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Purpose Proximal fibula fractures are often associated with tibial plateau fractures, but their relationship is poorly characterized. The purpose of this study was to better define the relationship between tibial plateau injury severity and presence of associated soft tissue injuries. Methods A retrospective review was performed on all operatively treated tibial plateau fractures at a Level 1 trauma center over a 5-year period. Patient demographics, injury radiographs, CT scans, operative reports and follow-up were reviewed. Results Queried tibial plateau fractures from 2014 to 2019 totaled 217 fractures in 215 patients. Fifty-two percent were classified as AO/OTA 41B and 48% were AO/OTA 41C. Thirty-nine percent had an associated proximal fibula fracture. The presence of a proximal fibula fracture had significant correlation with AO/OTA 41C fractures, as compared with AO/OTA 41B fractures (chi-square, p p = 0.004). There was also a higher rate of meniscal injury in patients with proximal fibula fractures (37% vs. 20%, p = 0.003). Conclusions There was a significant relationship between the higher energy tibial plateau fracture type (AO/OTA 41C) and the presence of an associated proximal fibula fracture. The presence of a proximal fibula fracture with a tibial plateau fracture is an indicator of a higher energy injury and a higher likelihood of meniscal injury.

To quantify soft tissue perfusion changes in pilon fractures during staged treatment using laser-assisted indocyanine green angiography (LA-ICGA).Level 1 trauma center.Prospective cohort study.Twelve patients with 12 pilon fractures participated in the study. Seven patients had OTA/AO classification of 43-C3, 3 had 43-C2, and 2 had 43-B2.LA-ICGA was performed with the SPY fluorescence imaging platform. Analysis via ImageJ was used to generate a fractional area of perfusion (FAP) based on fluorescent intensity to objectively quantify soft tissue perfusion. Anterior, medial, and lateral measurements were performed at the time of initial external fixation (EF) application and then at the time of definitive fixation.FAP within the region of interest was on average 64% medially, 61% laterally, and 62% anteriorly immediately before EF placement. Immediately before definitive open reduction internal fixation, fractional region of interest perfusion was on average 86% medially, 87% laterally, and 86% anteriorly. FAP increased on average 24% medially ( P = 0.0004), 26% laterally ( P = 0.001), and 19% anteriorly ( P = 0.002) from the time of initial EF to the time of definitive open reduction and internal fixation.Quantitative improvement in soft tissue perfusion was identified through the course of staged surgical management in pilon fractures. LA-ICGA potentially may be used to determine appropriate timing for definitive surgical intervention based on the readiness of the soft tissue envelope. Ultimately, these findings may influence clinical outcomes with respect to choice of surgical approach, soft tissue management, surgical timing, and wound healing.Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

We present a multi-wavelength study of the gaseous medium surrounding the nearby active galactic nucleus (AGN) Fornax A. Using MeerKAT, ALMA and MUSE observations we reveal a complex distribution of the atomic (HI), molecular (CO), and ionised gas in its centre and along the radio jets. By studying the multi-scale kinematics of the multi-phase gas, we reveal the presence of concurrent AGN feeding and feedback phenomena. Several clouds and an extended 3 kpc filament -- perpendicular to the radio jets and the inner disk ($r\lesssim 4.5$ kpc) -- show highly-turbulent kinematics, which likely induces nonlinear condensation and subsequent Chaotic Cold Accretion (CCA) onto the AGN. In the wake of the radio jets and in an external ($r\gtrsim 4.5$ kpc) ring, we identify an entrained massive ($\sim$ $10^7$ M$_\odot$) multi-phase outflow ($v_{\rm OUT}\sim 2000$ km s$^{-1}$). The rapid flickering of the nuclear activity of Fornax A ($\sim$ 3 Myr) and the gas experiencing turbulent condensation raining onto the AGN provide quantitative evidence that a recurrent, tight feeding and feedback cycle may be self-regulating the activity of Fornax A, in agreement with CCA simulations. To date, this is one of the most in-depth probes of such a mechanism, paving the way to apply these precise diagnostics to a larger sample of nearby AGN hosts and their multi-phase ISM., 22 pages, 20 figures, accepted for publication on Astronomy & Astrophysics

Purpose: A commercial 6D carbon fiber radiotherapy treatment couch (Imaging Couch Top, BrainLAB) has recently been reported to attenuate photon beams and increase skindose. To prevent skin toxicity and ensure the target dose, it is important to correct the attenuation properties of the treatment couch with the treatment planning system (TPS). In this study, we evaluated the accuracy of dose attenuation correction by a virtual couch technique integrated into the TPS. Methods: A virtual couch was modeled in the TPS (Eclipse v10.0, Varian). The CT value of the virtual couch was assigned with the CT value of the kilovoltage‐CT images of the treatment couch. A phantom consisting of several plastic water slabs was created. We selected an evaluation point within the phantom on the couch structure at a 9 cm depth from the couch surface, which was placed at the isocenter. The doses at this point were calculated and measured at several gantry angles, from 120 degree to 240 degree at 10 degree steps, and each field size was 10 cm × 10 cm. The prescribed dose was 100 monitor units for 6/10 MV photon beams and 6 MV‐SRS mode (Trilogy Tx, Varian). Dose measurements were performed with an ion chamber.Results: The largest difference between measured and calculated doses was 3.3% for a gantry angle of 120 degree and 6 MV‐SRS mode. The average dose difference was within 1.6% for all gantry angles and photon beams. In the case without attenuation correction, the largest difference was 8.2% and the average difference was 5.2%. Conclusions: Use of the virtual couch technique in TPS accomplished sufficient accuracy for dose attenuation correction of the 6D carbon fiber treatment couch, and it is an effective method for clinical use.

In acute glufosinate poisoning, sudden respiratory arrest and convulsion can occur after a latent period of 4-60 h. There is still no factor that accurately predicts the occurrence of these symptoms.To elucidate the predictors of severe effects following acute glufosinate poisoning.This study is a retrospective observational case series. The subjects were 16 patients who had acute glufosinate poisoning. They were divided into a group with respiratory arrest or convulsion during hospitalization (severe group) and a group without (non-severe group). The following characteristics (or predictors) were compared between the groups: age, sex, calculated amount of glufosinate (volume of ingested poison (glufosinate-containing herbicide) × glufosinate concentration of the product), time duration from poison ingestion to arrival at our hospital, use of gastric lavage, use of whole bowel irrigation, Glasgow Coma Scale, laboratory parameters, PaO₂/FiO₂ ratio (P/F ratio), shock index, and presence or absence of systemic inflammatory response syndrome (SIRS) on arrival.The P/F ratio was significantly lower in the severe group than in the non-severe group (median, 287.5 vs. 409.0; P = 0.049). The receiver operating characteristic (ROC) curve was plotted for the predictor of increasing severity based on the P/F ratio. The area under the curve was 0.714, and the optimal cutoff point for increasing severity was 374.0. The sensitivity was 75.0%, specificity of 71.4%, and accuracy of 75.0%. The shock index was significantly higher (median, 0.52 vs. 0.41; P = 0.031). Significantly more patients had SIRS in the severe group than in the non-severe group (P = 0.015). Logistic regression analysis was performed with a backward elimination procedure. SIRS was selected as the independent predictor of increasing severity (odds ratio, 29.810; 95% confidence interval, 1.011-878.952; P = 0.049).Severe effects following acute glufosinate poisoning were associated with two positive SIRS criteria. A low P/F ratio may be useful for predicting the occurrence of respiratory complications.

To consider the contribution of snowmelt in flood forecast, this paper presents an integrated model, which combines a rigorous snow model with a distributed run-off model, based on unstructured triangular meshes. Using precipitation, air temperature and wind speed as input data, the integrated model can continuously estimate temporal-spatial variation of both snow depth and amount of snowmelt and subsequently forecast river flow caused by snowmelt. The result of a long-term simulation of past floods showed a good match with observations. It is evinced that consideration of snowmelt in a flood forecast can help avoid incorrect prediction. This includes overestimation in the snow accumulation season and/or underestimation in the snowmelt season caused by using precipitation directly as the input data of the run-off model. A real-time flood forecasting system has been established for the Hii River basin, Japan, by using the model. This system now operates uninterruptedly to make a forecast 6 h ahead, with an interval of 10 min.

We investigate the properties of 12 ultra-massive passively evolving early type galaxies (ETGs) at z_phot>1.4 in the COSMOS 2 deg^2 field. These 12 ETGs were selected as pBzKs, have accurate 1.42.5x10^11 M_sun (Chabrier IMF). Contrary to previous claims, the half light radii estimated in very high S/N imaging data from HST+ACS are found to be large for most of the sample, consistent with local ellipticals. If the high redshift ETGs with M*, 9 pages, 7 figures, accepted by MNRAS

The aim of this study is to provide the optimum operating conditions for enhancing in-flight alumina particle heating as much as possible for particle spheroidization and aggregation of melted particles using a DC-RF hybrid plasma flow system even at constant low operating power based on the thermofluid considerations. It is clarified that the swirl flow and higher operating pressure enhance the particle melting and aggregation of melted particles coupled with increasing gas temperature downstream of a plasma uniformly in the radial direction at constant electrical discharge conditions.

Objective: This study was designed to establish a rat model of a critical size alveolar bone defect. Materials and methods: Standardized buccal or mesiobuccal alveolar bone defects were made around the right first mandibular molar of 12-week-old rats, and the left was used as a control. Alveolar bone healing was examined quantitatively by three-dimensional micro-computed tomographic imaging. Bone matrix production of osteoblasts and osteocytes during repair of alveolar bone defects was examined with in situ hybridization for type I collagen. Results: Buccal defects were repaired significantly and the volume decreased by 88.3% in week 24, whereas mesiobuccal defects were repaired little. Osteoblasts and osteocytes expressed type I collagen in both defects in week 3 but showed little expression by week 6 and thereafter, leaving the mesiobuccal defects largely unrepaired. Conclusion: The mesiobuccal defect is a critical-size defect that is not ultimately repaired with bone. It may be an appropriate experimental model for investigating the effectiveness of bone regenerative agents in human alveolar bone loss.

To investigate the effects of Platelet release products (PRPr) and their phagocytosis activators including ATP, ADP, and macromolecular activators of phagocytosis (MAPPs) on phagocytosis and oxidative burst activity by neutrophils in human whole blood. A whole blood-based flow cytometric assay was used to assess neutrophilic activity. Escherichia coli were used as the target organisms. Phagocytosis and oxidative burst by neutrophils were markedly increased after treatment with PRPr or MAPPs + ATP + ADP. The phagocytosis activation was more prominent in the first minute, and displayed a maximum enhancement of 4-fold. The maximum augmentation of oxidative burst was 5-fold which occurred at 5 mins. A striking finding was that the effect of MAPPs was evident from 5 mins onwards and increased with further incubation in both the phagocytosis and oxidative burst assays. These data suggest that the neutrophilic activity enhanced by PRPr depends more on ATP and ADP during the early phase and on MAPPs during the later phase of the phagocytic process. The present study reveals an important role for PRPr and their phagocytosis activators in the enhancement of neutrophilic activity in human whole blood.

The asymptotic method was applied to polymer solutions. The configurational partition function based on the lattice model was much improved by introducing free volumes into consideration. Consequently we were able to calculate the fractional volume change on mixing as the mean value through use of the configurational partition function, under the assumption of pairwise additivity of volume of mixing. The derived expression for the excess volume of mixing was compared with experimental results. Gibbs free energy was derived from Helmholtz free energy and the product of the volume of mixing and pressure, from this the critical pressure-dependent composition and temperature was obtained. Thus we have the relation between pressure and critical temperature. The data are displayed figures that it might be compared with experimental results.

We present a spectroscopic survey of galaxies in the COSMOS field using the Fiber Multi-Object Spectrograph (FMOS), a near-infrared instrument on the Subaru Telescope. Our survey is specifically designed to detect the Halpha emission line that falls within the H-band (1.6-1.8 um) spectroscopic window from star-forming galaxies with 1.4 < z < 1.7 and M_stellar>~10^10 Msolar. With the high multiplex capability of FMOS, it is now feasible to construct samples of over one thousand galaxies having spectroscopic redshifts at epochs that were previously challenging. The high-resolution mode (R~2600) effectively separates Halpha and [NII]6585 thus enabling studies of the gas-phase metallicity and photoionization state of the interstellar medium. The primary aim of our program is to establish how star formation depends on stellar mass and environment, both recognized as drivers of galaxy evolution at lower redshifts. In addition to the main galaxy sample, our target selection places priority on those detected in the far-infrared by Herschel/PACS to assess the level of obscured star formation and investigate, in detail, outliers from the star formation rate - stellar mass relation. Galaxies with Halpha detections are followed up with FMOS observations at shorter wavelengths using the J-long (1.11-1.35 um) grating to detect Hbeta and [OIII]5008 that provides an assessment of extinction required to measure star formation rates not hampered by dust, and an indication of embedded Active Galactic Nuclei. With 460 redshifts measured from 1153 spectra, we assess the performance of the instrument with respect to achieving our goals, discuss inherent biases in the sample, and detail the emission-line properties. Our higher-level data products, including catalogs and spectra, are available to the community., 26 pages, Updated version resubmitted to ApJSS; Data products and catalogs are now available at http://member.ipmu.jp/fmos-cosmos/

Most present-day galaxies with stellar masses ≥10(11) solar masses show no ongoing star formation and are dense spheroids. Ten billion years ago, similarly massive galaxies were typically forming stars at rates of hundreds solar masses per year. It is debated how star formation ceased, on which time scales, and how this "quenching" relates to the emergence of dense spheroids. We measured stellar mass and star-formation rate surface density distributions in star-forming galaxies at redshift 2.2 with ~1-kiloparsec resolution. We find that, in the most massive galaxies, star formation is quenched from the inside out, on time scales less than 1 billion years in the inner regions, up to a few billion years in the outer disks. These galaxies sustain high star-formation activity at large radii, while hosting fully grown and already quenched bulges in their cores.

We measured and compared plasma levels of GH and ghrelin in response to feeding in 4-week-old (milk replacer-fed) and 13-week-old (alfalfa hay cube-fed) goats, in order to elucidate whether or not the postprandial regulation of these hormone levels changes around weaning. Furthermore, we examined the effects of suckling from the dam or intravenous glucose administration on both hormone and insulin levels in kids. In 4-week-old goats, feeding of a milk replacer diet significantly increased plasma GH levels without changing level of ghrelin. In contrast, in 13-week-old goats, feeding of hay cubes did not change the levels of either ghrelin or GH. Suckling of milk directly from the dams significantly increased the levels of GH and insulin, but not ghrelin, in kids. Finally, intravenous injection of glucose (0.625 mmol/kg BW) did not cause any significant increase in the levels of GH or ghrelin, despite a significant increase in the levels of insulin and glucose. From these results, we conclude that the regulatory system of the somatotropic axis is altered by weaning or weaning-associated processes, and that ghrelin levels may not be involved in this alteration in young goats.

In order to assess the biological significance of weaning and water deprivation on the control of plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH) and metabolites in response to stimulation with arginine-vasopressin (AVP) and corticotropin-releasing hormone (CRH), we carried out three experiments in which male goats before and after weaning were intravenously injected with AVP or CRH alone, or in combination with each other. In experiment 1, 17-week-old (post-weaning) goats were intravenously injected with AVP or CRH alone at the doses of 0.1, 0.3 and 1.0 nmol/kg body weight (BW). The AVP injection significantly and dose dependently increased plasma levels of ACTH, cortisol, GH and metabolites, whereas the injection with CRH did not cause significant increases in the levels of these parameters. In experiment 2, 4-week-old (pre-weaning) and 13-week-old (post-weaning) goats were injected with either AVP or CRH alone, followed by a combined injection of both secretagogues at a dose of 0.3 nmol/kg BW. Although the basal levels of the hormones and metabolites, with the exception of glucose, were greater in the 4-week-old goats, the hormone responses induced by stimulation with AVP were weaker than those induced in 13-week-old goats. Additionally, there were no responses in any hormone patterns to CRH stimulation in 4-week-old goats. In experiment 3, 13-week-old goats were injected with CRH alone followed by injection with AVP for two consecutive days of water deprivation. The animals were subjected to withdrawal of up to 20% of the total blood volume and water deprivation for up to 28 h. However, no significant differences in plasma ACTH, cortisol or GH levels were observed between days 1 and 2. Based on these results, we concluded that: (1) AVP is a more potent stimulant than CRH in terms of its ability to induce increases in plasma levels of ACTH, cortisol and GH; (2) the role of AVP as a secretagogue of hypothalamus–pituitary–adrenal hormones is strengthened, whereas the ineffective role of CRH remains unaltered, by weaning; (3) acute stress such as massive withdrawal of blood volume and subjection to water deprivation may not be sufficient burdens to alter stress-related hormone levels in young goats.

Synthèse; International audience

The wire bonding technology that relies on subsequent wire separation of a connection has a possibility of becoming a key packaging technology in the environmentally friendly aspects of the recycling of mounting materials, such as the reworking of chip on board (COB) mounting and the application of the inter-poserless chip size package (CSP) in the manufacturing process. This study investigated how heat treatment before bonding affects separability at the ball bonding area. For the investigation, we used bonding pairs of Ag-plated Cu alloy substrate and An wire. Heating a board to 150/spl deg/C before wire bonding degraded wire bondability but improved separability. An analysis of Ag plating by Auger electron spectroscopy (AES) and x-ray photoelectron spectroscopy (XPS) revealed that the heat treatment caused the Cu on the board to diffuse into the Ag plating and to deposit concentrations of Cu in the form of Cu(OH)/sub 2/ and CuCl/sub 2/ on the Ag surface.

For decades, arid and semi-arid regions in Africa have faced issues related to water availability for drinking, irrigation and livestock purposes. To tackle these issues, a laboratory scale greywater treatment system based on high rate algal pond (HRAP) technology was investigated in order to guide the operation of the pilot plant implemented in the 2iE campus in Ouagadougou (Burkina Faso). Because of the high suspended solids concentration generally found in effluents of this system, the aim of this study is to improve the performance of HRAPs in term of algal productivity and removal. To determine the selection mechanism of self-flocculated algae, three sets of sequencing batch reactors (SBRs) and three sets of continuous flow reactors (CFRs) were operated. Despite operation with the same solids retention time and the similarity of the algal growth rate found in these reactors, the algal productivity was higher in the SBRs owing to the short hydraulic retention time of 10 days in these reactors. By using a volume of CFR with twice the volume of our experimental CFRs, the algal concentration can be controlled during operation under similar physical conditions in both reactors.

A data mining method is proposed for extracting feature regions and for suggesting design candidates from large-scale Computational Fluid Dynamics (CFD) results. The de- tected regions in this method are the regions where the pressure difference between the front and back sides is large. We introduce a medial-surface used in the structural analysis for the thin parts as an evaluation surface in order to apply complicated geometries, which have curved surfaces, holes, ribs, and steps. We applied this method to the laser diode (LD) cool- ing problem in optical disc drives, and the following results were obtained. (1) Three feature- regions are extracted from the CFD results. (2) Two of three regions were effective and were consistent with the actual product design.

We have irradiated p-on-n silicon microstrip detectors of initial bulk resistivity between 0.2 and 2.7 k/spl Omega/-cm with 55 MeV protons to fluences of 0.8, 2.2 and 11/spl times/10/sup 13/ p/cm/sup 2/ (equivalent to twice the fluence in high energy protons), and have measured the depletion voltage before and after irradiation using C-V methods. In addition, we have measured the charge collection of minimum ionization on a single strip with a fast amplifier as a function of bias voltage. We compare the depletion voltage deduced from both methods for samples with different initial resistivities.

Exogenously administered endothelin (ET) elicits both pressor and depressor responses through the ETAand/or the ETBreceptor on vascular smooth muscle cells and ETBon endothelial cells. To test whether ETBhas pressor or depressor effects under basal physiological conditions, we determined arterial blood pressure (BP) in ETB-deficient mice obtained by crossing inbred mice heterozygous for targeted disruption of the ETBgene with mice homozygous for the piebald ( s) mutation of the ETBgene ( ETBs/s). F1ETB−/sand ETB+/sprogeny share an identical genetic background but have ETBlevels that are ∼[Formula: see text]and [Formula: see text], respectively, of wild-type mice ( ETB+/+). BP in ETB−/smice was significantly higher, by ∼20 mmHg, than that in ETB+/sor ETB+/+mice. Immunoreactive ET-1 concentration in plasma as well as respiratory parameters was not different between ETB−/sand ETB+/smice. A selective ETBantagonist, BQ-788, increased BP in ETB+/sand ETB+/+but not in ETB−/smice. Pretreatment with indomethacin, but not with NG-monomethyl-l-arginine, can attenuate the observed pressor response to BQ-788. The selective ETAantagonist BQ-123 did not ameliorate the increased BP in ETB−/smice. Moreover, BP in mice heterozygous for targeted disruption of the ETAgene was not different from that in wild-type controls. These results suggest that endogenous ET elicits a depressor effect through ETBunder basal conditions, in part through tonic production of prostaglandins, and not through secondary mechanisms involving respiratory control or clearance of circulating ET.

Ten patients with adenosine deaminase deficiency (ADA−) have been enrolled in gene therapy clinical trials since the first patient was treated in September 1990. We describe a Japanese ADA− severe combined immune deficiency (SCID) patient who has received periodic infusions of genetically modified autologous T lymphocytes transduced with the human ADA cDNA containing retroviral vector LASN. The percentage of peripheral blood lymphocytes carrying the transduced ADA gene has remained stable at 10% to 20% during the 12 months since the fourth infusion. ADA enzyme activity in the patient's circulating T cells, which was only marginally detected before gene transfer, increased to levels comparable to those of a heterozygous carrier individual and was associated with increased T-lymphocyte counts and improvement of the patient's immune function. The results obtained in this trial are in agreement with previously published observations and support the usefulness of T lymphocyte-directed gene transfer in the treatment of ADA−SCID.

We studied respiratory functions in mutant mice deficient in endothelin-1 (ET-1) generated by gene targeting. In conscious adult mice heterozygous for ET-1 gene mutation (ET+/- heterozygous mice), arterial PO2 was significantly lower, PCO2 tended to be higher, and pH tended to be lower than in wild-type littermates. When these conscious mice breathed room air, respiratory minute volume and rate, determined by body plethysmography, were not significantly different between the two groups. However, when ET+/- heterozygous mice were subjected to systemic hypoxia (1:1 air-N2) or hypercapnia (5% CO2-95% O2), increases in respiratory minute volume were significantly attenuated. In conscious newborn ET-/- homozygous mice delivered by cesarean section and tracheotomized, ventilatory responses to systemic hypoxia and hypercapnia, regularly observed in newborn wild-type mice, were almost totally absent. In urethan-anesthetized adult ET+/- heterozygous mice, increases in phrenic nerve discharges in response to hypoxia and hypercapnia were significantly attenuated. Our results demonstrate that ventilatory responses to hypoxia and hypercapnia are impaired in ET-1-deficient mice and suggest that endogenous ET-1 participates in the physiological control of ventilation.

We have three-dimensionally reconstructed the lymphatic architecture of the rabbit tongue using a computer graphic three-dimensional reconstruction method together with histochemically stained serial cryo-sections. Three collecting lymphatic vessels lying in an anteroposterior orientation were identified in the tongue body. A superior longitudinal muscle accompanying collecting lymphatic (SLCL) that lies in the border between superior longitudinal muscle and transverse muscle was identified in this study, in addition to collecting lymphatics in the lingual septum (LSCL) and deep lingual artery accompanying collecting lymphatics (DLCL) that we reported previously. The vertical muscle accompanying collecting lymphatics (VCL) and the transverse muscle accompanying collecting lymphatics (TCL) were also identified as collecting lymphatics that joined the above three collecting lymphatics. Specific regional lymph flow was identified for each collecting lymphatic. A transverse right/left cross flow was identified for the LSCL, while the SLCL served the upper 1/3 of the tongue and the DLCL served the lower 2/3 of the tongue. Each collecting lymphatic that accompanied the internal lingual muscles joined to the SLCL, DLCL and LSCL, and were derived from blind-ended lymphatic capillaries that ran in the endomysium. Internal lingual muscle accompanying collecting lymphatics joined each other in the endomysium, and their blind-ended lymphatic capillaries had no branches.

In mice heterozygous for endothelin-1 gene mutation and wild-type littermates power spectrum of systolic arterial pressure (SAP) was determined in a conscious stare by forward-backward autoregressive model with maximum entropy method. It was composed of low (LF) and high frequency components (HF). LF reflected sympathetic vasoconstrictor activity, whereas HF was inversely related to respiratory movement. In ET-1 heterozygous mice LF and HF were both significantly elevated than in wild-type mice. The authors conclude that power spectral analysis is a useful mathematical tool to study the autonomic cardiovascular control and respiration in mice and that sympathetic vasoconstrictor activity was increased in ET-1 heterozygous mice. The latter finding may account for observed elevation of arterial pressure (AP) in these mutant mice.

Aim: IRIS is one of the standard regimens as second line treatment in mCRC since IRIS demonstrated the non-inferiority to FOLFIRI (FIRIS study) in Japan. From the results of 20050181 trial, FOLFIRI/panitumumab significantly improved PFS and is well-tolerated as second-line treatment in patients with KRAS wild type of mCRC. Thus we conduct the study of IRIS/Cet (HGCSG0902). Methods: HGSCG0902 is a multicenter phase ll study. Eligibility includes histologically confirmed colorectal cancer, previously received oxaliplatin-contained chemotherapy, PS: 0-1, EGFR positive and KRAS Exon2 wild type. Patients (pts) received S-1 80-120 mg/day p.o. on days 1-14 and irinotecan 100mg/m2 on days 1 and 15 repeated every 28 days. Cetuximab was administrated 400mg/m2 loading dose and continued 250mg/m2 every week or 500mg/m2 bi-weekly. The primary endpoint was response rate and the secondary endpoints were disease control rate, PFS, OS and safety. We estimated that a target sample size of 76 patients. Results: Between Mar 2010 and September 2013, 58 pts were enrolled. One patient was not administered (57 pts were safety analysis set), and 3 pts were ineligible (54 pts were efficacy analysis set). Patients characteristics were as follows: median age 66 years (range 35-79), Male: female 36:21, PS 0:1 38:19. Median number of cycles was 3. The main grade 3-4 AE were diarrhea (35.1%), neutropenia (26.8%), acne like rash (17.5%) and anorexia (15.8%). The median relative dose intensity of IRIS/Cet was 0.818. Response rate was 33.3% (95%CI 20.8-45.9%) and disease control rate was 79.6%. Median progression-free survival was 4.7 months (95%C.I. 3.3-6.1 months). Conclusions: IRIS/Cet appeared to be highly effective with a response rate of 33.3% and progression-free survival of 4.7 months, and had met the primary endpoint. Diarrhea was a major adverse event, but was manageable by dose reduction and supportive care. The final analysis will be presented in 2015 ASCO Annual meeting. Disclosure: S. Yuki: Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Takeda Pharmaceutical, Yakult Honsha;M. Nakamura: Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin;Y. Tsuji: Honoraria - Ono Pharmaceutical; Y. Sakata: Taiho Pharmaceutical, Daiichi Sankyo, Yakult Honsha, Otsuka Pharmaceutical, Merck Serono, Bristol-Myers Squibb, Synergy International; Y. Komatsu: Yakult Honsha, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Pfizer Japan, Novartis Pharma, Sawai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, Eli Lilly Japan, Kureha Corporation. All other authors have declared no conflicts of interest.

Aim: Panitumumab (Pmab) has demonstrated efficacy in patients with KRAS wild-type metastatic colorectal cancer (mCRC). Although the STEPP study (Lacouture M. E. et al. J Clin Oncol. 2010; 28: 1351-7.) showed that pre-emptive skin treatment reduced skin toxicities compared with reactive treatment among patients receiving Pmab, data for Asians has not been reported. We planned a randomized, open-label trial to verify the differences between pre-emptive and reactive treatment for skin toxicities in Japanese patients. Methods: Patients receiving third-line Pmab-containing regimens for mCRC were randomly assigned 1:1 to pre-emptive (skin moisturizers, sunscreen, topical steroid, and minocycline) or reactive (only skin moisturizers) skin treatment. The primary endpoint was the cumulative incidence of ≥grade 2 skin toxicities during the 6-week treatment period. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner, using photographs. Results: Of 95 enrolled patients, 47 were assigned to pre-emptive, and 48 to reactive treatment. The incidence of ≥grade 2 skin toxicities during the 6-week treatment period (investigators’ assessment) was 21.3% and 62.5% (risk ratio [RR], 0.34; 95% CI, 0.19 to 0.62; P Conclusions: Although pre-emptive skin treatment could not be affected with QOL, it could reduce the severity of skin toxicities during Pmab treatment. Our data clearly validate that pre-emptive treatment can also be recommended in Japanese patients. Disclosure: M. Nakamura: Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin; S. Yuki: Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Takeda Pharmaceutical, Yakult Honsha; Y. Sakata: Taiho Pharmaceutical, Daiichi Sankyo, Yakult Honsha, Otsuka Pharmaceutical, Merck Serono, Bristol-Myers Squibb, Synergy International; Y. Komatsu: Yakult Honsha, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Pfizer Japan, Novartis Pharma, Sawai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, Eli Lilly Japan, Kureha Corporation. All other authors have declared no conflicts of interest.

Severe combined immunodeficiency (SCID) caused by adenosine deaminase deficiency (ADA–) is the first genetic disorder to be treated with gene therapy. Since 1990 when the first trial started for 2 patients with ADA– SCID, five clinical trials enrolling 11 patients have been conducted with different clinical approaches and the results obtained from these trials have recently been reported. According to these reports, T cell-directed gene transfer was useful in the treatment of ADA– SCID whereas the retroviral-mediated gene transfer to hematopoietic stem cells was insufficient for achievement of clinical benefits. This chapter reviews several crucial problems inherent in the current retroviral technology based on the clinical data observed in these pioneering ADA gene therapy trials and presents our new retroviral vector system for the next stem cell gene therapy.

The common gamma chain (γc) of cytokine receptors is mutated in X-linked severe combined immunodeficiency, a lethal disorder characterized by the absence of both humoral and cellular immune defenses. Allogeneic bone marrow transplantation from HLA-identical siblings usually results in complete reconstitution of the immune system and is the current treatment of choice. Genetic correction and reinfusion of autologous hematopoietic stem cells represents an alternative therapeutic approach for those patients who lack suitable marrow donors. In this study, we show that retroviral-mediated transfer of the γc gene results in efficient expression in CD34+ cells and high transduction rate of colony-forming progenitors.

Three cases of bifid ribs were found in two cadavers during routine dissections at the Iwate Medical University School of Dentistry. All of the cases were found in the third or the fourth rib. The distal parts of the osseous rib bifurcated with an angle of 60 degrees and both of the branches had their own costal cartilage. The costal cartilage fused again to form the trunk which was connected to the sternum. The space between the two branches was filled with presumably normal intercostal muscles. Blood supply was maintained by a small branch from the interthoracic artery to the upper branches. However, the intercostal nerves did not branch toward the upper branch but only ran along the lower margins of the lower branches of the bifid ribs.

Recently generated knockout mice with disrupted genes encoding endothelin (ET)-1 showed an elevation of arterial blood pressure (AP) and supplied an evidence for intrinsic ET-1 as one of the physiological regulators of systemic AP. Little is yet known, however, why deficiency of ET-1, which was originally found as a potent vasoconstrictor, led to higher AP in these mice. To address this apparent paradox, we first developed a method to measure renal sympathetic nerve activity (RSNA) in mice using rats as reference and successively compared it between normal and ET-1 deficient mice. RSNA was successfully recorded in urethane-anesthetized and artificially ventilated mice by a slight modification of the method used for rats. At basal condition, mean AP (MAP) and RSNA in ET-1 deficient mice (105+/-2 mmHg and 9.71+/-1.49 muVs, n=20) were significantly higher than those in wild-type mice (96+/-2 mmHg and 5. 07+/-0.70 muVs, n=25). Basal heart rate (HR) and baroreflex-control of HR was not significantly different between the two. On the other hand, resting RSNA, RSNA range, and maximum RSNA were significantly greater in ET-1 deficient mice, and thus MAP-RSNA relationship was upwards reset. Hypoxia-induced increase in RSNA was not different between ET-1 deficient (73.4+/-9.4%) and wild-type mice (91.2+/-12.0%), while hypercapnia-induced one was significantly attenuated in ET-1 deficient mice (18.8+/-3.6 vs. 39.1+/-5.2% at 10% CO2). These results indicate that endogenous ET-1 participates in the central chemoreception of CO2 and reflex control of the RSNA. Baroreceptor resetting and normally preserved hypoxia-induced chemoreflex may explain a part of the elevation of AP in ET-1 deficient mice.

Transgenic (Tg) pigs expressing a fluorescent protein are extremely useful for research into transplantation and regenerative medicine. This study aimed to create Tg pigs expressing monomeric Plum (mPlum), a far-red fluorescent protein with a longer wavelength than enhanced green fluorescent protein (EGFP) and humanized Kusabira Orange (huKO), the two fluorescent proteins that have been used previously for Tg pig production. A linearized CAG-mPlum transgene construct was transferred into porcine fetal fibroblasts (PFF) by electroporation. mPlum fluorescence-positive cells were collected using a cell sorter and used as nuclear donors (mPlum-PFF) for somatic cell nuclear transfer (SCNT). In vitro-matured oocytes were obtained from porcine cumulus–oocyte complexes cultured in NCSU23-based medium and were used to obtain recipient oocytes for SCNT after enucleation. Then, SCNT was performed as reported previously (Matsunari et al., 2008). The reconstructed embryos were cultured for 7 days in porcine zygote medium-5 (PZM-5). mPlum fluorescence expression was screened during the early development of the embryos. After 5 or 6 days of culture, the SCNT embryos were surgically transferred to the uterus of a recipient gilt. We first obtained fetuses on Day 36 or 37 of gestation by Caesarean section and the PFF were retrieved from their skin. Fluorescence expression was analysed using fluorescence microscope, and the number of transgene copies in each fetus was determined by Southern blot analysis. We also analysed whether unique spectral properties of mPlum are suitable for multicolor imaging using confocal microscope and flow cytometer. The identification of mPlum-expressing PFF under the mixed culture of PFF expressing EGFP and huKO was examined. The 2 cell lines of PFF expressing EGFP and huKO were previously generated in our laboratory. Rates of normal cleavage and blastocyst formation occurred in the SCNT embryos generated with mPlum-PFF (mPlum embryos) were equivalent to those of SCNT embryos derived from nontransgenic PFF (34/42, 81.0%; 33/42, 78.6% v. 37/40, 92.5%; 30/40, 75.0%). Total cell numbers in mPlum and control blastocysts did not differ significantly (88.3 ± 6.0 v. 99.9 ± 8.8). Fluorescence expression in the mPlum embryos began at the 8-cell stage and became brighter from the morula stage. The gilt into which 103 mPlum embryos were transferred produced 3 fetuses. These fetuses expressed mPlum fluorescence systemically and had 1 to 5 copies of the transgene. Multicolor fluorescence imaging and flow cytometric analyses of a mixed culture of mPlum PFF and PFF expressing EGFP and huKO showed that clear identification and isolation of cells displaying each of the 3 fluorescence signals was possible. These observations demonstrate that the transfer of CAG-mPlum did not interfere with the development of porcine SCNT embryos and resulted in the successful generation of Tg cloned pigs that systemically expressed mPlum. This work was supported by JSPS KAKENHI Grant Number 25293279.

Retinoic acid (RA), a vitamin A derivative, exerts a wide range of biological effects related to cell proliferation and differentiation. The pleiotropic effects of RA are thought to be mediated through specific nuclear RA receptors (RARs). RARs are members of the steroid/thyroid hormone receptor superfamily and exhibit a molecular structure that possess discrete DNA-binding and RA (ligand)-binding domains. In hematopoietic system, RA and RARs, predominantly RAR alpha may play key roles for the proliferation and differentiation of hematopoietic progenitors. However, it is currently unknown how RA and RARs are involved in regulating normal hematopoietic differentiation. To make clear the roles of RA and RAR alpha in the normal hematopoiesis, I have introduced the construct of human RAR alpha (hRAR alpha) into murine bone marrow cells with retroviral vector, and selected infected cells with drug resistant marker (Neo(r)) cultured on the stroma cell line (PA6-neo), and analyzed the behavior of infected cells. All of procedure were done in vitro. Most cells infected with hRAR alpha exhibited promyelocytic morphology and were thought to be blocked at the promyelocytic stage in their myeloid differentiation. Furthermore, these immature cells differentiated terminally into mature granulocytes by adding with RA (10(-6) M). RAR alpha infected cells were also able to differentiate into mature macrophages in the both of long term culture and IL3 colony. These observations suggest that an overexpression of RAR alpha alone is effective to suppress myeloid cell differentiation and RAR alpha plays a crucial role in the terminal differentiation of myeloid precursors. The system described here may serve as a model for studying the the essential genes for differentiation of normal bone marrow cells.

The resistance of malignant tumors to chemotherapy with anticancer drugs has been considered to be due partly to overexpression of the multidrug resistance gene (mdr1) and its gene product, P-glycoprotein (P-GP), which acts as a drug efflux pump for several chemotherapeutic agents. In order to elucidate the mechanism of anticancer drug resistance in anaplastic thyroid carcinoma with very poor prognosis, we examined the expression of mdr1 mRNA and P-GP, and analyzed their relationships to chemotherapy response. Twenty surgical samples from 16 patients with anaplastic thyroid carcinoma were used. The mdr1 mRNA expression was examined by reverse transcription and polymerase chain reaction, and P-GP expression was evaluated by an immunohistochemical method using JSB-1 monoclonal antibody. Of the 20 clinical samples, expression of mdr1 mRNA and P-GP was observed in three and four samples, respectively. Three of the patients from whom the samples were obtained had been given anticancer drugs before biopsy. Of 12 patients who received chemotherapy for clinically evaluable diseases, 2 responded well, but 10 showed no response. All except one patient died of cancer progression. There was no relationship between the response to chemotherapy and the expression of mdr1 and P-GP. The expression of mdr1 mRNA and/or P-GP was observed in 5 of 16 patients with anaplastic thyroid carcinoma. However, the appearance of anticancer drug resistance in anaplastic thyroid carcinoma may not be explained solely by the expression of mdr1 and P-GP.

The nm 23 gene product, which possesses nucleoside diphosphate kinase activity, is a possible mediator of cancer cell invasion and metastasis. It has been divided into two distinct gene products, nm23-H1 and nm23-H2. We have developed a method for detecting nm 23-H1 and nm 23-H2 RNA using the polymerase chain reaction, based on the amplification of complementary DNA copies of nm 23-H1 and nm 23-H2 RNA. Using this method, the nm 23-H1 and nm 23-H2 messenger (m)RNA levels in 35 thyroid papillary carcinomas, 11 metastatic lymph nodes from patients with thyroid papillary carcinomas, five thyroid follicular adenomas, and three normal thyroid tissue samples were studied. Both nm 23-H1 and nm 23-H2 mRNA were expressed ubiquitously in normal and malignant thyroid tissues. However, in metastatic lymph nodes no (3 of 11) or weak expression (8 of 11) of nm 23-H1 mRNA was observed, the extent of which was inversely proportional to the degree of cancer cell occupancy, whereas nm 23-H2 mRNA was expressed and the levels were similar to those in other tissue tested. These results show that nm 23-H1 only may play a role in cancer cell invasion and metastasis although the exact mechanisms involved have yet to be elucidated.