Sporotrichosis: success of itraconazole treatment

An 82-year-old man with hypothyroidism presented with an ulcerated nodule on the dorsum of his left hand (Figure 1). The lesion had been present for about 3 months. Similar lesions were present along the lymphatic distribution of the dorsum of his left forearm, proximal to the first lesion, as well as the dorsum of his right forearm. Laboratory findings were normal. Immune complexes, complement 3, and complement 4 were negative. A biopsy from an ulcerated nodule was taken for both histologic examination and culture. Hematoxylin and eosin sections showed a nonspecific chronic granulomatous reaction. No fungi were detected by periodic acid-Schiff stain and methenamine silver stain. Culture of tissue obtained from a skin biopsy of 1 lesion placed directly on Sabouraud agar produced colonies of Sporothrix schenckii (Figure 2). The diagnosis of lymphocutaneous sporotrichosis was confirmed.     

Inhibition of tyrosine-kinase-mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis

BACKGROUND: The effects of the tyrosine kinase inhibitors, tyrphostin AG126 and AG556 in a murine model of acute pancreatitis are investigated. METHODS: Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis as well as elevation in the serum activities of amylase or lipase. RESULTS: Infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with signs of enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination showed a marked increase in immunoreactivity for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) in the pancreas of cerulein-treated mice. Pretreatment or posttreatment with tyrphostin AG126 and AG556, 2 different tyrosine kinase inhibitors, significantly reduced the degree of pancreatic inflammation and tissue injury (histologic score). In particular, the treatment with the 2 tyrosine kinase inhibitors reduced the cerulein-induced nitrotyrosine formation and PARP activation in the pancreas as well as the systemic release of tumor necrosis factor alpha. CONCLUSIONS: This study provides the first evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of acute pancreatitis, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of acute pancreatitis.     

Uptake of Malassezia furfur by human dermal fibroblasts: effect of ketoconazole and cytoskeleton inhibitors

Abstract We showed the ability of human dermal fibroblasts to take up Malassezia furfur and the effect of ketoconazole and cytoskeleton inhibitors, including cytochalasin D and colchicine, on invasivity. Engulfment was evaluated by May Grunwald Giemsa stain and confirmed by acridine orange staining and electron microscopy. Both revealed the different steps of engulfment, including a fusion event between lysosomes and phagosomes containing M. furfur. Subinhibitory concentrations of ketoconazole (5 μg/ml) reduced the invasive capacity compared to controls (52.0 ± 6.3 vs 10.0 ± 1.2). M. furfur induced changes in the cytoskeleton of human dermal fibroblasts, with signs of disaggregation of actin fibres. We also studied the effect of the cytoskeleton inhibitors, cytochalasin D (1 μg/ ml) and colchicine (1 μg/ml), on engulfment. Cytochalasin D, an inhibitor of actin polymers, inhibited the uptake of M. furfur by human dermal fibroblasts. Colchicine, a microtubule inhibitor, reduced the uptake of M. furfur less markedly. This suggests that the process of engulfment is F-actin-dependent, but the integrity of microtubules is also important in “non-professional” phagocytic cells such as dermal fibroblasts. Received: 25 May 2000 / Revised: 26 January 2001 / Accepted: 12 May 2001     

Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to heterozygous mutations in one of the three fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Hypofibrinogenemic patients are usually asymptomatic, whereas individuals bearing similar mutations in the homozygous or compound heterozygous state develop a severe bleeding disorder: afibrinogenemia. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations affecting fibrinogen assembly or secretion, distributed throughout the 50-kb fibrinogen gene cluster. In this study, we report the mutational screening of two unrelated hypofibrinogenemic patients leading to the identification of two missense mutations, one hitherto unknown (αCys45Phe), and one previously described (γAsn345Ser). The involvement of αCys45Phe and γAsn345Ser in the pathogenesis of hypofibrinogenemia was investigated by in-vitro expression experiments. Both mutations were demonstrated to cause a severe impairment of intracellular fibrinogen processing, either by affecting half-molecule dimerization (αCys45Phe) or by hampering hexamer secretion (γAsn345Ser).     

Evaluating the landscape of gene cooperativity with receptor tyrosine kinases in liver tumorigenesis using transposon-mediated mutagenesis

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