Architecture, implementation, and testing of a multiple-shell gas injection system for high current implosions on the Z accelerator.

Tests are ongoing to conduct ~20 MA z-pinch implosions on the Z accelerator at Sandia National Laboratory using Ar, Kr, and D2 gas puffs as the imploding loads. The relatively high cost of operations on a machine of this scale imposes stringent requirements on the functionality, reliability, and safety of gas puff hardware. Here we describe the development of a prototype gas puff system including the multiple-shell nozzles, electromagnetic drivers for each nozzle's valve, a UV pre-ionizer, and an inductive isolator to isolate the ~2.4 MV machine voltage pulse present at the gas load from the necessary electrical and fluid connections made to the puff system from outside the Z vacuum chamber. This paper shows how the assembly couples to the overall Z system and presents data taken to validate the functionality of the overall system.

Development and use of a two-dimensional interferometer to measure mass flow from a multi-shell Z-pinch gas puff.

For gas puff Z-pinches, the K-shell x-ray yield is maximized with the use of a multi-shell nozzle. Optimization of the yield, verification of hydrodynamic models of the nozzle flows, and plausible MHD code modeling of the implosions require data on the radial and axial (R,Z) distribution of mass in the nozzle's flow field. Interferometry is a well-established technique for acquiring such data. We describe the development and use of a two-dimensional interferometer with emphasis on the required data reduction methods. We also show that the instrument can derive the flow from each individual nozzle in a multi-shell system.

A comparison of planar, laser-induced fluorescence, and high-sensitivity interferometry techniques for gas-puff nozzle density measurements.

The distribution of argon gas injected by a 12-cm-diameter triple-shell nozzle was characterized using both planar, laser-induced fluorescence (PLIF) and high-sensitivity interferometry. PLIF is used to measure the density distribution at a given time by detecting fluorescence from an acetone tracer added to the gas. Interferometry involves making time-dependent, line-integrated gas density measurements at a series of chordal locations that are then Abel inverted to obtain the gas density distribution. Measurements were made on nominally identical nozzles later used for gas-puff Z-pinch experiments on the Saturn pulsed-power generator. Significant differences in the mass distributions obtained by the two techniques are presented and discussed, along with the strengths and weaknesses of each method.

Multicolor, time-gated, soft x-ray pinhole imaging of wire array and gas puff Z pinches on the Z and Saturn pulsed power generators.

A multicolor, time-gated, soft x-ray pinhole imaging instrument is fielded as part of the core diagnostic set on the 25 MA Z machine [M. E. Savage et al., in Proceedings of the Pulsed Power Plasma Sciences Conference (IEEE, New York, 2007), p. 979] for studying intense wire array and gas puff Z-pinch soft x-ray sources. Pinhole images are reflected from a planar multilayer mirror, passing 277 eV photons with <10 eV bandwidth. An adjacent pinhole camera uses filtration alone to view 1-10 keV photons simultaneously. Overlaying these data provides composite images that contain both spectral as well as spatial information, allowing for the study of radiation production in dense Z-pinch plasmas. Cu wire arrays at 20 MA on Z show the implosion of a colder cloud of material onto a hot dense core where K-shell photons are excited. A 528 eV imaging configuration has been developed on the 8 MA Saturn generator [R. B. Spielman et al., and A. I. P. Conf, Proc. 195, 3 (1989)] for imaging a bright Li-like Ar L-shell line. Ar gas puff Z pinches show an intense K-shell emission from a zippering stagnation front with L-shell emission dominating as the plasma cools.

Atypical antipsychotic-induced diabetes mellitus: an update on epidemiology and postulated mechanisms.

Diabetic ketoacidosis and hyperglycaemic hyperosmolar syndrome are rare, but potentially fatal complications of antipsychotic-associated hyperglycaemia. The mechanisms for this remain unclear, but are probably multifactorial. The suggested reasons include drug-induced weight gain and adiposity, development of the metabolic syndrome, antagonism of serotonin (5-hydroxytryptamine) receptors, drug-induced leptin resistance, dyslipidaemia mediated pancreatic beta-cell damage and hepatocyte transcription factor dysregulation. Patients with schizophrenia are known to be at a higher genetic risk of developing diabetes mellitus and cardiovascular disease. This review emphasizes a rare case of hyperosmolar hyperglycaemic syndrome in a young man with schizophrenia and discusses proposed mechanisms for the development of antipsychotic-associated diabetes mellitus.

Treatment of hypertension in the elderly.

Hypertension is present in over 50% of elderly patients and constitutes a major risk factor for cardiovascular morbidity and mortality. This paper reviews the rationale for treating hypertension in the elderly, discusses the choice of antihypertensive therapy and optimal target blood pressure, and summarizes ongoing clinical trials. The major questions that remain to be answered are the optimal level of blood pressure reduction in the elderly and the long-term efficacy and safety of newer antihypertensive agents compared with diuretics and beta-blockers.

Immobilization of manganese peroxidase from Lentinula edodes on alkylaminated Emphaze AB 1 polymer for generation of Mn3+ as an oxidizing agent.

Manganese peroxidase (MnP) is secreted by white-rot fungi and participates in the degradation of lignin by these organisms. MnP uses H2O2 as an oxidant to oxidize MnII to MnIII as the manganic ion Mn3+. The Mn3+ stabilized by chelation, is a highly reactive nonspecific oxidant capable of oxidizing a variety of toxic organic compounds. Previous attempts at immobilization of MnP, purified from Lentinula edodes through reactive amino groups, have been hindered by the protein's low lysing content of only 1% and its instability above pH 6.0. As an alternative to amine coupling, the enzyme has now been covalently immobilized through its carboxyl groups, using an azlactone-functional copolymer derivatized with ethylenediamine and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) as a coupling reagent. The immobilization reaction was performed under acidic (pH 5.25) conditions, and 90% coupling efficiency was achieved within 2h. Net immobilization efficiencies, expressed as the product of protein coupling efficiency and enzyme activity, have been measured at > 95% within 4h. The MnP-NH-polymer and the free soluble protein were characterized and compared for their pH, temperature, and storage stabilities, as well as their H2O2 dependence and kinetics. The tethered MnP, employed in an immobilized enzyme bioreactor for generation of chelated Mn3+ may have industrial applications as a nonspecific oxidant of organopollutants.

Lessons we most enjoy learning.

PIP: In the mid-1970s, the Philippine Commission on Population (POPCOM) began to use entertainment programs for reaching people with messages on population and development issues. 2 major motion pictures contained family planning (FP) messages. Radio dramas, print media, and theater also were used to convey FP messages. The early experiments were continued in the late 1980s through the work of the Philippine Center for Population and Development (PCPD). PCPD, with the assistance of the Johns Hopkins University/Population Communication Services (JHU/PCS) project, embarked on a program which used popular music to encourage young people to become sexually responsible adults. In 1990, the Philippine Non-Governmental Organization Council (PNGOC), the Department of Health (DOH) and JHU/PCS began an effort funded by USAID to form a coalition with the entertainment community for social development causes. DOH, JHU/PCS, and USAID wanted to promote FP and health through the Enter-Educate concept. PNGOC and JHU/PCS contacted over 20 entertainment organizations and held more than 75 conferences, work shops, and meetings which attended by more than 300 people. The movement of Entertainment for Social Change was launched in October 1991 with the creation of the Enter-Educate Foundation, Inc. (EEF). The aims of EEF include rewards, professional approach, and establishment of a network of dedicated entertainment and social development professionals. In 1993, a television comedy series will focus on FP as well as on maternal and child health. Further plans at the local level include: tree planting; discussions on migration; talks about FP; meetings on community population and environment activities; and networking of organizations involved with youth, the environment, and population. JHU/PCS provides technical assistance for the production, monitoring, and evaluation of the project. With these efforts, the EEF is attempting to focus on the country's biggest problems: population and the environment.^ieng

The enter-educate approach.

PIP: This article describes how the Population Communication Services (PCS) has seized on the "enter-educate" approach, the blending of popular entertainment with social messages, to change reproductive health behavior. The enter-educate approach spreads its message through songs, soap operas, variety shows, and other types of popular entertainment mediums. Because they entertain, enter-educate projects can capture the attention of an audience -- such as young people -- who would otherwise scorn social messages. And the use of population mediums makes it possible to reach a variety of audiences. Funded by USAID, PCS began its first enter-educate project in response to the increasing number of teenage pregnancies in Latin America. PCS developed 2 songs and videos, which featured popular teenage singers to serve as role models, to urge abstinence. The songs became instant hits. Since then, PCS has mounted more then 80 major projects in some 40 countries. Highlights of programs range from a successful multi-media family planning campaign in Turkey to humorous television ads in Brazil promoting vasectomy. Recently, PCS initiated projects to teach AIDS awareness. At the core of the enter-educate approach is the social learning theory which holds that much behavior is learned through the observation of role-models. Health professionals work alongside entertainers to produce works that have audience appeal and factual social messages. The enter-educate approach works because it is popular, pervasive, personal, persuasive, and profitable. PCS has found that enter-educate programs pay for themselves through cost sharing and cost recovery.^ieng

Enter-educate: new word from Johns Hopkins.

PIP: Social development communication activities are competing with all of the other communication activities for the attention of the audience. The Johns Hopkins University/Population Communication Services (JHU/PCS) strongly believes that one of the best ways to get the attention of a designated audience, and to keep it, is to entertain the audience and educate it at the same time. They call this concept enter-educate. The basic precepts of this approach include: 1) Choose the most appropriate medium to reach the intended audience; 2) Enlist professionals experienced in the chosen medium in order to have access to the best available resources; 3) Develop a high-quality product that will attract the commercial sector; 4) Use a medium which has a big regional or national audience; and 5) Make the program appealing by including entertainment elements appropriate for the intended audience and not obviously preachy. The most successful project that JHU/PCS has supported that incorporated the concept of enter-educate is the Communication for Young People project in Latin America, better known as the Tatiana and Johnny project. This project used popular music, and its spin offs, to reach young people in 11 Spanish-speaking countries with a sexual responsibility message. Other successful projects in Nigeria and Mali are also described. Nigeria used television shows with family planning skits; in Mali the traditional Koteba theatrical format was made into films for short cinema showings before the main feature.^ieng

Population communication services: a global perspective.

PIP: Communication support for health and family planning programs is receiving renewed attention. The johns Hopkins University (JHU) Population Communication Services (PCS) project was established in 1982 to respond to the increasing need for communication expertise, to provide a responsive source for advice, and to develop implement the new directions that are necessary to make family planning communication programs more effective. The project extends a range of services to government programs, private family planning associations, and to media that want to improve the content or coverage of family planning communication, JHU/PCS emphasizes the close links between good communication and good management and the need for managers at all levels, from the Minister of Health to the supervisor of grass-roots field workers, to understand the components of a communication program for the 1980s. Principles underlying the project's work include: communication as process rather than product, the audience as participant, linking mass media and interpersonal communication, coordination with and among agencies, training that is specific and relevant, IEC as institution building, use of the private sector, an attempt to recover some of the costs of IEC work, and ongoing evaluation of program activities. IEC activities can be strengthened considerably b a knowledgeable commitment at the top of the decision-making process; constant feedback from intended audiences; and interactions among service delivery personnel, influential community members, and the media. In turn, strong IEC activities can substantially strengthen existing family planning programs.^ieng

Music carries a message to youths.

PIP: The most widely played song in Mexico in March 1986 is a special record designed to encourage young people to be sexually responsible and not to bring into the world children they cannot care for. "It's OK to say 'no,'" is the message of a unique new family planning and health communication project designed to reach young people in 11 Spanish speaking countries of Latin America and the Caribbean. What makes this ambitious regional project so unique is not just the message or the remarkable success of the 1st song but the combination of materials that were produced, the way they were produced, and how they are now being used throughout the region. The Population Communication Services project in the Johns Hopkins School of Hygiene and Public Health (JHU/PCS) has been working in Latin America and elsewhere for 4 years to support innovative family planning communication projects. It became evident that 1 key group was not being reached, i.e., young people aged 13-18 who comprise approximately 30% of the total population in Latin America. The fertility and sexual behavior of young people have a significant impact on their own lives, their community, their country, and the region. Early pregnancy is a major health and social problem throughout the region and the world. To address this problem, the JHU/PCS decided to develop a regional Latin American project to make young people more sharply aware of the personal advantages to them of responsible parenthood. JHU/PCS put together a financial, marketing, and institutional package. The US Agency for International Development (USAID) provided the finances. Analysis showed that the common denominator for young people throughout the region is music. The decision was made to produce 2 songs, each with a music video, pressed on each side of 45 rpm single records and enclosed in a full-size, full-color, 2-sided record jacket which folds out into a poster. The next step was to refine the general message of sexual responsibility to a specific message, one that young people would listen to and that would not offend others. Once the artists and the messages had been identified, a contest was held for the music and lyrics, with more than 20 professional composers participating. An underlying concern built into the design of this project was that the materials had to appeal to young people as popular songs, not as educational materials. The marketing of what became known as the "Tatiana & Johnny Project" included sending: copies of the record to 3020 radio stations; copies of the record and music videos to 250 television stations; press kits to 350 newspapers, magazines, and journals; and brochures about the project to 3500 media representatives throughout the region. Initial reaction to the project has been overwhelmingly positive. Lessons learned from the project are identified.^ieng

Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells.

Incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone rapidly inhibits plasminogen activator (PA) activity secondary to the induction of a specific acid-stable inhibitor of plasminogen activation (Cwikel, B. J., Barouski-Miller, P.A., Coleman, P.L., and Gelehrter, T.D. (1984) J. Biol. Chem. 259, 6847-6851). We have further characterized this inhibitor with respect to its interaction with both urokinase and tissue plasminogen activator, and its protease specificity. The HTC PA inhibitor rapidly inhibits urokinase and tissue plasminogen activator with an apparent second-order rate constant of 3-5 x 10(7) M-1 X s-1. The inhibitor forms stable covalent complexes with both urokinase and tissue plasminogen activator, with which plasmin, trypsin, and factor Xa apparently do not compete. Complex formation is saturable and requires the active site of the PA. The mass of the inhibitor-PA complex is 50,000 daltons greater than that of PA alone, consistent with an Mr for the PA inhibitor of 50,000 as demonstrated directly by reverse fibrin autography. The HTC PA inhibitor does not inhibit thrombin and differs in its kinetic and biochemical properties from protease nexin.

The dexamethasone-induced inhibitor of plasminogen activator in hepatoma cells is antigenically-related to an inhibitor produced by bovine aortic endothelial cells.

Glucocorticoids decrease plasminogen activator (PA) activity in HTC rat hepatoma cells by inducing a specific inhibitor of PA activity (PAI). This inhibitor is similar in several biochemical properties to the PAI purified from bovine aortic endothelial cells (BAEs). We have used reverse fibrin autography and antiserum against BAE PAI to establish more fully the biochemical and immunological relationship of these inhibitors. Both inhibitors migrated with an apparent Mr of approximately 50,000, and the activity of both PAIs was stimulated by treatment with SDS suggesting that each of these molecules exists in both an active and a latent form. Antiserum to the BAE PAI immunoprecipitated all of the HTC PAI demonstrable by reverse fibrin autography. Finally, using this antiserum in a functional immunoassay, we have demonstrated that dexamethasone increases both active and latent PAI made by HTC cells. These results indicate that HTC PAI and BAE PAI are antigenically as well as biochemically related molecules.

Dexamethasone induction of an inhibitor of plasminogen activator in HTC hepatoma cells.

Incubation of HTC rat hepatoma cells with dexamethasone causes a rapid decrease in cellular plasminogen activator (PA) activity. Mixing experiments show the presence of an inhibitor of PA in dexamethasone-treated cells. This study investigates whether the decrease in PA activity is secondary to the induction of an inhibitor by glucocorticoids, to a decrease in the amount of PA, or to a combination of both mechanisms. PA and its inhibitor are dissociated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under non-reducing conditions, and both activities are then recovered and quantitated. HTC cells have two major forms of PA with Mr values of 110,000 and 64,000. Although PA activity in the unfractionated extracts from dexamethasone-treated cells is inhibited by 90% relative to control, there is no decrease in the total activity of sodium dodecyl sulfate-dissociated PA activity, suggesting that dexamethasone causes no decrease in the amount of the enzyme. PA inhibitor activity migrates as a single band of Mr = 50,000. The total activity of inhibitor increases in a time-dependent fashion, reaching a maximum of greater than 10 times control after a 4-6-h incubation with 0.1 microM dexamethasone. The induction of inhibitor requires both RNA and protein synthesis and shows a dependence on dexamethasone concentration identical to that for responses known to be mediated by glucocorticoid receptors. We conclude that dexamethasone inhibits PA activity by inducing the synthesis of an inhibitor rather than by decreasing the amount of PA.

Development and analytical performance of automated tests for antithrombin III and plasminogen on the Du Pont aca analyzer.

We describe assays for functional antithrombin III (AT III) and plasminogen in plasma with the Du Pont aca discrete clinical analyzer. Both are two-stage kinetic assays, based on synthetic substrate methodologies, and require 20-microL sample volumes. In the AT III assay the sample is incubated with excess thrombin and heparin to form the functionally inactive AT III-thrombin complex. Residual thrombin is measured through its rate of hydrolysis of a lysine thioester and is inversely related to analyte concentration. In the plasminogen assay excess streptokinase is reacted with the sample to form an enzymatically active complex. The substrate hydrolysis rate of this complex is measured, which is linearly related to the concentration of plasminogen in the sample. Reaction conditions for both assays were optimized by univariate and response surface techniques. The assay for AT III has a range of 0 to 150% of the value for normal human plasma (% NHP) with a CV of 3% at 80% NHP. The plasminogen assay is linear from 25 to 200% NHP with a CV of less than 2% at 80% NHP. No significant interferences with either method by common blood components or drugs were found.

Optimization of enzyme-based assays in coagulation testing.

Optimized assays for antithrombin III and plasminogen have been developed based on a study of the kinetic parameters Km and Kcat for four commercially available substrates: the p-nitroanilide derivatives of D-Phe-pipecolyl-Arg (S-2238), and toluenesulfonyl-Gly-Pro-Arg (Chromozym TH), which are thrombin substrates; D-Val-Leu-Lys (S-2251), a plasminogen/streptokinase substrate; and alpha-N-carbobenzoxy-L-lysine thiobenzyl ester, a substrate for both enzymes. We used a centrifugal analyzer system for rapid data acquisition and interactive analysis. Optimized conditions for assay of a particular enzyme are not constant for different substrates in the same buffering agent. For example, in 1,4-piperazine diethanesulfonic acid buffer at 37 degrees C, thrombin-catalyzed hydrolysis of Chromozym TH is optimal at 125 mmol/L buffer, 100 mmol/L NaCl, and pH 8.2, whereas substitution of S-2238, also a tripeptide p-nitroanilide, yields optimal hydrolysis at 85 mmol/L buffer, 300 mmol/L NaCl, and pH 7.2. We conclude that optimized assay conditions are best obtained by an extensive survey of available buffers and a detailed investigation of the effects of variation in pH and in the concentrations of the buffer and auxiliary reagents through use of both one-factor-at-a-time and multivariate response surface experimentation.

Hormonal regulation of plasminogen activator in rat hepatoma cells.

Plasminogen activators are membrane-associated, arginine-specific serine proteases which convert the inactive plasma zymogen plasminogen to plasmin, an active, broad-spectrum serine protease. Plasmin, the major fibrinolytic enzyme in blood, also participates in a number of physiologic functions involving protein processing and tissue remodelling, and may play an important role in tumor invasion and metastasis. In HTC rat hepatoma cells in tissue culture, glucocorticoids rapidly decrease plasminogen activator (PA) activity. We have shown that this decrease is mediated by induction of a soluble inhibitor of PA activity rather than modulation of the amount of PA. The hormonally-induced inhibitor is a cellular product which specifically inhibits PA but not plasmin. We have isolated variant lines of HTC cells which are selectively resistant to the glucocorticoid inhibition of PA but retain other glucocorticoid responses. These variants lack the hormonally-induced inhibitor; PA from these variants is fully sensitive to inhibition by inhibitor from steroid-treated wild-type cells. Cyclic nucleotides dramatically stimulate PA activity in HTC cells in a time- and concentration-dependent manner. Paradoxically, glucocorticoids further enhance this stimulation. Thus glucocorticoids exert two separate and opposite effects on PA activity. The availability of glucocorticoid-resistant variant cell lines, together with the unique regulatory interactions of steroids and cyclic nucleotides, make HTC cells a useful experimental system in which to study the multihormonal regulation of plasminogen activator.

The dexamethasone-induced inhibitor of fibrinolytic activity in hepatoma cells. A cellular product which specifically inhibits plasminogen activation.

Dexamethasone induces an inhibitor of plasminogen-dependent fibrinolysis in rat hepatoma (HTC) cells. The specificity of the inhibitor for urokinase and plasmin was investigated using both fibrinolytic and esterolytic assays. Urokinase, but not plasmin, was inhibited by serum-free conditioned medium from cells incubated with 0.1 microM dexamethasone. The specificity of the inhibitor for plasminogen activator was demonstrated directly by the inhibition of the urokinase-catalyzed activation of 125I-plasminogen to 125I-plasmin. The inhibitory activity was stable to pH 3 for 2 h at 37 degrees C, a condition which inactivated fibrinolytic inhibitors in serum, suggesting a cellular origin for the inhibitor. Further evidence for the cellular origin was the constant daily production of inhibitor throughout a 4-day incubation with dexamethasone in serum-free medium. SF HTC-H1 cells, selected for their ability to grow in serum-free medium (Thompson, E. B., Anderson, C. U., and Lippman, M. E. (1975) J. Cell Physiol. 86, 403-412), were grown for 76 days (at least 30 generations) in the presence or absence of serum; dexamethasone induced equivalent amounts of inhibitory activity in cells which had been grown under both conditions. We conclude that the dexamethasone-induced inhibitor from HTC cells is a cellular product which is specific for the inhibition of plasminogen activation and which differs from other reported fibrinolytic inhibitors.