Masaru Imamura

Expression of pentraxin 3 (PTX3) in human atherosclerotic lesions

Pentraxin 3 (PTX3) and C‐reactive protein (CRP) are members of the pentraxin superfamily. PTX3 expression is induced in response to inflammatory signals, and is produced at sites of inflammation by several types of cell, primarily monocytes/macrophages, dendritic cells (DCs), endothelial cells, smooth muscle cells (SMCs), and fibroblasts, but is not produced by hepatocytes, which are a major source of CRP. The aim of our study was to investigate the expression pattern of PTX3 in human atherosclerotic lesions using a novel monoclonal antibody against PTX3. We examined coronary arterial thrombi containing an atherosclerotic plaque component removed from patients with acute myocardial infarction and human aortic tissues with various degrees of atherosclerosis sampled from autopsy cases. Immunohistochemical study of paraffin and frozen sections indicated that macrophages, mainly foam cells, expressed PTX3 in advanced atherosclerotic lesions. Interestingly, we also clearly observed PTX3‐positive neutrophils infiltrating into atherosclerotic plaques, suggesting that PTX3 derived from neutrophils as well as macrophages plays an important role in atherogenesis. Copyright

Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15.

Natural killer (NK) cell survival and, hence, cytotoxicity requires cytokine support. We determined whether expression of interleukin-15 (IL-15) in a nonsecretory, membrane-bound form could sustain NK cell growth. We linked the human IL15 gene to that encoding CD8α transmembrane domain (mbIL15). After retroviral transduction, human NK cells expressed mbIL15 on the cell surface; IL-15 secretion was negligible. Survival of mbIL15-NK cells without interleukin-2 (IL-2) after 7-day culture was vastly superior to that of mock-transduced NK cells (P < .001, n = 15) and of NK cells expressing nonmembrane-bound IL-15 (P = .025, n = 9); viable mbIL15-NK cells were detectable for up to 2 months. In immunodeficient mice, mbIL15-NK cells expanded without IL-2 and were detectable in all tissues examined (except brain) in much higher numbers than mock-transduced NK cells (P < .001). Expansion further increased with IL-2. The primary mechanism of mbIL15 stimulation was autocrine; it activated IL-15 signaling and antiapoptotic signaling. NK cells expressing mbIL15 had higher cytotoxicity against leukemia, lymphoma, and solid tumor cells in vitro and against leukemia and sarcoma cells in xenograft models. Thus, mbIL15 confers independent growth to NK cells and enhances their antitumor capacity. Infusion of mbIL15-NK cells would allow NK cell therapy without the potential adverse effects of cytokine administration.

Duplication of chromosome 4q: renal pathology of two siblings.

We report on two sibs with partial 4q trisomy: dup (4)(q35.2‐q31.22) and their renal biopsy findings. Both of them show renal hypoplasia, although their chromosomal aberration lacks the minimal duplicated region 4q22‐q23 and/or 4q25‐q31.3, which had been shown to be associated with urogenital abnormalities and thumb malformations in previous reports. From the renal biopsy findings, the two sibs were diagnosed as oligonephronia. We summarize the 13 having published cases of duplication of chromosome 4q, and examine which segments have a close relationship to renal hypoplasia. We suggest that renal hypoplasia may be female‐prone, and may have a close relationship with duplication of 4q33‐q34.

Primary tuberculous osteomyelitis of the mandible

We present a case of a 3-year-old boy with primary tuberculous osteomyelitis of the mandible. He complained of a left submandibular mass. Radiographic examination revealed osteolytic lesions in the left mandibular angle, the left scapula and the left ulna. A biopsy from the mandible showed non-caseating epithelial granuloma. The mandibular mass spontaneously regressed in a month without definitive diagnosis. Swelling of the bilateral mandibular body was found 2 years later. He was diagnosed as having tuberculous osteomyelitis by culture study and treated with isoniazid and rifampicin without recurrence. Here we stress the importance of considering tuberculous osteomyelitis in the differential diagnosis of jaw lesions to prevent serious systemic spread.

Contingent negative variation in children with orthostatic dysregulation

Abstract Background : Children with orthostatic dysregulation (OD) appear to have hypodynamia, as well as the symptoms described in the OD criteira. Hypodynamia, which is greatly influenced by motivation, volition and concentration, is unexceptionally recognized in their everyday life. It has been suggested that the symptoms and hypodynamia aggravate considerably the quality of life (QOL) of children with OD. The purpose of this study was to distinguish the characteristics of contingent negative variation (CNV) and post imperative negative variation, which may reflect the level of attention and motivation in children with OD.

Prophylactic post-transplant dasatinib administration in a pediatric patient with Philadelphia chromosome-positive acute lymphoblastic leukemia

Philadelphia chromosome‐positive acute lymphoblastic leukemia has a poor prognosis, even in pediatric patients. Although imatinib‐containing chemotherapy can reportedly improve early event‐free survival, allogeneic hematopoietic stem cell transplantation is still considered to be the main curative treatment option. Dasatinib, a novel abl tyrosine kinase inhibitor, is being used for the treatment of relapsed or refractory Philadelphia chromosome‐positive acute lymphoblastic leukemia and is reported to have excellent efficacy. We used dasatinib after bone marrow transplantation prior to the anticipated relapse for the purpose of prophylaxis against relapse. After discontinuation of dasatinib administration, molecular remission has lasted for 7 months. Although preventive use of dasatinib is as yet uncommon, we consider that dasatinib may eradicate the minimal residual disease and prevent recurrence, and it is feasible to administer and appears to be safe. Further studies are needed to confirm our experience in this case.

Neonatal clinical outcome after elective cesarean section before the onset of labor at the 37th and 38th week of gestation

Background : Although elective cesareansections are often performed after the 37th week of gestation withoutany complicating factor that may influence the timing of delivery,there is a possibility that infants born in the 37th week of gestation,especially early in the 37th week of gestation, do not obtain asatisfactory clinical outcome due to premature birth.

Expression of liver X receptor α and lipid metabolism in granulocyte–macrophage colony‐stimulating factor‐induced human monocyte‐derived macrophage

Liver X receptor (LXR) is a nuclear receptor that acts as a sterol sensor and metabolic regulator of cholesterol and lipid homeostasis. The foam cell transformation of macrophages (Mϕ) is considered a critical process in atherosclerotic lesions. The relationship, however, of the foam cell transformation of Mϕ and LXR is not fully understood. The purpose of the present study was to examine the expression of LXRα, retinoid X receptor (RXR)α, ATP‐binding cassette transporter (ABCA1), and macrophage scavenger receptor A (MSR‐A), and lipid accumulation in human monocyte‐derived Mϕ. The expression of LXRα, ABCA1, MSR‐A in 7 day cultured granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐induced Mϕ (GM‐Mϕ) was significantly higher than that in 7 day cultured M‐CSF‐induced Mϕ (M‐Mϕ). The expression levels of LXRα, ABCA1 and MSR‐A protein decreased from 48 h to 5 days after the addition of lipopolysaccharide (LPS) in GM‐Mϕ, but only MSR‐A protein decreased at 5 days after the addition of LPS in M‐Mϕ. Intracellular lipid accumulation was clearly observed when GM‐Mϕ was pre‐stimulated with LPS for 48 h and incubated with oxidized LDL for an additional 5 days. These findings suggest that the inhibitory activity of LXRα, ABCA1 and MSR‐A by LPS may be related to the transformation of Mϕs, especially GM‐Mϕ into foam cells.

A novel homozygous 8-base pair deletion mutation in the glycoprotein Ibα gene in a patient with Bernard-Soulier syndrome

We present a patient with Bernard–Soulier syndrome harboring a novel mutation. Flow cytometric analysis showed that the glycoprotein (GP) Ib/IX complex was absent from the platelet surface. By immunoblotting, GPIbα, GPIbβ and GPIX were not detected in the platelet lysates. Glycocalicin, the soluble GPIbα fragment, was also absent in the plasma. Genetic analysis revealed a novel homozygous 8-base pair deletion in the GPIbα gene, 1136_1143delTTCACATG, which was predicted to cause a frame shift and the addition of 13 altered amino acids followed by premature termination. No mutation was found in the coding sequence of the GPIbβ or GPIX genes. We demonstrated that the novel deletion mutation resulted in complete defectiveness of the GPIbα protein and null expression of the entire GPIb/IX complex, and was responsible for the Bernard–Soulier syndrome phenotype in this patient. Although the presence of a truncated GPIbα protein has been often documented, complete absence of the protein has been scarcely reported in Bernard–Soulier syndrome patients with a GPIbα mutation causing a premature stop codon. An underlying molecular mechanism to explain how the synthesis of a truncated protein is inhibited in selected cases remains to be elucidated.

Juvenile myelomonocytic leukemia with less aggressive clinical course and KRAS mutation.

To the Editor: An 11-month-old male presented with hepatosplenomegaly and juvenile xanthogranuloma on the face and the trunk. Laboratory findings included leukocytosis (16 10/L) with monocytosis (3 10/L) and 0% leukemic blasts, anemia (hemoglobin 8.6 g/dl) and thrombocytopenia (platelets 65 10/L). The level of fetal hemoglobin (HbF) was 2.5%. A bone marrow aspirate revealed <3% blasts with normal karyotype. Spontaneous colony formation in the absence of added hematopoietic growth factors were demonstrated in the peripheral blood cells. Single nucleotide substitution at codon 12 of the KRAS gene from GGT to GTT was detected in the bone marrow cells, while NRAS mutations at codon 12, 13, or 61 were not detected. Examination of PTPN11 mutation was also performed later and indicated no abnormalities. The diagnostic criteria for JMML were fulfilled. During 3 months of observation, leukocytosis improved spontaneously and anemia and thrombocytopenia did not progress. Treatment with 13-cis retinoic acid was started 9 months from diagnosis, Although white cell counts showed no significant change, platelet counts increased up to 150 10/L (Supplemental Fig. 1). Twenty-eight months later, his parents decided to discontinue 13-cis retinoic acid, mainly due to economical reasons. White cell counts gradually decreased to 80–90 10/L, and platelet counts were sustained with 120– 170 10/L for 5 years. Splenomegaly and peripheral blood spontaneous colony formation remained, although reduced in size or in number, respectively. JMML is a progressive and often rapidly fatal disease. HSCT is currently considered the only curative treatment for this disease, but treatment-related mortality and relapse rates remain high [1–3]. Although JMML is usually aggressive, some patients have been shown to have a prolonged and stable clinical course without HSCT [3]. Recently, prognostic impact of genetic abnormalities has been debated. Matsuda et al. [4] reported three patients with RAS Gly12Ser mutation showing spontaneous improvement of hematological abnormalities lasting for 2–4 years with neither intensive chemotherapy nor HSCT. On the other hand, Flotho et al. [5] reported six patients with RAS mutations other than RAS Gly12Ser who had long-term survival lasting for 4–21 years without HSCT. The present case had a KRAS Gly12Val mutation and has survived for 8 years after diagnosis without HSCT. Our case received 13-cis retinoic acid for 28 months, during which time platelet counts worsened and then continued to be elevated even after stopping the treatment. It is impossible to assess whether the improvement was due to the drug or whether it reflected the natural course of the disease. The optimal timing of HSCT for JMML is unknown. Therefore, differentiation-inducing or RAS-targeting therapeutics prior to HSCT might be justified for some patients who have mismatched donor. Specific genetic abnormalities, such as RAS mutation, might be a surrogate marker for identifying those who might respond to such treatments. Further studies are needed to elucidate whether specific genetic abnormalities correlate with clinical courses in JMML.