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An 11-year-old boy presented with fever and abdominal pain, and was diagnosed with retroperitoneal lymphadenitis. At the same time, a painless right scrotal mass was observed. On imaging the testis and the epididymal mass both had abundant blood flow, although tumor markers were negative. Although the right testis had shrunk after antibiotic treatment, swelling was persistent and incisional biopsy was therefore performed, resulting in diagnosis of granulomatous orchitis (GO). No recurrence was found. In cases of scrotal swelling in both the testis and the epididymis of an older child, it is necessary to consider the possibility of inflammatory GO, and orchiectomy should not be performed without careful consideration.

Although the incidence of autoimmune hemorrhaphilia due to anti-Factor XIII (FXIII, not FVIII or FXII to avoid confusion) antibodies (AH13) or hemorrhagic "acquired FXIII deficiency due to anti-FXIII autoantibodies" was previously considered rare, it has been on the increase in the twenty-first century, at least in Japan. An 83-year-old woman with an unexplained hemorrhage was admitted to our hospital for intramuscular hematoma and severe anemia. Her FXIII activity was reduced to 10 % of normal; since FXIII inhibitors and anti-FXIII-A subunit autoantibodies were detected, she was definitively diagnosed with AH13. Despite developing cardiac tamponade due to pericardial hemorrhage, she clinically recovered from AH13 after hemostatic therapy with FXIII-concentrates and immunosuppressive treatment with rituximab and cyclophosphamide. However, her FXIII activity remained low and she died of hemorrhage 3.5 years after admission. AH13 patients should be monitored for a prolonged period, as this disease is very likely a chronic intractable hemorrhagic disorder.

To examine the roles for NF-kappaB family proteins in hematopoiesis, we first expressed dominant negative Rel/NF-kappaB(IkappaBSR) in a factor-dependent cell line, Ba/F3. Although IkappaBSR neither affected thrombopoietin-dependent nor gp130-mediated growth, it suppressed interleukin-3- and erythropoietin-dependent growth at low concentrations. In addition, IkappaBSR enhanced factor-deprived apoptosis through the accumulation of reactive oxygen species (ROS). When expressed in normal hematopoietic stem/progenitor cells, IkappaBSR induced apoptosis even in the presence of appropriate cytokines by accumulating ROS. We also expressed IkappaBSR in an inducible fashion at various stages of hematopoiesis using the OP9 system, in which hematopoietic cells are induced to develop from embryonic stem cells. When IkappaBSR was expressed at the stage of Flk-1(+) cells (putative hemangioblasts), IkappaBSR inhibited the development of primitive hematopoietic progenitor cells by inducing apoptosis through the ROS accumulation. Furthermore, when IkappaBSR was expressed after the development of hematopoietic progenitor cells, it inhibited their terminal differentiation toward erythrocytes, megakaryocytes, and granulocytes by inducing apoptosis through the ROS accumulation. These results indicate that NF-kappaB is required for preventing apoptosis at multiple steps of hematopoiesis by eliminating ROS.

The development of myoblasts is regulated by various growth factors as well as by intrinsic muscle-specific transcriptional factors. In this study, we analyzed the roles for STAT3 in the growth and differentiation of myoblasts in terms of cell cycle regulation and interaction with MyoD using C2C12 cells. Here we found that STAT3 inhibited myogenic differentiation induced by low serum or MyoD as efficiently as the Ras/mitogen-activated protein kinase cascade. As for this mechanism, we found that STAT3 not only promoted cell cycle progression through the induction of c-myc but also inhibited MyoD activities through direct interaction. STAT3 inhibited not only DNA binding activities of MyoD but also its transcriptional activities. However, the inhibited transcriptional activities were restored by the supplement of p300/CBP and PCAF, suggesting that STAT3 might deprive MyoD of these transcriptional cofactors. In addition, we found that MyoD inhibited DNA binding activities of STAT3, thereby inhibiting STAT3-dependent cell growth and survival of Ba/F3 cells. These results suggest that the development of muscle cells is regulated by the coordination of cytokine signals and intrinsic transcription factors.

An 11-year-old boy presented with fever and abdominal pain, and was diagnosed with retroperitoneal lymphadenitis. At the same time, a painless right scrotal mass was observed. On imaging the testis and the epididymal mass both had abundant blood flow, although tumor markers were negative. Although the right testis had shrunk after antibiotic treatment, swelling was persistent and incisional biopsy was therefore performed, resulting in diagnosis of granulomatous orchitis (GO). No recurrence was found. In cases of scrotal swelling in both the testis and the epididymis of an older child, it is necessary to consider the possibility of inflammatory GO, and orchiectomy should not be performed without careful consideration.

A 48-year-old woman was hospitalized because of severe thrombocytopenia, leg edema, and fever. Intravenous immunoglobulin therapy was administered, but no efficacy was obtained. Her bone marrow was dry-tap, and fibrosis was found in the biopsy specimens. A positron emission tomographic study showed FDG-avid lymphadenopathy and hepatomegaly. Biopsy specimens of axillary lymph nodes showed Castleman's disease-like findings. Since she then developed severe proteinuria and massive pleural effusion, steroid therapy was started, providing temporary relief of symptoms other than the thrombocytopenia. However, rapid worsening of her general condition prompted us to attempt rituximab as salvage therapy. The pleural effusion, edema, and proteinuria disappeared soon after starting rituximab administration. Platelet counts also normalized and fibrosis of the bone marrow showed amelioration. Recently, a variant of multicentric Castleman's disease, termed the TAFRO syndrome, has been proposed, and our patient's features fit the diagnosis of this syndrome. Rituximab might be considered as a therapeutic option in such cases.

We report a 39-year-old man with intravascular large B-cell lymphoma (IVLBCL) who had been treated as a case with pulmonary arterial hypertension (PAH) for one year. After he became worse, diffuse pulmonary (18)F-fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) suggested the existence of IVLBCL in the lung showing normal CT images. The diagnosis was confirmed with random transbronchial lung biopsy, and he was then successfully treated. Since IVLBCL presenting PAH has been rare and is difficult to diagnose, early application of FDG-PET may provide early recognition of the disorder, leading to a better outcome.

A 48-year old man was admitted with idiopathic fever, and subsequently diagnosed as having hemophagocytic lymphohistiocytosis (HLH). Though an extensive series of laboratory examinations failed to demonstrate an apparent etiology, empirical use of steroids achieved remission. About two years later, the patient developed Pneumocystis Jiroveci pneumonia and was diagnosed as HIV-positive. Based on this case, HIV-screening tests would be performed whenever we encounter HLH in Japan, where the number of HIV-positive patients is increasing.

GATA-2 is considered to be essential for the development, maintenance, and function of hematopoietic stem cells (HSCs). However, it was also reported that GATA-2 inhibits the growth of HSCs. To examine the role of GATA-2 in the growth of hematopoietic cells, we introduced an estradiol-inducible form of GATA-2 (GATA-2/estrogen receptor [ER]) into interleukin 3 (IL-3)-dependent cell lines, Ba/F3, 32D, and FDC-P1. Estradiol-induced GATA-2 suppressed c-myc mRNA expression and inhibited IL-3-dependent growth in these clones. As for this mechanism, GATA-2 was found to inhibit ubiquitin/proteasome-dependent degradation of p21(WAF1) and p27(Kip1) and to induce their accumulation by repressing the expression of Skp2 and Cul1, both of which are components of the ubiquitin ligase for p21(WAF1) and p27(Kip1). Overexpression of c-myc restored the expression of Skp2 and Cul1 mRNA, reduced the amounts of p21(WAF1) and p27(Kip1) proteins, and canceled GATA-2-induced growth suppression, suggesting that down-regulation of c-myc expression may be primarily responsible for GATA-2-induced growth suppression. Next, we transduced retrovirus containing GATA-2/ER into murine bone marrow mononuclear cells (MNCs) and stem/progenitor (Sca-1(+)Lin(-)) cells. GATA-2/ER suppressed cytokine-dependent growth of MNCs and Sca-1(+)Lin(-) cells by about 70%, which was also accompanied by the reduced expression of c-myc, Skp2, and Cul1 mRNA and the accumulation of p21(WAF1) and p27(Kip1) proteins. In addition, the amount of GATA-2 protein was found to decline in hematopoietic stem/progenitor cells that were promoted to enter cell cycle by the stimulation with cytokines. These results suggest that GATA-2 may regulate expression levels of p21(WAF1) and p27(Kip1), thereby contributing to the quiescence of hematopoietic stem/progenitor cells.

A 68-year-old man was admitted to our hospital for cough and dyspnea. Laboratory data showed positive human T-lymphotropic virus type 1 (HTLV-1) antibody and elevated level of soluble interleukin-2 receptor (4225 U/ml). Thoracic computed tomography showed emphysema, reticular shadow, ground-glass attenuation, and subpleural consolidation (Figure 1). Bronchofiberscopy was carried out and cytologic examination of bronchoalveolar lavage fluid revealed atypical lymphocytes. These cells showed positive reaction for CD2, CD3, CD4, CD5, and CD25 and negative for CD8 in flow cytometry. Specimens of transbronchial lung biopsy showed massive infiltration of malignant lymphocytes, which were

NF-kB family proteins have been reported to induce the expression of over 150 target genes, thereby crucially regulating immune responses, stress responses, and inflammation. These proteins also play important roles in cell growth and survival in various cell types. However, the precise roles of NF-kB in hematopoiesis and their mechanisms remain undetermined. To examine the roles for NF-kB family proteins in the growth and survival of hematopoietic cells, we expressed dominant negative NF-kB (IkBSR) in a murine IL-3-dependent cell line Ba/F3 using a Lac-inducible system, in which IkBSR was inducibly expressed by the IPTG treatment; this clone was designated Ba/F3/IkBSR. Furthermore, we introduced EPO receptor (R), TPOR, and G-CSFR/gp130 consisting of the extracelluar domain of G-CSFR and cytoplasmic domain of gp130 into this clone. At first, we confirmed that these clones could survive and proliferate under the cultures with IL-3, EPO, TPO, G-CSF, respectively. Although IPTG-induced IkBSR slightly suppressed IL-3- and EPO-dependent growth at low concentrations, it did not affect TPO- or gp130L-dependent growth, suggesting that NF-kB might not be so important for cytokine-dependent growth of hematopoietic cells. In contrast, IkBSR prominently enhanced factor-deprived apoptosis, which was accompanied by the ROS accumulation. To access the roles of ROS in IkBSR-enhanced apoptosis, we overexpressed ROS scavenger enzymes MnSOD and thioredoxin X (TRX) in Ba/F3/IkBSR, respectively. As a result, MnSOD and TRX significantly canceled IkB-SR-enhanced apoptosis, suggesting that ROS would be responsible for this apoptosis. We next analyzed the effects of IkBSR on the growth and survival of normal hematopoietic cells. When IkBSR was introduced into murine Lin−Sca-1+ hematopoietic stem/progenitor cells with the retrovirus system, it induced apoptosis even in the presence of appropriate cytokines. This apoptosis was also accompanied by the ROS accumulation due to the downregulated expression of anti-oxidants such as glutathione, MnSOD, glutathione peroxidase, and TRX. In addition, the expression of antiapoptotic BCl-2 family members, Bcl-XL, Bcl-2, and A1 was found to be repressed by IkBSR. However, since antioxidants such as MCI (3-methyl-1-phenyl-2-pyrazolin-5-one), N-acetylecysteine and TRX cancelled this apoptosis, ROS were supposed to be more important for IkBSR-induced apoptosis in normal hematopoietic stem/progenitor cells. To further analyze the roles for NF-kB proteins in the development of hematopoietic cells, we expressed IkBSR in an inducible fashion at various stages of hematopoiesis using the OP9 system, in which hematopoietic cells are induced to develop from ES cells. When IkBSR was expressed at the stage of hemangioblasts, IkBSR induced apoptosis and inhibited the development of hematopoietic stem cells, which was also cancelled by MCI. Furthermore, when IkBSR was expressed after the development of hematopoietic stem cells, it also inhibited terminal differentiation towards granulocytes, erythrocytes, and megakaryocytes through ROS-mediated apoptosis; IkBSR inhibited granulopoiesis before the development of myeloblasts, erythropoiesis after the development of proerythroblasts, and megakaryopoiesis during polyploidization of megakaryocytes. These results indicate that NF-kB family proteins play essential roles to prevent apoptosis at multiple steps of hematopoiesis by eliminating ROS.