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Recently, the prevalence of staphylococcal cassette chromosome mec (SCCmec) type IV isolates, which are the major community-acquired methicillin-resistant Staphylococcus aureus (MRSA), have increased in Japanese hospitals. The aim of this study was to elucidate the detailed molecular epidemiological features of the SCCmec type IV clones in Japanese hospitals. When 2589 MRSA isolated from four hospitals in Tokyo, Japan between 2010 and 2014 were analysed, the proportion of SCCmec type IV overtook that of type II, which was the major type of hospital-acquired MRSA in 2014. Multilocus sequence typing showed that CC1 was the most predominant clone in the SCCmec type IV isolates. The clinical departments that the patients belonged to, pulsed-field gel electrophoresis analysis and antimicrobial susceptibility profiles suggested that the origin of the CC1-SCCmec type IV (CC1-IV) clone was a community setting. Our data show that the CC1-IV clone is becoming a predominant MRSA clone in Japanese hospitals.

Recently, the prevalence of staphylococcal cassette chromosome

64 歳の女性がぶどう膜炎の原因精査目的で当院内科を受診した．症状として前腕の皮膚掻痒を訴えていた．血液検査では赤沈の亢進，胆道系酵素値の上昇，総コレステロール値の上昇，抗核抗体の上昇を認めた．胸部レントゲン写真では胸肋鎖関節部の異常骨化像を認めた．肝機能障害の精査中に抗ミトコンドリア M2 抗体の陽性が確認され，原発性胆汁性肝硬変症 (PBC) と診断した．ウルソデオキシコール酸の内服により皮膚掻痒は軽快し，肝機能異常も正常化した．超音波，腹部 CT など画像上，肝硬変症の所見は認められず，安定して経過している．胸肋鎖骨間異常骨化症 (ISCCO) は掌蹠膿疱症，乾癬などの皮膚疾患に合併することが多く，血清反応陰性脊椎関節症 (SpA) の一つと考えられている．PBCにはシェーグレン症候群や強皮症が時に合併し，関節症状を呈することがあるが，PBC と ISCCO との合併は文献上見当たらず稀である．

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are the most common autoimmune disorders, although they each have very different pathophysiology. In general, RA is considered to be a Th1-mediated disease, while SLE is a Th2-mediated disease. Thus, their overlapping, in so called "rhupus", is a rare condition. In Rembrandt van Rijn's (1606-1669) portrait of the middle-aged Maria Bockenolle, we have what may be the earliest depiction of a case of rhupus syndrome: the coexistence of a butterfly rash and digital deformities. This suggests the possible historical importance of an RA epidemic which took place in the early 17th century.

We report the case of a 32-year-old man who developed Wegener's granulomatosis complicated with refractory intestinal ulceration. In August 2001, he presented with a high fever, nasal bleeding, and bilateral leg numbness. These symptoms worsened, which prompted him to consult his home doctor on February 18, 2002. In spite of treatment with antibiotics, his symptoms did not improve. Furthermore, abdominal pain and melena occurred as additional symptoms in March 2002. He was admitted to our hospital on April 5, 2002. A deformed nose condition (the so-called saddle nose) was observed at this time. Laboratory data showed a high erythrocyte sedimentation rate (103 mm/h) and a high level of serum C-reactive protein (14.98 mg/dl), and hematuria and proteinuria were also observed. The patient was positive for an antineutrophil cytoplasmic antibody specific for proteinase-3 (PR3-ANCA). A chest computed tomography (CT) scan revealed multiple pulmonary nodules in the lung field. A biopsied-specimen from the nasal mucosa showed necrotizing granulomatosis with giant cells. Together with his symptoms and the laboratory and pathological findings, the patient was diagnosed as having Wegener's granulomatosis. A colon fiberscopy showed multiple ulcerations with bleeding from the terminal ileum to the ascending colon, and nodular lesions at the terminal ileum. We started a combination therapy of prednisolone (60 mg/day) and cylophosphamide (100 mg/day) orally. The patient's gastrointestinal symptoms disappeared and abnormal serological indicators improved. Although Wegener's granulomatosis complicated with refractory intestinal ulceration is rare, this case indicates that the gastrointestinal region is also a target organ of Wegener's granulomatosis.

To clarify hematological abnormalities following infection with human immunodeficiency virus (HIV), we examined the hematopoietic capability of bone marrow by using cynomolgus monkeys infected with pathogenic simian/human immunodeficiency virus (SHIV) strain C2/1, an animal model of HIV infection. The relationship between the progress of the infection and the CD4/CD8 ratio of T lymphocytes or the amount of SHIV C2/1 viral load in the peripheral blood was also investigated. A colony assay was performed to assess the hematopoietic capability of bone marrow stem cells during the early and advanced phases of the infection. Colonies of granulocytes-macrophages (GM) were examined by PCR for the presence of the SIVmac239 gag region to reveal direct viral infection. There was a remarkable decrease in the CFU-GM growth on days 1 and 3 postinoculation, followed by recovery on day 56. During the more advanced stage, the CFU-GM growth decreased again. There was minimal evidence of direct viral infection of pooled cultured CFU-GM despite the continuously low CD4/CD8 ratios. These results indicate that the decrease in colony formation by bone marrow stem cells is reversible and fluctuates with the advance of the disease. This decrease was not due to direct viral infection of CFU-GM. Our data may support the concept that, in the early phase, production of inhibitory factors or deficiency of a stimulatory cytokine is responsible for some of the bone marrow defects described in the SHIV C2/1 model.

Problem: The placenta is one of the few non-hematopoietic tissues to express granulocyte colony stimulation factor (G-CSF). Placental G-CSF production is considered to be one of the major causes of granulocytosis during pregnancy although its physiological role in pregnancy has not yet been examined. Method of study: The effects of G-CSF on interleukin (IL)-2 and/or IL-12 induced interferon (IFN)-γ production of magnetic cell sorting (MACS) sorted decidual lymphocytes was examined by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT). The effect of G-CSF on cytotoxicity of decidual lymphocytes against the choriocarcinoma cell line JEG-3 was examined by lactate dehydrogenase (LDH) release assay. Results: As previously reported by us, IL-2 and/or IL-12 activated decidual mononuclear cells were capable of killing choriocarcinoma cells. We observed that G-CSF abolished IFN-γ production and cytotoxicity of decidual mononuclear cells and MACS sorted CD56+ cells. Conclusions: In addition to its well-known trophic effects on hematopoiesis, our results suggest about new roles of G-CSF in reproductive immunology.

To clarify the prevalence of subclinical renal tubular acidosis (RTA) and its association with clinical and laboratory parameters in primary and secondary Sjögren's syndrome (SS), an acid-loading test was conducted. Subclinical RTA was found in 32% of patients with SS. The prevalence of subclinical RTA in primary and secondary SS was about the same (31.6% and 33.3%, respectively). Significant longer duration of illness, more severely decreased salivary excretion, decreased lymphocyte number, higher serum levels of IgG and IgA, and higher frequency of anti-SS-A (Ro) and SS-B (La) antibodies were found in patients with subclinical RTA. These results suggested that subclinical RTA may be a characteristic manifestation both in primary and secondary SS, along with the progression of immunologic dysfunction, when the illness seemed to be indolent.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) remains problematic in both hospital and community settings. Investigations of MRSA existing in the local area are necessary to understand the detailed epidemiology of healthcare-associated MRSA (HA-MRSA). In the present study, molecular epidemiological analysis was performed on 584 MRSA isolated from four hospitals in Tokyo, Japan. In the pulsed-field gel electrophoresis (PFGE) analysis, four epidemic pulsotypes (I to IV) were found. The isolates of the epidemic pulsotype I mainly consisted of the SCCmec type II, toxic shock syndrome toxin 1 gene (tst)-negative, spa type t002, and ST764 clones. The ST764 clone, which is a novel hybrid variant of the ST5 HA-MRSA lineage with the arginine catabolic mobile element (ACME), was first found in Niigata, Japan. However, no ACME genes were detected in the isolates of the epidemic pulsotype I. In contrast, the other isolates of the epidemic pulsotypes mainly consisted of the SCCmec type II, tst-positive, spa type t002, and ST5 clones, which are the most predominant clones of HA-MRSA in Japan. Resistance rates of non-β-lactams for the isolates of the epidemic pulsotype I were higher than those of the other epidemic pulsotypes. Our data showed that the novel ACME-negative ST764 clones are being distributed throughout multiple hospitals in Tokyo. The ST764 clones in Tokyo have the potential to acquire ACME in the future, because the ACME-positive ST764 clones have already been found in both hospital and community settings in other areas of Japan.

A 40-year-old woman with amyopathic dermatomyositis (ADM) developed acute pneumonitis. Despite pulse methylprednisolone therapy, the pneumonitis worsened. We therefore initiated cyclosporin-A (Cy-A) therapy with success, although Pneumocystis carinii (PC) pneumonia occurred. Coexistence of dermatomyositis (DM)-related pneumonitis and PC pneumonia was diagnosed by means of chest X-ray findings, KL-6, and polymerase chain reaction (PCR) for PC. We thus continued Cy-A therapy to ameliorate the pneumonitis. Cy-A appeared to be effective for corticosteroid-resistant pneumonitis in a patient with DM.

We studied isotype-specific rheumatoid factors (RFs) to clarify their significance in rheumatoid arthritis (RA) and to verify the difference in RF isotypes between RA and chronic liver diseases (CLD). Isotype-specific RFs in RA and in CLD were measured by enzyme-linked immunosorbent assay (ELISA). Most sera (n = 51, 94.1%) from RA patients contained some kind of RF isotypes (92.1% for IgM RF, 76.4% for IgG RF, and 43.1% for IgA RF), and seronegative RA by ELISA was seen in only 11.8% (n = 6). The most characteristic combination of RF isotypes in active RA was IgG, IgA, and IgM. This combination of RF isotypes changed to IgG plus IgM, according to the diminution of RA activity; then, we found only IgM RF in inactive RA. The titers of each RF isotype also decreased in parallel with the activity of RA. IgA RF seemed to be the most sensitive factor for evaluating the activity of RA. In CLD, almost the same high frequency (n = 49, 89.8% for IgM RF, 59.2% for IgG RF), with the same titer levels seen in RA, was observed. On the other hand, IgA RF was significantly lower in frequency (n = 9, 18.4%) and in titer, compared with the finding in RA. Surprisingly, even in CLD, true seronegativity by ELISA was also found in very few patients (n = 4, 8.1%). In CLD, positive RFs detected by agglutination assay were seen more often in chronic hepatitis than in liver cirrhosis. In RA patients, significant associations of IgA RF and the serum concentration of IgA, and IgG RF and the serum concentration of IgG, were observed. On the other hand, in CLD patients, significant associations of IgG RF and the serum IgG concentration, and of IgM RF and the serum IgM concentration, were observed. These results indicated that IgA RF in active RA is the most characteristic RF isotype distinguishing it from other nonrheumatic diseases, as well as from inactive RA. RF isotypes reflected the background polyclonal B-cell activation in different manners in both diseases. In CLD, RF isotypes seemed to be disease-related immunological disorders reflecting disease progression.

Problem Chemokine receptors of placental trophoblasts possibly act as co-receptors or alternative receptors of maternal fetal infection by HIV. To clarify their possible expression and the physiological roles of chemokines on human placentae, we studied chemokine chemokine receptor expression and the effects of exogenous chemokines on choriocarcinoma cell lines. Materials and methods Placental samples were obtained from 13 placentae of various gestational ages. Villous tissue was mechanically dissected from samples. Trophoblasts were enriched by anti-human chorionic gonadotropin (hCG)-coated magnetic beads. Human choriocarcinoma cell lines (JAR, BeWo, JEG-3) were maintained in RPMI 1640 media supplemented with 10% FCS. Expression of chemokine receptors was studied by RT-PCR. The effects of MIP-1alpha, RANTES, MCP-1 on hCG production were estimated by EIA. Effects of chemokines on proliferation of choriocarcinoma cell lines were examined by MTT assay. Results We observed mRNA expression of CCR-1, 2, 3, 4, 5 and CXCR-1, 2, 4 in 1st trimester placental villi, CCR-I, 2, 4 and CXCR-1, 2. 4 in 2nd trimester placental villi, CCR-1, 2, 4 and CXCR-4 in 3rd trimester placental villi. Using MACS enriched trophoblasts, we observed identical results. A choriocarcinoma cell line BeWo expressed CCR-1, 3, 4 and CXCR-1, 2, 4 while JEG-3 and JAR expressed CCR-1, 3, 4, 5 and CXCR-1, 2, 4. Expression of the CCR-5 and CXCR-4 protein in choriocarcinoma cell lines and MACS-enriched trophoblats were confirmed by flow cytometry. Chemokine MCP-3, MIP-1alpha, RANTES mRNA were expressed by the 1st, 2nd and 3rd trimester placental samples and the three choriocarcinoma cell lines examined. MCP-1 was expressed by 1st and 2nd trimester placental villi. Administration of chemokines up-regulated proliferation (10(-1) - 10 ng/mL) and hCG production (10(-1) - 10(-2)ng/ mL) of the three choriocarcinoma cell lines examined. Conclusions Our results suggest possible roles of chemokines/chemokine receptors on placental physiology and their involvement in HIV transmission as alternative receptors.

Objective To examine the relationship between serum levels of interleukin-1 receptor antagonist (IL-1Ra) and its gene expression in peripheral blood mononuclear cells (PBMC) from patients with polymyositis and dermatomyositis (PM/DM). Methods IL-1Ra levels in sera from patients and supernatants of unstimulated monocyte cultures were measured by enzyme-linked immunosorbent assay. Expression of IL-1Ra mRNA was analyzed by Northern blotting, and an 86-base pair variable repeat polymorphism in intron 2 of the IL-1Ra gene was determined by polymerase chain reaction. Results Serum IL-1Ra was significantly elevated in 27 patients with active-stage PM/DM when compared with levels in 16 patients with inactive-stage PM/DM and 19 normal controls. Serum concentrations of IL-1Ra were correlated with PM/DM disease activity. IL-1Ra mRNA was detected in freshly isolated PBMC from patients with activestage PM/DM, but not in controls. Moreover, IL-1Ra concentrations were increased significantly in unstimulated monocytes from patients with active-stage PM/DM compared with monocytes from normal controls. However, there were no significant differences in IL-1Ra allele frequencies between patients and normal controls. Conclusion Elevation of both IL-1Ra mRNA and protein in sera of patients with active-stage PM/DM suggest that higher levels of serum IL-1Ra may reflect increased IL-1Ra production in myositis, and that IL-1Ra may regulate IL-1-mediated muscle fiber damage in PM/DM.(Internal Medicine 39: 128-135, 2000)

Beyond the obvious step of limiting use of non-steroidal anti-inflammatory drugs (NSAIDs), the treatment of ulcers induced by NSAIDs remains controversial. We evaluated the efficacy of the proton-pump inhibitor lansoprazole on NSAID-induced ulcers. Ulcers were endoscopically diagnosed in 47 NSAID users. These patients received 30 mg/day lansoprazole, orally, for 6 or 8 weeks (6 weeks for duodenal ulcers and 8 weeks for other ulcers). Ulcer healing was assessed using an established classification system. The presence of immunoglobulin G antibody against Helicobacter pylori was also evaluated. The antibody was present in the sera of 51% of patients (24/47). Most of the ulcers reached scarring stages S1 (healing) or S2 (good healing), and the S2 healing rate was 35%. Two H. pylori seropositive patients did not reach these stages; their ulcers were improved by H. pylori eradication therapy, followed, in one case, by medication with misoprostol. Lansoprazole seemed to be useful for most patients with NSAID-induced ulcers, but a few needed additional treatments.

A 44-year-old woman was hospitalized with a 2-day history of cough, sputum, and fever. There was no history of atopic dermatitis or asthma. On admission, the chest X-ray revealed scattered infiltration in the left upper lung fields. Further examination revealed peripheral blood and bronchoalveolar lavage fluid eosinophilia. Transbronchial lung biopsy revealed eosinophilic pneumonia, with eosinophil infiltration of the alveoli, destroyed basal lumina, and connecting intraluminal fibrosis of the alveolar walls. Based on the findings, we made the diagnosis of chronic eosinophilic pneumonia. Treatment with prednisolone at 60 mg/day resulted in dramatic improvement of both the symptoms and the radiologic abnormalities.

A 59-year-old patient with schizophrenia developed Sjögren's syndrome. She also presented with the lupus anticoagulant attributed to long-term medication with chlorpromazine. Serial plasmapheresis treatments were performed to decrease the anti-coagulant activity. As a result, the activated partial thromboplastin time was temporarily improved, but the lupus anti-coagulant activity did not change. Because of her unstable emotional state, she continued to require chlorpromazine, but took a low dose of aspirin (87 mg/day) and never manifested any signs of thrombotic events. In view of the potential anti-thrombotic effects of chlorpromazine, it may not be necessary to use plasmapheresis in an attempt to reduce anti-coagulant activity among patients with chlorpromazine-induced lupus anti-coagulant.

A 76-year-old man was admitted to Kisen hospital because of lumbago and chest pain. Laboratory examinations revealed a chronic renal failure with marked elevation of the serum BUN (48.8 mg/dl) and creatinine levels (8.2 mg/dl). The serum electrophoresis demonstrated a hypergammaglobulinemia with M peaks. An immunoelectrophoresis demonstrated monoclonal IgD-lambda and IgG-kappa proteins in the serum, and lambda-type Bence Jones protein in the urine (0.4 g/day). Bone marrow smears revealed an abnormal proliferation of atypical plasma cells (43%). A systemic X-ray examination of the skeletal system showed systemic osteoporosis without punched out lesion. The patient was diagnosed as having IgD-lambda type multiple myeloma and IgG-kappa type benign monoclonal gammopathy by quantifying concentration of two M proteins (1,160 mg/dl in IgD, 1,179 mg/dl in IgG, respectively). A combination chemotherapy with melphalan and prednisolone was administered monthly for multiple myeloma, and hemodialysis for the renal failure was performed 3 times a week. A marked improvement of his laboratory findings including a diminution of the serum IgD-lambda M-protein was obtained. On the other hand, IgG-kappa M-protein level was unchanged. Two M-protein levels showed a different behavior after the combination chemotherapy. Although the patient died of congestive heart failure, the partial remission of multiple myeloma has been maintained for 16 months with chemotherapy.

We studied the effects of cytokines such as IL-1 alpha, IL-6 and TNF alpha, and lipopolysaccharide (LPS) on cultured human monocytes. Increased fibronectin (FN) production, as a indicator of the activation of monocytes, was observed with any cytokines or LPS stimulation those were added in the culture medium. These increased FN production by cytokines showed a dose dependent fashion, and 4 hours culture with these cytokines was enough to obtain the amount of FN measured with radioimmunoassay. The combination of sub-optimal dose of cytokines (IL-1 alpha + IL-6, IL-1 alpha, IL-6 + TNF alpha), that could not induce substantial amount of FN with any single cytokine, also could induce FN by cultured monocytes. The specificity of cytokines for the FN production by cultured monocytes was confirmed by the neutralization using monoclonal antibodies specific for each monokines. Northern blot analysis with cDNA specific for FN confirmed the expression of FN mRNA in cultured monocytes stimulated with cytokines or LPS. Cytokine network plays an essential role for immune and inflammatory reaction, and FN has been shown to induce monokines through VLA-5 receptor on cultured monocytes. Our data suggests that monocytes may not always require high concentration of cytokines for the activation of monocytes in vitro, and that the synergistic action of low concentration of cytokines for the activation was enough for the progression of immune or inflammatory reaction.

An alcohol abuser with hepatitis C developed multibacterial sepsis. His mean 100% alcohol intake reached 400 ml/day. In January 2001, he suddenly experienced fever (39°C) with no other symptoms. One week later, he was admitted to our hospital and was subsequently diagnosed with sepsis associated with four species of bacteria (Streptococcus constellatus, Fusobacterium mortiferum, Bacteroides thetaiotaomicron, and non-spore-forming anaerobic gram-positive bacillus). A drip infusion of imipenem/cilastatin was administrated, resulting in a successful therapeutic outcome. No underlying disorder was found except for gastric ulcers and hepatic cirrhosis. Damagedgastric mucosa was assumed to be the possible cause and route for the bacterial invasion.(Internal Medicine 42: 208-210, 200

高齢者インフルエンザ感染症経過中に,急速に進行する低酸素血症と胸部レントゲン写真上のびまん性肺野病変を呈し,さらに血小板減少,高γグロブリン血症,軽度肝機能障害を共通に併発し,症例により非特異的出血疹を呈する興味ある5症例を経験した.これら5症例には,抗生物質投与やヒト免疫グロブリン製剤も無効で,その発熱には解熱剤投与も無効であった.呼吸不全も憎悪し,精査の結果,播種性血管内凝固症候群(DIC)も否定的だったため,救命的に,ステロイドパルス療法(メチルプレドニゾロン1g/日×3日)を施行したところ,全症例に劇的改善がみられた.前述の症状の他,臨床検査所見も正常化した.また全例がパラインフルエンザ(III)抗体価1,024倍以上を呈した.検査上,基礎疾患としての膠原病は否定的だった.しかしながら,ステロイドパルス療法は全例に著効しており,その病態には,パラインフルエンザウイルス(III)感染症に伴う全身的なアレルギー状態の存在や,薬物アレルギーの存在が考察された.なお,今後とも症例を重ねて,免疫学的アプローチによる病態の解析も必要であると思われ,インフルエンザ流行期での高齢罹患者にはなお一層注意を要するものと思われた.

An epidemic of Lyme borreliosis on Hokkaido island, Japan, was surveyed by questionnaire in 587 hunters. The 308 returns (52.4%) revealed episodes of tick bite (usually 2 or more) in 210 cases. Skin rashes appeared in 164 cases. Associated itching, pain, etc., but not skin rash, were more frequent after 2 or more tick bite. Previous determinations of anti-Borrelia burgdorferi antibody titers in these subjects and in controls suggested an association with outdoor activities other than hunting, and among 33 cases of dermatological symptoms and 23 of articular symptoms, 4 and 2, respectively, were antibody-positive. Most of these antibody-positive subjects had suffered tick bite at least twice, but had had no antibiotic treatment. Three subjects with joint disorders were antibody-positive. These findings suggested that the many hunters exposed to Borrelia burgdorferi frequently carried latent infections, and that some had latent form of arthritis, dermatitis and other disorders.

われわれは, RA患者末梢血よりphorbol myristate acetate (PMA)刺激を行いB細胞株であるTKS-1を樹立した. TKS-1は, κ鎖, B細胞マーカーの二重染色, κ鎖遺伝子のrearrangementにより,単クローン性B細胞株であった.さらに従来,単球,顆粒球,ホジキン細胞マーカーとされていたCD 15抗原をその細胞表面に表現していた.このようなB細胞亜分画は,これまで報告されておらず,次に無刺激の末梢血中のLeu M1 (CD 15)+B細胞について検討した.間質性肺炎,蜂窩織炎などの合併症を有する活動性の高いRA患者3例でCD 15+B細胞が末梢血中に認められた.それらのCD 15+B細胞亜分画はステロイドの投与により臨床症状が改善するとともに速やかに消失し, RAの再燃により増加を認めた・他のsystemic lupus erythematosus (SLE)を含む膠原病,感染症,間質性肺炎では, CD 15+B細胞亜分画は末梢血中に認められなかった.ある特定の条件下におかれた活動性の高いRA患者の末梢血中にCD 15+B細胞を認めえた.

ヒト血清中の特異的自然抗体の動態を知る目的で,正常者,全身性エリテマトーデス(SLE)患者,多発性骨髄腫患者および臍帯血清中の抗フォスフォリルコリン抗体(抗PC抗体)価を測定した.正常血清中にはELISA法で十分に検出可能なIgGおよびIgMクラス抗PC抗体が存在した.多クローン性高ガンマグロブリン血症の存在するSLE患者血清中では両クラスの抗PC抗体が増加している例が多く, IgG抗PC抗体は28%に,抗IgM抗体は16%に増加例が認められた.反対に正常免疫グロブリンの低下する骨髄腫患者血清中では大部分の例で抗PC抗体が低下していた.母体由来のIgGのみが通過すると考えられている臍帯血清でもIgMクラスのみならずIgGクラス抗PC抗体の低下があり,胎盤でなんらかの選択機構が関与しているものと考えられた.末梢血におけるPC特異的B細胞の頻度を検討したところ,正常者ではpokeweed mitogen (PWM)で刺激後約6倍に増加するが, SLE末梢血ではPWM刺激後,むしろやや減少する傾向を示した.ヒト血清中の抗PC抗体はマウスの抗PC抗体とは異なりT15 idiotypeを表現しておらず,ヒトに固有のidiotypeをもつことが推測された.

Known causes of eosinophilia include parasitic infections, allergic diseases, autoimmune diseases, neoplasms, and drug allergies.[1] Corticosteroid derivatives such as prednisone, prednisolone, methylprednisolone, dexamethasone, etc. are often used as first-line drugs to ameliorate the condition.[2] The ESR is used as an evaluation of lupus activity in rheumatic diseases. This report documents a patient with systemic lupus erythematosus (SLE) in whom accelerated ESR and eosinophilia were resolved by substituting prednisolone for methylprednisolone.

To add to our knowledge of collagen diseases, plasma fibronectin (FN) in patients with systemic lupus erythematosus (SLE) has been measured, and it was determined that the plasma FN value in those with SLE was 454 +/- 36 micrograms/ml, is significantly higher than the FN value in normal subjects (234 +/- 21 micrograms/ml) than that of patients with FN value of patients with active SLE was significantly higher (591 +/- 46 micrograms/ml) that of the patients with non-active SLE (287 +/- 31 micrograms/ml). The plasma FN value of SLE patients was also seen to be associated with the peripheral blood platelet count and with the dose level of the corticosteroid hormone administered to patients. In active SLE patients, it was similarly found that the plasma FN value had a significant correlation with the peripheral blood lymphocyte count and with the dose level of the corticosteroid hormone given to patients. Since the plasma FN value is known to be high in untreated SLE patients, it was felt that the increase of the FN value in SLE patients is not due to the effect of the corticosteroid but to the disease itself.

Thrombophilic dysfibrinogen Tokyo V was identified in a 43-year-old man with recurrent thromboembolism. Based on analyses of the patient fibrinogen genes, the amino acid sequence of the aberrant fibrinogen peptide, and deglycosylation experiments, fibrinogen Tokyo V was shown to have an amino acid substitution of γ Ala327Thr and possibly extra glycosylation at γ Asn325 because the mutation confers the N-linked glycosylation consensus sequence Asn-X-Thr. The mutation resulted in impaired function and hypofibrinogenemia (hypodysfibrinogen). Polymerization of fibrin monomers derived from patient fibrinogen was severely impaired with a partial correction in the presence of calcium, resulting in very low clottability. Additionally, a large amount of soluble cross-linked fibrin was formed upon thrombin treatment in the presence of factor XIII and calcium. However, Tokyo V–derived fibrin was resistant to degradation by tissue plasminogen activator (tPA)–catalyzed plasmin digestion. The structure of Tokyo V fibrin appeared severely perturbed, since there are large pores inside the tangled fibrin networks and fiber ends at the boundaries. Taken together, these data suggest that Tokyo V fibrin clots are fragile, so that fibrinolysis-resistant insoluble fibrin and soluble fibrin polymers may be released to the circulation, partly accounting for the recurrent embolic episodes in the patient. (Blood. 2004;103:3045-3050)

The placenta is one of the few non-hematopoietic tissues to express granulocyte colony stimulation factor (G-CSF). Placental G-CSF production is considered to be one of the major causes of granulocytosis during pregnancy although its physiological role in pregnancy has not yet been examined.The effects of G-CSF on interleukin (IL)-2 and/or IL-12 induced interferon (IFN)-gamma production of magnetic cell sorting (MACS) sorted decidual lymphocytes was examined by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT). The effect of G-CSF on cytotoxicity of decidual lymphocytes against the choriocarcinoma cell line JEG-3 was examined by lactate dehydrogenase (LDH) release assay.As previously reported by us, IL-2 and/or IL-12 activated decidual mononuclear cells were capable of killing choriocarcinoma cells. We observed that G-CSF abolished IFN-gamma production and cytotoxicity of decidual mononuclear cells and MACS sorted CD56+ cells.In addition to its well-known trophic effects on hematopoiesis, our results suggest about new roles of G-CSF in reproductive immunology.

Objective. Regarding the interaction of Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs), we cannot accept unanimous conclusions in inducing gastric ulcer. We therefore evaluated the role of Helicobacter pylori and NSAIDs in inducing gastric ulcer. Methods. Dyspeptic patients receiving NSAIDs underwent endoscopic examination. Gastric ulcer formation and H. pylori status were investigated. Biopsy specimens from the antrum and lower body of the stomach were prepared for the rapid urease test and pathological evaluation. Anti-H. pylori antibody was measured by enzyme-linked immunosorbent assay. Results. Two hundred and twenty-six patients receiving NSAIDs (220 chronic and six on-demand users) underwent gastrofibrescopic examination. There were 110 patients with gastric ulcer and 111 non-ulcer patients with gastritis. The remaining five patients had neither. NSAID users with gastric ulcer showed a low prevalence of H. pylori compared with those without them w55u110 (50.0%) vs 79u111 (71.2%), P < 0.01x. The same tendency was seen when patients receiving low-dose aspirin and those with rheumatoid arthritis were analysed separately w13u29 (44.8%) vs 50u62 (80.6%), P < 0.01, and 11u33 (33.3%) vs 16u26 (61.5%), P < 0.06 with Yates’ correction, respectivelyx. Conclusion. Helicobacter pylori infection appeared to be a risk factor for developing gastritis, but we found no evidence that it increases gastric ulcer formation in NSAID users with dyspepsia.

We report two patients with scleroderma, 73-year-old female and 67-year-old female, who developed anti neutrophil cytoplasmic autoantibody (ANCA) associated rapid progressive glomerulonephritis (RPGN). Both patients have had a long history of scleroderma (23 and 14 years, respectively) when ANCA-associated glomerulonephritis occurred. In the first patient, scleroderma was localized in both fingers. She has been followed-up as CREST syndrome rather than systemic sclerosis. The complaints on admission were leg edema and left chest pain in the first patient, and a pyrexia and dyspnea in the second patient. Both patients showed pulmonary manifestation (pleural effusion in the first patient, interstitial pneumonia and alveolar hemorrhage in the second patient, respectively) and rapid progressive glomerulonephritis. Both patients died in spite of corticosteroid therapy. Autopsy findings in the second patient demonstrated crescentic glomerulonephritis and alveolar hemorrhage. Our cases demonstrated that MPO-ANCA associated glomerulonephritis could be associated with limited scleroderma as well as systemic scleroderma. In these condition, the prognosis will be poor if scleroderma seemed to be stable.

The objective of this study was to assess the effect of beraprost sodium, an oral prostacyclin analogue, on pulmonary function in patients with systemic sclerosis. Seventeen patients, with systemic sclerosis and predicted percent values of carbon monoxide diffusion capacity (%DLCO) of less than 95, received beraprost sodium for at least 12 months. Conventional testing for pulmonary function was performed at 12-month intervals and changes were evaluated with special reference to DLCO. Twelve patients completed the treatment. Nine patients showed improvement in DLCO (12.1 +/- 2.3 to 15.5 +/- 4.4 ml/min/mmHg, P0.006) and 10 patients showed an increase in %DLCO (66.6 +/- 11.9 to 87.7 +/- 23.2%, P0.004). Total lung capacity, vital capacity and forced expiratory volume remained unchanged. This study showed that DLCO levels in patients with systemic sclerosis improved after the administration of beraprost sodium, probably due to the decrease in pulmonary vascular resistance accompanied by increased cardiac output.

Idiopathic dilatation of the pulmonary artery (IDPA) is an uncommon anomaly occurring in 0.6% of patients with congenital heart disease,1 2 and may be bilateral or unilateral.3-9 We report on a patient with IDPA who concomitantly developed polymyositis (PM) and interstitial pneumonitis (IP). On 25 August 1997 a 63 year old woman was referred to our hospital because of dyspnoea, pyrexia, arthralgia, raised levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and bilateral diffuse shadows on chest x ray examination. On admission, a fine crackling sound was audible in the lung fields. We could not confirm Gottron's sign and heliotrope erythema. Laboratory examination disclosed increases of LDH (1194 IU/l), AST (61 IU/l), creatinine kinase (CK; 2078 IU/l), and aldolase (36.8 IU/l) in the serum …

Plasmacytoma is a tumor derived from plasma cells, the effector cells of the B lymphoid lineage. Among the extramedullary plasmacytomas, gastric plasmacytoma is rare and constitutes only 5% of these tumors.1 Recently Kinoshita et al.2 described an interesting patient with low-grade gastric mucosaassociated lymphoid tissue (MALT) lymphoma in whom monoclonal immunoglobulin (Ig) (IgM-λ) was detected in serum and gastric juice, suggesting a close pathogenic relationship between gastric MALT lymphoma and gastric plasmacytoma.2 Although a close causative association between Helicobacter pylori infection and gastric MALT lymphoma has been recognized,3 to our knowledge there has been only one report (in Spanish) detailing the relationship between H pylori and gastric plasmacytoma, which described a gastric plasmacytoma in a 14-yearold patient with H pylori infection in whom the tumor regressed after antibiotic therapy.4 This is the second case report of gastric plasmacytoma associated with H pylori infection.

The aim of the study was, to examine the relationship between serum levels of soluble tumour necrosis factor receptors (sTNF-R) and the gene expression of two types of receptor for TNF (TNF-R), a 55 a receptor (TNF-R1) and a 75 kDa receptor (TNF-R2), bloodin peripheral mononuclear cells (PBMC) from patients with polymyositis and dermatomyositis (PM/DM). Soluble tumour necrosis factor receptor 1 (sTNF-R1) and soluble tumour necrosis factor receptor 2 (sTNF-R2) levels in sera from patients were measured by enzyme-linked immunosorbent assay. Expression of TNF-R1 and TNF-R2 mRNAs in PBMC was analysed by Northern blotting. Serum sTNF-R1 and sTNF-R2 levels were elevated significantly in 25 patients with active-stage PM/DM, compared to those in 18 patients with inactive-stage PM/DM and 32 normal controls. Serum concentrations of sTNF-R1 and sTNF-R2 were correlated with PM/DM disease activity. TNF-R1 gene expression was enhanced in freshly isolated PBMC from patients with active-stage PM/DM. In contrast, TNF-R2 mRNA was expressed constitutively in patients with active-stage PM/DM and in normal controls. The expression of TNF-R1 and TNF-R2 mRNAs in PBMC and elevation of their soluble forms in the sera of patients with active-stage PM/DM suggest increased proteolytic cleavage of cell surface TNF-R from PBMC in patients with active-stage PM/DM, and that sTNF-R may regulate TNF-alpha-mediated muscle fibre damage in PM/DM.

It has been proposed that immune responses in mammalian normal pregnancy are Th2-like, thereby protecting the fetus and placenta from being rejected. Administration of exogenous Th1 cytokines into pregnant mice is reported to induce feto-placental resorption. However, the effects of exogenous Th2 cytokines and Th2 directed responses in pregnant animals have not been well studied. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1 responses, respectively, in the induction of fetal resorption and development of experimental pre-eclampsia. Transfer of either IL-4 and/or IL-12 stimulated splenocytes from BALB/C virgin female mice into BALB/C pregnant mice mated with either C57BL/6 or BALB/C male mice resulted in fetal resorption and glomerular nephritis associated with hypertension and proteinuria. In mice treated with IL-12 stimulated splenocytes, fatty liver degeneration associated with bile retention was observed. These results indicate that both excessive Th1 and Th2 activation contribute to the development of fetal resorption and pre-eclampsia, but that Th1 is critical to the development of liver degeneration.

SUMMARY We studied the effects of the cytokines IL-1α, IL-6, tumour necrosis factor-alpha (TNF-α), IL-4, IL-10, IL-13 and transforming growth factor-beta (TGF-β) on fibronectin (FN) production by cultured-human monocytes. IL-1α, IL-6 and TNF-α all increased FN production, an indicator of monocyte activation. These cytokines increased FN production in a dose-dependent fashion, with a 4-h treatment being sufficient to measure FN production by radioimmunoassay. Conversely, IL-4, IL-10 and IL-13 strongly inhibited cytokine-induced FN production, while TGF-β only partially inhibited FN production. The combination of suboptimal doses of cytokines (IL-1α+ IL-6, IL-1α+ TNF-α, IL-6 + TNF-α), which could not singly induce substantial amounts of FN, were able to induce FN production by cultured monocytes. Northern blot analysis with a cDNA specific for FN confirmed the expression of FN mRNA in cultured monocytes stimulated with a single cytokine or a combination of cytokines. Our data demonstrate that monocytes may not always require high concentrations of cytokines for activation in vitro, and that the synergistic or additive action of low levels of cytokines on monocyte activation may be sufficient to promote immune or inflammatory reactions. Our data also suggest that certain T cell cytokines may regulate monocyte activation.

The psychiatric and cognitive condition of a patient with lupus psychosis was evaluated. Using a device that detects the corneal reflection of infrared light, the patterns of eye tracking movements were recorded before the onset of lupus psychosis, after remission, and again 1 year later. Electroencephalographic findings and cerebrospinal fluid levels of both interferon alpha and interleukin-6 were also obtained longitudinally. Electroencephalographic findings and clinical signs were correlated to the levels of interferon alpha in cerebrospinal fluid. Analysis of exploratory eye movements revealed marked decreases in the number of eye fixation, mean eye-scanning length and total eye-scanning length. Even though the lupus psychosis resolved and the electroencephalographic findings became normal, the eye movement patterns showed remaining deterioration. It was concluded that analysis of exploratory eye movements in patients with systemic lupus erythematosus may be useful in diagnosing lupus psychosis, and may also present a diagnostic clue to subclinical lupus psychosis.

We reported a case of primary macroglobulinemia with stomach and pulmonary invasion. The patient was 71 years-old who had cervical lymphadenopathy and abdominal pain. Biopsy material of cervical lymph node showed non-Hodgkin's lymphoma, and he was diagnosed primary macroglobulinemia by IgM immunological histo-chemical staining of materials of stomach biopsies. Combination chemotherapies were not effective for the reduction of IgM-lambda protein, and organ invasion seemed to be progressive, so we tried interferon-alpha (IFN-alpha) to control M component. Daily injection of 6 megaunits of IFN-alpha induced significant reduction of M component and pulmonary invasion. This favorable changes were observed for 1 year. However, his pulmonary invasion on X-ray films relapsed and he died of respiratory failure by reason of severe pneumonia. IFN-alpha is currently available for myeloproliferative disease, especially chronic myelogenous leukemia and multiple myeloma. This case report showed that IFN-alpha was also available for primary macroglobulinemia.

β1 Integrins are considered to be essential for the differentiation of bone-marrow B cells through an interaction with fibronectin-expressed bone-marrow stromal cells. The expression of very late antigens-4 (VLA-4) and −5 (VLA-5) by CD38bright bone-marrow cells in patients with multiple myeloma was measured by flow cytometry using specific monoclonal antibodies. The percentage of CD38bright bone-marrow cells appeared to correlate with that of bone-marrow plasma cells as judged by examination of bone-marrow smears ( r = 0.911, P < 0.0001). Expression of VLA-4 and VLA-5 by CD38bright cells varied between patients, but the expression of VLA-4 was always equal to or greater than that of VLA-5. The ratio of VLA-4 to VLA-5 expression (VLA-4:VLA-5 ratio) was calculated and compared with the clinical features of the myeloma patients. A high VLA-4: VLA-5 ratio (> 2.0) was associated with the presence of plasmacytomas and urinary Bence-Jones protein was more common in this group. No other correlations between the clinical features of the disease and the expression of β1 integrins were found.

The clinical use of antithymocyte globulin is rarely reported in patients with rheumatic diseases. We describe the use of this agent in a patient with systemic lupus erythematosus who concomitantly developed severe pancytopenia. High-dose methylprednisolone therapy had been unsuccessful in controlling either the disease exacerbation or the pancytopenia. Antithymocyte globulin and cyclosporin A were therefore administered to achieve immunosuppression. The exacerbation of disease activity was gradually lessened, except for persistent thrombocytopenia and anaemia. Severe and persistent immunosuppression, however, led to a fatal brain abscess. The combined use of both antithymocyte globulin and cyclosporin A induced potent immunosuppression, and should be confined to selected patients with systemic lupus erythematosus, and administered under detailed monitoring.

The effect of fibronectin (FN) on IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6 production was investigated with cultured monocytes isolated from human peripheral blood. Monokine concentrations were determined by ELISA. FN markedly stimulated the secretion of IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6 from cultured monocytes. Northern blot analysis revealed the up-regulated expression of mRNA specific for each monokine on exposure of monocytes to FN. GM-CSF, IFN-gamma, and LPS synergistically enhanced FN-induced IL-1 alpha production. We further investigated the signal transduction pathways involved in FN-stimulated monokine secretion. FN-stimulated TNF-alpha secretion was markedly inhibited by either herbimycin A or genistein, inhibitors of protein tyrosine kinase (PTK), but was not affected by staurosporin, a inhibitor of protein kinase C (PKC). The results suggest that PTK is required for FN-stimulated TNF-alpha secretion. In contrast, LPS-stimulated TNF-alpha secretion was markedly inhibited by not only herbimycin A or genistein, but also staurosporin. Therefore, both PTK and PKC may be involved in LPS-stimulated TNF-alpha secretion. We also demonstrated that, in monocytes, cytoplasmic proteins of about 70 and 240 kDa were phosphorylated after FN stimulation. Our results indicate that FN may contribute to the inflammatory response of monocyte by inducing monokine production.

We present the unusual case of 16-year-old girl who developed intractable convulsions five days after the onset of a cold. Meningeal signs, lymphopenia, proteinuria, and lupus anticoagulant were also present. Treatment with anticonvulsants, antituberculous agents, and adenine arabinoside were ineffective. The initiation of methylprednisolone pulse therapy immediately resolved convulsions and fever. The diagnosis, suggested by the clinical course and the marked improvement of the meningoencephalitis by pulse therapy, was an encephalitic form of acute disseminated encephalomyelitis. Clinical and laboratory findings indicated that an immune disorder may have triggered an abnormal response to a viral infection leading to this patient's neurologic disorder.