Kensuke Matsumoto

Regulation of Scavenger Receptor Class BI Gene Expression by Angiotensin II in Vascular Endothelial Cells

High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. In this process, a scavenger receptor of the B class (SR-BI)/human homologue of SR-BI, CD36, and LIMPII analogous-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from high-density lipoprotein. In endothelial cells, high-density lipoprotein activates endothelial NO synthase via hSR-BI/CLA-1. Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis and modulates the expression of endothelial NO synthase. In the present study, we have examined the role of Ang II on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells. Our results showed that endogenous expression of hSR-BI/CLA-1 was suppressed by exposure to Ang II in human umbilical vein endothelial cells. Administration of the Ang II type-1 receptor blocker olmesartan inhibited Ang II–induced hSR-BI/CLA-1 protein repression. In Ang II–treated cells, high-density lipoprotein had no effect on endothelial NO synthase activation. Ang II decreased transcriptional activity of the hSR-BI/CLA-1 promoter. The inhibitory effect of Ang II on hSR-BI/CLA-1 promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of human umbilical vein endothelial cells to Ang II elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt inhibits the activity of the hSR-BI/CLA-1 promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the hSR-BI/CLA-1 abolished the ability of Ang II to suppress promoter activity. Together, these results indicate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway participates in Ang II suppression of hSR-BI/CLA-1 expression and suggests that the endothelial receptor for hSR-BI/CLA-1 is downregulated by the renin–angiotensin system.

Platelet derived growth factor regulates ABCA1 expression in vascular smooth muscle cells

The ATP‐binding cassette transporter A1 (ABCA1) regulates lipid efflux from peripheral cells to High‐density lipoprotein. The platelet‐derived growth factor (PDGF) is a potent mitogen that enables vascular smooth muscle cells to participate in atherosclerosis. In this report, we showed that PDGF suppressed endogenous expression of ABCA1 in cultured vascular smooth muscle cells. Exposure of CRL‐208 cells to PDGF elicited a rapid phosphorylation of a kinase downstream from PI3‐K, Akt. The constitutively active form of both p110, a subunit of PI3‐K, and Akt inhibited activity of the ABCA1 promoter. In conclusion, PI3‐K‐Akt pathways participate in PDGF‐suppression of ABCA1 expression.

Potentiated activation of VLA-4 and VLA-5 accelerates proplatelet-like formation

Fibronectin (FN) plays important roles in the proliferation, differentiation, and maintenance of megakaryocytic-lineage cells through FN receptors. However, substantial role of FN receptors and their functional assignment in proplatelet-like formation (PPF) of megakaryocytes are not yet fully understood. Herein, we investigated the effects of FN receptors on PPF using the CHRF-288 human megakaryoblastic cell line, which expresses VLA-4 and VLA-5 as FN receptors. FN and phorbol 12-myristate 13-acetate (PMA) were essential for inducing PPF in CHRF-288 cells. Blocking experiments using anti-β1-integrin monoclonal antibodies indicated that the adhesive interaction with FN via VLA-4 and VLA-5 were required for PPF. PPF induced by FN plus PMA was accelerated when CHRF-288 cells were enforced adhering to FN by TNIIIA2, a peptide derived from tenascin-C, which we recently found to induce β1-integrin activation. Adhesion to FN enhanced PMA-stimulated activation of extracellular signal-regulated protein kinase 1 (ERK1)/2 and enforced adhesion to FN via VLA-4 and VLA-5 by TNIIIA2-accelerated activation of ERK1/2 with FN plus PMA. However, c-Jun amino-terminal kinase 1 (JNK1), p38, and phosphoinositide-3 kinase (PI3K)/Akt were not stimulated by FN plus PMA, even with TNIIIA2. Thus, the enhanced activation of ERK1/2 by FN, PMA plus TNIIIA2 was responsible for acceleration of PPF with FN plus PMA.

Reversible cerebral vasoconstriction syndrome resulted in cerebral infarction after allogeneic stem cell transplantation: a case report

Dear Editor, Reversible cerebral vasoconstriction syndrome (RCVS) has been recognized as a syndrome of diverse conditions characterized by the reversible multifocal narrowing of cerebral arteries [1, 2]. RCVS has been detected in more patients in recent years because of the growing availability of noninvasive MRI and magnetic resonance angiography (MRA) diagnostic technology. Posterior reversible encephalopathy syndrome (PRES) is a form of acute encephalopathy [3]. PRES is responsible for vasogenic edema within the cerebral white matter, predominantly in the posterior of the cerebrum [4]. We report a case of RCVS followed by PRES, which progressed to cerebral infarction due to tacrolimus administration. In August 2004, we diagnosed a 49-year-old female with chronic myelogenous leukemia with 46, XX, t(9;22) [20/20]. She was treated with imatinib and nilotinib at initial doses of 400 and 200 mg/day, respectively, but the myelosuppression provided by these tyrosine kinase inhibitors was progressive. In November 2010, 6 months after the cessation of imatinib and nilotinib, pancytopenia persisted, and her bone marrow aspiration showed myelodysplasia harboring both the Philadelphia (Ph) chromosome [1/20] and an abnormal karyotype, monosomy 7 [7/20] on the Ph-negative clones. In August 2011, she underwent an allogeneic bone marrow transplantation from an unrelated healthy donor with a conventional conditioning regimen (cyclophosphamide 60 mg/kg) and total body irradiation (12 Gy; CY/TBI). She complained of tension headache after the start of the preparation regimen. After the initiation of a continuous intravenous administration of tacrolimus 1 day before the transplantation, the patient’s tension headache shifted to a periodic cluster headache with photoreactivity. On day 17, after transplantation, engraftment was achieved without the progression of any neurological symptoms. On day 27, the sudden onset of paralysis of the patient’s left lower limb prompted us to stop the continuous treatment with tacrolimus, and a cranial MRI showed a highintensity lesion in her posterior lobe on a T2-weighted image as a typical finding of PRES due to tacrolimus (Fig. 1a). MRA revealed vasoconstriction of cerebral basilar arteries (Fig. 1a). The immediate discontinuation of tacrolimus improved the patient’s paralysis. We followed up with MRI and MRA on day 39. The findings indicated a subacute cerebral infarction of her parietal lobe and improvement of the vasoconstriction of cerebral arteries (Fig. 1b). We concluded that the patient’s RCVS resulted in the cerebral infarction because of the severe vasospasm of the regional cerebral artery, most likely because of the tacrolimus. In this case, arterial vasoconstriction was “reversible,” but the infarction remained as an irreversible complication. The association between tacrolimus and the symptoms in this case emerged through the patient’s clinical course. That is, the first MRI/MRA revealed PRES with segmental narrowing signs in the territory of the brain’s basilar artery; after the tacrolimus discontinuation, the second MRI/MRA showed O. Imataki :M. Uemura : T. Shintani :K. Matsumoto Division of Endocrinology and Metabolism, Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan

Linezolid‐induced pure red cell aplasia in a patient with Staphylococcus epidermidis infection after allogeneic stem cell transplantation

Linezolid (LZD) is the first oxazolidinone antibiotic that is effective against drug‐resistant gram‐positive organisms. Hematological toxicities such as thrombocytopenia, anemia, and leukocytopenia are common in LZD therapy. However, LZD‐induced pure red cell aplasia (PRCA) is very rare. A 56‐year‐old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation from a human leukocyte antigen‐matched and ABO blood type‐matched unrelated male donor. He had bacteremia caused by Staphylococcus epidermidis after engraftment of neutrophils and red blood cells. We first administered vancomycin, but then changed to intravenous LZD because of kidney damage. Two weeks after LZD therapy, the patients hemoglobin and reticulocyte levels were 6.8 g/dL and 0.3%, respectively. Bone marrow examination revealed red blood cell aplasia (myeloid/erythroid ratio was 402). The patient showed rapid recovery of normal erythropoiesis within 2 weeks of LZD cessation. It is important to be aware of the hematological effects associated with LZD in the setting of stem cell transplantation,particularly for those with pre‐existing myelosuppression, renal insufficiency, and those receiving concomitant drugs that produce bone marrow suppression. We advocate that a reticulocyte count be performed periodically for detecting bone marrow suppression, including PRCA, during LZD therapy.

Yersinia pseudotuberculosis enterocolitis mimicking enteropathic γδ T-cell lymphoma with abnormal clonality

BackgroundYersinia pseudotuberculosis generally infects the gastrointestinal tract and causes enteropathy symptoms suggesting infection. Y. pseudotuberculosis infections are often complicated with intraceliac lymphoadenopathy mimicking malignant lymphoma. This is a first case of Yersinia pseudotuberculosis enteropathy mimicking enteropathic γδ T-cell lymphoma. This case highlighted the γδ T-cell reaction to Yersinia enterocolitis sometimes mimicking malignant lymphoma clinically.Case presentationA 72-year-old female was referred to our institute due to abdominal pain with skin rush, fever and diarrhea. Computed tomography (CT) scanning revealed mucosal swelling of the cecum with enlargement of regional lymph nodes. Laboratory data showed elevated CRP (7.74 mg/dL), an increased level of soluble interleukin-2 receptor (sIL-2R 3095 IU/mL), and CD3+ γδ T-cell circulation in peripheral blood and bone marrow (10.9% and 3.9%, respectively). Increased proportions of γδ T-cells supported the diagnosis of malignant lymphoma. Colonoscopy demonstrated hemorrhagic mucosal erosion with partial ulceration, and the subsequent pathological findings at the inflammation site suggested malignant lymphoma histopathology in the colon. These objective findings were entirely consistent with enteropathic γδ T-cell lymphoma. Thereafter, however, the microbiological results of the patient’s stool at admission showed Yersinia pseudotuberculosis, and she was diagnosed as having Yersinia enterocolitis. All abnormal findings including subjective symptoms were in remission or mitigated within 2 weeks after her onset. Even the γδ T-cell circulation disappeared (0.04% in peripheral blood), and we speculate that those cells were a reaction to the Yersinia infection.ConclusionIn this case, a differential diagnosis included infectious enterocolitis from other immunogenic or malignant diseases. Although a measurement of sIL-2R is critical in differentiating malignant lymphoma in patients suffering with lymph adenopathy, that is not confirmative. This patient’s case indicates that T cells expressing the γδ T-cell receptor might be associated with the acute and late phase reactions, in which T cells play a role in the construction of granulomas and the establishment of sequelae.

Chronic myelomonocytic leukemia presenting with polyserositis due to an immune-mediated monocyte activation.

Monocytosis is often profoundly implicated in chronic myelomonocytic leukemia (CMML). We diagnosed a 63‐year‐old woman with CMML involving heterochronological systemic polyserositis with infiltrating benign monocytes. The patients pleural effusion was eliminated completely with corticosteroid therapy. We speculate that our case represents an immunological reaction with activated monocytes triggered by infection.

S-1 induced secondary acute erythroid leukemia with a chromosome inv(12)(p13;q13)

Adjuvant chemotherapy by S-1 following gastrectomy is considered standard treatment in Japan. Analysis of follow-up data have proved the efficacy of S-1 administration, and that hematological adverse events were relatively rare. Pyrimidine anti-metabolites, including S-1, have shown relatively lower risks for secondary hematological malignancies in comparison to alkylating agents and topoisomerase-II inhibitors. We here report a case of therapy-related leukemia after S-1 administration. A patient who had received S-1as the sole adjuvant chemotherapy was diagnosed with acute erythroid leukemia. To the best of our knowledge, our patient represents the first report of S-1 induced acute leukemia.

Chronic Haemolytic Anemia and Splenomegaly in a Patient with an Isolated Adrenocorticotropin Deficiency

Herein we describe a case of a 56-years old patient presented with general malaise, anorexia and progressive weight loss for about 5years associated recently with diarrhoea and repeated syncopal attacks for 1month. On admission, he had splenomegaly and his laboratory studies showed macrocytic hyperchromic haemolytic anemia [Hb = 9.4g/dl] and a significant hyponatremia [Na+ = 111mmol/l]. Endocrinological evaluation revealed an isolated adrenocorticotropin deficiency (IAD) with a manifest hypoaldosteronism. On treatment with cortisone, both anemia and hyponatremia (but not splenomegaly) were markedly improved. Our case may represent an evidence for the pathogenesis of erythropoietic dysfunction in patients of adrenocortical insufficiency.