Molecular biologic and scintigraphic analyses of somatostatin receptor-negative meningiomas.

UNLABELLED: Somatostatin receptor scintigraphy (SRS) using 111In-octreotide has proven useful in the preoperative discrimination of expansive central nervous system lesions. Meningiomas, generally expressing human somatostatin receptor (hsst) on their surface, were detected with a sensitivity of about 100%. This finding was associated with the assumption that meningiomas lack an intact blood-brain barrier. However, this exclusion procedure became questionable when histologically proven meningiomas in which SRS was negative were reported. Therefore, the aim of this study was to discover why these meningiomas gave negative SRS results. METHODS: Before surgery, 46 patients with 47 meningiomas underwent standard MRI and SRS. Thirty-four of these patients with 35 tumors were also examined by 99mTc-diethylenetriaminepentaacetic acid (DTPA) brain scintigraphy. After surgical resection, hsst subtype 2 (hsst2) messenger RNA (mRNA) expression of 4 SRS-positive and 4 SRS-negative meningiomas was estimated semiquantitatively by reverse transcriptase polymerase chain reaction (RT-PCR). Translation of hsst2 mRNA into receptor proteins was proven immunocytochemically on the surface of 1 SRS-positive and 1 SRS-negative meningioma. Tumor specimens used for RNA extraction and RT-PCR and cultivated cells used for hsst2 immunostaining were tested for their meningioma nature by immunochemistry. RESULTS: SRS yielded positive results in 39 meningiomas with a tumor volume of 24.1 +/- 32.8 mL and negative results in 8 meningiomas with a volume of 3.9 +/- 6.5 mL. 99mTc-DTPA scintigraphy visualized 24 of 35 meningiomas. SRS was positive in all of them. In contrast, 11 meningiomas were (99mTc-DTPA negative. In these meningiomas, SRS was negative in 5 cases (5.4 +/- 8.1 mL), whereas the remaining 6 were positive (4.6 +/- 4.5 mL). None of the meningiomas was 99mTc-DTPA positive and SRS negative. RT-PCR revealed no significant difference of hsst2 mRNA expression between SRS-positive and SRS-negative meningiomas but showed varied expression among all meningiomas regardless of SRS results. Furthermore, hsst2 proteins were visualized immunocytochemically on the surface of cultivated cells of SRS-positive and SRS-negative meningiomas. CONCLUSION: SRS-negative meningiomas do express hsst2; thus, in these meningiomas SRS is false-negative. Because an insufficient sensitivity was excluded, 99mTc-DTPA scintigraphy identified a permeability barrier in SRS-negative meningiomas that explains their false-negative SRS results. SRS-negative meningiomas most likely meet the function of their tissue of origin (the meninges) to develop more-or-less intact permeability barriers.

Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept.

Using atomic absorption spectrum analysis, we found iron levels in exudates from chronic wounds to be significantly increased (3.71 +/- 1.56 micromol per g protein) compared to wound fluids from acute wounds derived from blister fluids (1.15 +/- 0.62 micromol per g protein, p < 0.02), drainage fluids of acute wounds (0.87 +/- 0.34 micromol per g protein, p < 0.002), and pooled human plasma of 50 volunteers (0.42 micromol per g protein). Increased free iron and an increase in reactive oxygen species released from neutrophils represent pathogenic key steps that --via the Fenton reaction - are thought to be responsible for the persistent inflammation, increased connective tissue degradation, and lipid peroxidation contributing to the prooxidant hostile microenvironment of chronic venous leg ulcers. We herein designed a selective pick-up dressing for iron ions by covalently binding deferoxamine to cellulose. No leakage occurred following gamma sterilization of the dressing and, more importantly, the deferoxamine-coupled cellulose dressing retained its iron complexing properties sufficient to reduce iron levels found in chronic venous ulcers to levels comparable to those found in acute wounds. In order to study the functionality of the dressing, human dermal fibroblasts were exposed to a Fenton reaction mimicking combination of 220 microM Fe(III) citrate and 1 mM ascorbate resulting in a 4-fold induction of matrix-degrading metalloproteinase 1 as determined by a matrix-degrading metalloproteinase 1 specific enzyme-linked immunosorbent assay. This induction was completely suppressed by dissolved deferoxamine at a concentration of 220 microM or by an equimolar amount of deferoxamine immobilized to cellulose. In addition, the Fe(III) citrate and ascorbate driven Fenton reaction resulted in an 8-fold increase in malondialdehyde, the major product of lipid peroxidation, as determined by high pressure liquid chromatography. This increase in malondialdehyde levels could be significantly reduced in the presence of the selective pick-up dressing coupled with deferoxamine suggesting that the deferoxamine dressing, in fact, prevents the development of a damaging prooxidant microenvironment and also protects from unfavorable consequences like matrix-degrading metalloproteinase 1 and lipid peroxide induction.

Adaptive antioxidant response protects dermal fibroblasts from UVA-induced phototoxicity.

In response to the attack of reactive oxygen species (ROS) produced upon UV irradiation, the skin has developed a complex antioxidant defense system. Here we report that, in addition to the previously published induction of manganese superoxide dismutase (MnSOD) activity, single and, to a higher extent, repetitive low-dose UVA irradiation also leads to a substantial upregulation of glutathione peroxidase (GPx) activity. This concomitant adaptive response of two antioxidant enzymes acting in the same detoxification pathway coincided with the protection from high-UVA-dose-induced cytotoxicity conferred by low-dose UVA preirradiation. Whereas an interval of 24 h did not, an interval of 12 h did lead to the induction of MnSOD activity and, under selenium-supplemented conditions, of GPx activity as well, conferring definite cellular protection from UVA-induced phototoxicity. Moreover, under selenium-deficient conditions, which abrogate the UVA-mediated induction of GPx activity, adaptive protection against the cytotoxic effects of high UVA doses was significantly lower compared with selenium supplementation. Isolated 4.6-fold overexpression of MnSOD activity in stably transfected fibroblasts led to specific resistance from UVA-mediated phototoxicity under selenium-deficient conditions. Collectively, these data indicate that the concomitant induction of MnSOD and GPx activity is related to the optimal adaptive protection from photooxidative damage. This adaptive antioxidant protection clearly depends on the irradiation interval and a sufficient selenium concentration, findings that may have important implications for the improvement of photoprotective and phototherapeutic strategies in medicine.

Treatment of pruritus by capsaicin in a patient with pityriasis rubra pilaris receiving RE-PUVA therapy.

Pityriasis rubra pilaris (PRP) is characterized by redness of the skin, scaling and a variable degree of pruritus. We present a patient with extremely itchy PRP successfully treated with oral retinoids and photochemotherapy with 8-methoxypsoralene (RE-PUVA) and topical capsaicin. The PRP-related pruritus which clearly preceded photochemotherapy and for which no other cause was apparent was relieved with capsaicin. This single case report provides evidence that topical capsaicin may be a useful therapeutic option in treating PRP-associated pruritus where antihistamines have been unsuccessful.

The first peak of the UVB irradiation-dependent biphasic induction of vascular endothelial growth factor (VEGF) is due to phosphorylation of the epidermal growth factor receptor and independent of autocrine transforming growth factor alpha.

Ultraviolet B (UVB) irradiation, the major damaging component of sunlight, has earlier been reported to enhance cutaneous angiogenesis in chronically sun-exposed skin. We herein provide first evidence for a biphasic induction of the vascular endothelial growth factor (VEGF) following UVB irradiation of the human epidermal cell line HaCaT. The first VEGF peak occurred on mRNA level at 1 h and on protein level at 4 h postirradiation and is fully mediated by the UVB-dependent phosphorylation of the epidermal growth factor receptor, which subsequent to its phosphorylation also initiates at least in part the synthesis of transforming growth factor alpha that confers as shown previously the second late VEGF peak at 8 h on mRNA and at 24 h on protein level.

Photoaging of the skin from phenotype to mechanisms.

The skin is increasingly exposed to ambient UV-irradiation thus increasing its risk for photooxidative damage with longterm detrimental effects like photoaging, which is characterized by wrinkles, loss of skin tone, and resilience. Photoaged skin displays prominent alterations in the cellular component and the extracellular matrix of the connective tissue with an accumulation of disorganized elastin and its microfibrillar component fibrillin in the deep dermis and a severe loss of interstitial collagens, the major structural proteins of the dermal connective tissue. The unifying pathogenic agents for these changes are UV-generated reactive oxygen species (ROS) that deplete and damage non-enzymatic and enzymatic antioxidant defense systems of the skin. As well as causing permanent genetic changes, ROS activate cytoplasmic signal transduction pathways in resident fibroblasts that are related to growth, differentiation, senescence, and connective tissue degradation. This review focuses on the role of UV-induced ROS in the photodamage of the skin resulting in biochemical and clinical characteristics of photoaging. In addition, the relationship of photoaging to intrinsic aging of the skin will be discussed. A decrease in the overall ROS load by efficient sunscreens or other protective agents may represent promising strategies to prevent or at least minimize ROS induced photoaging.