled by the circadian clock is described and the kind of regulation (transcriptional and translational control) is emphasized. The role and function of conserved clock-controlled RNA-binding proteins such as CCTR from Gonyaulaxor Chlamy 1 from Chlamydomonas are discussed.

Identification of target mRNAs for the clock-controlled RNA-binding protein Chlamy 1 from Chlamydomonas reinhardtii.

An endogenous clock regulates the temporal expression of genes/mRNAs that are involved in the circadian output pathway. In the green alga Chlamydomonas reinhardtii, a clock-controlled RNA-binding protein (Chlamy 1) was identified recently, which represents an analog of the circadian trans-acting factor CCTR from the phylogenetically diverse alga Gonyaulax polyedra. In order to identify in C. reinhardtii target mRNAs that can be recognized by Chlamy 1, gel mobility-shift assays and UV-crosslinking experiments were carried out, and revealed that this protein interacts specifically with the 3' untranslated regions of several mRNAs and recognizes them all via a common cis-acting element, composed of at least seven UG repeats. By using competition assays, it was found that the affinity of Chlamy 1 is highest for mRNAs whose products are key components of nitrogen and CO2 metabolism. Since the activities of enzymes involved in nitrogen metabolism vary in a temporal pattern that is opposite in phase to that of Chlamy 1 binding activity, the protein may repress the translation of the cognate mRNAs.

Acute hypercalcemia of the heart ("bony heart").

Cardiac abnormalities as a sign of hyperparathyroidism are common. A spectacular pitfall of peracute extended myocardiac hypercalcemia is reported. The history of a 30-year-old woman included symptoms such as insufficiency of the kidneys since childhood, secondary hyperparathyroidism, and hemodialysis for approximately 4 years. After kidney transplantation, the patient died from progressive heart failure. Three days before she died, CT showed a nearly white heart, and myocardial scintigraphy revealed a total infarction. The autopsy revealed a heart of normal size but with a weight of 590 g and with nearly bony texture. The histologic examination showed extended calcifications of the entire myocardium, thus explaining these findings. Laboratory photographs and electron microscopic images will be demonstrated. The metabolic pathogenesis of tertiary hyperparathyroidism and calciphylaxis is discussed. "Malignant" progression after kidney transplantation is stressed.

[Livedo racemosa with ulcerations. Cyclic therapy with iloprost infusions]. / Livedo racemosa mit Ulzerationen. Zyklische Therapie mit Iloprost (Ilomedin)-Infusionen : Zyklische Therapie mit Iloprost (Ilomedin)-Infusionen.

A 43 year old woman suffered from an intermittent painful livedo racemosa at the back since her childhood. Her clinical course was complicated by ulcerations. In careful clinical investigations no signs of an underlying disease could be found, in particular a Sneddon syndrome could be excluded. By means of both conservative and surgical treatments, initial healing of the ulcerations was achieved but relapses occurred. Cyclic infusions of iloprost achieved long-term clearing of the ulcerations and disappearance of the pain. To the best of our knowledge the effectiveness of this treatment has not been described for this disease in the literature.

A novel function of yeast fatty acid synthase. Subunit alpha is capable of self-pantetheinylation.

The prosthetic group of yeast fatty acid synthase (FAS), 4'-phosphopantetheine, is covalently linked to Ser180 of subunit alpha. It originates from coenzyme A and is transferred to the enzyme by a specific phosphopantetheine:protein transferase (PPTase). The present study demonstrates that the FAS-activating PPTase of yeast represents a distinct catalytic domain of the FAS complex and resides within the C-terminal portion of subunit alpha. The autoactivation capacity of yeast FAS became evident from in vitro pantetheinylation studies using purified apo-FAS preparations. These were readily converted to pantetheinylated holo-FAS simply upon addition of free coenzyme A. Pantetheinylation-competent apo-FAS was prepared in vitro by constructing hybrid oligomers containing alpha-subunits from two different pantetheine-less FAS-mutants. The respective mutants were selected according to their ability to complement each other, in vivo. In vitro formation of hybrid apo-FAS complexes was achieved by dimethylmaleic anhydride (DMMA) -induced reversible dissociation of mixtures of the two constituent mutant enzymes. This treatment was both necessary and sufficient to produce pantetheinylation-competent apo-FAS. Specific FAS activities were comparable independent of whether the apo-enzymes were pantetheinylated in vivo or in vitro. Apart from the induction of overall FAS activity, incorporation of phosphopantetheine into apo-FAS was also demonstrated by the use of 3H-labelled coenzyme A, leading to the formation of radioactively labelled FAS. It is concluded that pantetheinylation of yeast FAS is performed by an intrinsic catalytic activity of the apo-enzyme proper. The endogenous PPTase acts in trans between different subunits alpha in the alpha6beta6 oligomer. The self-pantetheinylation of yeast FAS represents the first example of an apo-enzyme being capable of post-translational autoactivitation.

Fibroblasts surrounding melanoma express elevated levels of matrix metalloproteinase-1 (MMP-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro.

Tumour growth and metastasis involve the degradation of extracellular matrix components by matrix degrading enzymes produced by tumour cells and stromal fibroblasts. In this study, fibroblasts were obtained from biopsies on the border (TB) and 1 cm distant from the melanoma (TD) and cultured separately. Similar studies were performed with fibroblasts surrounding melanocytic nevi as control. The expression of matrix metalloproteinase-1 (MMP-1) mRNA and tissue matrix metalloproteinase inhibitor 1 (TIMP-1) were studied by Northern blot analysis. The activation antigen intercellular adhesion molecule-1 (ICAM-1) in TB-and TD-fibroblasts was investigated by flow cytometry. In melanoma, TB-fibroblasts showed an increased expression of MMP-1 mRNA mainly in fibroblasts obtained from tumours with extended invasive growth demonstrated by Clark level whereas the expression of the major specific inhibitor TIMP-1 was unaltered. In contrast, fibroblasts surrounding benign melanocytic nevi did not express elevated levels of MMP-1. The upregulation of MMP-1 in TB-fibroblasts compared to TD-fibroblasts was maintained during cultivation. Furthermore, MMP-1 mRNA expression and MMP-1 total protein amount in normal fibroblasts were increased by melanoma cell conditioned medium. We demonstrated an increased expression of ICAM-1 in TB-fibroblasts compared to TD-fibroblasts in vitro depending on the amount of inflammatory infiltrate in situ. The differences of ICAM expression disappeared during continued cell culture. These results support the idea that fibroblasts surrounding melanoma are activated and are possibly involved in the degradation of matrix proteins surrounding the tumour.

[Progressive systemic scleroderma--prognosis determining involvement of internal organ systems]. / Die progressive systemische Sklerodermie--prognosebestimmender Befall innerer Organsysteme.

Prognosis of systemic sclerosis (scleroderma, Ssc) is largely depending on involvement of internal organs. Abnormalities of the gastrointestinal tract are found most frequently (85%), especially decreased motility of the oesophagus, which has little impact on the longterm clinical course of Ssc. Pulmonary manifestations can be demonstrated in 40-90% of patients; one must distinguish between pulmonary hypertension or fibrotic lung disease. The heart is affected in 50% of cases. Patchy or diffuse myocardial fibrosis, as well as pericarditis and pericardial effusions can induce symptoms of arrhythmia or congestive heart failure. Renal involvement is associated with increased mortality and occurs in 45% of Ssc, producing proteinuria, hypertension, scleroderma renal crisis and renal failure. In conclusion, involvement of the lungs, heart and kidneys are determining factors for the longterm course of systemic sclerosis.

Serum levels of soluble Fas/APO-1 receptor are increased in systemic sclerosis.

It has been suggested that rheumatic diseases may result from a deficit in Fas-mediated T-cell apoptosis. Recent studies have demonstrated increased soluble Fas in sera from lupus erythematosus patients. We were interested to determine whether elevated soluble Fas levels are associated with systemic sclerosis. Soluble Fas levels were retrospectively assayed using a sandwich enzyme-linked immunosorbent assay in serum from 30 patients with systemic sclerosis and 15 normal controls. Hospital medical records were retrospectively reviewed for clinical and laboratory characteristics of the patients. Soluble Fas levels were analysed in subsets of patients with limited (lcSSc) versus diffuse cutaneous systemic sclerosis (dcSSc) and correlated with inflammatory activity. In systemic sclerosis soluble Fas serum levels (lcSSc, 2.19 +/- 0.71 ng/ml, dcSSc 2.53 +/- 1.37 ng/ml) were significantly higher than in normal controls (1.26 +/- 0.36 ng/ml). However, there were no significant differences in soluble Fas levels between lcSSc and dcSSc and poor correlation between soluble Fas levels and inflammatory activity status. Detection of elevated soluble Fas might serve as a clinical marker for immunological dysregulation in systemic sclerosis, but not for inflammatory disease activity.

[Grönblad-Strandberg syndrome from the angiological viewpoint]. / Das Grönblad-Strandberg-Syndrom aus angiologischer Sicht.

HISTORY AND CLINICAL FINDINGS: A 42-year-old man was admitted for treatment of peripheral vascular disease in the left leg (stage III of Fontaine). A year before he had undergone a right aortofemoral bypass operation. On admission there was stenosis of the left pelvic axis and bilateral femoral artery occlusion. In addition there were changes in the skin with abnormal folds, loss of elasticity and yellowish spots over the sides of the neck and the flexor surfaces of all large joints. In addition vision in the left eye was impaired. These findings suggested connective tissue disease involving the skin, eye and arterial system. INVESTIGATIONS: Routine haematological tests were normal as were clotting parameters. Serum concentration of GOT, GPT, gamma-GT were slightly increased. There was a dysproteinaemia with raised HDL and LDL levels. Resting electrocardiogram was normal, showing sinus rhythm and left axis deviation. The crurobrachial pressure index was clearly abnormal: 0.6 on the right and 0.5 on the left. Angiography of the pelvic and left arteries revealed long-segment femoral and partial lower-leg occlusions bilaterally. Abdominal sonography indicated diffuse parenchymal calcifications in both kidneys and angioid streaks on bilateral fundoscopy. Skin biopsy showed defects of elastic fibres and perivascular inflammatory infiltration, while capillary microscopy revealed twisting of the capillaries, most of them with normal lumen. These findings taken together indicated pseudoxanthoma elasticum (PXE) or Grönblad-Strandberg syndrome. TREATMENT AND COURSE: A thrombendarterectomy was performed on the left superficial femoral artery, after which the left popliteal artery became palpable, the pressure indices for the left leg were slightly better, and the patient was discharged home without further complications and improved leg perfusion. CONCLUSION: Possible cardiovascular involvement had to be taken into account in patients with PXE, and long-term angiological monitoring is indicated.

The mRNA level of the circadian regulated Gonyaulax luciferase remains constant over the cycle.

The expression of luciferin-binding protein (LBP) and luciferase (LCF), two proteins that are involved in bioluminescence in Gonyaulax polyedra, is controlled by a cellular circadian clock. In the case of LBP, its temporal expression is reported to be regulated at the translational level, involving both 5' and 3' untranslated regions (UTRs) of lbp mRNA. Here, we show that the amounts of lcf mRNA are constant throughout the day-night cycle, indicating that the circadian expression of LCF is also regulated at the translational level.