Low ocean-floor rises regulate subpolar sea surface temperature by forming baroclinic jets.

Sea surface temperature (SST) fronts in mid- to high-latitude oceans have significant impacts on extratropical atmospheric circulations and climate. In the western subarctic Pacific, sharp SST fronts form between the cold subarctic water and the recently found quasi-stationary jets that advect warm waters originating in the Kuroshio northeastward. Here we present a new mechanism of the jet formation paying attention to the propagation of baroclinic Rossby waves that is deflected by eddy-driven barotropic flows over bottom rises, although their height is low (~500 m) compared with the depth of the North Pacific Ocean (~6000 m). Steered by the barotropic flows, Rossby waves bring a thicker upper layer from the subtropical gyre and a thinner upper layer from the subarctic gyre, thereby creating a thickness jump, hence a surface jet, where they converge. This study reveals an overlooked role of low-rise bottom topography in regulating SST anomalies in subpolar oceans.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice.

BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.

Diagnostic usefulness of FDG-PET/CT in advanced malignant lymphoma of the uterus: report of two cases.

Summary Malignant lymphoma of the uterus is difficult to diagnose because of its rarity and nonspecific symptoms. However, recently, 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become an important non-invasive diagnostic tool for the management of lymphoma patients. The authors report two cases of malignant lymphoma of the uterus, in which FDG-PET/CT was useful for diagnosis. Examination using ultrasonography or magnetic resonance imaging (MRI) demonstrated a normal-sized uterus and normal endometrium, but FDG-PET/CT showed FDG accumulation in the uterine body in both cases. Endometrial biopsy revealed diffuse large B-cell lymphoma, and chemotherapy with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) was initiated immediately. Primary malignant lymphoma of the female genitalia is reported to be rare. The present authors' experience with FDG-PET/CT suggests that malignant lymphoma of the female genitalia (including metastasis) may not be as rare as previously reported. Uterine malignant lymphoma may be overlooked by the examination of ultrasound, CT, or MRI.

Variability of parvovirus B19 genotype 2 in plasma products with different compositions in the inactivation sensitivity by liquid-heating.

BACKGROUND AND OBJECTIVES: Our previous report showed that parvovirus B19 genotype 1 in different solutions derived from plasma preparations showed different heat-sensitivity patterns during liquid-heating. In this study, we similarly examined B19 genotype 2. MATERIALS AND METHODS: Two plasma samples one containing B19 genotype 1 and the other genotype 2 DNA were used. Four process samples collected immediately before the heat treatment step in the manufacture of albumin, immunoglobulin, haptoglobin and antithrombin preparations were spiked with B19 and subsequently treated at 60°C for 10 h. A low pH immunoglobulin solution was also spiked with B19 and treated at room temperature for 14 days. Infectivity was then measured. RESULTS: B19 genotype 2, similar to genotype 1, showed three patterns of inactivation: (i) a rapid inactivation in the albumin and immunoglobulin preparations, (ii) a slow inactivation in the haptoglobin preparation and (iii) only limited inactivation in the antithrombin preparation. Its sensitivity in the low pH immunoglobulin solutions also resembled that of genotype 1. CONCLUSION: Both genotypes 1 and 2 of B19 varied in sensitivity to liquid-heating and low pH among different plasma preparations.

Extent of hepatitis E virus elimination is affected by stabilizers present in plasma products and pore size of nanofilters.

BACKGROUND AND OBJECTIVE: To investigate the physico-chemical properties of hepatitis E virus (HEV) with regard to inactivation/removal, we have studied four isolates with respect to sensitivity to heat during liquid/dry-heating as well as removal by nanofiltration. MATERIALS AND METHODS: Hepatitis E virus in an albumin solution or phosphate-buffered saline (PBS) was liquid-heated at 60 degrees C for a preset time. HEV in a freeze-dried fibrinogen containing stabilizers was also dry-heated at 60 or 80 degrees C for a preset time. In addition, to clarify the removal of HEV, the purified virus in PBS was filtered using several types of virus-removal filter (nanofilters) that have different pore sizes. HEV infectivity or genome equivalents before and after the treatments were assayed by a semiquantitative cell-based infectivity assay or quantitative polymerase chain reaction assay, respectively. RESULTS: Hepatitis E virus isolates in albumin solutions were inactivated slowly at 60 degrees C for 5 h and the resultant log reduction factor (LRF) was from 1.0 to > or = 2.2, whereas the virus in PBS was inactivated quickly to below the detection limit and the LRF was > or = 2.4 to > or = 3.7. The virus in a freeze dried fibrinogen containing trisodium citrate dihydrate and l-arginine hydrochloride as stabilizers was inactivated slowly and the LRF was 2.0 and 3.0, respectively, of the 72 h at 60 degrees C, but inactivated to below the detection limit within 24 h at 80 degrees C with an LRF of > or = 4.0. The virus in PBS was also confirmed as to be approximately 35 nm in diameter by nanofiltration. These results are useful for evaluating viral safety against HEV contamination in blood products. CONCLUSION: The sensitivity of HEV to heat was shown to vary greatly depending on the heating conditions. On the other hand, the HEV particles were completely removed using 20-nm nanofilters. However, each inactivation/removal step should be carefully evaluated with respect to the HEV inactivation/removal capacity, which may be influenced by processing conditions such as the stabilizers used for blood products.

Preventive therapy for non-steroidal anti-inflammatory drug-induced ulcers in Japanese patients with rheumatoid arthritis: the current situation and a prospective controlled-study of the preventive effects of lansoprazole or famotidine.

BACKGROUND: There is a lack of evidence for the efficacy of preventive medications for peptic ulcers (PUs) among long-term users of non-steroidal anti-inflammatory drugs (NSAIDs) in Japan. AIM: To estimate the preventive effect by normal dose, not high-dose histamine-H2 receptor antagonists (H2RA) for NSAID-induced ulcers. METHODS: We designed two different studies to assess the efficacy of anti-ulcer agents in rheumatoid arthritis (RA) in patients treated over a long term with NSAIDs. An investigative survey divided patients into those not taking anti-ulcer agents (non-medication group); those taking mucosal protective agents (mucosal protectant group), H2RA (H2RA group), proton pump inhibitors (PPI group), or a prostaglandin E1 analog (PG) (PG group). The second study compared prospectively the preventive effects of either famotidine 20 mg bd (famotidine group) or lansoprazole 15 mg daily (lansoprazole group) in patients with PU scars. RESULTS: The prevalence of PU in the H2RA group was significantly lower compared to the mucosal protectant group (P < 0.05), and the mucosal protectant group was not significantly different to the non-medication group. The prospective study revealed that the PU onset rate of the famotidine group was 8% (1/13), and lansoprazole group was 15% (2/13), indicating no significant differences between the two. CONCLUSIONS: In Japan, normal-dose H2RA is expected to be a new PU preventive treatment strategy in patients requiring long-term NSAID therapy.

Implications of corpus gastritis, atrophy and cyclooxygenase in the development of gastric erosions after curing Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori eradication decreases recurrence of peptic ulcers with marked improvement in histological inflammation, but gastric mucosal injuries may be developed even after eradication. PURPOSE: To investigate the mechanisms responsible for the development of gastric erosions after eradication, we analysed the relationship between clinicopathological risk factors and the occurrence of gastric erosion after curing H. pylori infection. PATIENTS: Sixty patients underwent endoscopy before, and 3, 6 and 12 months after the completion of H. pylori eradication. METHODS: Risk factors associated with the development of gastric erosions after eradication were assessed by multivariate analysis, and cyclooxygenase-1 and -2 immunoreactivity was histologically examined in the gastric mucosa before and after eradication. RESULTS: The cumulative prevalence of gastric erosions after H. pylori eradication was 38.3% within 1 year. Using multivariate analysis, corpus gastritis scores (inflammation score+activity score), corpus atrophy scores and an age of more than 50 years were found to be independent factors associated with the development of gastric erosion after eradication with odds ratios of 7.39, 0.13 and 5.00, respectively. Cyclooxygenase-2 immunoreactivity of the corpus was decreased for the non-erosion group after eradication, but not for the erosion group. CONCLUSIONS: Severe gastritis or less severe atrophy in oxyntic glands but not in pyloric glands before eradication may be involved in the development of gastric erosions after curing H. pylori infection.

Monocyte chemoattractant protein 1 (MCP-1) released from Helicobacter pylori stimulated gastric epithelial cells induces cyclooxygenase 2 expression and activation in T cells.

BACKGROUND: and aims: To clarify the interaction between gastric epithelial and mucosal T cells, we examined the role of cytokines released from epithelial cells in response to Helicobacter pylori water extract protein (HPWEP) in regulating T cell cyclooxygenase 2 (COX-2) expression and activation. METHODS: Media from MKN-28 cells incubated with HPWEP for 48 hours were added to Jurkat T cells and human peripheral T cells. C-C and CXC chemokine concentrations in MKN-28 cell media, and COX-2 expression, interferon gamma (IFN-gamma), and interleukin (IL)-4 secretions in T cells were determined by western blot analysis and ELISA methods. Distributions of COX-2 positive T cells and monocyte chemoattractant protein 1 (MCP-1) in tissue specimens with H pylori associated gastritis were determined as single or double labelling by immunohistochemistry. RESULTS: MCP-1, IL-7, IL-8, and RANTES were detected in media from MKN-28 cells incubated with HPWEP. Media as a whole, and MCP-1 alone, stimulated COX-2 expression and peripheral T cell proliferation. Anti-MCP-1 antibody inhibited media stimulated COX-2 mRNA expression in Jurkat T cells. Media stimulated IFN-gamma but not IL-4 secretion from peripheral T cells, while MCP-1 stimulated IL-4 but not IFN-gamma secretion. Both stimulated cytokine release, and peripheral T cell proliferation was partially inhibited by NS-398, a specific COX-2 inhibitor. In mucosa with gastritis, COX-2 was expressed in T cells and MCP-1 was localised mainly in epithelial and mononuclear cells. MCP-1 levels and the intensity of COX-2 expression in tissue samples were closely related. CONCLUSIONS: Cytokines such as MCP-1, released from gastric epithelial cells in response to HPWEP, seem to modulate T cell immune responses, at least in part via COX-2 expression.

Interphase detection of t(4;14)(p16.3;q32.3) by in situ hybridization and FGFR3 overexpression in plasma cell malignancies.

The immunoglobulin (Ig) genes are frequently involved in chromosomal rearrangements with a wide variety of partner loci in multiple myeloma (MM). However, several partner chromosomes have not been detected by conventional cytogenetic methods; for example, 4p16.3 (FGFR3), 6p25.3 (IRF4), and 16q23 (c-maf). To clarify the incidence of t(4;14)(p16.3;q32.3) in primary tumors of MM and to evaluate possible correlations with specific manifestations of the disease, G-banding, double-color fluorescence in situ hybridization (DC-FISH), and/or reverse-transcriptase polymerase chain reaction (RT-PCR) were performed on 40 patients with MM-two with plasmacytoma (PCM) and three with plasma cell leukemia (PCL). All patients were studied by DC-FISH; 40 were studied by G-banding and 36 were studied by RT-PCR. The FISH probes consisted of a cosmid pC385.12 containing the FGFR3 gene, a YAC Y6 containing VH, and a phage Iggamma1-10 containing the gamma1 constant region (Cgamma). We identified eight patients with either FGFR3/Cgamma fusion or FGFR3 overexpression: six patients with both FGFR3/Cgamma fusion and FGFR3 overexpression, one patient with FGFR3/Cgamma, and one with FGFR3 overexpression. FGFR3/Cgamma fusion was demonstrated at a frequency of 19% to 38% on interphase nuclei in seven of the 45 patients. Lytic bone lesions were found to be associated with FGFR3 overexpression. Interphase FISH with FGFR3 and Cgamma probes combined with RT-PCR proved to be an effective tool for detection of this fully cryptic translocation, thus facilitating the characterization of clinical features of MM patients with t(4;14).

CD38-mediated signaling events in murine pro-B cells expressing human CD38 with or without its cytoplasmic domain.

To elucidate the signaling mechanism of CD38 (a transmembrane molecule highly expressed in immature hemopoietic cells), we transfected Ba/F3 murine pro-B cells with a cDNA encoding human CD38. CD38 ligation with anti-CD38 Abs caused rapid, transient, dose-dependent tyrosine phosphorylation of several proteins, including the tyrosine kinase TEC and the adaptor molecule CBL, and association of tyrosine-phosphorylated proteins with phosphatidylinositol 3-kinase p85. Exposure to anti-CD38 Abs or their F(ab')2 and Fab also induced tight aggregation of CD38-transfected Ba/F3 cells, which appeared to be Ca2+ and Mg2+ independent and did not involved LFA-1. Aggregation was abrogated by addition of the tyrosine kinase inhibitor herbimycin A and was delayed by the phosphatidylinositol 3-kinase inhibitor wortmannin, suggesting a link between biochemical events and cellular effects induced by CD38. Cell aggregation was accompanied by a decrease in cell recovery. After 3 days of culture on bone marrow-derived stroma, the mean (+/-SD) cell recovery in the presence of anti-CD38 (T16) was 10.5 +/- 9.2% (n = 7) of that in parallel cultures with an isotype-matched nonreactive Ab. Finally, CD38 ligation in Ba/F3 cells expressing a mutant human CD38 lacking the cytoplasmic domain induced tyrosine phosphorylation with intensity and kinetics similar to those seen with the entire protein. It also induced cell aggregation and decreased cell recovery. We conclude that CD38 triggers remarkably similar signaling pathways in human and murine immature B cells. This signaling is independent of the CD38 cytoplasmic domain, suggesting the existence of accessory transmembrane molecules associated with CD38.

Transoral joint release of the dislocated atlantoaxial joints combined with posterior reduction and fusion for a late infantile atlantoaxial rotatory fixation. A case report.

STUDY DESIGN: A case of a late infantile atlantoaxial rotatory fixation is reported for which transoral anterior release was performed. OBJECTIVES: To report a patient who underwent transoral anterior release of the dislocated atlantoaxial joint for a case of late infantile atlantoaxial rotatory fixation and quadriparesis. SUMMARY OF BACKGROUND DATA: Infantile atlantoaxial rotatory fixation is diagnosed easily by using recently developed imaging techniques such as computed tomography, magnetic resonance imaging, and three-dimensional computed tomography. Nevertheless, patients in whom the condition has been overlooked still are encountered, and the reduction in these patients becomes impossible by traction or by simple posterior open reduction. Few reports on the management of type II-IV chronic atlantoaxial rotatory fixation in which an anterior surgery was performed exist in the literature, and no report exists in which atlantoaxial joint release on the both sides was attained. METHODS: A 9-year-old girl had a type III atlantoaxial rotatory fixation and quadriparesis. She received direct skull traction and repeated manual reduction while she was awake or under general anesthesia. Neither reduction nor movement was obtained, according to the radiographs. Therefore, it was necessary to perform open reduction posteriorly and transorally to release the fixed and contracted joints between C1 and C2. RESULTS: After the anterior release of the joints, there was an inherent force preventing a complete rotational reduction. However, after a successful posterior reduction and fusion, and for more than 4 years after surgery, neither rotatory displacement nor neurologic deterioration was noted. CONCLUSIONS: The authors suggest that careful transoral anterior release of the atlantoaxial joint permits successful reduction in a case of chronic fixed atlantoaxial rotatory fixation combined with cord compression.

Genotype configuration in a case of primary gastric lymphoma with T-cell phenotype.

T-cell malignant lymphoma of the gastrointestinal tract is rare. The genotype of gastric T-cell lymphoma remains unclear. The aim of this study was to elucidate the pathogenesis of a case of primary gastric T-cell lymphoma by using cytogenetics and molecular biology. Gastric biopsy specimens and lymphoma cells in the ascites were examined by immunocytology, cytogenetic analysis, and Southern blot analysis. The histological diagnosis of the gastric lymphoma was diffuse large cell type. T-cell markers were positive in immunocytochemistry of the gastric lymphoma cells and in FACS analysis of lymphoma cells in the ascites. All lymphoma cells in the ascites had complex abnormal karyotypes containing t(8;14)(q24;q32). Southern blot analysis revealed rearrangement of the IgH and C-MYC genes of the lymphoma cells in both the stomach and the ascites, but no comigration of the C-MYC with the JH locus could be detected. The TCR-beta and -gamma genes were in their germ-line configurations. In this patient, although the phenotype was T-cell lymphoma, the karyotype t(8;14)(q24;q32) and genotype had the characteristics of B-cell lymphoma. The unique B-cell genotype configuration and the C-MYC activation suggested that the cellular origin of this rare case of malignant lymphoma with a T-cell phenotype was quite immature lymphocytes.

Prevalence and growth characteristics of malignant stem cells in B-lineage acute lymphoblastic leukemia.

We used a stroma-supported culture method to study the prevalence and growth characteristics of malignant stem cells in acute lymphoblastic leukemia (ALL). In 51 of 108 B-lineage ALL samples, bone marrow-derived stroma not only inhibited apoptosis of ALL cells but also supported their proliferation in serum-free medium. When single leukemic cells were placed in the stroma-coated wells of microtiter plates, the percentage of wells with leukemic cell growth after 2 to 5 months of culture ranged from 6% to 20% (median, 15%; 5 experiments). The immunophenotypes and genetic features of cells recovered from these cultures were identical to those noted before culture. All cells maintained their stroma dependency and self-renewal capacity. Leukemic clones derived from single cells contained approximately 10(3) to 10(6) cells after 1 month of culture; other clones became detectable only after prolonged culture. Cell growth in stroma-coated wells correlated with the number of initially seeded cells (1 or 10; r = .87). However, the observed percentages of positive wells seeded with 10 cells always exceeded values predicted from results with single-cell-initiated cultures (P < .003 by paired t-test), suggesting stimulation of leukemic cell growth by paracrine factors. In conclusion, the proportion of ALL cells with clonogenic potential may be considerably higher than previously thought.

Clinical significance of thallium-201 and gallium-67 scintigraphy in pulmonary tuberculosis.

One hundred and thirty-nine patients with pulmonary tuberculosis were evaluated by means of gallium-67 and thallium-201 scintigraphy. The disease was clinically active in 83 and inactive in 56. The uptake ratio between the lesion and the contralateral normal lung field was calculated. The ratio determined by 67Ga scintigraphy was expressed as GR, and that determined by 201T1 scintigraphy (early or delayed) as ER or DR. The 201T1 retention index (RI) was calculated using the following equation: RI = DR - ER/ER x 100. The sensitivity, specificity and accuracy of 201T1 scintigraphy with respect to the activity of pulmonary tuberculosis were better than those of 67Ga scintigraphy (the figures for 201T1 scintigraphy were 88.0%, 82.1% and 85.6%, respectively, and those for 67Ga scintigraphy, 83.1%, 60.7% and 74.1%). We found a significant correlation between GR and ER, but there was no significant correlation between RI and ER. When the relationships between ER, C-reactive protein and 1-h erythrocyte sedimentation rate were examined among patients with abnormal uptake, no significant relationships were noted. In the 27 patients who could be followed up, GR and ER decreased with duration of the therapy, indicating a decrease in disease activity which was consistent with clinical findings. The RI was significantly higher in the early stages of therapy than in the later stages (P < 0.01), suggesting a temporary delay in 201T1 washout in the early stages. The washout seemed to be promoted by the effects of the therapy. Overall, it is concluded that 201T1 scintigraphy is more useful and more suitable than 67Ga scintigraphy for the evaluation of disease activity and therapeutic effects in patients with pulmonary tuberculosis.

Human B-cell progenitors and bone marrow microenvironment.

Apoptosis of normal and leukemic immature B-cells in vitro is suppressed by contact with bone marrow-derived stromal layers. In stroma-supported cultures of immature B-cells, we found that ligation of CD38, a type II transmembrane protein, inhibited the cell growth and induced apoptosis. CD38 ligation also induced tyrosine phosphorylation and activation of intracellular substrates, including syk, phospholipase C-gamma, c-cbl, and phosphatidylinositol 3-kinase (PI 3-K). Wortmannin and LY294002, two potent inhibitors of PI 3K, rescued immature B cells from CD38-mediated growth suppression. In vitro culture of leukemic lymphoblasts may have potentially important clinical application. First, stroma-supported cultures of acute lymphoblastic leukemia (ALL) cells can determine the growth potential of leukemic cells. In a series of 70 children enrolled in a single program of chemotherapy, cell growth on stroma was a powerful and independent prognostic indicator. Second, a culture system capable of maintaining the majority of ALL blast cells at high levels of viability is also ideally suited for testing antileukemic drugs. Promising results were obtained with 2-chloro-deoxyadenosine and interleukin-4, leading to clinical trials of these two compounds in children with refractory ALL. In addition, we compared the direct antileukemic activities of dexamethasone and prednisolone and found that dexamethasone is five to six times more cytotoxic (on a molar basis) than prednisolone, in agreement with the anti-inflammatory activities of these drugs. This finding may serve to guide the selection of dexamethasone dosage in the treatment of ALL.

[Three-dimensional CT angiography of the portal vein using multiple threshold display].

To evaluate the usefulness of three-dimensional (3D) CT angiography of the portal vein obtained by using a multiple threshold display, 3D reconstructions were performed in 15 patients. The CT scanner employed was the Toshiba Xvigor. A volume of 150 ml of lopamidol 300 mg1/ml was administered at 3.3 ml/sec intravenously. Portal venous phase helical scanning was initiated 80 seconds after the start of the injection. Helical CT data were acquired using up to 25 continuous 1.0-sec rotations during a single breath-hold with an X-ray beam width of 7 mm and a couchtop movement speed of 7 mm/sec. Axial images were reconstructed at a section interval of 3 mm. Both the shaded surface display (SSD) and multiple threshold display (MTD) were generated by using Xtension with Sparc20. MTD was performed as follows. First, voxels, with higher CT values than that of liver parenchyma, were selected. Then, selected voxels were divided into eight parts, which were each assigned gradations of white to grey. The highest part of selected voxels, with higher CT values than that of the second branch of the portal vein, were set to white and a transparency of 0%. The other seven parts were each assigned transparencies of more than 0%. MTD images were compared with SSD in 15 cases by two radiologists. MTD images were superior to SSD images in quality, because MTD diminished surrounding artifacts due to liver parenchyma and enabled small vessels to be depicted clearly. Based on the above results, it was considered that MTD was a useful method for 3D CT angiography using enhanced helical CT.

[Three-phase dynamic helical CT for hepatocellular carcinoma: optimal scanning protocol].

To assess the optimal scanning protocol for three-phase dynamic helical CT, 20 patients were examined according to the following 4 methods (5 cases each) : (1) 100 ml Iopamidol (300 mgI/ml), at a rate of 2 ml/sec ; (2) 120 ml,3 ml/sec, (3) 150 ml, 3 ml/sec ; (4) biphasic method, initial 100 ml, 3.3 ml/sec ; remaining 50 ml, 1.6 ml/sec. Assessment of the time-density curve of the aorta, and the liver parenchyma, indicated that protocol (4) was superior to the others. Using protocol (4), 32 patients (62 nodules) with hepatocellular carcinoma underwent three-phase scanning, consisting of early, late, and delayed phases. Out of 61 nodules, 43 nodules were detected as high density areas in the early phase, 7 nodules as low density areas only in the late phase, and 3 nodules as low density areas only in the delayed phase. Compared with MRI, three-phase dynamic helical CT demonstrated numerous nodules, especially those less than 10 mm in diameter, and, therefore, was useful for the detection of hepatocellular carcinoma.

CD38-mediated growth suppression of B-cell progenitors requires activation of phosphatidylinositol 3-kinase and involves its association with the protein product of the c-cbl proto-oncogene.

The signalling pathways that arrest the cell cycle and trigger cell death are only partially known. Dimerization of CD38, a 45-kD transmembrane type II glycoprotein highly expressed in immature B cells, inhibits cell growth and causes apoptosis in normal and leukemic B-cell progenitors, but the molecular mechanisms underlying these cellular responses are unknown. In the present study, we found that CD38 ligation in the immature B-cell lines 380, REH, and RS4;11 caused rapid tyrosine phosphorylation of the protein product of the proto-oncogene c-cbl. Dimerization of CD38 was accompanied by the association of cbl with the p85 subunit of phosphatidylinositol 3-kinase (Pl 3-K), resulting in markedly increased Pl 3-K activity in antiphosphotyrosine and anti-cbl immunoprecipitates. Wortmannin and LY294002, two potent inhibitors of Pl 3-K, rescued immature B cells from CD38-mediated growth suppression. This effect was observed not only in model B-cell lines, but also in cultures of leukemic lymphoblasts from patients, and in normal bone marrow B-cell progenitors as well. Concentrations of inhibitors that reversed cellular responses to CD38 significantly decreased Pl 3-K activity. By contrast, rapamycin, a p70 S6-kinase inhibitor, did not rescue immature B cells from CD38-mediated suppression. These results suggest that Pl 3-K activity is essential for CD38-mediated inhibition of lymphopoiesis and that cbl and Pl 3-K are regulatory molecules whose activation can result in suppression of cell proliferation and apoptosis in immature lymphoid cells.

[Two cases of breast cancer detected by 99mTc-tetrofosmin myocardial scintigraphy].

Breast cancer ranks the second position among the cancer of women in Japan. We report two cases of breast cancer detected by 99mTc-tetrofosmin. First case was 51 years old female with breast cancer (invasive papillotubular carcinoma) and dextrocardia. She received 99mTc-tetrofosmin myocardial scintigraphy to evaluate dextrocardia and suspicious coronary artery disease. A planar image of 99mTc-tetrofosmin myocardial scintigraphy showed myocardium at the right side, gall bladder at the left lower side and abnormal uptake on the left chest wall. Transaxial images of 99mTc-tetrofosmin myocardial SPECT showed myocardium at the right side and abnormal uptake on the left chest wall. Second case was 78 years old female with breast cancer (intracystic papillary carcinoma) and arrhythmia. 99mTc-tetrofosmin myocardial scintigraphy was performed to evaluate arrhythmia and suspicious coronary artery disease. A planar image of 99mTc-tetrofosmin myocardial scintigraphy shows hot nodule at the lateral side of the myocardium. Transaxial images of 99mTc-tetrofosmin myocardial SPECT showed abnormal uptake at the left lateral side on the chest wall. Both cases appeared illed foci as abnormal uptake with 99mTc-tetrofosmin scintigraphy, although histological diagnosis was different. We conclude that 99mTc-tetrofosmin scintigraphy is helpful for evaluating breast cancer.

CD38 signal transduction in human B cell precursors. Rapid induction of tyrosine phosphorylation, activation of syk tyrosine kinase, and phosphorylation of phospholipase C-gamma and phosphatidylinositol 3-kinase.

Ligation of CD38 inhibits proliferation and induces apoptosis of human immature B cells, but the molecular mechanisms underlying this function are unknown. We found that CD38 dimerization with the specific mAbs T16 and IB4 induces rapid and transient tyrosine phosphorylation of several intracellular proteins in the immature B cell lines RS4;11, REH, 380, Nalm6, and OP-1. This effect could be markedly reduced by incubating cells with the tyrosine kinase inhibitors genistein, staurosporine, and herbimycin A. CD38 dimerization induced tyrosine phosphorylation of the protein kinase syk and increased syk kinase activity. CD38 dimerization also induced tyrosine phosphorylation of phospholipase C-gamma and of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). The latter was accompanied by a distinct increase in PI 3-kinase activity in the immunoprecipitates obtained with an anti-phosphotyrosine Ab. In contrast to the signaling triggered by surface Ig engagement in B lymphocytes, CD38 ligation did not appear to induce tyrosine phosphorylation of the src-like protein tyrosine kinases lyn, fyn, and btk, or of vav- and ras-GTPase-activating protein, nor did it induce detectable changes in cytosolic CA2+ concentrations. CD38 signaling also differed from cytokine-induced signaling in that it did not cause tyrosine phosphorylation of Jak1 and Jak2. Finally, CD38 ligation did not inhibit IL-3-induced tyrosine phosphorylation of Jak2. These results identify CD38 as a cell surface receptor with signal transduction properties activated by dimerization. Induction of signal transduction by CD38 ligation implies the existence of a yet unidentified natural ligand of CD38.