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I recently purchased a Ruger .44 Magnum Blackhawk with a four-digit serial number dating to the first year of production. It has some light rust in a few areas and [...]

AbstractAn imminent gyrotron body current fault can now be detected and avoided in less than 10 µs using a high-resolution, real-time, high-voltage reference waveform generator with signal analyzer subroutines. The gyrotron is restarted and full power resumed in a little over 10 ms.

ObjectiveDesmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery.DesignGemcitabine metabolites were analysed in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre(KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation.ResultsGemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2′,2′-difluorodeoxycytidine-5′-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2′,2′-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5′-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%.ConclusionsOur findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

Objective:To evaluate the implementation of early screening for critical congenital heart defects (CCHDs) in the neonatal intensive care unit (NICU) and potential exclusion of sub-populations from universal screening.Study Design:Prospective evaluation of CCHD screening at multiple time intervals was conducted in 21 NICUs across five states (n=4556 infants).Results:Of the 4120 infants with complete screens, 92% did not have prenatal CHD diagnosis or echocardiography before screening, 72% were not receiving oxygen at 24 to 48 h and 56% were born ⩾2500 g. Thirty-seven infants failed screening (0.9%); none with an unsuspected CCHD. False positive rates were low for infants not receiving oxygen (0.5%) and those screened after weaning (0.6%), yet higher among infants born at <28 weeks (3.8%). Unnecessary echocardiograms were minimal (0.2%).Conclusion:Given the majority of NICU infants were ⩾2500 g, not on oxygen and not preidentified for CCHD, systematic screening at 24 to 48 h may be of benefit for early detection of CCHD with minimal burden.

AbstractSince the first plasma in Korea Superconducting Tokamak Advanced Research (KSTAR), the electron cyclotron heating (ECH) system has been an essential tool for ECH-assisted start-up using second-harmonic 84-GHz and 110-GHz ECH and for experimental studies of other physics issues such as edge-localized mode control, rotation control, sawtooth control, tearing mode control, and core impurity control for long-pulse discharge and noninductive start-up. The loop voltage in KSTAR is limited by superconducting ohmic coils and a thick vacuum vessel. The ECH-assisted start-up was useful to overcome burn-through during the ramp-up phase with limited loop voltage by the electron cyclotron beam injection before or after the onset of the inductive loop voltage to reduce resistive power consumption. Later, the 170-GHz ECH system is installed as a main electron heating and local current drive for the control of magnetohydrodynamic modes such as sawteeth and neoclassical tearing modes. The 170-GHz gyrotron is an ITER preprototype gyrotron developed by the Japan Atomic Energy Agency. Second-harmonic 170-GHz ECH-assisted start-up was also attempted with a raised toroidal magnetic field of 3 T in the 2011 KSTAR campaign, and flux saving in the ramp-up phase was observed. This lecture describes the physics issues and experimental results of the KSTAR ECH system. The present status and an upgrade plan of the KSTAR ECH system is also described.

AbstractThe KSTAR (Korea Superconducting Tokamak Advanced Researc pursued to develop key technologies for superconducting tokamak operation and to contribute to a few research items for ITER relevant issues. As a result, the KSTAR achieved highly confined mode (H-mod in 2010 campaign and successfully demonstrated suppression of Edge Localized Mode (ELM) using n=1 Resonant Magnetic Perturbation (RMP) coils. The KSTAR is also initiating machine performance based on the designed machine parameters. The plasma current we achieved was 1 MA, and longest plasma pulse length has been extended to 10 s. In spite of limited heating power to 3.5 MW, several key actuators satisfactorily supported to implement a few scientific researches such as ELM control. On the basis of big progress in both the plasma performance and the experimental results, the KSTAR operation will explore key scientific and technical research issues under steady state operation condition in phase-2 operation.

Since the 1990s, autoimmune pancreatitis (AIP) has been increasingly recognized as a special type of chronic pancreatitis. Clinically, AIP patients commonly present with jaundice, weight loss and abdominal pain. Radiologically, there is diffuse or focal enlargement of the pancreas, often with narrowing of the pancreas and bile duct. Histologically, AIP is characterized by periductal infiltrates of lymphocytes and plasma cells, cellular fibrosis and obliterative phlebitis. Recently, two types of AIP were distinguished and called type 1 and type 2 AIP. They share the symptomatology and some histopathological features such as periductal lymphoplasmacytic infiltrate and storiform fibrosis, but differ in a particular duct change, called granulocytic epithelial lesion, which characterizes type 2 AIP. In addition, type 2 AIP usually has none or very few (<10 cells/ high power field (hpf)) IgG4-positive plasma cells. Clinically, type 1 AIP patients are roughly 10 years older than type 2 AIP patients, show a slight preponderance of men and reveal extrapancreatic manifestations of IgG4 associated systemic disease in approximately 50 of the cases. Type 2 AIP patients frequently show an association with inflammatory bowel disease and usually lack serological elevation of IgG4. The main differential diagnosis of AIP is pancreatic ductal adenocarcinoma. In many instances the diagnosis of AIP can be made by imaging together with serological markers. In difficult cases, particularly in type 2 AIP, the diagnosis has to be established by core needle biopsy. Both type 1 and type 2 AIP patients respond to steroid treatment, but a significant proportion of type 1 AIP patients suffer from recurrence of the disease. We describe the clinical and histological features of the two types of AIP as well as the treatment. In connection with pathogenesis and diagnosis, recent findings on immune complex deposition, autoantibodies in AIP and relevant patents are discussed.

AbstractSecond-harmonic X-mode (X2) electron cyclotron (EC) heating (ECH) has been used in DIII-D in conjunction with plasma initiation and current ramp-up. Although the toroidal inductive electric field Eϕin DIII-D is high enough (0.9 to 1.0 V/m) to allow robust start-up without EC assist, start-up in fusion devices such as ITER will have lower fields (Eϕ= 0.3 V/m), and EC assist can provide a reproducible breakdown and an increased margin for burnthrough of low-Z impurities. ECH, applied before the inductive electric field, is used to separate the various phases of plasma breakdown and start-up and is defined as preionization. Preionization first occurs near the X2 resonance location and then expands in the vessel volume. Perpendicular launch (k[parallel]= 0) is found to produce the strongest preionization. The power threshold for preionization can be reduced by optimizing the prefill and the vertical field, although the lowest power threshold is not at the optimum value for ohmic start-up alone. An orbit-following code confirms that cold electrons (0.03 eV) can be sufficiently heated by ECH to energies above the threshold of ionization of hydrogen. This code predicts heating in new tokamaks such as KSTAR and ITER to energies where preionization can occur. The ITER start-up scenario has been simulated in DIII-D experiments, and X2 ECH assist has been applied at reduced toroidal loop voltage to assist burnthrough and plasma current ramp-up.

AbstractRecent experiments on the DIII-D tokamak have examined the effect of particle transport on the electron cyclotron current drive (ECCD) profile using measurements of the magnetic field pitch angles by motional Stark effect polarimetry. While previous ECCD studies on DIII-D did not observe any clear effects of transport, these new experiments at high ECCD power, low density, and radiation temperatures above 20 keV clearly demonstrate that the ECCD profile can be reduced and broadened compared to the Fokker-Planck code CQL3D predictions assuming no radial transport. A diffusion coefficient of [approximate]0.4 m2/s is required in CQL3D to reproduce the experimental ECCD profile at high relative power densities, while smaller diffusion coefficients are needed at low relative power densities. This level of transport is comparable to the effective particle transport rate needed to maintain the density profile but an order of magnitude less than the electron thermal diffusivity. While radial transport of the current-carrying electrons is potentially detrimental for applications that rely on strong localization of the noninductive current, this effect should be negligible on ITER owing to its large size and low relative power density.

Objective: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the “exome” (all exons) and “spliceome” (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome-profiling to discern transcriptomic biomarkers of psychosis. Methods: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. Results: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are reconciled with an analysis of the ontologies, the pathways and the protein domains significantly over-represented among the alternatively spliced genes, several of which support prior discoveries. Conclusions: To our knowledge, this is the first blood-based spliceome-profiling study of schizophrenia and bipolar disorder to be reported. The battery of alternatively spliced genes and exons identified in this discovery-oriented exploratory study, if replicated, may have potential utility to discern the molecular subtypes of psychosis. Spliceomeprofiling, as a new methodological approach in transcriptomics, warrants further work to evaluate its utility in personalized medicine. Potentially, this approach could also permit the future development of tissue-sampling methodologies in a form that is more acceptable to patients and thereby allow monitoring of dynamic and time-dependent plasticity in disease severity and response to therapeutic interventions in clinical psychiatry.

AbstractThe measurement of the power injected by the electron cyclotron heating (ECH) system in the DIII-D tokamak is a critical requirement for analysis of experiments, for tuning the gyrotrons for maximum power and efficiency, for tracking long-term operational trends, and for providing a warning of problems with the system. The ECH system at General Atomics consists of six 110-GHz, 1-MW-class gyrotrons. The radio-frequency (rf) power generated by each gyrotron is determined from calorimetry, using the relevant temperature and flow measurements from the cooling circuits of the cavity, matching optics unit, and dummy loads (DLs). The rf pulse length and time dependence are measured using an rf monitor at the first miter bend in the transmission line. The cavity power loading measured directly gives the generated rf power using a previously determined relationship between cavity loading and rf production. The direct measurement of the efficiencies of four of the transmission lines was performed using a high-power DL placed alternately in two positions of each DIII-D waveguide line, at accessible points close to the beginning and the end of each line. Total losses in the transmission lines range from 21.2 to 30.7%. Experimental results are compared to theoretical predictions of the performance of the components and waveguide lines.

Active feedback control for regulation of the safety factor (q) profile at the start of the high stored energy phase of an advanced tokamak discharge has been demonstrated in the DIII-D tokamak. The time evolution of the on-axis or minimum value of qis controlled during and just following the period of ramp-up of the plasma current using electron heating to modify the rate of relaxation of the current profile. In L-mode and H-mode discharges, feedback control of qis effective with the appropriate choice of either off-axis electron cyclotron heating or neutral beam heating as the actuator. The qprofile is calculated in real time from a complete equilibrium reconstruction fitted to external magnetic field and flux measurements and internal poloidal field measurements from the motional Stark effect diagnostic.

The effect of plasma shape on sawtooth oscillations in the DIII-D tokamak plasmas is investigated by comparing discharges with cross-sections shaped like a bean and an oval. The two shapes are designed so that the Mercier instability threshold is reached when the axial safety factor is below unity for the bean and above unity for the oval cross-sections. This allows the role of interchange modes to be differentiated from that of the kink-tearing mode. The differences in the nature of the sawtooth oscillations in the bean and oval discharges are found to be determined primarily by extreme differences in the electron heat transport during the reheat. In both cases, the axial safety factor is found to be near unity following the crash.

Active control of plasma profiles is an essential requirement for operating within plasma stability limits, for steady-state operation and for optimization of the plasma performance. In DIII-D, plasma profiles have been actively controlled using various actuators in the following manner: (a) real time closed loop control of the qprofile evolution using electron cyclotron heating and neutral beam injection as actuators; (b) active control of the density and pressure profiles in quiescent H-mode and quiescent double barrier plasmas using electron cyclotron current drive (ECCD) and pellet injection; (c) active control of the edge profiles to suppress edge localized modes using resonant magnetic perturbation with toroidal mode number n= 3, (d) real time control of the current density profile to suppress neoclassical tearing modes using localized deposition of co-ECCD.

The advanced tokamak programme on DIII-D is to develop the scientific basis for steady state, high performance operation in future devices. We report on experiments attempting to demonstrate sustainment of 100% noninductive current for several seconds at high beta, using up to 2.5 MW of off-axis electron cyclotron current drive and up to 15 MW of neutral beam injection with q95 ≈ 5. A 100% noninductive condition was achieved with βT = 3.6%, βN = 3.5, H89 = 2.4 and improved current drive alignment. However, the duration of this phase was limited by the pressure profile evolution leading to magnetohydrodynamic instabilities after about 0.7 s. In a separate discharge, a nearly (∼90%) noninductive, stationary condition was maintained for one current relaxation time (1.8 s) only limited by the duration of the hardware system. These experiments have achieved normalized fusion performance with bootstrap current fraction fBS ≈ 60%, consistent with requirements for the ITER Q = 5 steady-state scenarios. The modelling tools that were successfully employed to devise experiments in DIII-D are applied to ITER, indicating that full noninductive operation is plausible for an ITER steady-state scenario with Q ≈ 5.

Advanced tokamak (AT) research in DIII-D seeks to provide a scientific basis for steady-state high performance operation in future devices. These regimes require high toroidal beta to maximize fusion output and high poloidal beta to maximize the self-driven bootstrap current. Achieving these conditions requires integrated, simultaneous control of the current and pressure profiles and active magnetohydrodynamic stability control. The building blocks for AT operation are in hand. Resistive wall mode stabilization by plasma rotation and active feedback with non-axisymmetric coils allows routine operation above the no-wall beta limit. Neoclassical tearing modes are stabilized by active feedback control of localized electron cyclotron current drive (ECCD). Plasma shaping and profile control provide further improvements. Under these conditions, bootstrap supplies most of the current. Steady-state operation requires replacing the remaining inductively driven current, mostly located near the half radius, with non-inductive external sources. In DIII-D this current is provided by ECCD, and nearly stationary AT discharges have been sustained with little remaining inductive current. Fast wave current drive is being developed to control the central magnetic shear. Density control, with divertor cryopumps, of AT discharges with ELMing H-mode edges facilitates high current drive efficiency at reactor relevant collisionalities. An advanced plasma control system allows integrated control of these elements. Close coupling between modelling and experiment is key to understanding the separate elements, their complex nonlinear interactions, and their integration into self-consistent high performance scenarios. This approach has resulted in fully non-inductively driven plasmas with βN ≤ 3.5 and βT ≤ 3.6% sustained for up to 1 s, which is approximately equal to one current relaxation time. Progress in this area, and its implications for next-step devices, will be illustrated by results of these and other recent experiment and simulation efforts.

The first suppression of the important and deleterious m = 2/n = 1 neoclassical tearing mode (NTM) is reported using electron cyclotron current drive (ECCD) to replace the ‘missing’ bootstrap current in the island O-point. Experiments on the DIII-D tokamak verify that the maximum shrinkage of the m = 2/n = 1 island occurs when the ECCD location coincides with the q = 2 surface. The DIII-D plasma control system is put into a ‘search and suppress’ mode to make small changes in the toroidal field to find and lock onto the optimum position, based on real time measurements of dB_θ/dt, for complete m = 2/n = 1 NTM suppression by ECCD. The requirements of the ECCD for complete island suppression are well modelled by the modified Rutherford equation for the DIII-D plasma conditions.

Recent experiments on the DIII-D tokamak have focused on determining the effect of trapped particles on the electron cyclotron current drive (ECCD) efficiency. The experimental ECCD efficiency increases as the deposition location is moved towards the inboard midplane or towards smaller minor radius for both co- and counter-injection; the ECCD efficiency also increases with increasing electron density and/or temperature. The experimental ECCD is compared to both the linear theory (TORAY-GA) as well as a quasilinear Fokker–Planck model (CQL3D) and is found to be in better agreement with the more complete Fokker–Planck calculation, especially when the rf power density and/or loop voltage exceed criterion for substantial nonlinear modification of the electron distribution function. The width of the measured ECCD profile is consistent with the theoretically expected width in the absence of radial transport for the current carrying electrons.

Electron cyclotron current drive (ECCD) experiments on the DIII-D tokamak are solidifying the physics basis for localized, off-axis current drive, the goal being to validate a predictive model for ECCD. The ECCD profiles are determined from the magnetic field pitch angles measured by motional Stark effect polarimetry. The measured ECCD switches from the co- to the counter-direction as the toroidal injection angle is varied with a profile width that is in accordance with ray tracing calculations. Tests of electron trapping in low beta plasmas show that the ECCD efficiency decreases rapidly as the deposition is moved off-axis and towards the outboard side of the plasma, but the detrimental effects of electron trapping on the current drive are greatly reduced in high beta plasmas. Overall, the measured ECCD is in good agreement with theoretical calculations using a quasilinear Fokker–Planck code over a wide range of injection angles and plasma parameters.

The 110 GHz Electron Cyclotron Heating System on the DIII–D tokamak is being upgraded by the installation of additional gyrotrons, versatile launchers, and an improved control system. A total of six gyrotrons in the 1 MW class will be available for experiments during the 2001 experimental campaign. The installation will be described and the operational experience to date will be presented.

The maternal transcription factor VegT is important for establishing the primary germ layers in Xenopus. In previous work, we showed that the vegetal masses of embryos lacking maternal VegT do not produce mesoderm-inducing signals and that mesoderm formation in these embryos occurred ectopically, from the vegetal area rather than the equatorial zone of the blastula. Here we have increased the efficiency of the depletion of maternal VegT mRNA and have studied the effects on mesoderm formation. We find that maternal VegT is required for the formation of 90% of mesodermal tissue, as measured by the expression of mesodermal markers MyoD, cardiac actin, Xbra, Xwnt8 and alphaT4 globin. Furthermore, the transcription of FGFs and TGFbetas, Xnr1, Xnr2, Xnr4 and derrière does not occur in VegT-depleted embryos. We test whether these growth factors may be endogenous factors in mesoderm induction, by studying their ability to rescue the phenotype of VegT-depleted embryos, when their expression is restricted to the vegetal mass. We find that Xnr1, Xnr2, Xnr4 and derrière mRNA all rescue mesoderm formation, as well as the formation of blastopores and the wild-type body axis. Derrière rescues trunk and tail while nr1, nr2 and nr4 rescue head, trunk and tail. We conclude that mesoderm induction in Xenopus depends on a maternal transcription factor regulating these zygotic growth factors.

Nonperfused proximal S2 segments from rabbit kidney cortex have been shown to keep cell volume constant as medium osmolality is slowly raised but to shrink and not exhibit regulatory volume increase (RVI) if medium osmolality is abruptly elevated (J. Lohr and J. Grantham. J. Clin. Invest. 78: 1165-1172, 1986). In the current study, 0.5 mM butyrate in the medium 1) extended the range from 361 to 450 mosmol/kgH2O over which cells maintained volume constant as osmolality was gradually raised and 2) restored RVI after cell shrinkage when osmolality was rapidly raised from 295 to 400 mosmol/kgH2O. Volume regulation was associated with net increases in intracellular Na+ and Cl- but no change in K+ (measured by electron probe). The increments in Na+ and Cl- were insufficient to account for the total addition of osmolytes required for volume maintenance or restoration. The fraction of the expected increase in intracellular osmoles accounted for by the increase in [(K+)i + (Na+)i + (Cl-)i] was 52 and 21% for gradual and rapid osmotic changes, respectively. We conclude that butyrate enhances the capacity of S2 segments to regulate volume in hyperosmotic medium by promoting addition of Na+ and Cl- and by other undermined factors.

The heterodimeric alpha 4 integrins alpha 4 beta 7 lymphocyte Peyer's patch adhesion molecule ([LPAM]-1) and alpha 4 beta 1 (very late antigen-4) are cell surface adhesion molecules involved in lymphocyte trafficking and lymphocyte-cell and matrix interactions. Known cellular ligands include vascular cell adhesion molecule (VCAM)-1, which binds to alpha 4 beta 1 and alpha 4 beta 7, and the mucosal addressin cell adhesion molecule (MAdCAM)-1, which binds to alpha 4 beta 7. Here we show that the alpha 4 chain of these integrins can itself serve as a ligand. The alpha 4 chain, immunoaffinity purified and immobilized on glass slides, binds thymocytes and T lymphocytes. Binding exhibits divalent cation requirements and temperature sensitivity which are characteristic of integrin-mediated interactions, and is specifically inhibited by anti-alpha 4 integrin antibodies, which exert their effect at the cell surface. Cells expressing exclusively alpha 4 beta 7 (TK-1) or alpha 4 beta 1 (L1-2) both bound avidly, whereas alpha 4-negative cells did not. A soluble 34-kD alpha 4 chain fragment retained binding activity, and it inhibited lymphocyte adhesion to alpha 4 ligands. It has been shown that alpha 4 integrin binding to fibronectin involves an leucine-aspartic acid-valine (LDV) motif in the HepII/IIICS region of fibronectin (CS-1 peptide), and homologous sequences are important in binding to VCAM-1 and MAdCAM-1. Three conserved LDV motifs occur in the extracellular sequence of alpha 4. A synthetic LDV-containing alpha 4-derived oligopeptide supports alpha 4-integrin-dependent lymphocyte adhesion and blocks binding to the 34-kD alpha 4 chain fragment. Our results suggest that alpha 4 beta 7 and alpha 4 beta 1 integrins may be able to bind to the alpha 4 subunit on adjacent cells, providing a novel mechanism for alpha 4 integrin-mediated and activation-regulated lymphocyte interactions during immune responses.

Development of asymmetry along the left-right axis is a critical step in the formation of the vertebrate body plan. Disruptions of normal left-right patterning are associated with abnormalities of multiple organ systems, including significant congenital heart disease. The mouse nodal gene, and its homologues in chick and Xenopus, are among the first genes known to be asymmetrically expressed along the left-right axis before the development of organ asymmetry. Alterations in the expression pattern of mouse nodal and the chick homologue (cNR-1) have been associated with defects in the development of left-right asymmetry and cardiac looping (Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M. and Tabin, C. (1995) Cell 82, 803-814; Collignon, J., Varlet, I. and Robertson, E. J. (1996) Nature 381, 155-158; Lowe, L. A., Supp, D. M., Sampath, K., Yokoyama, T., Wright, C. V. E., Potter, S. S., Overbeek, P. and Kuehn, M. R. (1996) Nature 381, 158-161). Here, we show that the normal expression patterns of the Xenopus nodal-related gene (Xnr-1) are variable in a large population of embryos and that Xnr-1 expression is altered by treatments that perturb normal left-right development. The incidence of abnormal Xnr-1 expression patterns correlates well with cardiac reversal rates in both control and experimentally treated Xenopus embryos. Furthermore, dorsal midline structures, including notochord and/or hypochord and neural floorplate, regulate Xnr-1 expression prior to the specification of cardiac left-right orientation by repression of Xnr-1 expression in the right lateral plate mesoderm during closure of the neural tube. The correlation of Xnr-1 expression and orientation of cardiac looping suggests that Xnr-1 is a component of the left-right signaling pathway required for the specification of cardiac orientation in Xenopus, and that dorsal midline structures normally act to repress the signaling pathway on the right side of the embryo.

To determine the extent of antiviral activity present in a number of plant extracts, hot glycerin extracts were prepared from Rheum officinale, Aloe barbadensis, Rhamnus frangula, Rhamnus purshianus, and Cassia angustifolia and their virucidal effects were tested against herpes simplex virus type 1. All the plant extracts inactivated the virus. The active components in these plants were separated by thin-layer chromatography and identified as anthraquinones. A purified sample of aloe emodin was prepared from aloin, and its effects on the infectivity of herpes simplex virus type 1 and type 2, varicella-zoster virus, pseudorabies virus, influenza virus, adenovirus, and rhinovirus were tested by mixing virus with dilutions of aloe emodin for 15 min at 37 degrees C, immediately diluting the sample, and assaying the amount of infectious virus remaining in the sample. The results showed that aloe emodin inactivated all of the viruses tested except adenovirus and rhinovirus. Electron microscopic examination of anthraquinone-treated herpes simplex virus demonstrated that the envelopes were partially disrupted. These results show that anthraquinones extracted from a variety of plants are directly virucidal to enveloped viruses.

This study reviews the clinical outcome of knee artroplasty (Microloc, Johnson & Johnson Orthopedics, Norderstedt, Germany) with a resurfacing metal-backed patellar component. Thirty patients were available for clinical and radiographic reexamination with follow-up periods of 36 and 72 months. There were 21 women and 9 men, with an average age of 71.1 years. At the follow-up examination, seven patients demonstrated a metallic friction noise, and three had only mild crepitation at the patellofemoral joint level. In the group complaining of knee pain, the average knee score dropped from 76.9 +/- 9.9 at 36 months to 44.7 +/- 15.3 (P < .05) prior to revision surgery on average at 66 months. The function score dropped during the same time from 72.0 +/- 19.7 to 53.5 +/- 14.9. In contrast, the pain-free group did not demonstrate any significant changes in either knee or function score. Radiographic evaluation showed a patellar tilt of 8.1^o +/- 4.0^o in the group complaining of pain, compared with 2.5^o +/- 2.3^o in the pain-free patient collective. All 10 patients complaining of pain and increasing disability underwent revision surgery. At the time of surgery, an obvious polyethylene particle-induced synovitis was found, and in 7 patients it was associated with a metallosis. One of the main reasons for failure of metal-backed polyethylene components is thought to be the undue high stresses forced onto the insert. High loading of only a small fraction of the surface will lead to increased polyethylene creep and particle formation, resulting in synovitis and finally metallosis. Early revision seems to be the best solution to prevent progressive destruction of the entire joint. Previously reported results on metal-backed patellar components show a failure rate of 8.4% after 12 to 24 months. In this study, this rate had already increased to 33.3% after 6 years. One might therefore speculate that at 10 years, revision surgery might become necessary in more than 50% of the surviving patients with this type of implant.

The choline metabolite betaine has been shown to be an important organic osmoregulatory solute in the kidney. The isolated perfused rat kidney and kidney slice incubations were used to investigate the effect of 2-dimethylaminoethanol (DMAE), a choline oxidase inhibitor, on the renal excretion and metabolism of choline. In the isolated perfused kidney, [14C]choline, at an initial perfusate concentration of 300 microM, was effectively removed from the perfusate over 25 min, with nearly all the 14C in the perfusate accounted for by betaine during the remainder of the 90-min perfusion. DMAE at concentrations of 3.0 or 5.0 mM significantly decreased the rate of removal of [14C]choline from the perfusate and the rate of addition of [14C]betaine to the perfusate, yet [14C]betaine remained the only metabolite of choline in perfusate and urine. In kidney tissue slice experiments, conversion of [14C]choline to [14C]betaine was found in cortical, outer medullary and inner medullary regions of rat kidney. DMAE at 5.0 mM significantly inhibited [14C]betaine production in each of the three regions studied. These data show that DMAE is an effective inhibitor of betaine production by the kidney and, as such, may be an important agent for the study of osmoregulation by the kidney.

Purpose: The purpose of this study was to determine whether laser Doppler skin perfusion pressure (LD-SPP) could accurately predict amputation wound healing. Methods: We studied a total of 62 limbs in 52 patients (28 men and 24 women) with a mean age of 62.2 years (range 34 to 93 years). From this, 39 limbs underwent major amputation (15 above-the-knee, 24 below-the-knee), and 23 limbs underwent minor amputations (4 transmetatarsal and 19 toes). There were five postoperative deaths, leaving a total of 57 limbs available for analysis. Results: Three of 13 above-knee amputations failed to heal. Twenty-one of 23 below-knee amputations healed. Three of four transmetatarsal amputations failed to heal and eight of 17 toe amputations failed to heal. Binary table analysis showed that an LD-SPP value of 30 mm Hg or greater had a negative predictive value (healing occurred) of 90%. An LD-SPP value of less than 30 mm Hg at the amputation site had a positive predictive value (healing failure) of 75%, (p<0.001, chi square analysis). For major amputations, negative predictive value was 100%, and positive predictive value was 83%, (p<0.001). For minor amputations, negative predictive value was 75% and positive predictive value was 66.7%, (p<0.09). Conclusion: These data support the use of the LD-SPP test in the selection of major amputation level consistent with healing in ischemic limbs. Further study of the value of this parameter in the determination of minor amputation wound healing is necessary.

The amino acid motif LDV is the principal binding site for alpha4 integrins in fibronectin, and homologous motifs are recognized in vascular cell adhesion molecule-1 and MAdCAM-1. Three conserved LDV motifs (LDV-1 to 3) occur in the ectodomain of the human and mouse alpha4-subunit, the functions of which are unknown. We demonstrate here that alpha4-transfected fibroblasts with mutation in LDV-1 (D489N) behaved like alpha4-wild type but that LDV-2 (D698N) and LDV-3 (D811N) mutants were impaired in binding and spreading on alpha4-specific substrates. On the RGD-containing fibronectin fragment FN-120 there was an inverse behavior; now the alpha4-wild type and the LDV-1 mutant could not adhere whereas the two other mutants could. The beta1 chain was critical for the differential integrin response. Biochemical analysis demonstrated that the LDV-2 and -3 mutations reduced the strength of the alpha4beta1 association, favored the formation of alpha5beta1, and prevented the expression of alpha4beta7 on the cell surface. Our results indicate that LDV-2 and LDV-3 are critical for the formation of a functional heterodimer. The presence of similar amino acid motifs in ligands and the alpha4-subunit suggest that metal coordination plays an important role in integrin-ligand binding as well as for heterodimer formation.

Infections with Herpesvirus hominis type 1 were associated with 11.5% of acute respiratory illnesses of university students who were admitted to the student infirmary over a 6-year period. Over three-quarters of these infections were detected in students with pharyngitis or tonsillitis; 42% had ulcerated lesions on tonsils or posterior pharynx but only 11% had lesions in the anterior portion of the mouth or lips. Almost all of the H. hominis infections were accompanied by significant rises in neutralizing antibodies and few students had detectable antibodies in the initial serum collected during the acute phase of illness. Special studies revealed herpes-specific IgM antibodies in the early convalescent sera of some of these patients. The data demonstrate that 80% of the infections detected were primary infections with H. hominis. Only 30% of university students possessed neutralizing antibodies to H. hominis and about 10% of those without antibodies acquired antibodies each year. These data suggest that the majority of persons from middle income families reach young adulthood without acquiring infections of H. hominis and the spread of the virus requires close and intimate contact.

Neutral-beam-heated expanded-boundary (XB) divertor discharges have been obtained in Doublet III with high heating efficiency for wide ranges of plasma parameters (Ip: 300-800 kA; BT: 8-24kG; e:(2-10) × 1013cm?3; Pb< 4.5 MW, ?p? 1.6, ?t? 2.8%). The improved heating efficiency is well correlated with a configurational change from limiter discharges to XB discharges. The beam-heated, fully diverted expanded-boundary discharges with a limiter/separatrix distance greater than 1.5 cm exhibit an improvement of up to a factor of two in energy confinement time. The ?Eincreases approximately linearly with Ip, but is insensitive to variations of a factor of two in eand BT. Over the inner two-thirds of the plasma radius (r/a ? 0.7), the shape of the Teprofile for XB discharges is similar to that for limiter discharges. Hence, the improvement of the global energy confinement is consistent with a reduction of thermal conductivity over most of the plasma radius. With 2 MW of neutral-beam injection into a high-current (Ip= 750 kA) XB discharge, energy confinement times ?E? 115 ms and e?E? 1 × 1013cm?3· s?1have been obtained. At high beam power (Pb> 3 MW), a mild deterioration of the energy confinement time has been observed.

Observation of the intensity of the recycling particle flux at the main plasma edge for various limiter and divertor discharges indicates that the gross energy confinement of beam-heated discharges is closely related to the intensity of the edge particle flux. In limiter discharges, the global particle confinement time and the energy confinement time ?Eshow many similarities: 1) linear Ipdependence at Ip< 600 kA, 2) no BTdependence, and 3) deterioration against injection power. Improvement of ?Eby increasing Ip, for example, is associated with high temperatures at the plasma edge region accompanied by reduced particle recycling. - Divertor discharges with low particle recycling around the main plasma show better energy confinement than limiter discharges at high plasma densities. The improvement of ?Eis primarily originated in the reduction of heat transport at the main plasma edge region, which is associated with the reduction of recycling particle flux at the main plasma edge. Under certain operation condition, for example, excessive cold-gas puffing, the discharge shows relatively high scrape-off plasma density and strong particle recycling between the main plasma and the limiter. The energy confinement time of these discharges degrades somewhat or reduces completely to that of the limiter discharge. - In low-recycling divertor discharges, the central electron and ion temperature is proportional to the injection power, and the plasma stored energy is proportional to ePabs(scales as INTOR scaling). With ? 4 MW beam injection, high-temperature and high-density plasmas were obtained (stored energy up to 280 kJ, Te(0) ? Ti(0) ? 2.5-3.0 keV at e? (6-7) × 1013cm?3, ?E* ? 70 ms).

A method has been developed to transform plasmid deoxyribonucleic acid into protoplasts of the insect pathogen Bacillus thuringiensis. Protoplasts were formed by treatment of cells with lysozyme. The efficiency of formation of protoplasts was affected by the strain, the media, and the cell density. Deoxyribonucleic acid uptake was induced by polyethylene glycol. Deoxyribonucleic acid from the Staphylococcus aureus plasmid pC194 was used for transformation. Although this plasmid could not be isolated as a stable extrachromosomal element, its chloramphenicol resistance was transferred to the recipient protoplasts. This was confirmed by assay for the enzyme chloramphenicol acetyltransferase, which confers resistance to chloramphenicol. This suggested that pC194 acts as an insertion element in B. thuringiensis.