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The mortality rate due to coronavirus disease 2019 (COVID-19) reached 5.3 million. However, identifying the novel treatment targets that ultimately reduce or prevent disease aggravation will be possible by understanding the mechanism and pathophysiology underlying the COVID-19 aggravation. Authors of previous studies have identified the "cytokine storm" that constitutes the secretion of inflammatory cytokines driven by the coagulation/fibrinolytic system as an inflammatory cytodynamic control mechanism that contributes to the aggravated COVID-19 pathology and the pathophysiology of related diseases. Vasculature-lining endothelial cells are bioreactors that produce or contribute to the modulation status of cytokines and coagulation and fibrinolytic system factors. The key steps in the pathophysiology of organ damage include the destabilization of the angiocrine system triggered by vascular endothelial damage during severe COVID-19. Overproduced or imbalanced angiocrine factors and inflammatory cytokines contribute to major COVID-19 complications. Within its scope, this study outlines the significance of the fibrinolytic system in the pathophysiology of inflammatory diseases, focusing on the research results. The possibility of molecular that target these angiocrine and fibrinolytic factors for inflammatory diseases as novel treatment approaches for inflammatory diseases, such as COVID-19, was discussed.

Rituximab is a highly effective agent that is used in the treatment of B-cell lymphoma. Rituximab-induced acute thrombocytopenia is a rare side effect that has previously been reported in a small number of patients with malignant lymphoma; its mechanism is still unknown. We herein report the case of a 74-year old man who was diagnosed with follicular lymphoma and who developed severe acute thrombocytopenia the day after the administration of rituximab. Coagulation abnormality, which mimicked disseminated intravascular coagulation, also appeared. When physicians use rituximab to treat high-risk patients, the platelet count should be closely monitored to avoid possible adverse events.

Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; Serpine1) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as Plat-/- and Serpine1-/- In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1-/- mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.

Cytokine storm syndrome is a general term applied to maladaptive cytokine release in response to infection and other stimuli. It occurs during graft versus host disease after hematopoietic stem cell transplantation. Recent evidence suggested that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patient`s health with Coronavirus Disease 2019 (COVID-19) was compatible with symptoms as they are known for the cytokine storm syndrome. The cytokine storm syndrome in COVID-19 is associated with the development and progression of macrophage activation syndrome (MAS), vascular endotheliitis like Kawasaki disease, and acute respiratory distress syndrome. Abnormalities of coagulation and fibrinolysis are known clinical features of COVID-19 or MAS. We reported previously that plasmin inhibition reduced GVHD associated lethality and prevented increases in inflammatory cytokines in mice. But the role of the fibrinolytic system and its key player, plasmin, in the development of COVID-19 is not well defined. Toll-like receptors (TLRs) might contribute to the pathogenesis of the disease. We established a murine model of fulminant MAS by repeated injections of TLR-9 agonist and D-galactosamine in immunocompetent mice. We found increases in circulating urokinase and the angiocrine factor tissue-type plasminogen activator (tPA) levels during the progression of fulminant MAS in mice, which causes the enhanced conversion of the proenzyme plasminogen into plasmin. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines, chemokines, and proteases like soluble forms or membrane forms of matrix metalloproteases generating an amplification loop. Based on these data, we hypothesize that COVID-19-induced vascular endothelial dysfunction causes the aggravation of COVID-19 leading up to cytokine storm or MAS syndrome, endotheliitis, and hypercoagulability with the induction of disseminated intravascular coagulation syndrome(Fig.1.). In summary, we propose that plasmin and potentially MMPs inhibitors might offer a novel treatment to control the deadly cytokine storm syndrome in patients with MAS or COVID-19, thereby preventing multiple organ failure. Figure Disclosures No relevant conflicts of interest to declare.

Tissue plasminogen activator (tPA), aside from its vascular fibrinolytic action, exerts various effects within the body, ranging from synaptic plasticity to control of cell fate. Here, we observed that by activating plasminogen and matrix metalloproteinase-9, tPA expands murine bone marrow-derived CD45(-)TER119(-)Sca-1(+)PDGFRα(+) mesenchymal stromal cells (PαS-MSCs) in vivo through a crosstalk between PαS-MSCs and endothelial cells. Mechanistically, tPA induces the release of Kit ligand from PαS-MSCs, which activates c-Kit(+) endothelial cells to secrete MSC growth factors: platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor 2 (FGF2). In synergy, FGF2 and PDGF-BB upregulate PDGFRα expression in PαS-MSCs, which ultimately leads to PαS-MSC expansion. These data show a novel mechanism by which the fibrinolytic system expands PαS-MSCs through a cytokine crosstalk between niche cells.

Limited data are available on micafungin breakthrough fungemia (MBF), fungemia that develops on administration of micafungin, in patients with hematological disorders. We reviewed medical and microbiological records of patients with hematological disorders who developed MBF between January 2008 and June 2015. A total of 39 patients with MBF were identified, and Candida (30 strains) and non- Candida (9 strains) fungal species were recognized as causative strains. Among 35 stored strains, Candida parapsilosis (14 strains), Trichosporon asahii (7 strains), Candida glabrata (5 strains), and other fungal species (9 strains) were identified by sequencing. Neutropenia was identified as an independent predictor of non- Candida fungemia ( P = 0.023). T. asahii was the most common causative strain (7/19) during neutropenia. The 14-day crude mortality rate of patients treated with early micafungin change (EMC) to other antifungal agents was lower than that of the patients not treated with EMC (14% versus 43%, P = 0.044). Most of the stored causative Candida strains were susceptible (80%) or showed wild-type susceptibility (72%) to micafungin. The MICs of voriconazole for T. asahii were low (range, 0.015 to 0.12 μg/ml), whereas the MICs of amphotericin B for T. asahii were high (range, 2 to 4 μg/ml). MBF caused by non- Candida fungus should be considered, especially in patients with neutropenia. EMC could improve early mortality. Based on epidemiology and drug susceptibility profiling, empirical voriconazole-containing therapy might be suitable for treating MBF during neutropenia to cover for T. asahii .

The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.

Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. Although abnormalities of coagulation and fibrinolysis are major components of MAS, the role of the fibrinolytic system and its key player, plasmin, in the development of MAS remains to be solved. We established a murine model of fulminant MAS by repeated injections of Toll-like receptor-9 (TLR-9) agonist and d-galactosamine (DG) in immunocompetent mice. We found plasmin was excessively activated during the progression of fulminant MAS in mice. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines/chemokines. Collectively, our findings identify plasmin as a decisive checkpoint in the inflammatory response during MAS and a potential novel therapeutic target for MAS.

Spatial characteristics of tsunami flow caused by the 2011 off the Pacific coast of Tohoku Earthquake were described focusing the relationships between tsunami inundation processes and coastal and fluvial geomorphology in the northern and middle coast of the Tohoku district. Different tsunami inundation processes were recognized in the four types of areas having different geomorphological characteristics, the Miyako City area in the valley bottom plain of the Hei River , Otsuchi area of small coastal lowland with small rivers, the Aneyoshi area of a tiny cove with a small and steep slope stream, and the Natori River , and surroundings in the Sendai Plain largest plain in Tohoku district. The megatsunami got over the seawalls to inundate coastal lowlands and valley bottom plain, and it also ascended banked rivers . The tsunami flow ascending the banked river reached upstream area faster than the inundated flow in the habitation side of the floodplain . The tsunami flow in the river got over the river embankments to flood the habitation side. In the coastal area, the deep tsunami flow directly inundated landward is less affected by geomorphological characteristics and it caused geomorphological processes by erosion and sedimentation on land. The tsunami flow ascending the steep slope and small valley reached high elevation area whose elevation was double of the tsunami height in the coast. In the coastal and valley bottom plains, depth of the tsunami flow got shallower landward. In the landward area, the extent of the shallower tsunami flow was strongly affected not only by geomorphological characteristics but also by artificial constructions . In the area near the landward limit of tsunami inundation, micro-landforms , such as former river courses , affected tsunami inundation processes and spatial characteristics of the tsunami flow.

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Pontine omnipause neurons (OPNs) are inhibitory neurons projecting to saccade-related premotor burst neurons. OPNs exhibit sustained discharge during fixations and cease firing before and during saccades. The pause in OPN discharge releases the burst neurons from tonic inhibition, resulting in generation of saccadic eye movements. OPNs are thought to receive two major inhibitory inputs during saccades: an early component that determines the pause onset and a late component that controls the pause duration. Although there is evidence that numerous glycinergic and GABAergic terminals contact OPNs, their physiological roles remain unclear. To reveal functions of glycinergic and GABAergic inputs, we investigated effects of iontophoretic application of strychnine, a glycine receptor antagonist, and bicuculline, a GABAA receptor antagonist, on discharge patterns of OPNs in alert cats. Application of strychnine reduced the ratio of pause duration to saccade duration. Analysis of the timing of pause relative to saccades showed that pause onset was delayed and pause end was advanced. These effects were observed for saccades in all directions. Application of bicuculline, in contrast, had no effect on the OPN pause duration or timing. Both strychnine and bicuculline increased tonic firing rate during intersaccadic intervals. These results suggest that glycinergic, but not GABAergic, afferents convey inhibitory signals that determine the onset as well as duration of pause in OPN activity during saccades.

The tumor microenvironment is recognized as a key factor in the multiple stages of cancer progression, mediating local resistance, immune-escape and metastasis. Cancer growth and progression require remodeling of the tumor stromal microenvironment, such as the development of tumor-associated blood vessels, recruitment of bone marrow-derived cells and cytokine processing. Extracellular matrix breakdown achieved by proteases like the fibrinolytic factor plasmin and matrix metalloproteases is necessary for cell migration crucial for cancer invasion and metastasis. Key components of the fibrinolytic system are expressed in cells of the tumor microenvironment. Plasmin can control growth factor bioavailability, or the regulation of other proteases leading to angiogenesis, and inflammation. In this review, we will focus on the role of the fibrinolytic system in the tumor microenvironment summarizing our current understanding of the role of the fibrinolytic factors for the modulation of the local chemokine/cytokine milieu, resulting in myeloid cell recruitment, which can promote neoangiogenesis.

Introduction: Atherosclerosis is a chronic inflammatory disease and the primary cause of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions. Extended survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. The objective of this study was to examine the antiatherosclerotic effects of CPA and the underlying mechanism in a murine model of atherosclerosis. Hypothesis: CPA treatment can alter inflammatory processes pivotal for the development of atherosclerosis, therefore limiting disease progression. Method: Apolipoprotein E deficient (ApoE-/-) mice fed a high fat diet received CPA resuspended in drinking water (37.5 g/kg /day p.o.) or water for 12 weeks, respectively. In an interventional protocol, mice fed a high fat diet received the same dose of CPA or water from week 14 to 18, respectively. Mice were sacrificed at week 12, 14 and 18, and aorta, peripheral blood cells, spleen cells and peritoneal cells of treated mice were analysed using histological methods and FACS analysis. Result: In a preventive protocol, continuous oral administration of low-dose CPA prevented disease initiation in ApoE-/- mice fed with a high fat diet. Encouraged by these data we treated mice with pre-established atherosclerosis for 4 weeks with CPA, in an interventional protocol. CPA treatment delayed disease progression in mice with advanced atherosclerosis and reduced the macrophage infiltration in plaques. Importantly, improved plaque stability with a thicker fibrous cap, and an increase in collagen deposition and decreased matrix metalloproteinase-2 and -9 expression, and a reduction of classical inflammatory macrophage (M1) numbers was observed. In addition, CPA treatment reduced the numbers of IFN-γ-producing TH1, but not TH2 lymphocytes in vivo. Conclution: Our data demonstrate that oral treatment with CPA inhibits atherosclerosis initiation and progression in ApoE-/- mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, CPA may be a valuable drug for treating advanced atherosclerosis.

Wear state of a gear drive is the most frequent fault in rotating machinery, but there is not a acceptable method to diagnose the wear state in practical plant, and the condition monitoring of gear wear state has been carried out mainly by statistical way and experience. In order to overcome the difficulties, in the 1st report, we have pointed out the problems of the traditional diagnosis method using only the dynamic model of normal state, and clarify the dynamic characteristics on failure gears by the locus analysis of the meshing contact point. In this report, we show the dynamic characteristics by simulation and experiment, and propose feature parameters for diagnosing wear state of gear drive. The efficiency of the method proposed in this paper is verified by the results of simulation and experiment.

Gear drive is one of important parts on plant machinery. However, up to now, the method of failure diagnosis of gear drive has not been clarified theoretically, and the condition monitoring of gear drive has been carried out mainly by statistical way and experience. So the main problems are : (1)the failure signal is hardly extracted from measured signal for early diagnoisis, (2)the failure type can not been easily recognized. In onder to overcome the difficulties, in this study we develop the diagnosis theory for gear drive by clarifying the change of dynamic characteristics between normal and abnormal states, and using theories of signal processing, fuzzy and neural network etc. In the 1st report, we point out the problems of the traditional diagnosis method using only the dynamic model of normal state, and clarify the dynamic characteristics on failure gears by the locus analysis of the meshing contact point, and show the results of analysis and experiment on eccentric gear to verify the efficiency of the method proposed in this paper.

1. Extracellular recordings were made from medium-lead burst neurons (MLBNs) in the paramedian pontomedullary reticular formation rostral and caudal to the abducens nucleus in the alert cat. 2. Single-pulse stimulation of the contralateral superior colliculus during intersaccadic intervals evoked no response in most MLBNs. When collicular stimulation was applied at the beginning of saccades, spikes of MLBNs were consistently evoked with short latencies. The shortest latency was 0.8 ms, indicating monosynaptic activation of MLBNs from the superior colliculus. 3. Results suggest that monosynaptic excitatory effects from the colliculus are concealed by inhibitory input from omnipause neurons (OPNs) during intersaccadic intervals and that the monosynaptic collicular activation is disclosed when this inhibition is removed by a pause in OPN activity at the beginning of saccades.

Single-dose toxicity studies of prulifloxacin, a new antibacterial agent, were conducted in mice, rats and dogs. In addition, a single-dose toxicity study of (+/-)-6-fluoro-1-methyl-4-oxo-7- (1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline- 3-carboxylic acid (NM394), an active metabolite of prulifloxacin, was performed in rats. Prulifloxacin was administered orally, intraperitoneally (i.p.) or subcutaneously (s.c.) to mice and rats, and orally to dogs. NM394 was administered intravenously (i.v.) to rats. When prulifloxacin was administered orally or s.c., LD50 values were more than 5000 mg/kg in both sexes of mice and rats; when it was administered i.p., LD50 values were 1757 mg/kg in male mice, 1652 mg/kg in female mice, 915 mg/kg in male rats, and 1076 mg/kg in female rats. The lethal doses of this drug were more than 5000 mg/kg in both sexes of dogs by the oral route. The LD50 values of NM394 were 226 mg/kg in male rats and 238 mg/kg in female rats by the i.v. route. In mice, the major clinical signs observed following the administration of prulifloxacin were sedation, oligopnea, abnormal gait, piloerection, closed eye and tremor by the i.p. route and a scab at the site of injection by the s.c. route; in rats, decreased spontaneous locomotor activity by any of the three routes, oligopnea, lacrimation, hypothermia, piloerection and abnormal gait by the i.p. route, and a scab at the site of injection by the s.c. route; and in dogs, vomiting, reddening of the skin, and loose stool by the oral route. When NM394 was administered i.v., rats showed clonic convulsion and dyspnea. The site of injection was hyperemic, swollen and necrotic. Mice showed a decrease in body weight or an inhibition in weight gain when prulifloxacin was administered i.p. and rats showed the same effects when prulifloxacin or NM394 was administered by any of the above-mentioned routes. Macroscopic findings detected following the i.p. administration of prulifloxacin in mice were pale color of the liver and spleen, thickening of the liver, and adhesion of intra-abdominal organs; and in rats, hydrothorax, congestion and edema of the lung, adhesion of intra-abdominal organs, swelling of the kidney accompanied by fine yellowish-white foci, and atrophy of the testis. When NM394 was administered i.v. to rats, congestion of the lung was macroscopically observed.

Extra- and intracellular recordings were made from pontine pause neurons (PNs) in the cat. Spontaneous spikes of PNs were suppressed after single shock stimulation of excitatory burst neuron (EBN) area immediately rostral to the abducens nucleus. The most effective stimulation site for the suppression was the region where long-lead burst neurons (LLBNs) were predominantly located. Intracellular recordings from PNs showed that stimulation of the LLBN area induced short-latency inhibitory postsynaptic potentials (IPSPs) in PNs and that steep hyperpolarization of PNs associated with quick phases of nystagmus occurred prior to an abrupt change in abducens nerve activity. Results suggest that a pause of PN spikes associated with quick phases is, at least in part, produced by inhibitory action mediated through LLBNs.

A series of novel (imidazo[1, 2-b]pyridazin-6-yl)oxyalkylsulfonamides was synthesized and evaluated for the ability to inhibit platelet activating factor (PAF)-induced bronchoconstriction in guinea pigs. The compounds bearing a gem-dialkyl or a cycloalkylidene group at the 2 position of the sulfamoylpropyloxy group in the side chain were found to have potent activity. Among them, 3-(imidazo[1, 2-b]pyridazin-6-yl)oxy-2, 2-dimethylpropanesulfonamide (6) showed excellent anti-asthmatic activity and the longest duration of action. The compounds bearing a methyl group at the 7 or 8 position of the imidazo[1, 2-b]pyridazine ring were found to have enhanced activity. Among them, 3-(7-methylimidazo[1, 2-b]pyridazin-6-yl)oxy-2, 2-dimethylpropanesulfonamide (25) showed the most potent inhibitory effect, and its anti-asthmatic effect in an experimental model of allergic asthma was superior to that of theophylline. The structure-activity relationships in this series of compounds are discussed.

A series of novel alkylthioimidazo[1,2-b]pyridazines was synthesized and evaluated for ability to inhibit platelet activating factor (PAF)-induced bronchoconstriction in guinea pigs. Among them, 3-(imidazo[1,2-b]pyridazin-6-yl)thio-2,2-dimethylpropanesulfona mide (15) showed the most potent inhibitory effect. The structure-activity relationships in this series of compounds, in particular, the effects of conversion of the imidazopyridazine ring into other heterocyclic rings, introduction of a substituent group at the 2 or 3 position of the imidazopyridazine ring and introduction of a substituent group into the alkyl side chain, are also discussed.

The stress evaluation becomes important for the prior prevention of stress-related illnesses. One of the methods is to analyze the fluctuations of heartbeat called by heart rate variability (HRV), since the heartbeat interval is constantly fluctuating by reflecting autonomous nerve activity. The HRV has been obtained from peak intervals in an electrocardiogram (ECG). However, the use of the ECG is not suitable for a long time monitor, since several electrodes have to be attached to a human body. We report here on an evaluation method of the heart rate variability and stress using a microwave reflectometer with frequency of 10 GHz. The key technical developments (phase detector with AGC amplifier, data processing for HRV evaluation) are described. The protocol for stress evaluation examination is prepared in order to apply to various testee. The values of HRV and its spectra obtained by a reflectometer are in good agreement with those obtained by ECG.

Hazards along a river course in a drainage basin are characterized by three types of events: debris flow, turbidity flow and flood. Each has its own channel segment with different sediment transport processes. The sediment transport process is controlled by transportation force: tractive force and slope-direction component of sediment weight, both of which are significantly affected by channel slope. Along large rivers in Japan the boundary between the upstream turbidity flow segment and the downstream flood segment is located at the position with a channel slope of about 1/1000. Along steep, small rivers the boundary between the upstream debris flow segment and the downstream turbidity flow segment is located at the position with a channel slope of about 80/1000. The channel slope depends on the shapes of longitudinal profiles of rivers. The longitudinal profiles of Japanese rivers, main rivers and tributaries, can be described by an exponential, power or linear function. The transportation force of the rivers fitted with exponential functions markedly decreases downstream due to the large curvature of the profiles, causing noticeable sediment deposition in the middle courses. The transportation force of the rivers fitted with power or linear functions maintains its strength through the whole river courses due to the small curvature, causing sediment transportation down to the lower courses. The function types are strongly affected by relief in the drainage basins. The rivers flowing in small relief areas are fitted with exponential functions and those flowing in large relief areas are fitted with power or linear functions. Thus, the distribution of hazard types along a river course in a drainage basin is controlled by the distribution of relief in the drainage basin.

This study was designed to determine the effects of food restriction and fasting on fetal development during major organogenesis in Sprague-Dawley rats. The maternal body weight gain markedly decreased during the 60%- and 90%-restricted feeding and fasting periods with a concomitant decrease in the plasma glucose levels. The number of resorptions slightly increased in the 90%-restricted feeding and fasting groups with lower fetal viability. The mean fetal body weight of the restricted feeding and fasting groups and the mean placental weight of male fetuses of the 60%-restricted feeding group were significantly lower than those of the control groups. Ossification of the metacarpi and metatarsi was slightly but significantly retarded by 60%-restricted feeding. The incidence of cardiovascular malformations (mainly ventricular septal defect and abnormal origin of the right subclavian artery) and visceral variations apparently increased in the restricted feeding and fasting groups. Abnormal fetuses tended to be lighter than normal fetuses. In conclusion, maternal food restriction and fasting during major organogenesis caused the fetal growth retardation with slightly delayed ossification and a high incidence of cardiovascular abnormalities in rats. This possibility must be taken into consideration when teratology data with a reduction in maternal food consumption are evaluated.

Microwave reflectometric measurement is applied to diagnose human vital signal. The reflectometer signal is processed by a quadrature phase detector in order to obtain both phase and amplitude components of the signal. The phase component is analyzed by using fast-Fourier transform and wavelet transform to evaluate the frequency spectrum of the heartbeat and respiration. In this report, we focus on some challenges such as overnight monitoring and the performance during driving vehicle. The system using Automatic Gain Control (AGC) and integration of reflectometry system are also discussed.

Omnipause neurons (OPNs) are midline pontine neurons that are thought to control a number of oculomotor behaviors, especially saccades. Intracellular recordings were made from OPNs in alert cats to elucidate saccade-associated postsynaptic events in OPNs and thereby determine what patterns of afferent discharge impinge on OPNs to cause their saccadic inhibition. The membrane potential of impaled OPNs exhibited steep hyperpolarization before each saccade that lasted for the whole period of the saccade. The hyperpolarization was reversed to depolarization by intracellular injection of Cl− ions, indicating it consisted of temporal summation of inhibitory postsynaptic potentials (IPSPs). The duration of the saccade-related hyperpolarization was almost equal to the duration of the concurrent saccades. The time course of the hyperpolarization was similar to that of the radial eye velocity except for the initial phase. During the falling phase of eye velocity, the correlation between the instantaneous amplitude of hyperpolarization and the instantaneous eye velocity was highly significant. The amplitude of hyperpolarization at the eye velocity peak was correlated significantly with the peak eye velocity. The time integral of the hyperpolarization was correlated with the radial amplitude of saccades. The initial phase disparity between the hyperpolarization and eye velocity was due to the relative constancy of peak time (∼20 ms) of the initial steep hyperpolarization regardless of the later potential profile that covaried with the eye velocity. The initial steep hyperpolarization led the beginning of saccades by 15.9 ± 3.8 (SD) ms, which is longer than the lead time for medium-lead burst neurons. These results demonstrate that the pause of activity in OPNs is caused by IPSPs initiated by an abrupt, intense input and maintained, for the whole duration of the saccade, by afferents conveying eye velocity signals. We suggest that the initial sudden inhibition originates from central structures such as the superior colliculus and frontal eye fields and that the eye velocity-related inhibition originates from the burst generator in the brain stem.

Pamiteplase (genetical recombination), YM866, is a novel recombinant modified human tissue-type plasminogen activator developed by Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan. An intended route of administration in the clinical use of this drug is intravenous administration. We conducted an intravenous fertility and general reproduction studies of this drug in male and female rats and teratology study of this drug in rabbits at the dose levels of O (vehicle control), 0.1, 0.3 or 1 mg/kg/day. In the rat, no treatment-related abnormalities were observed up to the maximum dose in parental animals and their offspring. In the teratology study in rabbits, prolonged coagulation time at the injection site was observed at 0.3 mg/kg or more. One death and one abortion occurred at 1 mg/kg on days 22 and 23 of pregnancy, respectively. No toxic effects on the litters were observed up to the maximum dose. Results of evaluation of the mutagenicity of YM866 and its ability to induce chromosome aberrations using the L5178Y TK+/- mouse lymphoma assay, human lymphocyte chromosome aberration assay and the micronucleus assay in mice were negative. Evaluation of the immunogenicity of YM866 by repeated intravenous injection in chimpanzees elicited no confirmed antibody titers.

A three-stage model is proposed to describe river processes after rapid valley-filling due to large landslides, based on surveys on the Shirayuki river basin in northeast Japan. At Stage I slightly entrenched debris avalanche deposits get covered with fluvial sediments. At Stage II the river along the upper reaches deeply cuts into fill deposits while fan aggradation occurs along the lower reaches. At Stage III river incision occurs along all the courses. This sequence of river processes reflects the changing amounts of post-landslide debris supply from the landslide scar and river banks. The three-stage model is also applicable to other examples of post-landslide river processes, although some lack the Stage I. Morphometric analyses suggest that the presence or absence of the Stage I depends on the ratio of debris supply from the landslide scar to river competence of sediment delivery.

Effects of stimulation of the superior colliculus on saccade-related brain stem neurons were studied in the alert cat. Extracellular recordings were made from medium-lead burst neurons (MLBNs), omnipause neurons (OPNs) and burster-driving neurons (BDNs) in the paramedian pontomedullary region rostral and caudal to the abducens nucleus. MLBNs were activated from the contralateral superior colliculus with monosynaptic latencies when single-pulse stimulation was given during saccades or ipsilateral head rotation, although this activation was not observed during fixation periods. The caudal SC was more effective than the rostral SC in monosynaptic activation of MLBNs. Most OPNs were also activated monosynaptically from the SC. In constrast to MLBNs, the activation of OPNs was more frequently induced from the rostral SC than from the caudal SC. Stimulation of the caudal SC often induced suppression of spikes in OPNs. BDNs received excitation from the ipsilateral SC through a di- or trisynaptic pathway. Like MLBNs, BDNs tended to receive stronger input from the caudal SC than the rostral SC. Results indicate the existence of tectofugal excitatory pathways to MLBNs and BDNs and an inhibitory pathway to OPNs. It seems likely that these pathways originate from saccade-related burst cells in the SC. Since excitation of BDNs and inhibition of OPNs increase the excitability of MLBNs, all of these pathways may contribute to burst activity in MLBNs and thereby saccade generation. Results also support the current idea that cells in the rostral SC may participate in fixation by activating OPNs.

Progress in microwave and millimeter-wave technologies has made possible advanced diagnostics for application to various fields, such as, plasma diagnostics, radio astronomy, alien substance detection, airborne and spaceborne imaging radars called as synthetic aperture radars, living body measurements. Transmission, reflection, scattering, and radiation processes of electromagnetic waves are utilized as diagnostic tools. In this report we focus on the reflectometric measurements and applications to biological signals (vital signal detection and breast cancer detection) as well as plasma diagnostics, specifically by use of imaging technique and ultra-wideband radar technique.

Abstract 1260 Although the efficacy of cord blood transplantation (CBT) from unrelated donors as viable alternative for patients in need of hemtopoietic stem cell transplantation (HSCT) is supported by growing evidences, viral infections related to delayed immune reconstitution remains important problems for further improvement of clinical outcomes. To evaluate incidences and outcomes of late viral infections after CBT by comparison with those after unrelated bone marrow transplantation (uBMT), we retrospectively analyzed the records of 281 Japanese adult patients who underwent allogeneic unrelated HSCT for the first time at the Toranomon Hospital between January, 2002 and March, 2010, and who survived more than 100 days after HSCT without the lost-to-follow-up or retransplantation before day 100. Between 50 days and 5 years after HSCT, 116 patients had at least one late infectious episode with a cumulative incidence of 52.2%, at a median of 157 (50-1597) days after HSCT. The 5-year cumulative incidence of any late viral infections was greater in CBT versus uBMT recipients (60.7% vs. 42.2%, respectively; P=0.039, Figure 1). Thirty-three patients (28.4%) had 2 or more episodes caused by different viruses, and a total of 152 late infectious episodes were documented. The median onset of the episodes was similar between the both groups (median onset 226 days vs 222 days, P=0.89). The most common late viral infection is varicella-zoster virus (VZV) reactivation, accounting for 28.8% (disseminated 10, localized 34), followed by hemorrhagic cystitis associated with adeno- and/or BK viruria (28.2%), cytomegalovirus (CMV) diseases (16.4%; gastrointestinal diseases 23, retinitis 1, pneumonia 1), and respiratory tract infections caused by influenza virus, parainfluenza virus or respiratory syncytial virus (15.8%; upper 26, lower 8), and Epstein-barr virus lymphoproliferative diseases (4.6%). The remaining 10 infectious episodes were caused by relatively rare type of viruses including herpes simplex virus, JC virus, measles virus, mumps virus, norovirus and parvovirus, all of which occurred only in CBT recipients. Of all these viral infections, only VZV reactivation developed significantly more frequent in CBT than in uBMT recipients (P=34.0% vs 17.0%, P=0.023). There was no difference of dissemination rate between the both groups, and all the patients responded well to treatment with antiviral agents. The late viral infection was a primary cause of death in 3 episodes, all of which were pneumonia caused by CMV, influenza virus and parainfluenza virus. The 5-year incidence of infection-related mortality did not differ between CBT and uBMT recipients (0.7% vs 3.1%, P=0.46). Non-relapse mortality occurred in 11.8 % and 16.4 % patients in the CBT and uBMT groups (P=0.71). These findings suggested that cord blood might be as an acceptable and useful stem-cell source as bone marrow from unrelated donors in terms of risks of viral infection in the late posttransplant period. Disclosures: No relevant conflicts of interest to declare.

As the importance of advanced millimeter-wave diagnostics increases, the fabrication of high-performance devices and components becomes essential. In this paper, we describe the development of millimeter-wave planar antennas using low-loss fluorine substrates. The problems to be solved in this study are the low degree of adhesion between copper foil and the fluorine substrate and the accuracy of device pattern using conventional fabrication techniques. In order to solve these problems, a new surface treatment of fluorine films and a fabrication method using electro-fine-forming (EF2) are proposed. In order to confirm the performance of the treated films, microstrip lines (MSLs) and planar patch antennas with a low sidelobe level in the E-plane are designed and fabricated on conventional fluorine substrates and grafted poly(tetrafluoroethylene) (PTFE) films.

Abstract 2295 Poster Board II-272 Introduction: Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning has been widely applied to those who have advanced hematologic diseases and are not eligible for conventional conditioning. Although bone marrow or peripheral blood from related donors (rBM/PB) have been the first choice of graft when available, followed by unrelated adult donor or cord blood (CB), true superiority of rBM/PB over others can still be controversial. Elderly patients have difficulty finding related donors since their siblings are also in their elderly who have higher chance of having co-morbidity relative to younger patients. Rapid availability is the advantage of rBM/PB and CB share over unrelated adult donor, which enabled adapting similar policy of performing transplant possible, especially for elderly patients, given the significantly higher treatment-related mortality for elderly. Design and Methods: We retrospectively reviewed patients aged 55 and older who underwent reduced intensity allogeneic stem-cell transplantation using CB or rBM/PB at our institute from Jan. 2004 to Dec. 2008 consecutively. Patients who were considered for allogeneic transplant and had available 6/6 or 5/6 HLA-matched relatives performed rBM/PB transplants, whereas those who lacked rBM/PB donors underwent CB transplants. Patients who had prior history of transplantation, were in poor performance status (ECOG PS 2 and greater), had active bacterial or fungal infections at the time of conditioning, had diagnosed as multiple myeloma, adult T-cell leukemia, non-malignant diseases were excluded. Results: Two-hundred and thirty-two (171 CB and 60 rBM/PB) RI transplantation were performed from Jan. 2004 to Dec. 2008 at our institute, and 82 (61 CB and 21 rBM/PB) were eventually subjected to the analysis after excluding those who were ineligible according to the above mentioned criteria. The diagnoses included were AML (n=51), MDS (n=9), ALL (n=9) CML/MPD (n=4), and ML (n=9). Fifty-eight (71%) had high risk diseases, and 24 (29%) were in ECOG PS 2. Recipients of CB and rBM/PB were comparable in terms of diagnosis, disease risk (standard vs high), ECOG PS (0-1 vs 2), and year of transplant (2004-2005 vs 2006-2008). The median age for rBM/PB recipients was slightly younger (median 60, range 55-66) than that for CB (median 62, range 55-69, P < .03). CB recipients received more serologically HLA-mismatched grafts (98% vs. 3%, P Conclusions: These data suggest that, for elderly patients, comparable results can be expected using CB, which opens more opportunity for elderly patients to undergo allogeneic transplants who generally have difficulty finding healthy related donors compared to younger patients. However, before CB become the first choice of graft, higher rate of engraftment failure and non-relapse mortality, particularly during early period post-transplant, need to be overcome, and, at this moment, rBM/PB is still the optimal graft of choice when available over CB. Disclosures: No relevant conflicts of interest to declare.

Although cord blood (CB) transplantation with reduced-intensity (RI) conditioning (RICBT) has been widely applied to those who lack available related or unrelated donors and are not eligible for conventional conditioning, indication of RICBT to elderly patients relative to other stem-cell sources is still controversial due to higher early mortality post-transplant and undefined long-term outcome. Since there has been not much data available regarding this issue, we retrospectively reviewed patients aged 55 and older who underwent RI allogeneic stem-cell transplantation at our institute from Nov. 2000 to Dec. 2006 consecutively. The study includes 121 recipients of CB (n=42), unrelated bone marrow (UBM, n=41), and related mobilized peripheral blood (RPB, n=38) for AML / MDS (n=66), ALL (n=11), CML (n=4), ML (n=31), MF (n=3), and AA (n=6). The median age for CB, UBM, and RPB recipients were 61 (range 56–69), 60 (55–70), and 60 (55–66), respectively. CB recipients had more serologically HLA-mismatched grafts (98% vs. 24% vs. 5%, P < .05), were conditioned more frequently with melphalan (90% vs. 34% vs. 32%, P < .05) and with total body irradiation (88% vs. 71% vs. 16%, P < .05), used more tacrolimus (100% vs. 71% vs. 18%, P < .05) and less methotrexate (0% vs. 76% vs. 74%, P < .05) for GVHD prophylaxis, had shorter duration of donor search (median 41 days (14–151) vs. 166 (93–345) vs. 130 (41–311), P < .05), and were transplanted more recently (2005–2006: 71% vs. 56% vs. 37%, P < .05). CB recipients tended to have high-risk disease status (76%) relative to UBM (59%) and RPB (66%) recipients, although not statistically significant. Other characteristics such as sex, diagnosis, and body weight were balanced among three groups. Median follow-up time of survivors was 554 days (25–1132), 667 days (315–1794), and 703 days (57–2214) for CB, UBM, and RPB recipients, respectively. CB recipients tended to show slower neutrophil recovery (median 19 days (12–36) vs. 16 (10–27) vs. 13 days (10–21)), and lower rate of myeloid engraftment (86% vs. 90% vs. 100%), although not statistically significant. The incidence of grades II–IV acute GVHD among evaluable CB recipients (61%) was lower than that of UBM (83%, P < .05) and comparable to that of RPB recipients (50%). The incidences of chronic GVHD for evaluable CB, UBM, and RPB recipients were 45%, 71%, and 71%, respectively (N.S.). The disease-free survival and overall survival (OS) at 2 years post-transplant were 23+/–7% and 33+/–8% for CB, 42+/–8% and 47+/–8% for UBM, and 35+/–9% and 40+/–9% for RPB recipients, respectively (N.S.). Within those who had standard risk diseases, 2-year OS were 67+/–15.7%, 48+/–13%, and 59+/–14% for CB (n=10), UBM (n=17), and RPB (n=13) recipients, respectively (N.S.). These data suggest that CB could be a viable stem-cell source for elderly patients as UBM or RPB, not just expanding opportunity of transplant. A larger-sized, randomized study is needed to further define the position of CB for this population of patients.