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Disease-specific cytogenetic abnormalities involving BCL2 gene rearrangement frequently co-exist with other cytogenetic abnormalities, contributing to disease progression in follicular lymphoma (FL). In the present study, we retrospectively investigated the prognostic impact of BCL2-unrelated cytogenetic abnormalities in FL. Of 139 consecutively diagnosed patients with FL at two independent institutes, metaphase spreads of tumor cells were obtained for use in G-banding analysis in 77 patients. The recurrent additional cytogenetic abnormalities included chromosome gains +5 (n = 8), +7 (n = 16), +12 (n = 10), and +X (n = 12), and losses -8 (n = 7), -13 (n = 12) -15 (n = 7), and 6q- (n = 7). While -15 was associated with shorter progression-free survival (PFS) in all 77 analyzed patients with evaluable G-banding results (p = 0.04), this negative impact was not evident in 42 patients treated using an R-CHOP-like regimen as first-line treatment. By contrast, 6q- was predictive for shorter PFS in patients who were initially treated with R-CHOP-like regimens without maintenance therapy (p < 0.01), while this negative impact was not evident in all 77 patients with evaluable G-banding results. These results suggest the presence of a molecular region in chromosome 6q that is responsible for the shorter PFS following R-CHOP-like chemotherapy.

We report the case of a 72-year-old man who presented with non-producing multiple myeloma (MM) with three additional concomitant solid tumors that were identified by postmortem autopsy. The disease was refractory to anti-MM therapy including bortezomib and lenalidomide, and he finally died of bacterial pneumonia with diffuse alveolar damage 8 months after the diagnosis. An autopsy revealed that he was also affected by three other solid cancers, cholangiocellular carcinoma, medullary thyroid cancer and papillary thyroid cancer that were clinically asymptomatic and remained undiagnosed before death. A review of the literature suggests that primary quadruple cancers including MM are extremely rare.

Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles., (©2014 American Association for Cancer Research.)

Galectin-3 is induced in chronic myelogenous leukemia (CML) cells by co-culture with bone marrow stromal cells, making paracrine growth promotion of CML cells in conditioned medium (CM) from galectin-3 overexpressing CML cells more potent. We used gel filtration chromatography to demonstrate that the bovine SERPINA1-fetal bovine serum albumin (BSA) complex was specifically suppressed in CM from galectin-3 overexpressing cells. The SERPINA1-BSA complex as well as human plasma SERPINA1 inhibited the growth of CML cells, while exogenous galectin-3 partly offset this effect. These findings suggest that galectin-3 overexpression promotes paracrine growth of CML cells by interfering with the action of the growth inhibitory SERPINA1-albumin complex., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This report concerns a 62-year-old man with primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type that developed during methotrexate (MTX) treatment for rheumatoid arthritis (RA). Several tumors were observed on the left lower leg. A histological analysis showed diffuse proliferation of large neoplastic B-cells that were immunophenotypically CD10-/MUM1+/BCL6-/BCL2+ and cytogenetically had IgH/c-MYC translocation without translocation involving BCL6 or IgH/BCL2. No evidence of Epstein-Barr virus (EBV) infection was found. The discontinuation of MTX resulted in a 20-month disease-free period. No previous cases of PCLBCL, leg type associated with RA or MTX therapy have been reported. The phenotypes of our patient were partly different from those of typical PCLBCL, leg type or RA/MTX-associated lymphoma.

Azacitidine is the first-line therapeutic option for myelodysplastic syndrome (MDS). This report describes a case of MDS in a patient who developed fatal acute interstitial pneumonitis (AIP) after the first seven-day course of intravenous azacitidine (75 mg/m(2)/day) treatment. A review of previous and present studies of azacitidine-associated AIP suggests that azacitidine may cause life-threatening AIP during or after the first seven-day course of treatment, with pyrexia commonly preceding AIP. Although the non-hematologic adverse events associated with azacitidine are generally relatively mild, further accumulation of evidence may help to make an earlier diagnosis of azacitidine-associated AIP.

PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia (CML), however, the cell killing mechanism underlying its anti-leukemic activity has remained to be verified. We investigated the precise mechanisms underlying the apoptosis induction by FTY720, especially focusing on the roles of BH3-only proteins, and the therapeutic potency of FTY720 for CML. Enforced expression of either BCL2 or the dominant-negative protein of FADD (FADD.DN) partly protected CML cells from apoptosis by FTY720, indicating the involvement of both cell extrinsic and intrinsic apoptosis pathways. FTY720 activates pro-apoptotic BH3-only proteins: BIM, which is essential for apoptosis by BCR-ABL1 tyrosine kinase inhibitors (TKIs), and BID, which accelerates the extrinsic apoptosis pathway. Gene knockdown of either BIM or BID partly protected K562 cells from apoptosis by FTY720, but the extent of cell protection was not as much as that by overexpression of either BCL2 or FADD.DN. Moreover, knockdown of both BIM and BID did not provide additional protection compared with knockdown of only BIM or BID, indicating that BIM and BID complement each other in apoptosis by FTY720, especially when either is functionally impaired. FTY720 can overcome TKI resistance caused by ABL kinase domain mutations, dysfunction of BIM resulting from gene deletion polymorphism, and galectin-3 overexpression. In addition, ABT-263, a BH3-mimetic, significantly augmented cell death induction by FTY720 both in TKI-sensitive and -resistant leukemic cells. These results provide the rationale that FTY720, with its unique effects on BIM and BID, could lead to new therapeutic strategies for CML.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma characterized by aggressive symptoms and various abnormal laboratory test results. One of the rare immunologic abnormalities in AITL is exuberant polyclonal plasmacytosis, but its clinical significance has not been evaluated. This report concerns three AITL cases with exuberant polyclonal plasmacytosis and investigates its clinical impact by comparison with 12 patients without plasmacytosis. Our study found that the performance status (PS) of the former was significantly worse and their serum immunoglobulin levels were significantly higher. All other parameters, including B symptoms, various prognostic scores, blood cell counts other than plasmacyte, and serum levels of lactate dehydrogenase, C-reactive protein and soluble interleukin-2 receptor, showed no significant differences. More importantly, although the diagnosis of AITL with plasmacytosis was not straightforward in our series, outcomes of treatment with conventional chemotherapy or immunosuppressive therapy with cyclosporine A were favorable. To conclude, AITL should be considered a candidate underlying disease of exuberant polyclonal plasmacytosis. Provided a correct diagnosis is made early and is followed by adequate treatment, the prognosis for AITL with plasmacytosis may not be worse than that for those without plasmacytosis despite the severe exhaustion at first presentation.

Disseminated intravascular coagulation (DIC) is a life-threatening complication, and its control is essential for therapeutic success. Recombinant human soluble thrombomodulin alfa (rTM) is a novel therapeutic agent for DIC. The efficacy of rTM in the treatment of DIC is reportedly superior to that of conventional anti-DIC treatments, such as unfractionated heparin or low molecular weight heparin, but hemorrhagic events occasionally interfere with the therapeutic benefits of rTM. We assessed the clinical features of 20 consecutive patients who were given rTM for DIC associated with various hematologic disorders. Eight patients achieved remission of both primary disease and DIC, eight died due to progression of the primary disease, and four died of various hemorrhagic complications. Assessment of 16 biomarkers for coagulation showed that the four patients who died of hemorrhagic complications despite remission of their primary disease showed lower ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13) plasma activity than other patients (P = 0.016). The optimal cut-off level of ADAMTS-13 for predicting risk of hemorrhagic complications was 42 % (P = 0.007). Plasma ADAMTS-13 activity determined at diagnosis of DIC may help predict the risk of hemorrhagic events during and/or following DIC treatment with hematologic disorders.

Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2(Ser227), which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma-derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2(Ser227) by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21(WAF1/CIP1), and MCL1. RSK2(Ser227) inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6-mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLX(L) inhibitors. These results suggest that RSK2(Ser227) is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL), which originates from activated mature gamma-delta T cells with a cytotoxic phenotype is a rare T-cell lymphoproliferative disease. The prognosis of PCGD-TCL has been rather unfavorable due to poor response to conventional chemotherapy, and its molecular features and pathophysiology underlying disease development remain unknown. We report here a case with primarily treatment-resistant PCGD-TCL featuring highly complex cytogenetic and genetic aberrations detected by spectral karyotyping and genome-wide single nucleotide polymorphism (SNP) array. Chromosomal aberrations included several chromosomal translocations involving breakpoints at 9p21, 14q11.2, 14q32.1, or 16q23.1, suggesting the involvement of WWOX, TCL gene cluster, and BCL11B, which are crucial for tumorigenesis in T-cell lymphomas. SNP analysis also identified genome copy number gains and losses in various regions, which can potently deregulate expression of various pro- and anti-oncogenic genes involved in RAS-related protein pathways, PI3K/AKT/MTOR-related pathways, MYC-related signaling, or TP53-related signaling. Thus, this case report may shed some light on the complex molecular abnormalities involved in the development of PCGD-TCL and on information that can aid the search for druggable target molecules in this disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We retrospectively investigated the prognostic impact of high-risk cytogenetic abnormalities (CAs) on the outcome of treatment with bortezomib plus dexamethasone (BD) in 43 relapsed/refractory (Rel/Ref) multiple myeloma patients. Fluorescence in situ hybridization (FISH) analysis identified del(13q) in 25 patients, t(4;14) in 14, t(14;16) in 4, 1q21 abnormality in 12 and del(17p) in 2, while G-banding also detected chromosome 13 monosomy (-13) in metaphase spreads from 7 patients. Eighteen of 25 patients with FISH-detected chromosome 13 abnormalities also exhibited other abnormalities. Median observation period was 510 days, and median overall survival (OS) and progression-free survival (PFS) were 912 days and 162 days, respectively. Detection of del(13q), t(4;14), t(14;16) or 1q21 abnormalities by FISH and co-occurrence of chromosome 13 abnormality with other abnormalities were not associated with poorer outcomes. In contrast, detection of -13 by G-banding in metaphase spreads showed significant association with shorter OS, although the overall response rate and PFS were not inferior to those for patients without -13 detected by G-banding. BD therapy may be a potent weapon for overcoming most classical high-risk CAs, while the detection of -13 in metaphase spreads may serve as a predictor of highly progressive disease, even when treated with BD.

No standard therapeutic approaches have so far been established for the treatment of relapsed angioimmunoblastic T-cell lymphoma (AITL), a subtype of non-Hodgkin lymphoma. This case report describes an AITL patient who relapsed with hemophagocytic syndrome (HPS) two months after receiving high-dose chemotherapy (HDCT) supported by autologous peripheral blood stem cell transplantation (PBSCT). The patient was successfully treated with cyclosporine A (CsA) and subsequent allogeneic PBSCT with reduced intensity conditioning regimen (RIST). RIST may deserve consideration for treatment of AITL patients with severe complications such as HPS. Additionally, CsA could be a less-toxic therapeutic option for pre-RIST induction therapy against AITL.

Intravascular B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma, which is characterized by the growth of lymphoma cells within blood vessel lumina without nodular lesions, and which predominantly affects elderly patients. IVLBCL is characterized by B-symptoms and a variety of systemic symptoms due to focal obstruction of blood flow, but may be difficult to diagnose due to its peculiar intravascular localization and the lack of nodular lesions. While hypercalcemia is one of the complications of various types of cancerous diseases, it has rarely been reported as the first presentation of IVLBCL. In this report, we present the case of a 71-year-old male with IVLBCL who showed hypercalcemia accompanied by elevation of serum parathyroid hormone-related protein (PTH-rP) as the initial presentation. Interestingly, immunohistochemical staining revealed that the intravascular lymphoma cells expressed high levels of PTHrP. Six courses of immunochemotherapy, consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and two courses of high-dose methotrexate induced complete remission (CR) and retained CR for 4 months. We also reviewed other IVBCL cases in which hypercalcemia was the initial presentation. We suggest that IVLBCL, although rare, should be considered as a possible causative in hypercalcemia of unknown underlying disease.

Bone marrow (BM) microenvironment (BMME) constitutes the sanctuary for leukemic cells. In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the β-gal-binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migration to HS-5-derived soluble factors in CML cell lines independently of Bcr-Abl tyrosine kinase. The conditioned medium from Gal-3-overexpressing CML cells promoted in vitro cell proliferation of CML cells and HS-5 cells more than did the conditioned medium from parental cells. Moreover, the in vivo study in a mice transplantation model showed that Gal-3 overexpression promoted the long-term BM lodgment of CML cells. These results demonstrate that leukemia microenvironment-specific Gal-3 expression supports molecular signaling pathways for disease maintenance in BM and resistance to therapy in CML. They also suggest that Gal-3 may be a candidate therapeutic target to help overcome BMME-mediated therapeutic resistance.

Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a rare subtype of non-Hodgkin lymphoma for which a definitive therapeutic strategy has not been established yet. We report a case of chemotherapy-resistant SPTL with hemophagocytic syndrome (HPS) which was successfully treated with cyclosporine A (CsA) plus methylprednisolone (mPSL), and also reviewed 11 SPTL cases treated with CsA, previously reported in the literature. Our patient was a 38-year-old female with SPTL. The disease progressed despite conventional chemotherapy using cytotoxic agents including alkylators, anthracyclins or purine analogues, and, after 2 months of chemotherapy, was eventually complicated by HPS and disseminated intravascular coagulation (DIC). CsA (4 mg/kg/day) plus mPSL treatment dramatically improved HPS with DIC, reduced subcutaneous tumors within 2 weeks, and finally induced complete remission (CR) after 3 months. Currently, the patient has maintained CR while being treated with CsA for 12 months. In addition to our case, 9 of 11 SPTL cases were successfully treated with CsA, and 8 were induced to CR. Time to first response to CsA was within 2 weeks in most cases, regardless of prior treatment or the co-occurrence of HPS. Our case and this first comprehensive review on CsA for SPTL suggest that CsA may constitute a candidate treatment strategy for SPTL., (Copyright © 2011 S. Karger AG, Basel.)

We conducted a retrospective collaborative investigation of bortezomib (Bor) plus dexamethasone (Dex) therapy (BD Tx) for 88 relapsed or refractory (Rel/Ref) MM patients at six institutes. One cycle BD Tx comprised of Bor (1.3 mg/m²/day) on days 1, 4, 8 and 11, and Dex on days 1, 2, 4, 5, 8, 9, 11 and 12, every 21 days, and the mean number of BD Tx cycles was 3. The overall response rate was 66.9%, the median overall survival (OS) was 510 days, and the median progression-free survival (PFS) was 113 days. Attainment of partial response (PR) with the first course of BD Tx associated with the longer OS and PFS and late good responder, while no patient who did not achieve PR with the first cycle attained better than very good PR (VGPR) with the subsequent BD Tx. Patient age of less than 64 years old also associated with the longer OS and PFS. In addition, both an earlier disease stage and Dex dosage had a significant impact on OS, while the attainment of VGPR within 2 cycles had a significantly longer PFS. Earlier BD Tx courses may be predictive for the subsequent therapeutic pathway of Rel/Ref MM.

Objective: To determine when to begin examination for retinopathy of prematurity (ROP)., Methods: We retrospectively reviewed the medical records of 663 infants with birth weights of less than 1,500 g in Tokyo Metropolitan Bokutoh Hospital between June 1999 and March 2009, and investigated the timing of onset and initial treatment. In addition, we investigated visibility of fundus for infants of less than 27 weeks gestational age (GA)., Results: The mean GA was 28.7 weeks and the mean birth weight was 1,032.6 g. For infants of less than 27 weeks GA, the earliest onset was 29 weeks postmenstrual age (PMA) and the earliest initial treatment was performed at 30 weeks 0 days PMA. Regarding the visibility of the fundus, zone I could be seen for 50.8% of those infants receiving examination during the latter half of 29 weeks PMA and 71.7% of those infants receiving examination during the former half of 30 weeks. For the infants of a GA of 27 weeks or more, the earliest onset was 2 weeks chronologic age (CA) and the earliest initial treatment was performed at 3 weeks 3 days CA., Conclusions: The optimum timing of initial examination for ROP proved to be between the latter half of 29 weeks and 30 weeks 0 days PMA for infants of a GA of less than 27 weeks; and 3 weeks CA for the infants of a GA of 27 weeks or more.

START-GAP2, also termed as DLC2, is a START domain-containing RhoGAP and a negative regulator of RhoA and Cdc42. Although it was reported as a tumor suppresser gene product, the molecular basis for function of START-GAP2 remains to be clarified. Here, we demonstrate that START-GAP2 is localized in focal adhesions through a "FAT (focal adhesion targeting)" region in the N-terminal half. START-GAP2 competes with START-GAP1/DLC1, another START domain-containing RhoGAP, in focal adhesion targeting. Moreover, the C-terminus of tensin2, one of focal adhesion components and reported to bind START-GAP1, also directly interacts with START-GAP2. These results suggest that START-GAP2 and START-GAP1 share the same molecular mechanism in targeting to focal adhesions.

There is a class of GTPase activating proteins for the Rho family GTPases (RhoGAPs) that contain the steroidogenic acute regulatory protein (STAR)-related lipid transfer (START) domain. In mammals three genes encode such proteins and they are designated START-GAP1-3 or deleted in liver cancer 1-3 (DLC1-3). In this study, we examined the intracellular localization and roles of START-GAP1/DLC1 in cell motility. Immunofluorescence microscopic analysis of NRK cells and HeLa cells revealed that START-GAP1 was localized in focal adhesions. Amino acid residues 265-459 of START-GAP1 were found to be necessary for focal adhesion targeting and we name the region "the focal adhesion-targeting (FAT) domain." It was previously known that ectopic expression of START-GAP1 induced cell rounding. We demonstrated that the FAT domain of START-GAP1 was partially required for this morphological change. Furthermore, expression of this domain in HeLa cells resulted in dissociation of endogenous START-GAP1 from focal adhesions as a dominant negative modulator, reducing cell migration and spreading. Taken together, START-GAP1 is targeted to focal adhesions via the FAT domain and regulates actin rearrangement through down-regulation of active RhoA and Cdc42. Its absence from focal adhesions could, therefore, cause abnormal cell motility and spreading.

In the human genome there are three genes encoding RhoGAPs that contain the START (steroidogenic acute regulatory protein (StAR)-related lipid transfer)-domain. START-GAP3/DLC3 is a tumor suppressor gene similar to two other human START-GAPs known as DLC1 or DLC2. Although expression of START-GAP3/DLC3 inhibits the proliferation of cancer cells, its molecular function is not well understood. In this study we carried out biochemical characterization of START-GAP3/DLC3, and explored the effects of its expression on cell morphology and intracellular localization. We found that START-GAP3/DLC3 serves as a stimulator of PLCdelta1 and as a GAP for both RhoA and Cdc42 in vitro. Moreover, we found that the GAP activity is responsible for morphological changes. The intracellular localization of endogenous START-GAP3/DLC3 was explored by immunocytochemistry and was revealed in focal adhesions. These results indicate that START-GAP3/DLC3 has characteristics similar to other START-GAPs and the START-GAP family seems to share common characteristics.

Fundamental studies were conducted to develop a facility having an adequate air circulation system for growing healthy plants over a long term under microgravity conditions in space. To clarify the effects of gravity on heat and gas exchanges between plant leaves and the ambient air, surface temperatures and net photosynthetic rates of barley leaves were evaluated at gravity levels of 0.01, 1.0, and 2.0 g for 20 sec each during parabolic airplane flights. Thermal images were captured using infrared thermography at an air temperature of 22 degrees C, a relative humidity of 18%, and an irradiance of 260 W/m2. The net photosynthetic rates were determined by means of a chamber method with an infrared gas analyzer at an air temperature of 20 degrees C, a relative humidity of 50%, and photosynthetic photon fluxes (PPFDs) of 250 and 500 micromol/m2/sec. Mean leaf temperatures increased by 1.9 degrees C with decreasing gravity levels from 1.0 to 0.01 g and decreased by 0.6 degrees C with increasing gravity levels from 1.0 to 2.0 g. The increase in leaf temperatures was greater at the regions closer to the leaf tip and at most 2.5 degrees C over 20 sec as gravity decreased from 1.0 to 0.01 g. The net photosynthetic rate decreased by 20% with decreasing gravity levels from 1.0 to 0.01 g and increased by 10% with increasing gravity levels from 1.0 to 2.0 g at a PPFD of 500 micromol/m2/sec. The heat and gas exchanges between leaves and the ambient air were suppressed more at the lower gravity levels. The retardation would be caused by heat and gas transfers with less heat convection. Restricted free air convection under microgravity conditions in space would limit plant growth by retarding heat and gas exchanges between leaves and the ambient air.

Plant defenses against photo-oxidative stress have been studied almost exclusively with respect to stress responses, and little is known about how non-enzymic antioxidants change under constant conditions without a time cue or an environmental stress. Here, we show that, in both the flagellated alga Euglena gracilis Z and the angiosperm Spinacia oleracea L., the potent antioxidant L-ascorbic acid (Asc) displays a circadian rhythm with a maximum at subjective midday, a physiological state reflecting that attained at noon under daily light/dark cycles. Thus, photosynthetic organisms can maximize antioxidant levels in anticipation of midday, when photo-oxidative stress is most severe. These results may partly explain the in-phase circadian UV-C resistance rhythm recently identified in the alga. However, the Asc, but not the resistance, rhythm wanes in continuous darkness. This suggests the presence of persistent circadian rhythms in the levels of other antioxidants in continuous darkness, which may account for the UV-C resistance rhythm.

Radiation-induced stress, either from visible or UV light, is strongest at midday. We found that, in the absence of stress or time cues, Euglena gracilis Z was the most resistant to UV-C and UV-B at subjective midday, whether judged from immediate or reproductive survival. The circadian UV-resistance rhythms were free-running in stationary cultures under 1-h light/1-h dark cycles or continuous darkness, indicating that cell-cycle dependent DNA susceptibility to UV was not involved. We moreover examined what was the primary cause of the circadian UV resistance, estimated as the immediate cell survival. The half-maximal lethal dose (LD(50)) of UV-C at subjective midday (the most resistant phase) was 156 J/m(2), which is approximately 3-fold that at subjective midnight. The same was true for UV-B, except the LD(50) was approximately 13-fold that of UV-C. Temperature during UV irradiation had little effect, indicating that survival was not mediated via enzymatic reactions. Non-enzymatic antioxidants were added 5 min before UV irradiation. Dimethylsulfoxide (a hydroxyl radical scavenger) increased survival after UV-B, but had little effect after UV-C; conversely, sodium ascorbate increased survival after UV-C, but not after UV-B. These findings suggest that circadian rhythms of resistance to UVs involve a common mechanism for maximizing non-enzymatic antioxidative capacity at subjective midday, but the specific antioxidants differ.

Two new bisindole alkaloids, named cinereapyrrole A (1) and B (2), were isolated from wild fruit bodies of Arcyria cinerea and three new bisindole alkaloids (3-5) were isolated from wild fruit bodies of Lycogala epidendrum. Seven known bisindoles (6-12) were concomitantly obtained from them. The structures of the new compounds were elucidated by spectral data. Among these bisindole alkaloids, compound 12 showed cytotoxicity against cultured tumor cell lines.

Microalgae culture is likely to play an important role in aquatic food production modules in bioregenerative systems for producing feeds for fish, converting CO2 to O2 and remedying water quality as well as aquatic higher plants. In the present study, the effects of culture conditions on the cellular multiplication of microalgae, Euglena gracilis, was investigated as a fundamental study to determine the optimum culture conditions for microalgae production in aquatic food production modules including both microalgae culture and fish culture systems. E. gracilis was cultured under conditions with five levels of temperatures (25-33 degrees C), three levels of CO2 concentrations (2-6%), five levels of O2 concentrations (10-30%), and six levels of photosynthetic photon flux (20-200 micromoles m-2 s-1). The number of Euglena cells in a certain volume of solution was monitored with a microscope under each environmental condition. The multiplication rate of the cells was highest at temperatures of 27-31 degrees C, CO2 concentration of 4%, O2 concentration of 20% and photosynthetic photon flux of about 100 micromoles m-2 s-1. The results demonstrate that E. gracilis could efficiently produce biomass and convert CO2 to O2 under relatively low light intensities in aquatic food production modules., (c2005 Published by Elsevier Ltd on behalf of COSPAR.)

We have investigated the cellular distribution of p122RhoGAP, a GTPase-activating protein of Rho small GTPase and an activator of phospholipase C-delta(1). Immunofluorescence studies demonstrated that endogenous p122 is localized at the tips of actin stress fibres and co-localizes with vinculin in normal rat kidney cells. In immunoprecipitation studies, p122 co-precipitated with vinculin, indicating that p122 is localized at the sites of focal adhesion. We have also shown that the N-terminal half of p122 is responsible for this localization. It is conceivable, therefore, that p122 is involved in the reorganization of the actin cytoskeleton and focal adhesions that regulate cell-substratum adhesion and cell migration.

Background: Quite often medical students or novice residents have difficulty in ruling out diseases even though they are quite unlikely and, due to this difficulty, such students and novice residents unnecessarily repeat laboratory or imaging tests., Objective: To explore whether or not a carefully designed short training course teaching Bayesian probabilistic thinking improves the diagnostic ability of medical students., Participants and Methods: Ninety students at 2 medical schools were presented with clinical scenarios of coronary artery disease corresponding to high, low, and intermediate pretest probabilities. The students' estimates of test characteristics of exercise stress test, and pretest and posttest probability for each scenario were evaluated before and after the short course., Results: The pretest probability estimates by the students, as well as their proficiency in applying Bayes's theorem, were improved in the high pretest probability scenario after the short course. However, estimates of pretest probability in the low pretest probability scenario, and their proficiency in applying Bayes's theorem in the intermediate and low pretest probability scenarios, showed essentially no improvement., Conclusion: A carefully designed, but traditionally administered, short course could not improve the students' abilities in estimating pretest probability in a low pretest probability setting, and subsequently students remained incompetent in ruling out disease. We need to develop educational methods that cultivate a well-balanced clinical sense to enable students to choose a suitable diagnostic strategy as needed in a clinical setting without being one-sided to the "rule-in conscious paradigm."

To obtain basic data for adequate air circulation for promoting plant growth in closed plant production modules in bioregenerative life support systems in space, effects of air velocities ranging from 0.1 to 0.8 m s-1 on photosynthesis in tomato seedlings canopies were investigated under atmospheric CO2 concentrations of 0.4 and 0.8 mmol mol-1. The canopy of tomato seedlings on a plug tray (0.4 x 0.4 m2) was set in a wind-tunnel-type chamber (0.6 x 0.4 x 0.3 m3) installed in a semi-closed-type assimilation chamber (0.9 x 0.5 x 0.4 m3). The net photosynthetic rate in the plant canopy was determined with the differences in CO2 concentrations between the inlet and outlet of the assimilation chamber multiplied by the volumetric air exchange rate of the chamber. Photosynthetic photon flux (PPF) on the plant canopy was kept at 0.25 mmol m-2 s-1, air temperature at 23 degrees C and relative humidity at 55%. The leaf area indices (LAIs) of the plant canopies were 0.6-2.5 and plant heights were 0.05-0.2 m. The net photosynthetic rate of the plant canopy increased with increasing air velocities inside plant canopies and saturated at 0.2 m s-1. The net photosynthetic rate at the air velocity of 0.4 m s-1 was 1.3 times that at 0.1 m s-1 under CO2 concentrations of 0.4 and 0.8 mmol mol-1. The net photosynthetic rate under CO2 concentrations of 0.8 mmol mol-1 was 1.2 times that under 0.4 mmol mol-1 at the air velocity ranging from 0.1 to 0.8 m s-1. The results confirmed the importance of controlling air movement for enhancing the canopy photosynthesis under an elevated CO2 level as well as under a normal CO2 level in the closed plant production modules., (c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.)

A fundamental study was conducted to develop a facility having an adequate air circulation system for growing healthy plants over a long-term under microgravity conditions in space. To clarify the effects of gravity on heat exchange between plant leaves and the ambient air, surface temperatures of sweet potato and barley leaves and replica leaves made of wet paper and copper were evaluated at gravity levels of 0.01, 1.0, 1.5 and 2.0 g for 20 s each during parabolic aeroplane flights. Thermal images were captured using infrared thermography at an air temperature of 26 degrees C, a relative humidity of 18% and an irradiance of 260 W m-2. Mean leaf temperatures increased by 0.9-1.0 degrees C with decreasing gravity levels from 1.0 to 0.01 g and decreased by 0.5 degrees C with increasing gravity levels from 1.0 to 2.0 g. The increase in leaf temperatures was at most 1.9 degrees C for sweet potato leaves over 20 s as gravity decreased from 1.0 to 0.01 g. The boundary layer conductance to sensible heat exchange decreased by 5% when the gravity decreased from 1.0 to 0.01 g at the air velocity of 0.2 m s-1. The decrease in the boundary layer conductance with decrease in the gravity levels was more significant in a lower air velocity. Heat exchange between leaves and the ambient air was more retarded at lower gravity levels because of less sensible and latent heat transfers with less heat convection.

To obtain basic data on adequate air circulation to enhance plant growth in a closed plant culture system in a controlled ecological life support system (CELSS), an investigation was made of the effects of the air current speed ranging from 0.01 to 1.0 m s-1 on photosynthesis and transpiration in sweetpotato leaves and photosynthesis in tomato seedlings canopies. The gas exchange rates in leaves and canopies were determined by using a chamber method with an infrared gas analyzer. The net photosynthetic rate and the transpiration rate increased significantly as the air current speeds increased from 0.01 to 0.2 m s-1. The transpiration rate increased gradually at air current speeds ranging from 0.2 to 1.0 m s-1 while the net photosynthetic rate was almost constant at air current speeds ranging from 0.5 to 1.0 m s-1. The increase in the net photosynthetic and transpiration rates were strongly dependent on decreased boundary-layer resistances against gas diffusion. The net photosynthetic rate of the plant canopy was doubled by an increased air current speed from 0.1 to 1.0 m s-1 above the plant canopy. The results demonstrate the importance of air movement around plants for enhancing the gas exchange in the leaf, especially in plant canopies in the CELSS., (c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.)

Objective: To explore the diagnostic thinking process of medical students., Subjects and Methods: Two hundred twenty-four medical students were presented with 3 clinical scenarios corresponding to high, low, and intermediate pre-test probability of coronary artery disease. Estimates of test characteristics of the exercise stress test, and pre-test and post-test probability for each scenario were elicited from the students (intuitive estimates) and from the literature (reference estimates). Post-test probabilities were calculated using Bayes' theorem based upon the intuitive estimates (Bayesian estimates of post-test probability) and upon the reference estimates (reference estimates of post-test probability). The differences between the reference estimates and the intuitive estimates, and between Bayesian estimates and the intuitive estimates were used for assessing knowledge of test characteristics, and ability of estimating pre-test and post-test probability of disease., Results: Medical students could not rule out disease in low or intermediate pre-test probability settings, mainly because of poor pre-test estimates of disease probability. They were also easily confused by test results that differed from their anticipated results, probably because of their inaptitude in applying Bayes' theorem to real clinical situations. These diagnostic thinking patterns account for medical students or novice physicians repeating unnecessary examinations., Conclusions: Medical students' diagnostic ability may be enhanced by the following educational strategies: 1) emphasizing the importance of ruling out disease in clinical practice, 2) training in the estimation of pre-test disease probability based upon history and physical examination, and 3) incorporation of the Bayesian probabilistic thinking and its application to real clinical situations.

To clarify the effects of gravity on heat/gas exchange between plant leaves and the ambient air, the leaf temperatures and net photosynthetic rates of plant leaves were evaluated at 0.01, 1.0, 1.5 and 2.0 G of 20 seconds each during a parabolic airplane flight. Thermal images of leaves were captured using infrared thermography at an air temperature of 26 degrees C, a relative humidity of 15% and an irradiance of 260 W m-2. The net photosynthetic rates were determined by using a chamber method with an infrared gas analyzer at an air temperature of 20 degrees C, a relative humidity of 50% and a photosynthetic photon flux of 0.5 mmol m-2 s-1. The mean leaf temperature increased by 1 degree C and the net photosynthetic rate decreased by 13% with decreasing gravity levels from 1.0 to 0.01 G. The leaf temperature decreased by 0.5 degree C and the net photosynthetic rate increased by 7% with increasing gravity levels from 1.0 to 2.0 G. Heat/gas exchanges between leaves and the ambient air were more retarded at lower gravity levels. A restricted free air convection under microgravity conditions in space would limit plant growth by retarding heat and gas exchanges between leaves and the ambient air., (c2001 COSPAR. Published by Elsevier Science Ltd. All rights reserved.)

Silver in the three species of pinnipeds [northern fur seal (Callorhinus ursinus), Steller sea lion (Eumetopias jubatus), and harbor seal (Phoca vitulina)] caught in the North Pacific Ocean were analyzed using inductively coupled plasma-mass spectrometry, in order to understand accumulation and distribution of silver in pinnipeds. In northern fur seals, relatively high concentrations of silver were observed in the liver and body hair. Some 70% of the silver burden was concentrated in the liver. Hepatic silver concentrations were significantly correlated to age in northern fur seals (r = 0.766, P < 0.001, n = 49) and Steller sea lions (r = 0.496, P < 0.01, n = 28). Levels of silver concentrations per wet weight (microgram g-1) in the three pinnipeds ranged from 0.04 to 0.55 for northern fur seals, from 0.1 to 1.04 for Steller sea lions and from 0.03 to 0.83 for harbor seals. Silver concentrations in liver for all pinnipeds were significantly correlated with mercury, and selenium (P < 0.001). Molar ratios between silver to selenium approximated 1:180 in northern fur seals, 1:120 in Steller sea lions, and 1:60 in harbor seals. The silver-mercury molar ratios were approximately 1:170 in northern fur seals, and 1:80 both in the other species. Increase in silver accumulation in the liver was caused by the retention in nuclei and mitochondria fraction together with mercury and selenium in the cells of northern fur seals.

Vanadium in four species of pinnipeds (northern fur seals [Callorhinus ursinus], Steller sea lions [Eumetopias jubatus], harbor seals [Phoca vitulina], and ribbon seals [Phoca fasciata]) caught in the Northern Pacific was analyzed using ICP-MS to understand its accumulation and distribution. In northern fur seals, relatively high concentrations of vanadium were observed in the liver, hair, and bone. Ninety percent of the vanadium burden in the body was concentrated in these three tissues, which comprise <20% of total body weight. Hepatic vanadium concentrations in the four pinniped species were significantly correlated to age, although the levels varied with species. An increase in vanadium accumulation in the liver of northern fur seals was caused by an increase of retention in nuclei and mitochondria fraction in the cells. Vanadium concentrations in liver were significantly correlated with mercury, silver, and selenium concentrations in northern fur seals, Steller sea lions, and harbor seals.

Cucumbers (Cucumis sativus L. cv. Naoyosi) were grown hydroponically at air temperatures of 28/24 degrees C (D/N) and photosynthetic photon flux (PPF) of 300 micromoles m-2 s-1, in a walk-in type growth cabinet equipped with 3-band fluorescent lamps. Plants were subjected to supplemental blue lighting applied daily just before the 14-h photoperiod (morning twilight) under PPFs of 0, 10, 30, 100, and 200 micromoles m-2 s-1. Treatment periods were 0, 5, 30, or 120 min. Growth and morphological parameters were measured after 12 and 14 days of treatment. On the 13th day of treatment, the stomatal conductance (gs), transpiration rate (Tr), and net photosynthetic rate (Pn) were measured under 3-band fluorescent lamps at a PPF of 200 micromoles m-2 s-1. After 17-19 days of treatment, changes in Pn effected by supplemental blue light were measured continuously for 30 min. Treatment with 5 min of blue lighting promoted more growth than treatment for 30 or 120 min. Similarly, gs, Tr, and Pn were the greatest in plants grown with supplemental blue light of 30 micromoles m-2 s-1 and 100 micromoles m-2 s-1 PPF for 5 min. Pn in plants grown under blue light of 30 micromoles m-2 s-1 for 5 min increased by 60% compared with that of control plants. Pn rose and was maintained at a higher level with 5-min blue lighting treatment. Supplemental lighting with blue light in the morning twilight is considered to be effective for seedling growth, and can be utilized for bionursery facilities to increase efficiency of plant production.

Effect of wind velocity on ethylene release rate of intact lettuce plant was investigated. Lettuce plants were grown at wind velocities of 0.1, 0.4, 0.8, and 1.4 m s-1 for 25 to 33 days and then used for ethylene measurement. When ethylene release rate of the plants grown at a wind velocity of 0.1m s-1 was measured at wind velocities of 0.2, 0.6 and 1.0m s-1 the rate was not affected by wind velocity. This result indicates that ethylene diffusion from lettuce leaf to atmosphere is not affected by boundary layer conditions. When ethylene release rate of the plants grown at wind velocities of 0.1, 0.4, 0.8 and 1.4 m s-1 was measured at the same wind velocity as growing conditions, the rate was scarcely increased by high velocity of wind. A strong wind (4.0 m s-1), which induced wounding damage in small areas of the leaves, had no measurable effect on a ethylene release of the whole plant.

To obtain the basic data of gas exchange of rice (Oryza sativa L. cv. Nipponbare), rates of ethylene release, photosynthesis and transpiration of the rice plant were measured by using a closed-type chamber. Each rate increased until the heading stage and thereafter decreased. Ethylene release rate (E) gradually increased with day after seeding and rates of photosynthesis (P) and transpiration (T) did exponentially. At the heading stage, E, P and T were maximum and had values of about 2.0 mmol plant-1 h-1, 3.0 mmol plant-1 h-1 and 0.60 mol plant-1 h-1, respectively. E in the light period was 1.5-3 times as much as that in the dark period, whereas T in the light period was 5-6 times as much as that in the dark period. E of rice per plant was lower than those of lettuce and Brassica genera which were reported previously. Especially, the rate of rice was about one-tenth that of lettuce. However, when ethylene release rates were estimated on a growth area basis, the rate of rice was about half that of lettuce, and was more than those of Brassica genera.

It is possible to cultivate plants under an artificial gravity field generated by a centrifugal device in space. In order to determine an optimal magnitude of gravity, there is a need to investigate the relationship between plant and growth and gravity, including not only reduced gravity but also gravity greater than 1G. A prototype centrifugal phytotron was designed and fabricated in order to investigate the relationship between plant growth and increased gravity. This device enables us to cultivate plants over the long term by controlling environmental conditions in the phytotron such as temperature, relative humidity, CO2 concentration and light intensity. The results of our experiment indicate that plant seeds can germinate and grow even under an artificial gravity which changes sinusoidally from 2G to 4G.

Trace contaminants generated in closed facilities can cause abnormal plant growth. We present measurement data of trace contaminants released from soils, plants, and construction materials. We mainly used two closed chambers, a Closed-type Plant and Mushroom Cultivation Chamber (PMCC) and Closed-type Plant Cultivation Equipment (CPCE). Although trace gas budgets from soils obtained in this experiment are only one example, the results indicate that the budgets of trace gases, as well as CO2 and O2, change greatly with the degree of soil maturation and are dependent on the kind of substances in the soil. Both in the PMCC and in the CPCE, trace gases such as dioctyl phthalate (DOP), dibutyl phthalate (DBP), toluene and xylene were detected. These gases seemed to be released from various materials used in the construction of these chambers. The degree of increase in these trace gas levels was dependent on the relationship between chamber capacity and plant quantity. Results of trace gas measurement in the PMCC, in which lettuce and shiitake mushroom were cultivated, showed that ethylene was released both from lettuce and from the mushroom culture bed. The release rates were about 90 ng bed-1 h-1 for the shiitake mushroom culture bed (volume is 1700 cm3) and 4.1 approximately 17.3 ng dm-2 h-1 (leaf area basis) for lettuce. Higher ethylene release rates per plant and per unit leaf area were observed in mature plants than in young plants.

Interactions between plants and trace gases, especially ethylene, were investigated from two different viewpoints; ethylene is toxic for plant growth, whereas the ethylene release rate of plants can be utilized as a plant growth indicator. When lettuce plants and shiitake mushroom mycelium were cultivated in closed chambers, ethylene concentration increased with time. Ethylene was released both from lettuce plant and from shiitake mushroom mycelium. Dioctyl phthalate (DOP) and Dibutyl phthalate (DBP) were detected, and these concentrations reached 3.7 ngL-1 for DOP and 2.4 ngL-1 for DBP 4 days after closing. Organic solvents such as xylene and toluene and organic siloxane were detected with GCMS. Visible injury was observed in lettuce plants cultivated in the chambers and it seemed to result from trace contaminants such as DOP, DBP, organic solvents, dimethylsiloxane polymer, and ethylene. In order to obtain basic data of ethylene evolution from plants, ethylene concentration in a closed chamber in which the plants were cultivated under a controlled environment (25 degrees C air temperature, 60-70% relative humidity, 250-300 micromoles m-2 s-1 photosynthetic photon flux density (PPFD)) was measured. Lettuce (Lactuca sativa L. cv. Okayama) released ethylene more than Brassica rapa var. pervidis, Brassica campestris var. communis, and Brassica campestris var. narinosa. Ethylene release rate of intact lettuce plant was highly correlated with plant growth parameters such as dry weight, leaf area and photosynthetic rate. Ethylene release rates of intact lettuce plant were affected by cultivation conditions such as ambient CO2 concentration, light intensity and light/dark period. Increase in ambient ethylene level influenced lettuce growth even at the concentration of 0.1 microliter L-1. The level of ethylene inhibited leaf expansion and slightly accelerated chlorophyll degradation. It did not affect photosynthesis and transpiration, and also little affected dry matter accumulation. Thus, ethylene release characteristics were clarified and an effect of ethylene on lettuce growth was revealed. These findings are useful for determination of a threshold level of ethylene and a capacity of ethylene removal system in CELSS. On the other hand, a possibility of plant growth diagnosis by measuring ethylene concentrations was evaluated. As a result, it became clear that the measurement of ethylene concentration in CELSS is one of the useful non-destructive measurement methods for plant growth diagnosis. Further research is needed to investigate the applicability of the method to environmental stresses other than Ni and Co in nutrient solution.

The physical effects of dust accumulating on leaf surfaces, on leaf physiology, such as photosynthesis, transpiration, stomatal conductance and leaf temperature of cucumber and kidney bean plants were investigated by the use of chemically inert dust. It was found that dust decreased stomatal conductance in the light, and increased it in the dark by plugging the stomata, when the stomata were open during dusting. When dust of smaller particles was applied, the effect was greater. However, the effect was negligible when the stomata were closed during dusting. The dust decreased the photosynthetic rate by shading the leaf surface. The dust of smaller particles had a greater shading effect. Moreover, it was found that the additional absorption of incident radiation by the dust increased the leaf temperature, and consequently changed the photosynthetic rate in accordance with its response curve to leaf temperature. The increase in leaf temperature also increased the transpiration rate.

The concentrations of iron, manganese, zinc, copper, cadmium, and mercury were determined in muscle, liver and kidney of 67 northern fur seals (Callorhinus ursinus) collected off Sanriku, Japan, and from the Pribilof Islands, Alaska. Almost all the elements except cadmium were highest in liver. Cadmium levels in kidney were higher than those in liver and muscle for all animals analyzed. Concentrations of mercury increased significantly with age in muscle, liver and kidney, as did iron levels in muscle and liver and cadmium levels in muscle, while manganese concentrations decreased with age in muscle and kidney. The kidney also showed decreased copper concentration with age. Cadmium concentrations of the northern fur seals in this study were higher than the other otariids, reflecting a predominantly squid diet. Concentrations of manganese and mercury were found to be higher in the fur seals caught off Sanriku than in animals from the Pribilof Islands, while those of zinc and cadmium were found to be lower. Variable concentrations of cadmium might have been attributed to those in seawaters. Discriminant analysis of heavy metal concentrations was used to identify habitat. Sixty-three of 67 animals (94%) were correctly classified using this technique. Heavy-metal concentrations in tissues may provide a useful method to elucidate the primary feeding grounds of fur seals.

In order to obtain basic data for construction of a plant cultivation system incorporating a mushroom cultivation subsystem in the CELSS, plant growth and atmospheric CO2 balance in the system were investigated. The plant growth was promoted by a high level of CO2 which resulted from the respiration of the mushroom mycelium in the system. The atmospheric CO2 concentration inside the system changed significantly due to the slight change in the net photosynthetic rate of plants and/or the respiration rate of the mushroom when the plant cultivation system combined directly with the mushroom cultivation subsystem.

Infective endocarditis in pregnancy is uncommon. A 37-week pregnant woman presented with infective endocarditis. Echocardiography revealed prominent mitral valve vegetations. The patient underwent cesarean section and a 2,800 g male infant was delivered. In order to prevent embolization, mitral valve replacement was performed 3 days after cesarean section with SJM valve. Both mother and child are doing well now.

The present study was conducted to determine the residue levels of persistent organochlorines such as PCB homologues, DDT and its metabolites, and HCH isomers in the ventral blubber of female northern fur seal (Callorhinus ursinus) collected off Sanriku, the Pacific coast of northern Japan, since 1971. Among the organochlorines examined, the concentrations of PCBs and DDTs were found to be high in all samples. The residue levels of these two contaminants showed a drastic reduction following maturity and then a slight increase after the retirement from pregnancy/menopause. Temporal variation of PCB and DDT residues showed maximum levels around 1976 and then decreased, whereas HCH residue levels revealed a very slow declining pattern. Considering the concentrations and compositions of the residues, the northern fur seal is likely to be exposed to organochlorine contamination deriving from global terms. In this context, continuous contamination has been foreseen with regard to PCB and HCH residues. The pattern of organochlorine residues indicated that the northern fur seal has higher metabolic capacity than Dall's porpoise, while it is comparable to those of larga seal and Steller sea lion.