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Objective: To investigate the clinical characteristics of patients with Churg-Strauss syndrome (CSS), including symptoms, blood chemistry and immunological findings., Patients and Methods: We retrospectively investigated the records of 11 patients (six female and five male) with CSS admitted to our hospital from September 2003 to October 2009., Results: Eight patients had preceding symptoms including bronchial asthma and allergic rhinitis. Seven patients showed eosinophilia. Nine patients had mononeuritis multiplex. Positive findings of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) were found in five patients. Neither clinical manifestations nor laboratory findings were correlated with positivity for MPO-ANCA. However, the MPO-ANCA-positive group showed a higher level of blood urea nitrogen and proteinuria than those negative for MPO-ANCA. Ten patients recovered after starting steroid or immunosuppressive therapy, although one patient died of unknown etiology., Conclusion: Although general assessments based on various factors such as medical history, clinical manifestation and laboratory studies are indispensable in CSS, MPO-ANCA might be useful as a predictor of renal dysfunction in patients with CSS.

We retrospectively observed the clinical efficacy and safety of tocilizumab (TCZ) in 74 patients with rheumatoid arthritis (RA) at 13 hospitals, without any restrictions on disease duration or stage, treatment history, and other influencing factors. TCZ was infused by the approved method, and disease activity was evaluated every 4 weeks until week 24 using a joint disease activity score (DAS28). Remission and treatment response were categorised using European League Against Rheumatism (EULAR) definitions. We also analysed the impact of previous treatment with other biologics and of concomitant methotrexate (MTX) therapy on the efficacy of TCZ. At week 24, the DAS28 had improved from 5.5 to 2.7 and the EULAR remission rate was 55.2%. Good and moderate responses according to the EULAR criteria were obtained in 61 and 36% of the patients, respectively. The biologic-naïve group had a significantly better DAS28 (2.1 vs. 2.8) and a significantly higher "good" response rate (86% vs. 54%) than the biologic-exposed group. Although the TCZ + MTX treatment group and the TCZ monotherapy group had a good response rate of 71 and 48%, respectively, the difference was not significant. Based on these results, we conclude that TCZ is able to significantly alleviate disease symptoms in a wide range of patients with RA in a normal clinical context.

Objective: To clarify the clinical usefulness of cerebrospinal fluid (CSF) interleukin-6 (IL-6) measurement in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), we studied CSF IL-6 levels in patients with NPSLE and analyzed the association between CSF IL-6 levels and other clinical findings of NPSLE., Patients and Methods: We retrospectively analyzed records of 37 patients (33 females and four males) with NPSLE admitted to our hospital between January 2003 and December 2008., Results: All patients showed neuropsychiatric symptoms. Fourteen patients showed abnormalities in brain magnetic resonance imaging (MRI) and 12 patients had abnormal findings in electroencephalography (EEG). Increased CSF cell counts and elevated levels of CSF IL-6 were found in 11 and 30 patients, respectively. Elevated levels of CSF IL-6 were not statistically correlated with specific abnormalities in the blood analysis, in increased CSF cell counts, and in abnormalities in the brain MRI and EEG. In addition, a group of NPSLE patients positive for antiphospholipid antibodies (aPL) showed lower CSF IL-6 than the patients negative for aPL., Conclusion: These results indicated that CSF IL-6 might be useful in diagnosis of NPSLE. However, general assessments of patients based on various factors (clinical manifestations, imaging findings and CSF examinations) are also required.

We report a 29-year-old woman with a 2.5 year history of mixed connective tissue disease (MCTD) who developed idiopathic portal hypertension (IPH) and thrombocytopenia as a result of hypersplenism. She had recurrent esophagogastric variceal rupture. Hematological examination also revealed low levels of protein C activity. The liver biopsy specimen showed non-specific mild inflammation and no thrombi. However, portal vein thrombosis developed after splenectomy. This was a rare case of severe complications of IPH accompanying MCTD and protein C deficiency.

A 63-year-old-man was diagnosed in March 2002 with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis because of mononeuritis multiplex, interstitial pneumonia and a positive finding for myeloperoxidase (MPO)-ANCA. Although treated with prednisolone and oral cyclophosphamide, he suffered repeated remission and deterioration of his conditon, which was complicated by hypertrophic pachymeningitis and sinusitis. In July 2006, he was diagnosed with an exacerbation of ANCA-associated vasculitis because of pyrexia, general malaise, numbness in his face and legs, and elevated serum CRP level. Steroid pulse therapy was thus initiated and the patient's clinical symptoms improved. However, serum CRP levels elevated again (5.18 mg/dl) in September 2006. We began administration of rituximab (500 mg/bodyx4 times) in November 2006 and his symptom and laboratory data significantly improved. The dose of prednisolone was slowly decreased without suffering a relapse. Rituximab has been administered every one year, and good disease control has been achieved. Diagnosis of Wegener's granulomatosis was made from the findings of a nodular lesion in the left lung. Rituximab should be considered for patients with refractory ANCA-associated vasculitis.

The appearance of tumor necrosis factor blockers changes the treatment goal of rheumatoid arthritis (RA) to include not only the inhibition of bone destruction, but also the induction of remission. We, herein, report two cases with RA that showed a prolonged remission after the discontinuation of etanercept. The two cases were 27 and 38 years of age, and their disease durations were 6 and 14 months, respectively. Their disease activity score 28 (DAS28) before treatment were 4.43 and 5.07, respectively. Case two was resistant to infliximab as determined by previous treatment with this therapy. Both cases showed a dramatic clinical response and discontinued etanercept in the 15th month and the 14th month after the start of treatment, respectively. No exacerbation of arthritis was evident after the discontinuation of etanercept as supported by the maintenance of DAS28 at less than 2.6. Moreover, after the discontinuation of etanercept, radiographic progression was not evident and decreased modified Sharp scores were observed for at least 1 year in both cases. These findings indicate that clinical and radiographic remission is possible in some patients with RA after the discontinuation of etanercept.

A 62-year-old male was admitted to a local hospital due to a clouding of consciousness in October 2006. On admission, his renal function was observed to have severely deteriorated, which is thought to cause disturbance of consciousness. Laboratory data showed blood urea nitrogen to be 160 mg/dl and the serum creatinine level was 25 mg/dl and, as a result, continuous hemodiafiltration (CHDF) was started. Although his general condition improved, his renal function did not recover. Therefore, regular hemodialysis was started in December 2006. The cause of renal dysfunction was uncertain, because MPO-ANCA was negative, and a renal biopsy could not be done due to the lack of a clear corticomedullary border in his kidneys. In January 2008, he was diagnosed to have microscopic polyangiitis (MPA) because of hemoptysis, elevated serum CRP levels and a positive finding for MPO-ANCA (408.0 EU). An alveolar hemorrhage was also ascertained in a broncoscopic examination. Steroid pulse therapy and intravenous pulse therapy of cyclophosphamide were thus started. The patient's clinical symptoms thereafter significantly improved and his MPO-ANCA level became normalized. This is a rare case characterized by a late appearance of MPO-ANCA, which occurred after more than one year after the onset of renal failure in MPA.

Relapsing polychondritis (RP) is a rare multisystemic disease characterized by the recurrent inflammation of the cartilaginous structures of the external ear, nose, joint, larynx, and tracheobronchial tree, whose etiology might involve an immunological mechanism. Five patients with RP were analyzed. They consisted of 4 males and 1 female, with ages of onset ranging from 27 to 75. Duration from onset to diagnosis varied from 10 months to 5 years. All 5 patients had auricular chondritis and arthritis. Laringotracheal involvement was detected in 4 patients, scleritis in 2 patients, nasal chondritis, and costal chondritis in one patient. One patient was diagnosed to have MAGIC syndrome, complicated with oral and genital ulcers. Antibodies to type II collagen were detected in 4 patients, and the antibody titer correlated with the level of C-reactive protein. Corticosteroids were given to 5 patients. After treatment, the symptoms improved in 5 patients, but 3 patients had a recurrence as reducing corticosteroids. One of them received steroid pulse therapy, one received immunosuppressive drugs, and one patient received both treatments. To prevent an impairment of organs, an early diagnosis involving the use of antibodies to type II collagen and steroid therapy are important in this disease.

Current therapeutic strategies against rheumatoid arthritis (RA) employ increasingly aggressive regimens from an early stage of the disease ; thus, serological markers more specific than IgM-rheumatoid factor (IgM-RF) are desirable. Anti-cyclic citrullinated peptide (anti-CCP) antibody has been reported as a useful and highly specificity marker for the diagnosis of RA. To clarify the diagnostic utility of anti-CCP antibody in early RA, we measured serum concentrations of anti-CCP antibody, IgM-RF, anti-agalactosyl IgG antibody and matrix metalloproteinase (MMP)-3 in 184 polyarthritis patients who showed onset symptoms within the previous 2 years. The diagnostic sensitivity of anti-CCP antibody in early RA was 60.0%, equivalent to IgM-RF (66.3%) and anti-agalactosyl IgG antibody (66.0%). Specificity, positive predictive values and diagnostic accuracy of anti-CCP antibody were the best among the four tested makers. In 38 patients who initially did not meet the ACR criteria for RA, but were diagnosed with RA during the course, the diagnostic sensitivity of anti-CCP antibody was 55.3%. On the other hand, the disease activity score (DAS) 28 of anti-CCP antibody positive and the negative patients was 5.16 and 5.34, respectively. Our data indicated that determination of anti-CCP antibody was useful for early diagnosis of RA.

A 51-year-old woman was admitted to our hospital because of systemic jaundice, general fatigue in August 24, 2007. She was diagnosed with systemic lupus erythematosus (SLE) as a result of a discoid rash, photosensitivity, lymphocytopenia, elevated serum anti ds-DNA antibody and a positive test for antinuclear antibody. Her laboratory data revealed severe liver dysfunction, suggesting autoimmune hepatitis (AIH). She was also diagnosed with thrombotic thrombocytic purpura (TTP) because of thrombocytopenia, hemolytic anemia, renal dysfunction and decreased ADAM-TS13 activity. The patient was treated by methylprednisolone pulse therapy, fresh frozen plasma infusion and ursodeoxycholic acid. Her symptoms and laboratory data rapidly improved and a liver biopsy was carried out. Interface hepatitis and lymphocyte infiltration were observed in the specimen. A diagnosis of definite AIH was made from her International AIH group score of 20 points. AIH and TTP are rare complications of SLE. The prevalence of the complication of SLE and AIH has been reported as 1.7 approximately 2.7%, and that of SLE and TTP as 1 approximately 4%. We reported here a rare case of SLE complicated with AIH and TTP.

Abstract Human herpes virus 8 (HHV-8) is known to be reactivated in immunocompromised situations and it is associated with Kaposi's sarcoma (KS) and some hematological diseases. The aim of this study was to analyze the effect of HHV-8 on HIV-1 infection, especially on thrombocytopenia complicated with HIV infection. The HHV-8 DNA load was determined by a quantitative real-time PCR, using leukocytes from 125 HIV-1-infected individuals. HHV-8 DNA was detected in 37 individuals. The increased HIV-1 load and reduced percentage of CD4-positive T cells were significantly associated with the presence of HHV-8. The prevalence and load for HHV-8 are higher in patients with KS than in patients without KS, but the difference is not significant. The increased HHV-8 DNA load was significantly correlated with thrombocytopenia, and platelet counts were significantly lower in individuals with HHV-8 than in individuals without HHV-8. We also obtained the negative correlations between changes in platelet counts and changes in HHV-8 DNA loads. The association between thrombocytopenia and HHV-8 has never been reported previously, apart from some case reports of Castleman's disease and KS. Various cytokines or chemokines are produced by HHV-8-infected cells, some of which have been reported to inhibit hematopoiesis. This may be one of the mechanisms by which HHV-8 infection induces thrombocytopenia. These results indicate that HHV-8 DNA in leukocytes may provide useful information for the assessment of the clinical appearance of HIV-1 infection.

Objective: High molecular weight (HMW)-adiponectin has been found to be a better negative regulator of insulin resistance than total adiponectin. The aim of this study was to investigate the influence of HMW-adiponectin on antiretroviral therapy (ART)-induced dyslipidemia in Japanese human immunodeficiency virus (HIV)-infected individuals. We also examined the effect of some antiretroviral drugs (ARVs) on adipocytes in vitro., Patients and Methods: Fifty-seven HIV-infected patients were enrolled in four clinical groups; (I) patients who started ART containing efavirenz (EFV); (II) patients who started ART containing a protease inhibitor without atazanavir (ATV); (III) patients who started ART containing ATV; (IV) patients who switched from ART without ATV into ART containing ATV. We measured the serum HMW-adiponectin before and one year after starting or changing ART, using an enzyme-linked immunoSorbent assay (ELISA). Furthermore, we treated the mouse adipocytes (3T3-L1) with some ARVs. The lipid content was assessed using Oil Red O staining. The expression of adiponectin was measured by quantitative real-time PCR., Results: The serum HMW-adiponectin decreased significantly in groups (I) and (II) after starting ART, and increased significantly in group (IV) after changing from ART without ATV to ART with ART. EFV, ritonavir (RTV) and nelfinavir (NFV) inhibited the expression of adiponectin mRNA in mature 3T3-L1 and to a greater extent in pre-mature 3T3-L1. This phenomenon was reversible when ARV was changed to ATV., Conclusion: Effects of the ARVs on adiponectin may vary depending on the administration of different drugs. These data suggest that the distinct metabolic effects of ARV could therefore be a consequence of their differential effects on the production of adiponectin.

Although not common, thrombotic thrombocytopenic purpura (TTP) is one of the most serious complications in patients with systemic lupus erythematosus (SLE). This study aimed to characterize the association between SLE and TTP by examining clinical features and treatment outcomes. We evaluated eight patients diagnosed over two years in our hospital. The mean disease duration of SLE until TTP onset was 13.2 years. One patient had a simultaneous diagnosis of SLE and TTP. CNS lupus and lupus nephritis were involved in 6 patients, respectively. The mean value of the SLE disease activity index was 40.5. Five out of 7 patients who have been examined the von Willebrand factor cleaving protease showed moderately decreased activity. Seven out of the 8 patients were treated with plasmapheresis, and 7 received immunosuppressive therapy including cyclophosphamide and rituximab. Seven patients recovered, but one died from an exacerbation of the disease. These data indicated that plasmapheresis and immunosuppressive therapy improved prognosis of TTP associated with SLE.

A 47-year-old man was admitted to our hospital in January, 2006 because of a huge cutaneous ulcer in his lower limb. He was diagnosed with polyarteritis nodosa due to the cutaneous ulcer, mononeuritis multiplex, muscular pain, elevated serum CRP level and from histological findings of a skin biopsy. He was initially treated with 60 mg/day of prednisolone, followed by 1000 mg/day of intravenous cyclophosphamide (IVCY) therapy. In June, skin grafting to the cutaneous ulcer was carried out, although the graft did not survive. He revealed therapy-resistance to high dose corticosteroid and IVCY therapy, and so was treated with intravenous high dose immunoglobulin therapy. Serum CRP level then decreased and in October skin grafting was once again undertaken, this time the graft successfully survived. In December, serum CRP level increased again and cutaneous ulcer relapsed, thus he was treated with leukocyte apheresis therapy, although it was ineffective. In February 2007, he subsequently received rituximab (375 mg/m(2)/week x 3). Then, serum CRP level decreased rapidly, and cutaneous ulcer also improved. Recently the efficacy of rituximab against rheumatoid arthritis, systemic lupus erythematosus, polymyositis/dermatomyositis and ANCA-associated vasculitis has been recognized. This case suggests that rituximab is also effective against corticosteroid-resistant polyarteritis nodosa.

We herein report the successful use of rituximab in a 55-year-old woman with refractory PR3-ANCA-associated Wegener's granulomatosis. She responded to treatments with high dose methylprednisolone (mPSL), oral and intravenous cyclophosphamide, intravenous gammaglobulin, immunoabsorption, oral prednisolone (PSL), and oral ciclosporin, although she frequently relapsed with various symptoms, such as perforation of the small intestine, scleritis, orbital granuloma, complete AV block, multiple lung nodules, cerebellar infarction, and pharyngeal granuloma with a high level of PR3-ANCA. During her latest relapse, she was given high dose mPSL and 2 infusions of 600 mg (375 mg/m(2)) of anti-CD20 monoclonal antibody rituximab with an interval of 4 weeks, followed by a tapering of the administered PSL. The patient's PR3-ANCA levels normalized within 2 months, but at 6 months after the beginning of the administration of rituximab, the PR3-ANCA level gradually increased without any clinical symptoms. Therefore, two more infusions of rituximab were again administered and thereafter the PR3-ANCA level finally normalized. At present, at 14 months after the initial rituximab treatment, the patient's remission continues to be maintained. The successful treatment of this patient by rituximab therefore suggests that it is an effective and new therapeutic approach for the treatment of refractory Wegener's granulomatosis.

The role of secondary amyloidosis in determining the prognosis of dialyzed patients with rheumatoid arthritis (RA) was examined in 22 patients with a mean age of 60.1 years included 21 renal amyloidosis. RA duration until the start of dialysis was 19.5 +/- 7.2 years and the observation period after introduction 27.1 +/- 26.4 months. Of the 14 dead cases, four died due to sepsis, three due to gastrointestinal tract bleeding, two due to congestive heart failure, and eight cases died within 5 months after starting dialysis. When comparing the eight survivors and the nine non-survivors who died within 2 years after the start of dialysis, the former patients showed significantly higher serum albumin, and lower electrocardiogram score and cardiothoracic ratios at the time of introduction to dialysis. The careful prevention and treatment of infection, cerebrovascular and/or gastrointestinal tract complications seem to be necessary to improve the prognosis of RA patients after the initiation of renal replacement therapy.

HIV-1 infection is known to lead to a massive depletion of CD4(+) T cells, and the Fas/FasL and TRAIL/TRAIL-receptor systems have been reported to be one of the mechanisms of CD4(+) T cell apoptosis in HIV-1 infection. RCAS1 (a receptor-binding cancer antigen expressed on SiSo cells) is also an apoptosis-associated protein that induces apoptosis in receptor positive-cells including T cells, and NK cells. To investigate the role of RCAS1 in HIV-1 infection, we stimulated CD4(+) T cells, monocytes, and several cell lines by HIV-Tat protein and thus showed that Tat significantly increased the mRNA transcription levels and the secretion of soluble RCAS1 in CD4(+) T cells and monocytes. We also showed that the apoptosis induced by HIV-Tat was blocked by inhibiting the expression of RCAS1, using small interfering RNA (siRNA), which was specific for RCAS1. These results indicate that RCAS1 is one of the mechanisms of CD4(+) T cell depletion induced by HIV infection.

Pure red cell aplasia (PRCA) is a rare cause of anemia associated with SLE. We herein report a case presenting with SLE and PRCA. A 33-year-old woman, who had been suffering from photosensitivity, proteinuria, and pancytopenia, was diagnosed to have SLE. She showed normochromatic normocytic anemia. The serum level of haptoglobin was <10 mg/dl, and Direct Coombs' test was negative. Her reticulocyte count was 0.8%. Her clinical and laboratory features, except for anemia, had recovered in response to 50 mg/day of prednisolone. The serum level of haptoglobin had normalized, but the reticulocyte count remained low. The bone marrow findings revealed erythroid hypoplasia, and she was diagnosed to have PRCA complicated with SLE. No viral DNA of human parvovirus B19 in her bone marrow was detected. The anemia gradually improved following the further use of 50 mg/day prednisolone. In order to disclose the mechanism of PRCA in this patient, we examined the effects of her peripheral T lymphocytes on erythrogenesis, using erythroid colony-forming cells (ECFC) in her peripheral blood. When we co-cultured peripheral T cells and ECFC, her T cells inhibited erythroid colony formation in a dose dependent manner. Several reports have shown the presence of inhibitory factors in SLE patients' serum such as antibodies against erythroid progenitors or erythropoietin, while other reports have shown abnormal T cells that inhibit the growth of erythroid progenitors. Our study suggests that these inhibitory T cells may therefore have played an important role in the pathogenesis of this patient.

CD4(+)CD25(+) regulatory T cells play an important role in preventing autoimmunity. We investigated the presence of CD4(+)CD25(+) regulatory T cells in the peripheral blood of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), using flow cytometry. The percentage of CD4(+)CD25(+) regulatory T cells was significantly decreased in RA, especially in patients with high serum levels of either CRP or MMP-3. In SSc and SLE, the percentage of CD4(+)CD25(+) regulatory T cells was higher in patients than in controls, but not significant. We also investigated the serum levels of IL-10, which influences the function of CD4(+)CD25(+) regulatory T cells and other regulatory T cells. In RA, on contrast to CD4(+)CD25(+) regulatory T cells, the serum levels of IL-10 increased in patients with higher serum levels of CRP, or MMP-3. In SLE and SSc, the serum level of IL-10 increased significantly in patients than in controls. These data thus indicated that CD4(+)CD25(+) regulatory T cells contributes to occurrence and progression of RA, and other regulatory T cells or cytokines contribute to occurrence and progression of SSc and SLE.

We reported here on a case of limited cutaneous systemic sclerosis (lcSSc) with aplastic anemia treated by anti-thymocyte globulin and cyclosporin A. The use of this therapy resulted not only in marrow recovery but also in resolution of the skin sclerosis. A 68 year-old woman was diagnosed as lcSSc accompanied by Hashimoto's thyroiditis and primary biliary cirrhosis. Treatment by D-penicillamine was started. After 11 months, She complained of nasal bleeding and subcutaneous bleeding. Her laboratory data revealed pancytopenia. White blood cell count, hemoglobin concentration and platelet count were decreased at 2300/microl, 8.2 g/dl, and 3000/microl respectively. Bone marrow was severely hypoplastic, suggesting aplastic anemia. The etiology of hypopastic marrow was considered to be D-penicillamine which had been frequently reported to cause hematopoietic cell suppression. We immediately started methylprednisolone pulse therapy combined with G-CSF and cyclosporin A, which showed little effectiveness. Next we tried the anti-thymocyte globulin therapy combined with G-CSF and cyclosporin A. Her blood cell counts gradually improved. After 4 months, she did not need the blood transfusion anymore. Furthermore, the sclerosis of her skin began to improve gradually, and the titer of anti-centromere antibody also decreased. Thus, anti-thymocyte globulin and cyclosporin A combined therapy can be considered among the therapies of systemic sclerosis.

There are a lot of difficulties in the estimation of interstitial pneumonia and subsequent pulmonary fibrosis associated with connective tissue diseases. Recently, serum KL-6 (KL-6) and serum surfactant protein D (SP-D) have been reported to be useful to estimate the severity of interstitial pneumonia. We investigated the usefulness of these serum markers comparing to the spirometric parameters in patients with interstitial pneumonia associated with connective tissue diseases. We found significant inverse correlation between KL-6 and spirometric % VC. Furthermore, KL-6 was more significantly inverse-related with %DLco. On the other hand, we found neither correlation between SP-D and %VC, nor between SP-D and %DLco, suggesting SP-D level seems to be not affected by the degree of pulmonary fibrosis itself. These results indicate that KL-6 is useful to estimate the severity of pulmonary fibrosis more precisely than SP-D in patients with interstitial pneumonia associated with connective tissue diseases.

We herein report a case of systemic sclerosis associated with microscopic polyangitis. The patient was a 54-year-old woman, who was diagnosed to have systemic sclerosis at a hospital in 1992, but she did not receive any medical treatment. She had been suffering from pyrexia, paresthesia and muscle weakness of both lower limbs since the beginning of 2001, and was introduced to our hospital. She showed hardened skin extending from her fingers to upper arms, weakness in both lower limbs and livedo reticularis. Her laboratory test showed WBC 11, 600/microliter, CRP 6.63 mg/dl, CH 50 24 U/ml, anti Scl-70 antibody 90.1 index, and MPO-ANCA 281 EU, but no impaired renal function was recognized. Chest computed tomography showed interstitial pneumonia while necrotising vasculitis of the right sural nerve was found in a biopsy specimen. Based on these findings, we diagnosed her to have systemic sclerosis accompanied with microscopic polyangitis (MPA). She received steroid treatment after the diagnosis was made, and her symptoms and the laboratory findings thereafter immediately improved. Many cases have been reported to have ANCA positive systemic sclerosis among patients with systemic sclerosis that are complicated MPO-ANCA-related vasculitis. However, since our patient demonstrated necrotising vasculitis in a sural nerve biopsy and no evidence of an impaired renal function, we diagnosed her to have systemic sclerosis complicated with MPA instead of ANCA positive systemic sclerosis. The pathological state of this patient thus seemed to be different from that of ANCA-positive systemic sclerosis. We concluded that this patient had both systemic sclerosis and MPA. It is therefore important to note that some patients who have been reported to have ANCA-positive systemic sclerosis may also have systemic sclerosis complicated with MPA.

Vitamin K2 is reported to induce apoptosis or differentiation of leukemic cell lines in vitro. We administered a vitamin K2 analog, menatetrenone, at 45 mg daily to 23 patients with myelodysplastic syndrome (MDS): 13 patients with RA, 2 with RARS, 6 with RAEB and 2 with RAEB-T. Good response (GR) and partial response (PR) were defined as an increase of hemoglobin concentration exceeding 2 g/dl and 1-2 g/dl without transfusion, respectively. Six of the RA patients showed improvement of anemia (GR, 3 patients; PR, 3 patients). RA patients who did not have a hypocellular bone marrow and were transfusion-independent tended to be responsive to vitamin K2 therapy in combination with vitamin D3 or anabolic steroids. No adverse effect of vitamin K2 was observed, and the time required to obtain the hematological response was short, being 3 months on average. We believe that vitamin K2 therapy has potential as a treatment for patients with MDS.

Object: We describe the characteristics of three patients with CD56+CD7+ stem cell leukemia/lymphoma., Methods: These blasts were analyzed for morphologic, karyotypic, immunophenotypic, and immunogenotypic features using Southern blot and polymerase chain reaction analysis., Materials: Peripheral blood, bone marrow aspirates, or biopsied mediastinal tumor specimens of three CD56+CD7+ stem cell leukemia/lymphoma patients were investigated., Results: The bone marrow of all patients showed myeloperoxidase (MPO) negative blast cells with basophilic cytoplasm and distinct nucleoli with no azurophilic granules. The blasts of two patients were classified as acute lymphoblastic leukemia (L2). The liver, spleen, and lymph nodes were unaffected in all patients. All had an aggressive clinical course. The blasts were strongly positive for both CD7 and CD56 but negative for other T-lineage associated antigens, including CD1, CD2, surface membrane CD3, cytoplasmic CD3c (2/2), CD4, CD5 and CD8. The additional antigens were recognized as follows: CD19 (1/3 cases) as a B lineage, CD33 (1/3) as a myeloid marker, CD34 (2/3) as a stem cell, CD38 (1/1) and HLA-DR (2/3). When the patients relapsed, the phenotypes changed to blasts positive for CD5, CD10 and CD13 in patient 1, CD5 in patient 2, and CD33 in patient 3. MPO, however, remained negative. Cytogenetic analysis showed no common abnormal karyotype. All had a common D2-Jdelta1 induced by T-cell specific enhancer. Rearrangement of TCR beta and gamma genes occurred in patient 2, and IgH and TCR beta underwent rearrangement in patient 3., Conclusion: Although a more comprehensive case analysis is necessary, these data suggest the possibility that the blasts of the present cases come from a common lymphoid precursor (T, NK, and B cell) or from a NKT precursor as the fourth lymphoid lineage.

One hundred and nine patients with infections concurrent with hematopoietic disorders were treated with imipenem/cilastatin sodium (IPM/CS) either alone (IPM/CS monotherapy) or in combination with other antimicrobial drugs (IPM/CS combination therapy). The following results were obtained. 1. One hundred and nine patients were allocated at random to two groups: 53 patients to IPM/CS monotherapy and 56 patients to IPM/CS combination therapy. Fourteen patients (6 and 8 in the 2 groups, respectively) were excluded from the clinical evaluation. There were not significant differences between the two groups with respect to the background. 2. The efficacy rates of the 2 treatments against bacterial infections were as follows: in the IPM/CS monotherapy group, 62.5% in 8 patients with sepsis, 75.0% in 23 patients with fever of undetermined origin (FUO), 50.0% in 10 patients with pneumonia, and 68.3% in the 47 patients, and in the IPM/CS combination group, 85.7% in 7 patients with sepsis, 63.6% in 24 patients with FUO, 50.5% in 8 patients with pneumonia, and 67.4% in the 48 patients. The differences between the two groups were not significant. 3. Among the drugs used in combination with IPM/CS, antibiotics other than penicillins, cephalosporins, and aminoglycosides were used in 12 patients and a high efficacy rate of 91.7% was obtained. 4. Bacteriologically, 19 and 17 strains were isolated from the IPM/CS monotherapy and combination therapy groups respectively, and the eradication rates were 100% and 88.9% respectively. 5. Side effects were noted in 2 patients in the IPM/CS monotherapy group and 7 in the combination therapy group, but all of these resolved after discontinuation or completion of the treatment. The efficacies against severe bacterial infections in the presence of hematopoietic disorders were not different between IPM/CS alone and IPM/CS in combination with other antibiotics. Adverse reactions were uncommon with the monotherapy.

A rare case of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia is described in a 49-year-old Japanese diabetic woman. Primary biliary cirrhosis was diagnosed by characteristic liver histology and positive serum mitochondrial antibody test. Ulcerative colitis was diagnosed by typical findings of barium enema and colonoscopy, negative fecal test for pathogens and compatible rectal histology. Chronic myelocytic leukemia was determined by representative hematologic findings and positive result for Ph1 chromosome. This is the first case with combination of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia.

We examined the effect of silver ion on Ca2+ mobilization from intracellular stores in permeabilized HL-60 cells using a filtration method and 45Ca2+. In HL-60 cells preloaded with Ca2+ in the presence of ATP, micromolar concentrations of AgNO3 elicited marked Ca2+ release within 1 min. The AgNO3-induced Ca2+ release was not affected by the free Ca2+ concentration in the medium. Equivalent concentrations of AgNO3 inhibited energy-dependent Ca2+ uptake as well as oxalate-supported Ca2+ uptake. In passive Ca2+ release experiments when ATP was completely depleted in the solution, AgNO3 also triggered Ca2+ release. Sulfhydryl protecting agents such as 2-mercaptoethanol, dithiothreitol, and glutathione (reduced form) blocked the AgNO3-induced Ca2+ release. From these results, we conclude that the apparent Ca2+ release induced by AgNO3 is mainly due to inhibition of the Ca2+ pump with increased permeability for Ca2+ and partly due to a direct effect on the Ca2+ release channel, probably by modification of sulfhydryl groups on these proteins.

It is generally acknowledged that calcium plays a major role in the generation of vascular tone. However, in recent years it has become increasingly evident that relatively calcium-insensitive pathways of excitation-contraction coupling also exist in the vascular smooth muscle cell. Possible mechanisms of vascular smooth muscle contraction and their possible role in the pathophysiology of hypertension are reviewed. The rationale for the use of calcium channel blockers in the treatment of hypertension is discussed.

We report two cases of mosaic karyotype (45XO/46XiXq) Turner's syndrome with unique bone appearance. The cases were 44 and 34 year-old women and latter was complicated by Hashimoto's thyroiditis (hypothyroidism). Following the systemic bone surveys, we found the patients showed not only osteoporotic bone change and short stature, but also spondyloepiphyseal dysplasia (SED) like bone appearance (thinness of vertebral bodies, irregularity of vertebral end-plates, shortness of femoral necks, Coxa valga, Coxa magna and hypoplasia of acetabula). Those findings can not be explained by degenerative bone changes like osteoporosis, rather are suggestive the sequelae of malgrowth of the bone system in Turner's syndrome.

A case of hereditary thrombocytopenia with large platelets (familial macrothrombocytopenia, FM) is reported. Studies on the platelets from the propositus showed decreased glycosylation of platelet membrane glycoprotein IV, which would distinguish the case from other FM previously described.

Effects of N-formyl chemotactic peptides on the Ca2+ influx and efflux were investigated in guinea-pig peritoneal macrophages using an isotope tracer. fMet-Leu-Phe did not enhance the influx of 45Ca2+ into macrophages, whereas it stimulated the efflux of 45Ca2+ from macrophages at concentrations ranging from 10(-10) M to 10(-7) M. fMet-Met-Met and fMet-Leu also stimulated the 45Ca2+ efflux, albeit at much higher concentrations, while there was no stimulation with fMet. The mitochondrial inhibitors, oligomycin and NaN3, did not modify the 45Ca2+ efflux induced by the chemoattractants, yet they did induce the release of 45Ca2+ from the mitochondria. On the other hand, higher concentrations of the calmodulin antagonists, chlorpromazine and trifluoperazine, induced the release of 45Ca2+ from the NaN3-insensitive Ca2+ store site and mimicked the enhancement of the 45Ca2+ efflux by N-formyl chemotactic peptides. Thus, N-formyl chemotactic peptides appear to increase the levels of intracellular free Ca2+ in guinea-pig peritoneal macrophages, probably by inducing the release of Ca2+ from the NaN3-insensitive Ca2+ store site.

We describe two cases of gastrointestinal lymphoma associated with rapid bone marrow dissemination after surgical resection. Case 1: A 73-year-old male was diagnosed as having malignant lymphoma originating from ileocaecal region (diffuse medium-sized, B cell type). Tumor (8 x 8 cm) was resected but infiltrated to the peritoneum and curative operation could not be done. Two weeks after operation, elevation of LDH, pancytopenia and bone marrow infiltration of lymphoma cells developed and he died of respiratory failure. Case 2: A 69-year-old female was diagnosed as having remnant gastric lymphoma (diffuse large, B cell type). Tumor size was 5 x 4 cm and swelling of the third lymph nodes was found, so curative operation could not be done. Two months after operation bone marrow infiltration of lymphoma cells was observed and she is now undergoing chemotherapy. Surgical resection is performed in the majority of patients with localized gastrointestinal lymphoma. But the operation of the advanced case must be carefully done, because the operative procedure may sometimes facilitate growth and metastasis of tumor.

We describe a case of adult T-cell leukemia (ATL) with vertebral bone invasion, who developed acute paraplegia and responded well to irradiation and combined chemotherapy. A 36-year-old man born in Tsushima Island was admitted to our hospital in May 1987, because of a sudden onset of paraplegia, hypesthesia below the level of 7th thoracic vertebra and vesicorectal disturbance. The white blood cell count was 9,500/microliter with 16% of abnormal lymphocytes showing lobulated nuclei. The surface marker analysis revealed that CD3, CD4, CD8 and CD25 positive cells were 88.1, 83.9, 6.4 and 1.3% of the peripheral mononuclear cells, respectively. Anti-ATLA antibody was positive. Serum calcium level was elevated. Bone scintigraphy showed multiple vertebral bone lesions. Vertebral bone mass and a compressed spinal cord in the 7th thoracic level were confirmed by CT scanning and MR imaging. Cerebral spinal fluid was negative for tumor cells. A diagnosis of ATL was made. Irradiation and combination chemotherapy improved bone lesions and neurological signs and the disease was well controlled by maintenance chemotherapy up to the present (August, 1988).

The release of Ca2+ from the intracellular store site, as induced by inositol 1,4,5-trisphosphate, was studied in relation to free Ca2+ concentrations or amounts of stored Ca2+ in smooth muscle cells. The maximal Ca2+ release induced by inositol 1,4,5-trisphosphate was observed when the amount of Ca2+ in the store site was about 50% of the maximal capacity of the Ca2+ storage, and when the extravesicular free Ca2+ concentration was less than 1.5 X 10(-6) M. The Ca2+ release induced by inositol 1,4,5-trisphosphate was accelerated by ATP and 5'-adenylylimidodiphosphate (AMPPNP), but not by ADP and AMP. This inositol 1,4,5-trisphosphate-induced Ca2+ release appeared to be specific for intracellular Ca2+ store sites (mainly sarcoplasmic reticulum), and this Ca2+ release was not apparent in the sarcolemmal fraction.

The effects of guanosine triphosphate (GTP) on the release and uptake of Ca2+ in nonmitochondrial intracellular store sites of human peripheral lymphocytes were examined. GTP in the presence of 3% polyethylene glycol released Ca2+ from the intracellular store sites of lymphocytes in a dose-dependent manner, and the maximal release was obtained at 10 microM GTP. GDP and 5'-GMP also enhanced the release of Ca2+. On the other hand, Ca2+ uptake in the presence of oxalate by saponin-treated lymphocytes was stimulated by GTP and this stimulation was abolished when polyethylene glycol was concomitantly present. The dose dependence of the stimulated Ca2+ uptake by GTP was much the same as that of the Ca2+ released by GTP. These results indicate that GTP has an inherent activity to release Ca2+ as well as to stimulate the uptake of Ca2+ in nonmitochondrial intracellular store sites of saponin-treated lymphocytes. The stimulatory effect of polyethylene glycol on GTP-mediated Ca2+ release may occur by inhibiting functions of the Ca2+ pump.

Passive permeability of the endoplasmic reticulum of saponin-treated macrophages to Ca2+ was studied by the filtration method using 45Ca. The Ca2+ release from the endoplasmic reticulum of macrophages was enhanced by the presence of submicromolar concentrations of Ca2+ in the medium. The Ca2+ release was enhanced by caffeine, and suppressed by MgCl2. These phenomena are similar to the Ca2+-induced Ca2+ release reported for the sarcoplasmic reticulum of skeletal muscle. On the other hand, adenine suppressed the Ca2+ release from the endoplasmic reticulum, while it reportedly enhanced the Ca2+-induced Ca2+ release of the skeletal muscle. The threshold concentration of Ca2+ for the Ca2+-induced Ca2+ release was approximately 10(-8) M in the presence of 0.95 mM MgCl2 in macrophages. The spontaneous spreading of macrophages and spontaneous migration of macrophages were inhibited by adenine, and also by caffeine in spite of the enhancement of the Ca2+-induced Ca2+ release.

Sarcolemmal fractions of vascular smooth muscles were prepared from porcine thoracic aortae by differential and sucrose density gradient centrifugation. In these fractions, there was a high activity of 5'-nucleotidase, a putative marker enzyme of plasma membrane, and a low activity of rotenone insensitive NADH-cytochrome c reductase a marker of sarcoplasmic reticulum. In these fractions, the Ca2+ uptake was ATP-dependent. A low concentration of saponin which inhibited Ca2+ uptake by the plasma membrane but not by the sarcoplasmic reticulum, inhibited 65% of the Ca2+ uptake of this fraction. The Ca2+ uptake of this fraction was enhanced by cAMP- and cGMP-dependent protein kinases, and by calmodulin. The cAMP-dependent protein kinase enhanced the phosphorylation of 28 and 22 kDa proteins, while the cGMP-dependent protein kinase phosphorylated the 35 kDa protein. The phosphorylation of 100, 75, 65, 41 and 22 kDa proteins was enhanced by Ca2+ and calmodulin. These results indicate that cAMP- and cGMP-dependent protein kinases as well as calmodulin play important roles in Ca2+ transport in the sarcolemma, and that the phosphorylated proteins may be associated with an enhancement of Ca2+ transport in the sarcolemma.

Inositol 1,4,5-trisphosphate (InsP3) releases Ca2+ from the non-mitochondrial Ca2+ store site of various types of cells. To study the mechanisms of the Ca2+ release from the store site, the effect of InsP3 on the passive Ca2+ release and influx, and the active Ca2+ uptake in the presence of oxalate, was examined using saponin-treated guinea pig peritoneal macrophages. InsP3 stimulated the passive Ca2+ release and influx. Although InsP3 slightly inhibited the active Ca2+ uptake in the presence of oxalate, it seems unlikely that the Ca2+ release by this agent is caused by the inhibition of the Ca2+ uptake, because the addition of apyrase or hexokinase (which removes ATP within 30 s, so that no more Ca2+ can be accumulated) or vanadate (which inhibits the Ca2+ uptake) resulted in very slow release of Ca2+. These results suggest that the Ca2+ permeability of the Ca2+ store membrane is increased by InsP3. InsP3 did not cause an increase in the Ca2+ permeability of phospholipid vesicles (liposomes), indicating that this agent may bring about Ca2+ release by a specific effect on the physiologically relevant Ca2+ channels or carriers in the non-mitochondrial Ca2+ store site. The passive Ca2+ release by InsP3 was enhanced by ATP and an unhydrolyzable ATP analogue, 5'-adenylyimidodiphosphate, but not by ADP or AMP. The passive Ca2+ release by InsP3 was observed even at 0 degree C.

Effects of inositol 1,4,5- trisphosphate , extracted from human erythrocyte ghosts, on Ca2+ release from intracellular store sites were studied in saponin-treated single muscle cells of the porcine coronary artery. Application of micromolar concentrations of inositol 1,4,5- trisphosphate released Ca2+ from the intracellular non-mitochondrial store sites, within 1 min. However, when the concentrations of free Ca2+ were over 1.5 X 10(-6) M, the release of Ca2+ by this agent was inhibited. The Ca2+ releasing mechanism differed from that seen with A23187, therefore this release of Ca2+ from store sites was not due to Ca2+ ionophore actions. This agent may play the role of messenger in increasing the cytosolic Ca2+, provoking pharmaco-mechanical coupling, and thus producing the contraction.