Time-Resolved Fuel Density Profiles of the Stagnation Phase of Indirect-Drive Inertial Confinement Implosions.

The implosion efficiency in inertial confinement fusion depends on the degree of stagnated fuel compression, density uniformity, sphericity, and minimum residual kinetic energy achieved. Compton scattering-mediated 50-200 keV x-ray radiographs of indirect-drive cryogenic implosions at the National Ignition Facility capture the dynamic evolution of the fuel as it goes through peak compression, revealing low-mode 3D nonuniformities and thicker fuel with lower peak density than simulated. By differencing two radiographs taken at different times during the same implosion, we also measure the residual kinetic energy not transferred to the hot spot and quantify its impact on the implosion performance.

Investigating the relationship between noise transfer inside the x-ray framing cameras and their imaging ability.

We apply a cascaded linear model analysis to a micro-channel plate x-ray framing camera. We establish a theoretical expression of the Noise Power Spectrum (NPS) at the detector's output and assess its accuracy by comparing it to the NPS of Monte Carlo simulations of the detector's response to a uniform illumination. We also demonstrate that fitting the NPS of experimental data against a parametric model based on this expression can yield valuable information on the imaging ability of framing cameras, offering an alternative approach to the usual method employed to measure their modulation transfer functions.

Spatial resolution measurements of the advanced radiographic capability x-ray imaging system at energies relevant to Compton radiography.

Compton radiography provides a means to measure the integrity, ρR and symmetry of the DT fuel in an inertial confinement fusion implosion near peak compression. Upcoming experiments at the National Ignition Facility will use the ARC (Advanced Radiography Capability) laser to drive backlighter sources for Compton radiography experiments and will use the newly commissioned AXIS (ARC X-ray Imaging System) instrument as the detector. AXIS uses a dual-MCP (micro-channel plate) to provide gating and high DQE at the 40-200 keV x-ray range required for Compton radiography, but introduces many effects that contribute to the spatial resolution. Experiments were performed at energies relevant to Compton radiography to begin characterization of the spatial resolution of the AXIS diagnostic.

A comparison of "flat fielding" techniques for x-ray framing cameras.

Gain can vary across the active area of an x-ray framing camera by a factor of 4 (or more!) due to the voltage loss and dispersion associated with pulse transmission in a microstripline-coated microchannel plate. In order to make quantitative measurements, it is consequently important to measure the gain variation ("flat field"). Moreover, because of electromagnetic cross talk, gain variation depends on specific operational parameters, and ideally a flat field would be obtained at all operating conditions. As part of a collaboration between Lawrence Livermore National Laboratory's National Ignition Facility and the Commissariat à l'Énergie Atomique, we have been able to evaluate the consistency of three different methods of measuring x-ray flat fields. By applying all three methods to a single camera, we are able to isolate performance from method. Here we report the consistency of the methods and discuss systematic issues with the implementation and analysis of each.

Advances in x-ray framing cameras at the National Ignition Facility to improve quantitative precision in x-ray imaging.

We describe an experimental method to measure the gate profile of an x-ray framing camera and to determine several important functional parameters: relative gain (between strips), relative gain droop (within each strip), gate propagation velocity, gate width, and actual inter-strip timing. Several of these parameters cannot be measured accurately by any other technique. This method is then used to document cross talk-induced gain variations and artifacts created by radiation that arrives before the framing camera is actively amplifying x-rays. Electromagnetic cross talk can cause relative gains to vary significantly as inter-strip timing is varied. This imposes a stringent requirement for gain calibration. If radiation arrives before a framing camera is triggered, it can cause an artifact that manifests as a high-intensity, spatially varying background signal. We have developed a device that can be added to the framing camera head to prevent these artifacts.

Development of a dual MCP framing camera for high energy x-rays.

Recently developed diagnostic techniques at LLNL require recording backlit images of extremely dense imploded plasmas using hard x-rays, and demand the detector to be sensitive to photons with energies higher than 50 keV [R. Tommasini et al., Phys. Phys. Plasmas 18, 056309 (2011); G. N. Hall et al., "AXIS: An instrument for imaging Compton radiographs using ARC on the NIF," Rev. Sci. Instrum. (these proceedings)]. To increase the sensitivity in the high energy region, we propose to use a combination of two MCPs. The first MCP is operated in a low gain regime and works as a thick photocathode, and the second MCP works as a high gain electron multiplier. We tested the concept of this dual MCP configuration and succeeded in obtaining a detective quantum efficiency of 4.5% for 59 keV x-rays, 3 times larger than with a single plate of the thickness typically used in NIF framing cameras.

A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents.

AIM: Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. METHODS: AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala(2) ]GIP(1-42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F ß-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu(14) ] exenatide. Human GIP or [d-Ala(2) ]GIP(1-42) were used for comparison. RESULTS: AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. CONCLUSIONS: These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.

Methods for characterizing x-ray detectors for use at the National Ignition Facility.

Gated and streaked x-ray detectors generally require corrections in order to counteract instrumental effects in the data. The method of correcting for gain variations in gated cameras fielded at National Ignition Facility (NIF) is described. Four techniques for characterizing the gated x-ray detectors are described. The current principal method of characterizing x-ray instruments is the production of controlled x-ray emission by laser-generated plasmas as a dedicated shot at the NIF. A recently commissioned pulsed x-ray source has the potential to replace the other characterization systems. This x-ray source features a pulsed power source consisting of a Marx generator, capacitor bank that is charged in series and discharged in parallel, producing up to 300 kV. The pulsed x-ray source initially suffered from a large jitter (∼60 ns), but the recent addition of a pulsed laser to trigger the spark gap has reduced the jitter to ∼5 ns. Initial results show that this tool is a promising alternative to the other flat fielding techniques.

GLUT4 overexpression in db/db mice dose-dependently ameliorates diabetes but is not a lifelong cure.

We previously reported that overexpression of GLUT4 in lean, nondiabetic C57BL/KsJ-lepr(db/+) (db/+) mice resulted in improved glucose tolerance associated with increased basal and insulin-stimulated glucose transport in isolated skeletal muscle. We used the diabetic (db/db) litter mates of these mice to examine the effects of GLUT4 overexpression on in vivo glucose utilization and on in vitro glucose transport and GLUT4 translocation in diabetic mice. We examined in vivo glucose disposal by oral glucose challenge and hyperinsulinemic-hyperglycemic clamps. We also evaluated the in vitro relationship between glucose transport activity and cell surface GLUT4 levels as assessed by photolabeling with the membrane-impermeant reagent 2-N-(4-(1-azi-2,2,2-trifluoroethyl)benzoyl)-1,3-bis(D-mannose-4-yloxy)-2-propylamine in extensor digitorum longus (EDL) muscles. All parameters were examined as functions of animal age and the level of GLUT4 overexpression. In young mice (age 10-12 weeks), both lower (two- to threefold) and higher (four- to fivefold) levels of GLUT4 overexpression were associated with improved glucose tolerance compared to age-matched nontransgenic (NTG) mice. However, glucose tolerance deteriorated with age in db/db mice, although less rapidly in transgenic mice expressing the higher level of GLUT4. Glucose infusion rates during hyperinsulinemic-hyperglycemic clamps were increased with GLUT4 overexpression, compared with NTG mice in both lower and higher levels of GLUT4 overexpression, even in the older mice. Surprisingly, isolated EDL muscles from diabetic db/db mice did not exhibit alterations in either basal or insulin-stimulated glucose transport activity or cell surface GLUT4 compared to nondiabetic db/+ mice. Furthermore, both GLUT4 overexpression levels and animal age are associated with increased basal and insulin-stimulated glucose transport activities and cell surface GLUT4. However, the observed increased glucose transport activity in older db/db mice was not accompanied by an equivalent increase in cell surface GLUT4 compared to younger animals. Thus, although in vivo glucose tolerance is improved with GLUT4 overexpression in young animals, it deteriorates with age; in contrast, insulin responsiveness as assessed by the clamp technique remains improved with GLUT4 overexpression, as does in vitro insulin action. In summary, despite an impairment in whole-body glucose tolerance, skeletal muscle of the old transgenic GLUT4 db/db mice is still insulin responsive in vitro and in vivo.

Molecular scanning analysis of hepatocyte nuclear factor 1alpha (TCF1) gene in typical familial type 2 diabetes in African Americans.

Type 2 diabetes mellitus (T2DM) is strongly inherited, but the major genes for this disease have been elusive. In contrast, early-onset, autosomal-dominant diabetes results from at least 5 loci, of which hepatocyte nuclear factor 1a (HNF1alpha or TCF1) is the most common cause. Mutations in HNF1alpha also cause later-onset diabetes in some Caucasian populations, but the role of these mutations has not been tested in African American populations. We used a variety of screening methods, including both single-strand conformation polymorphism (SSCP) analysis and dideoxy fingerprint analysis, to search for mutations in 51 African American subjects with onset of diabetes before age 50 years. Potential mutations were confirmed by direct sequencing. We identified 21 different variants, of which 11 were unique to African Americans. Four mutations either altered the amino acid sequence (Gly52Ala and Gly574Ser) or were close to a splice site (intron 1 and intron 10). A 5-nucleotide insertion in intron 1 was present in both diabetic members of a small family, but Gly52Ala, Gly574Ser, and the intron 10 mutation did not segregate with diabetes. Gly574Ser was present in 2 large families and 5% of controls, all of which appeared to share the same common HNF1alpha haplotype. Surprisingly, radioactive SSCP analysis under 2 room-temperature conditions performed as well as methods using fluorescent labeling that were expected to be more sensitive. We conclude that in African American individuals under age 50, variation in the HNF1a gene is common but unlikely to be a significant cause of T2DM.

A rural mental health research agenda: defining context and setting priorities.

This article provides a brief overview of research perspectives on rural mental health services and suggests the importance of building an agenda to bring coherence to studies in this area. The need for sound theory and methodology to guide research is emphasized. The importance of better conceptualization of the rural context as a focus of research is addressed, and 14 propositions concerning issues the authors think will advance rural research are presented. This article is intended to stimulate discussion about a research agenda that will lead to better understanding of rural needs for mental health services as well as more responsive service models.

Modulation of insulin secretion and glycemia by selective inhibition of cyclic AMP phosphodiesterase III.

The effects of selective inhibition of cyclic AMP phosphodiesterase type III on insulin and glucose levels during an oral glucose challenge were evaluated in obese, diabetic ob/ob mice and in lean, non-diabetic littermates using the selective inhibitor, milrinone. Oral administration of milrinone increased plasma insulin levels both in ob/ob and in lean mice. Glucose tolerance was improved in lean, but not in ob/ob mice, where glucose levels were increased by milrinone treatment. In isolated hepatocytes from normal rats incubation with 200 microM milrinone caused a 30% increase in glucose release with a corresponding depletion of glycogen stores. Stimulation of isolated rat adipocytes with 200 microM milrinone increased glycerol release 7-fold. We conclude that selective inhibitors of cyclic AMP phosphodiesterase III are effective insulin secretagogues, but their therapeutic utility may be limited by their concurrent stimulation of lipolysis and hepatic glucose output.

Glucose transport-enhancing and hypoglycemic activity of 2-methyl-2-phenoxy-3-phenylpropanoic acids.

A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ob mice. Some compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food consumption observed with some of these compounds was shown by a pair-feeding experiment not to be the primary cause of the hypoglycemia observed.

Comparison of the glucose dependency of glucagon-like peptide-1 (7-37) and glyburide in vitro and in vivo.

The purpose of the present study was to compare the glucose dependency of the insulin secretagogue activity of the sulfonylurea, glyburide, versus that of glucagon-like peptide-1(7-37) [GLP-1(7-37)] in vitro and in vivo. In freshly isolated rat islets, maximally effective concentrations of glyburide (10 micromol/L) and GLP-1(7-37) (10 nmol/L) were equally effective in stimulating insulin secretion in the presence of 15 mmol/L glucose (2.4-fold increase relative to 15 nmol/L glucose alone). At 5 nmol/L glucose, both agents increased insulin secretion, but the effect for glyburide was threefold greater than for GLP-1(7-37) (122% and 41% increase in insulin secretion, respectively). In conscious catheterized rats infused with glucose at a variable rate to clamp plasma glucose concentration at 11 mmol/L, glyburide (1 mg/kg orally) and GLP -1(7-37) (infused intravenously [IV] at 5 pmol/min/kg) produced similar increase in insulin levels (1.8-fold relative to the respective vehicle controls) that were sustained through 60 minutes of measurement. These doses of GLP-1(7-37) and glyburide were then administered to fasted and fed rats (basal plasma glucose concentration, 5.8 and 7.3 mmol/L, respectively). Relative to the vehicle control group, GLP-1(7-37) infusion produced a transitory increase (30%) in plasma insulin concentration and a modest sustained decrease (10% to 20%) in glucose in both fasted and fed rats, whereas glyburide induced a sustained 2.4- and 1.7-fold increase in plasma insulin concentration in fasted and fed rats, respectively, and a 50% decrease in plasma glucose in both fasted and fed rats. Results of these studies demonstrate the higher glucose threshold for the insulin secretagogue activity of GLP-1(7-37) relative to glyburide in vitro and in vivo.

Critical issues in reforming rural mental health service delivery.

Critical issues in reforming rural mental health service delivery systems under health care reform are outlined. It is argued that the exclusive focus on health care financing reform fails to include obstacles to effective mental health service delivery in rural area, which should focus on issues of availability, accessibility, and acceptability, as well as financing and accountability. Characteristics of rural areas are delineated and three assumptions about the structure of rural communities which are shaping the dialogue on rural health and mental health service delivery are examined. These assumptions include the notion that rural communities are more closely knit than urban ones, that rural services can be effectively delivered through urban hubs, and that rural dwellers represent a low risk population which can be effectively served through existing facilities and by extending existing services.

Glucose-dependent action of glucagon-like peptide-1 (7-37) in vivo during short- or long-term administration.

In vitro, truncated glucagon-like peptides [GLP-1(7-36)-amide and GLP-1(7-37)] increase insulin secretion in a glucose-dependent manner, and desensitization to the action of GLP-1(7-37) has been demonstrated acutely with high concentrations. The purpose of these studies was to evaluate the glucose dependency and threshold of GLP-1(7-37) action in normal rats and in a rat model of type II diabetes and to assess the effects of long-term administration in vivo. All studies were conducted in conscious catheterized rats. An intravenous (IV) infusion of GLP-1(7-37) at 0.5, 5, or 50 pmol/min/kg during the second hour of a 2-hour 11-mmol/L hyperglycemic clamp in Sprague-Dawley rats produced a dose-related enhancement of the glucose-induced increase in plasma insulin concentration. A 1-hour infusion of a submaximal dose of GLP-1(7-37) (5 pmol/min/kg IV) in fasted and fed Sprague-Dawley rats produced small transient increases in plasma insulin (incremental increases above basal, 72 +/- 27 and 96 +/- 28 pmol/L, respectively) and decreases in plasma glucose (to levels > or = 5.2 mmol/L). Infusion of GLP-1(7-37) (5 pmol/min/kg IV) during a hyperglycemic clamp at two sequentially increasing concentrations of glucose, 11 and 17 mmol/L, produced incremental increases in insulin of 600 and 1,200 pmol/L, respectively, relative to levels in clamped control rats. Similarly, infusion of GLP-1(7-37) (5 pmol/min/kg IV) in hyperinsulinemic, hyperglycemic Zucker diabetic fatty (ZDF) rats produced a transitory increase in plasma insulin concentration and normalized the plasma glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Food security: what the community wants. Learning through focus groups.

We used focus groups to learn the range of issues threatening food security of low income residents in our community. Five major themes emerged from the discussions: literacy, money, time, mental health and self-esteem, suggesting several approaches that could help ensure food security: 1) education, 2) sharing of resources, 3) coalition building, and 4) advocacy. Education programs have to be practical, allowing for demonstrations and hands-on learning while emphasizing skill building and problem solving. Incorporating a social aspect into learning may compensate for the social isolation and would capitalize on the impressive mutual support we witnessed. Strategies based on self-help and peer assistance may counteract low self-esteem and overcome suspicion of health professionals. A community-wide effort is needed to address the factors contributing to food insecurity. We envision the formation of a coalition of professionals, agencies, and low income people to develop a comprehensive strategy for achieving food security.

Enhanced peripheral glucose utilization in transgenic mice expressing the human GLUT4 gene.

Human GLUT4 protein expression in muscle and adipose tissues of transgenic mice decreases plasma insulin and glucose levels and improves glucose tolerance compared with nontransgenic controls (Liu, M.-L., Gibbs, E. M., McCoid, S. C., Milici, A. J., Stukenbrok, H. A., McPherson, R. K., Treadway, J. L., and Pessin, J. E. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11346-11350). We examined the basis of improved glycemic control in hGLUT4 transgenic mice by determining glucose homeostasis and metabolic profiles in vivo. Glucose turnover experiments indicated a 1.4-fold greater systemic glucose clearance in hGLUT4 mice relative to controls (p < 0.05), whereas hepatic glucose production was similar despite 26% lower (p < 0.05) glucose levels. Glucose infusion rate during an euglycemic-hyperinsulinemic clamp was 2-fold greater (p < 0.05) in hGLUT4 mice versus controls, and skeletal muscle and heart glycogen content were increased 3-5-fold (p < 0.05). The increased peripheral glucose clearance in hGLUT4 mice was associated with increased (25-32%) basal and insulin-stimulated glucose transport rate in soleus muscle (p < 0.01), and increased muscle plasma membrane-associated GLUT4 protein. Fed hGLUT4 mice displayed 20-30% lower plasma glucose and insulin levels (p < 0.05) and 43% elevated glucagon levels (p < 0.001) compared with controls. Triglycerides, free fatty acids, and beta-hydroxy-butyrate were elevated 43-63% (p < 0.05) in hGLUT4 mice due to hypoinsulinemia-induced lipolysis. Free fatty acids and beta-hydroxybutyrate levels in hGLUT4 mice increased further upon fasting, and skeletal muscle glycogen levels decreased markedly compared with controls. The data demonstrate that high level expression of hGLUT4 increases systemic glucose clearance and muscle glucose utilization in vivo and also results in marked compensatory lipolysis and muscle glycogenolysis during a fast.

Kittens choose a high leucine diet even when isoleucine and valine are the limiting amino acids.

This study was conducted to determine the effect of excess leucine on the dietary choice of kittens. The basal diets contained 16% (low nitrogen) or 24% (adequate nitrogen) amino acids and were limiting in isoleucine and valine. The addition of leucine to either of these basal diets has been shown to cause a transitory adverse effect on the growth and food intake of kittens. In separate experiments each basal diet was used to test three sets of choices: basal vs. basal + 10% leucine; basal + alanine vs. basal + leucine (isonitrogenous) and basal vs. basal + alanine. When offered basal vs. basal + excess leucine, the kittens chose significantly more of the excess leucine diet regardless of the level of nitrogen in the basal diet. When offered an isonitrogenous choice of excess alanine vs. excess leucine, the kittens selected somewhat more of the excess leucine diets over the excess alanine diets; this selection was sustained longer in kittens fed low nitrogen. In the third choice experiment (basal vs. basal + alanine), the group offered the low nitrogen diets exhibited no preferences, and the group offered adequate-nitrogen diets selected significantly more of the excess alanine diet. These results for kittens are opposite to those for rats, a species that will select a low protein basal or even a protein-free diet over a diet containing excess leucine.

The vulnerability-stress model of schizophrenia: advances in psychosocial treatment.

Vulnerability models of schizophrenia are reviewed, along with psychosocial rehabilitation methods addressing functional abilities and social competence. Their relationship is discussed with a view to developing a framework in which biological and psychosocial approaches to schizophrenia can be integrated for purposes of effective clinical intervention. Such intervention is designed to improve social competence, cognitive appraisal, and coping skills for mediation of stress in vulnerable individuals.