Hemophagocytic syndrome associated with hypercytokinemia in a patients with rheumatoid arthritis]

A 65-year old female, who had been suffered from rheumatoid arthritis, was admitted to our hospital because of fever, oral ulcers, perianal skin ulcers, petechiae in the both legs, hepatosplenomegaly and cervical lymphadenopathy. Her laboratory data showed severe anemia, leukocytopenia, and thrombocytopenia as well as low PT activity, prolonged APTT, decreased fibrinegen and elevated FDP. In addition to raised values of liver enzymes and triglyceride, marked elevation of several cytokines were found. IgM and IgG class antibodies to cytomegalovirus were demonstrated positive and their titers were 2.60 and 938.0, respectively. The study for the aspiration of bone marrow revealed hemophagocytosis of erythrocytes, leukocytes and thrombocytes. Based upon these findings, she was diagnosed as having hemophagocytic syndrome associated with cytomegalovirus infection. Steroid treatment inducing mini-pulse therapy was introduced to her and bought full recovery from the illness. The association of hemophagocytic syndrome to rheumatoid arthritis was reviewed in the literature and five cases were documented to have good prognosis with steroid treatment.     

Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy

Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of “idiopathic” cardiomyopathy. Recent molecular genetic analyses have now revealed that “idiopathic” cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy-associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.     

Concurrent occurrence of allergic granulomatous angiitis and temporal arteritis: a case report and review of the literature

Allergic granulomatous angiitis (AGA) is a disease entity that was first distinguished from classical polyarteritis nodosa by Churg and Strauss in 1951, and is characterized by the clinical features of allergic rhinitis or bronchial asthma, eosinophilia, and vasculitis. Allergic granulomatous angiitis has been described to mainly involve small vessels. We herein describe a case of Churg–Strauss syndrome which demonstrated the clinical and laboratory findings supporting a diagnosis of AGA and was also associated with the clinical and pathological findings for temporal arteritis, which was characterized by eosinophil infiltration and granuloma formation of the temporal artery (middle-sized vessel).     

Subconjunctival administration of bucillamine suppresses choroidal neovascularization in rat

PURPOSE: Bucillamine is an antirheumatic drug with antiangiogenic properties that is currently used in clinical practice. Because bucillamine inhibits the production of VEGF, it is possible that this drug may inhibit choroidal neovascularization (CNV). Thus, the effect of bucillamine on the eyes of rats with experimental CNV was investigated in vivo by subconjunctival injection or oral intake. METHODS: CNV was induced in rat eyes by diode laser photocoagulation. The intensity of fluorescein leakage from the photocoagulated lesions was studied 7 and 14 days after photocoagulation. The areas of CNV lesions were measured histologically and studied immunohistochemically at days 4, 7, and 14. In addition, the concentration of the drug in ocular tissue and blood was measured by high-performance liquid chromatography-tandem mass spectrometry after the drug was delivered orally or subconjunctivally. RESULTS: After subconjunctival injection, fluorescein leakage from the CNV lesions decreased significantly compared with the control eyes throughout the study period. Histologic and immunohistochemical analyses 4, 7, and 14 days after photocoagulation demonstrated that the average size of the CNV lesions was reduced in the bucillamine-treated eyes compared with the control eyes. Subconjunctival injection maximized the ocular drug concentration while minimizing the blood concentration of the drug compared with oral intake. CONCLUSIONS: Subconjunctival injection of bucillamine significantly reduced the leakage and size of experimental CNV. These results suggest that bucillamine may be beneficial in treating CNV and that further studies can be considered to evaluate this possibility.     

Analysis of cyclin D1 and CDK expression in colonic polyps containing neoplastic foci: a study of proteins extracted from paraffin sections

Overexpression or amplification of G1 cyclins has been demonstrated in various types of human cancers. Overexpression of cyclin D1, an accelerator of cell cycle, is thought to be an early event in colonic multistage carcinogenesis, but its expression at transformation from benign to neoplastic foci is not clear. We analyzed the expression of cyclin D1 and its catalystic partner CDK4 in colon polyps containing neoplastic foci. For direct comparison of the expression in adenomatous tissues and neoplastic foci, proteins in adequate amounts were extracted from paraffin embedded sections. Western blot and densitometry analyses showed that cyclin D1 expression was 2.3-times and 2.5-times higher in adenomatous tissues and neoplastic foci, compared with normal colonic mucosa. In contrast, the levels of CDK4 and CDK2 expression were only modestly increased in adenomatous tissues but significantly higher in neoplastic foci, relative to normal mucosa. Expression of PCNA, a cell proliferation marker, increased from normal mucosa to adenoma to focal cancer. Our findings suggest that overexpression of cyclin D1 may be associated with high proliferative activity in adenomatous tissues and that concurrent high expression of cyclin D1 and CDK4 may further perturb cell cycle progression and play a pivotal role in colonic carcinogenesis.     

Preoperative Iron Supplementation and Intraoperative Transfusion During Colorectal Cancer Surgery

Purpose To investigative whether giving an iron preparation to anemic patients before colorectal cancer surgery improves their anemia and reduces the need for intraoperative blood transfusion.Methods Among 569 patients who underwent colorectal cancer surgery between 1998 and 2003, we studied 32 anemic patients who received iron supplementation for at least 2 weeks preoperatively (group A) and 84 anemic patients who did not (group B). Anemia was defined as a hemoglobin (Hb) level at first presentation of 10.0g/dl. Hemoglobin and hematocrit (Ht) levels were measured at first presentation, then immediately before and after surgery. We also calculated intraoperative blood loss and compared intraoperative transfusion rates.Results There were no significatnt differences between groups A and B in age, sex, surgical technique, tumor stage, and operating time. Their Hb and Ht values were similar at first presentation, but significantly different immediately before surgery (both P < 0.0001). There were no significant differences in intraoperative blood loss between the groups, but significantly fewer patients in group A needed an intraoperative blood transfusion (9.4% vs 27.4%, P < 0.05).Conclusion Iron supplementation for at least 2 weeks before colorectal cancer surgery increases Hb and Ht values in anemic patients, and reduces the need for intraoperative transfusion.     

Subconjunctival doxifluridine administration suppresses rat choroidal neovascularization through activated thymidine phosphorylase

PURPOSE: Doxifluridine (5'-deoxy 5-fluorouridine) is an oral anticancer drug with antiangiogenic effects, with vasoclastic action that is enhanced by a major member of the pyrimidine phosphorylases, thymidine phosphorylase (TP). Previous studies have demonstrated that TP is upregulated in the lesions where pathologic angiogenesis occurs and TP itself promotes angiogenesis. To investigate the possible role of TP and doxifluridine in choroidal neovascularization (CNV), the expression level of TP was measured and the effect of doxifluridine was investigated in rat eyes with experimental CNV. METHODS: CNV was induced in rat eyes by diode laser photocoagulation. The expression level of TP in the laser-treated and control eyes was examined with high-performance liquid chromatography (HPLC). For the evaluation of CNV activity, the intensity of fluorescein leakage from the photocoagulated lesions was scored, and the areas of CNV lesions were measured histologically in the control eyes and eyes treated with a subconjunctival injection of doxifluridine 14 days after photocoagulation. RESULTS: The expression level of TP was higher in the laser-treated eyes than in the control eyes. Fluorescein leakage from the CNV lesions significantly decreased in the eyes given a subconjunctival injection of doxifluridine compared with the control. Histologic analysis demonstrated that both the areas of CNV lesions and the degree of vascular formation in the subretinal membrane were reduced in the doxifluridine-treated eyes compared with the control eyes. CONCLUSIONS: TP may be involved in the formation of CNV. Subconjunctival injection of doxifluridine significantly reduced experimental CNV activity without apparent adverse effects. These results suggest the possibility that doxifluridine can be beneficial in treating CNV.