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ABSTRACT: Accumulating lines of evidence have suggested that regulatory T-cells (Tregs) play a central role in T-cell mediated immune response and the development of type 1A and fulminant type 1 diabetes. CD4(+) FOXP3(+) T-cells are composed of three phenotypically and functionally distinct subpopulations; CD45RA(+) FOXP3(low) resting Tregs (r-Tregs), CD45RA(-) FOXP3(high) activated Tregs (a-Tregs) and CD45RA(-) FOXP3(low) nonsuppressive T-cells (non-Tregs). We aimed to clarify the frequency of these three subpopulations in CD4(+) FOXP3(+) T-cells and the function of a-Tregs with reference to subtypes of type 1 diabetes. We examined 20 patients with type 1A diabetes, 15 patients with fulminant type 1 diabetes, 20 patients with type 2 diabetes and 30 healthy control subjects. A flow cytometric analysis in the peripheral blood was performed for the frequency analysis. Suppressive function of a-Tregs was assessed by their ability to suppress the proliferation of responder cells in a 1/2:1 co-culture. A flow cytometric analysis in the peripheral blood demonstrated that the frequency of a-Tregs was significantly higher in type 1A diabetes, but not in fulminant type 1 diabetes, than the controls. Further, the proportion of a-Tregs among CD4(+) FOXP3(+) T-cells was significantly higher in patients with type 1A diabetes with detectable C-peptide but not in patients with type 1A diabetes without it and with fulminant type 1 diabetes. A proliferation suppression assay showed that a-Tregs were functionally impaired both in fulminant type 1 diabetes and in type 1A diabetes. In conclusion, a-Tregs were functionally impaired, related with residual insulin-secreting capacity and may be associated with the development of type 1 diabetes.
Clinical & Experimental Immunology 04/2013; · 3.36 Impact Factor
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ABSTRACT: The efficacy and safety of liposomal amphotericin B (L-AMB) in the treatment of invasive fungal infections (IFIs) were retrospectively evaluated for patients with connective tissue diseases (CTDs) during treatment with immunosuppressive therapy. Subjects were 13 patients with CTDs complicated by IFI, on the basis of clinical symptoms, imaging findings, and microbiological and histological examinations. All patients were treated with L-AMB. Efficacy and safety were evaluated before and after administration of L-AMB. Underlying diseases were systemic lupus erythematosus for 4 patients, rheumatoid arthritis for 3, microscopic polyangiitis for 2, adult-onset Still disease for 1, dermatomyositis for 1, and mixed connective tissue disease for 1. Eight patients were resistant to other antifungal drugs. Prednisolone was given to 11 patients and the median dose was 10 mg/day. Immunosuppressants were used for 8 patients. The median duration of administration of L-AMB was 8.5 days (range 4-38 days). In proven and probable diagnosis patients (n = 5), the treatment was effective for 3 patients and ineffective for 2 (efficacy rate 60 %). Serum 1,3-β-D-glucan antigenemia (BG) levels decreased after treatment in the 2 patients who were positive for BG. Serum Aspergillus galactomannan antigen levels decreased in 3 of 4 patients with Aspergillus infection. No patient died of IFI. Regarding potential adverse reactions, there were no significant changes in serum creatinine and potassium levels. L-AMB is effective and well-tolerated for treatment of IFI in patients with CTDs.
Journal of Infection and Chemotherapy 01/2013; · 1.80 Impact Factor
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ABSTRACT: Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete destruction of pancreatic β cell. The most common form of type 1 diabetes mellitus with onset during pregnancy has been shown to be FT1DM at least in Japan. We previously reported that the ratio of glycated albumin (GA) to HbA1c (GA/HbA1c ratio) is elevated in FT1DM patients at the diagnosis. In the present study, we investigated whether the GA/HbA1c ratio is also elevated in FT1DM with onset during pregnancy (P-FT1DM). The study subjects consisted of 7 patients with P-FT1DM. Ten patients with untreated type 2 diabetes mellitus (T2DM) discovered during pregnancy (P-T2DM) and 9 non-pregnant women with untreated T2DM (NP-T2DM) were used as controls. All study patients satisfied HbA1c < 8.7%, the diagnostic criteria for FT1DM. The GA/HbA1c ratio in the P-FT1DM patients at the diagnosis was significantly higher than that in the P-T2DM patients and the NP-T2DM patients. The GA/HbA1c ratio was ≥ 3.0 in all P-FT1DM patients, whereas it was < 3.0 in 8 of 10 P-T2DM patients and all NP-T2DM patients. The GA/HbA1c ratio was also elevated in P-FT1DM patients at the diagnosis compared with T2DM with or without pregnancy. J. Med. Invest. 60: 41-45, February, 2013.
The Journal of Medical Investigation 01/2013; 60(1.2):41-45.
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ABSTRACT: Eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids, is a neuroprotective lipid with anti-inflammatory properties. We investigated the possible therapeutic effect of EPA on experimental autoimmune encephalomyelitis (EAE). EAE mice were fed a diet with or without EPA. The clinical EAE scores of the EPA-fed mice were significantly lower than those of the non-EPA mice. In the EPA-treated mice, IFN-γ and IL-17 productions were remarkably inhibited and the expression levels of peroxisome proliferator-activated receptors were significantly enhanced in the CNS-infiltrating CD4T cells. Thus EPA shows promise as a potential new therapeutic agent against multiple sclerosis.
Journal of neuroimmunology 12/2012; · 2.84 Impact Factor
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British Journal of Haematology 12/2012; · 4.94 Impact Factor
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ABSTRACT: BACKGROUND: Microscopic polyangiitis (MPA) is a necrotizing vasculitis of the small vessels. Among the nerve lesions of MPA, the incidence of multiple mononeuritis is high, but cranial nerve palsy is rarely reported. CASE: A female patient with oculomotor nerve palsy associated with MPA. OBSERVATIONS: The 68-year-old patient was admitted to our hospital with a high fever, numbness and weakness of the extremities, and muscle weakness. Multiple mononeuritis and purpura were observed. The urine was positive for occult blood and protein and the creatinine level was 1.2 mg/dL, indicating renal impairment. The levels of C-reactive protein (15.5 mg/dL) and myeloperoxidase-antineutrophil cytoplasmic antibody titers (600 ELISA units) were elevated. MPA was diagnosed, and 45 mg/day prednisolone was initiated. On the fifth day after the initiation of treatment, the patient suddenly developed diplopia and blepharoptosis of the left eye. Anisocoria and decreased light reflex as well as limited supraduction, infraduction, and adduction were also observed in the eye. Left oculomotor nerve palsy was diagnosed. The palsy gradually improved with continued prednisolone treatment. CONCLUSIONS: We encountered a rare case of MPA complicated by oculomotor nerve palsy.
Japanese Journal of Ophthalmology 12/2012; · 0.92 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disease often complicated by vasculitis. Pericarditis is a serious complication caused by vasculitis, resulting in retention of pericardial effusion that sometimes induces cardiac tamponade. We report a patient with RA in whom pericarditis improved after tocilizumab administration. A male patient was diagnosed with RA and chronic renal failure in 1980 and was treated with salazosulfapyridine, but disease activity remained high. In January 2012, at the age of 73 years, he developed organizing pneumonia as a complication and was admitted to our hospital. Treatment with prednisolone 30 mg/day was initiated. However, 20 days after initiation of treatment, chest pain and palpitation developed, and chest computed tomography (CT) and echocardiography (ECG) revealed retention of pericardial effusion without cardiac tamponade. Rheumatoid nodules and interstitial pneumonia were also observed, and serum C3 level was decreased. A diagnosis of pericarditis caused by vasculitis was made based on these findings, and tocilizumab 8 mg/kg was administered. His symptoms improved gradually, and chest CT and ECG showed no pericardial effusion after about 3 weeks. No adverse effects of tocilizumab were observed during the clinical course. Although there are only a few reports of the effects of tocilizumab on vasculitis associated with RA, tocilizumab administration appears worthwhile in RA patients with vasculitis who do not respond to conventional treatment.
Modern Rheumatology 12/2012; · 1.58 Impact Factor
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British Journal of Haematology 12/2012; · 4.94 Impact Factor
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Shoko Nakayama,
Taiji Yokote,
Kazuki Iwaki,
Nobuya Hiraoka,
Yuji Hirata,
Toshikazu Akioka,
Takuji Miyoshi,
Ayami Takayama,
Uta Nishiwaki,
Yuki Masuda,
Motomu Tsuji, Toshiaki Hanafusa
Acta oncologica (Stockholm, Sweden) 12/2012; · 2.27 Impact Factor
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Shoko Nakayama,
Taiji Yokote,
Kazuki Iwaki,
Toshikazu Akioka,
Takuji Miyoshi,
Yuji Hirata,
Ayami Takayama,
Uta Nishiwaki,
Yuki Masuda,
Motomu Tsuji, Toshiaki Hanafusa
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ABSTRACT: BACKGROUND: Clear cell sarcoma (CCS) and malignant melanoma share overlapping immunohistochemistry with regard to the melanocytic markers HMB45, S100, and Melan-A. However, the translocation t(12; 22)(q13; q12) is specific to CCS. Therefore, although these neoplasms are closely related, they are now considered to be distinct entities. However, the translocation is apparently detectable only in 50%--70% of CCS cases. Therefore, the absence of a detectable EWS/AFT1 rearrangement may occasionally lead to erroneous exclusion of a translocation-negative CCS. Therefore, histological assessment is essential for the correct diagnosis of CCS. Primary CCS of the bone is exceedingly rare. Only a few cases of primary CCS arising in the ulna, metatarsals, ribs, radius, sacrum, and humerus have been reported, and primary CCS arising in the pubic bone has not been reported till date. CASE PRESENTATION: We present the case of an 81-year-old man with primary CCS of the pubic bone. Histological examination of the pubic bone revealed monomorphic small-sized cells arranged predominantly as a diffuse sheet with round, hyperchromatic nuclei and inconspicuous nucleoli. The cells had scant cytoplasm, and the biopsy findings indicated small round cell tumor (SRCT). Immunohistochemical staining revealed the tumor cells to be positive for HMB45, S100, and Melan-A but negative for cytokeratin (AE1/AE3) and epithelial membrane antigen. To the best of our knowledge, this is the first case report of primary CCS of the pubic bone resembling SRCT. This ambiguous appearance underscores the difficulties encountered during the histological diagnosis of this rare variant of CCS. CONCLUSION: Awareness of primary CCS of the bone is clinically important for accurate diagnosis and management when the tumor is located in unusual locations such as the pubic bone and when the translocation t(12; 22)(q13; q12) is absent.
BMC Cancer 11/2012; 12(1):538. · 3.01 Impact Factor
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ABSTRACT: Aim: Previous studies have revealed that blockade of the renin angiotensin system attenuates plaque vulnerability and reduces cardiovascular events; however, few studies have compared the effects of an angiotensin-converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB) and evaluated combination therapy. The objective of this study was to compare the efficacy and mechanisms of plaque stabilization by ACEI or ARB and to determine the effects of combination therapy.Methods: Twenty-eight male Japanese white rabbits were fed a high-cholesterol diet after balloon injury of the carotid arteries, then separated into ACEI (n= 7; imidapril 0.5 mg/kg/day), ARB (n= 7; TA606 4.5 mg/kg/day), combination (n= 7; imidapril 0.5 mg/kg/day+TA606 4.5 mg/kg/day), and vehicle (n= 7) groups.Results: No difference in plaque volume was identified among the 4 groups. ACEI or ARB increased the thickness of the fibrous cap, collagen content and the number of smooth muscle cells in the intima (% smooth muscle cell in intima: ACEI, 36.3%; ARB, 36.4%; vehicle, 14.9%), and reduced the accumulation of macrophages (% macrophages in intima: ACEI, 20.1%; ARB, 24.0%; vehicle, 37.9%), suggesting the plaque-stabilizing effects of each drug. ACEI reduced matrix metalloproteinase (MMP)-9 expression and gelatinolytic activity in the intima. While ARB did not change gelatinolytic activity, accumulation ot T cell in the intima was suppressed. Combination therapy did not show additive effects.Conclusion: These results suggest that ACEIs and ARBs have similar, but not additive, plaque-stabilizing effects. Each agent showed specific effects, with ACEIs decreasing gelatinolytic activity and ARBs suppressing T cell accumulation.
Journal of atherosclerosis and thrombosis 11/2012; · 2.69 Impact Factor
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ABSTRACT: BACKGROUND: Valvular aortic stenosis (AS) is not an infrequent condition in the aged population. Activation of renin-angiotensin system (RAS) is presumed to be involved in the development of AS; however, but direct evidence seems to be limited. We herein examined the effect of the administration of angiotensin II (Ang II) on the development of aortic valve thickening in apolipoprotein-E (ApoE)-deficient mice. METHODS AND RESULTS: Male ApoE-deficient mice were divided into three groups: control (saline, n = 8), mice that were administered low-dose Ang II (500 ng/kg/min, n = 11), and those with high-dose Ang II (1000 ng/kg/min, n = 11) administration for 4 weeks. Administration of high-dose, but not low-dose, Ang II significantly induced aortic valve thickening. It was found that in the aortic valve leaflets of high-dose Ang II group, integrity of endothelial cells was impaired and the number of myofibroblasts was increased. These phenomena induced by high-dose Ang II were suppressed by Ang II type 1 receptor blocker olmesartan (n = 15), but not by the dilatator, hydralazine (n = 13). Olmesartan also suppressed dilatation of aortic diameter, although it did not significantly affect the plaque area, in the abdominal aorta in ApoE-deficient mice. CONCLUSION: Administration of Ang II to genetically hyperlipidemic mice induced aortic valve thickening by a pressor-independent mechanism. Role of RAS activation in the development of AS in dyslipidemic patients should further be investigated.
Atherosclerosis 11/2012; · 3.79 Impact Factor
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Shoko Nakayama,
Taiji Yokote,
Yuji Hirata,
Kazuki Iwaki,
Toshikazu Akioka,
Takuji Miyoshi,
Uta Nishiwaki,
Yuki Masuda,
Nobuya Hiraoka,
Ayami Takayama,
Yasuichiro Nishimura,
Motomu Tsuji, Toshiaki Hanafusa
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ABSTRACT: The accurate determination of cytoplasmic immunoglobulin (cIg) light chain (LC) expression is important to differentiate reactive plasmacytosis from a clonal plasma cell neoplasm such as plasma cell myeloma (PCM). Through retrospective analysis, we studied the cytoplasmic kappa/lambda ratio of CD38-positive plasma cells in the bone marrow from 19 PCM patients and 19 controls. To demonstrate cIg LC expression, the bone marrow was immunostained for IgA, IgG, IgM, kappa, and lambda. The kappa/lambda ratio was defined as the ratio of the kappa-positive cell to the lambda-positive cell in plasma cells. PCM cells were distinguished from normal plasma cells by cut-off levels between 0.59 and 4.0, a sensitivity of 94.7%, and a specificity of 94.7%. The detection of the cytoplasmic kappa/lambda ratio of CD38-positive plasma cells may be a useful tool in the diagnosis of PCM and the correct diagnosis of PCM may be achieved more simply.
Hematology (Amsterdam, Netherlands) 11/2012; 17(6):317-20. · 1.33 Impact Factor
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ABSTRACT: Context:Fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes characterized by an extremely abrupt onset. FT1D cases associated with the drug-induced hypersensitivity syndrome (DIHS) have recently been reported.Objective:The clinical characteristics of FT1D associated with DIHS were investigated in this study.Methods:Case reports of FT1D associated with DIHS in Japanese subjects were collected and analyzed by means of a questionnaire to the authors. A nationwide questionnaire survey was administered to dermatology specialists, concerning the frequency of FT1D associated with DIHS.Results:In 15 case reports, the mean age at onset of FT1D was 53.4 yr and the mean time for its development from the onset of DIHS was 39.9 d. A higher frequency of human leukocyte antigen (HLA) B62, but not of HLA DR was found in FT1D with DIHS than that for cases without DIHS (P < 0.001). The reactivation of herpes virus 6 and cytomegalovirus was detected in 11 and four cases, respectively. Among 746 patients with DIHS in the nationwide survey, four developed FT1D during a 3-yr period. The frequency of FT1D in DIHS (0.54%) was much higher than that in the general Japanese population (0.010%).Conclusions:The clinical characteristics of FT1D with DIHS were similar to those without DIHS except for the high frequency of HLA B62, which may be involved in the pathogenesis of FT1D with DIHS. Because the frequency was much higher than that in the general Japanese population, FT1D should be kept in mind when DIHS develops.
The Journal of clinical endocrinology and metabolism 10/2012; · 6.50 Impact Factor
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Shoko Nakayama,
Taiji Yokote,
Yuji Hirata,
Kazuki Iwaki,
Toshikazu Akioka,
Takuji Miyoshi,
Ayami Takayama,
Uta Nishiwaki,
Yuki Masuda,
Toshiyuki Ikemoto,
Hidema Tanaka,
Yasuichiro Nishimura,
Motomu Tsuji, Toshiaki Hanafusa
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ABSTRACT: BACKGROUND: World Health Organization (WHO) criteria are commonly used to diagnose plasma cell myeloma (PCM); however, these criteria are complex and require several laboratory parameters. For differentiating reactive plasmacytosis from clonal plasma cell (PC) neoplasms such as PCM, it is important to accurately determine the expression of cytoplasmic immunoglobulin light chains. METHODS: We retrospectively analyzed the records of 27 selected patients with PCM who underwent bone biopsies for confirmative diagnosis according to WHO criteria. Twenty-three controls were also investigated. In the present study, all the samples were analyzed using flow cytometry (FC) in the side scatter vs. CD38 histogram mode, and the CD38-gated PC population was identified. Bivariate histograms of CD138/kappa and CD138/lambda were assessed, and the ratios of dual-positive cells to the CD138+ PC population were calculated. The kappa/lambda ratio was defined as the ratio of CD138/kappa to CD138/lambda. RESULTS: PCM cells were distinguished from normal PCs using cutoff levels between 0.76 and 1.5, at a sensitivity of 96.3% and specificity of 95.7%. CONCLUSIONS: Three-color FC analysis is simple to perform and inexpensive, with clinically relevant data obtained soon after the completion of FC measurements. The detection of the cytoplasmic kappa/lambda ratio of CD38-gated CD138+ PCs may be a useful tool in the diagnosis of PCM. To the best of our knowledge, this report represents the first diagnostic assessment of the cytoplasmic kappa/lambda ratio in CD38-gated CD138+ PCs using FC analysis. This method may help in more simple, efficient, rapid, and accurate diagnosis of PCM.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1568085959771735.
Diagnostic Pathology 09/2012; 7(1):131. · 1.64 Impact Factor
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ABSTRACT: Apolipoprotein B-48 (Apo B-48) is a constituent of chylomicrons and chylomicron remnants, and is thought to be one of the risk factors for atherosclerosis. We evaluated the effect of L-thyroxine (L-T(4)) replacement on serum Apo B-48 levels in patients with primary hypothyroidism. Eighteen patients with overt hypothyroidism (OH) and 18 patients with subclinical hypothyroidism (SH) participated in the study. The lipid profiles, including Apo B-48, were measured in patients with hypothyroidism before and 3 months after L-T(4) replacement. After L-T(4) replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein (a) [Lp(a)], were significantly decreased in patients with OH. In patents with SH, the serum levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), apolipoprotein B (Apo B), and Apo B-48 decreased significantly after L-T(4) replacement. The serum levels of triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (Apo A1), and Lp(a) did not change significantly. In all 36 patients, the reduction in the Apo B-48 levels correlated significantly with the reduction in TSH levels (r = 0.39, P<0.05). This study showed clearly that L-T(4) replacement might reduce serum levels of Apo B-48 in both OH and SH patients. Such altered serum levels of Apo B-48 in patients with OH and SH may be related to the disturbed metabolism of chylomicron remnants in patients with hypothyroidism.
Endocrine Journal 09/2012; · 2.03 Impact Factor
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Shoko Nakayama,
Taiji Yokote,
Kazuki Iwaki,
Yuji Hirata,
Ayami Takayama,
Toshikazu Akioka,
Takuji Miyoshi,
Uta Nishiwaki,
Yuki Masuda,
Motomu Tsuji, Toshiaki Hanafusa
Leukemia & lymphoma 09/2012; · 2.40 Impact Factor
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ABSTRACT: Matrix metalloproteinase 9 (MMP-9) is a risk factor for cardiovascular events. The serum MMP-9 levels were measured before and 2 weeks after treatment with infliximab (3 mg/kg) in 12 rheumatoid arthritis (RA) patients. The serum average MMP-9 level was 238.5 ng/ml before treatment with infliximab in RA patients (normal range: less than 43.8 ng/ml). Infliximab reduced the serum average MMP-9 level significantly (161.66 ng/ml, P = 0.0425). The serum MMP-9 level was high in the RA patients with active disease, and it was reduced by infliximab independently of the reduction in disease activity. Thus, infliximab may reduce the risk of cardiovascular events directly.
Journal of Pharmacological Sciences 08/2012; 120(1):50-3. · 2.08 Impact Factor
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ABSTRACT: Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related pulmonary complication with rapidly progressing dyspnea, and occasionally induces sudden death. Here, we describe a postmortem-diagnosed PTTM case caused by gastric cancer, with the complaint of progressing dyspnea for 5 days.He did not have any abdominal symptoms or cancer history. PTTM should be considered in patients with rapidly worsening respiratory conditions, even if there is no cancer history.
Annals of thoracic medicine. 07/2012; 7(3):168-9.
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Leukemia research 05/2012; 36(8):e171-4. · 2.36 Impact Factor
