Preparations for a European R&D roadmap for an inertial fusion demo reactor.

A European consortium of 15 laboratories across nine nations have worked together under the EUROFusion Enabling Research grants for the past decade with three principle objectives. These are: (a) investigating obstacles to ignition on megaJoule-class laser facilities; (b) investigating novel alternative approaches to ignition, including basic studies for fast ignition (both electron and ion-driven), auxiliary heating, shock ignition, etc.; and (c) developing technologies that will be required in the future for a fusion reactor. A brief overview of these activities, presented here, along with new calculations relates the concept of auxiliary heating of inertial fusion targets, and provides possible future directions of research and development for the updated European Roadmap that is due at the end of 2020. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

First Liquid Layer Inertial Confinement Fusion Implosions at the National Ignition Facility.

The first cryogenic deuterium and deuterium-tritium liquid layer implosions at the National Ignition Facility (NIF) demonstrate D_{2} and DT layer inertial confinement fusion (ICF) implosions that can access a low-to-moderate hot-spot convergence ratio (1230) DT ice layer implosions. Although high CR is desirable in an idealized 1D sense, it amplifies the deleterious effects of asymmetries. To date, these asymmetries prevented the achievement of ignition at the NIF and are the major cause of simulation-experiment disagreement. In the initial liquid layer experiments, high neutron yields were achieved with CRs of 12-17, and the hot-spot formation is well understood, demonstrated by a good agreement between the experimental data and the radiation hydrodynamic simulations. These initial experiments open a new NIF experimental capability that provides an opportunity to explore the relationship between hot-spot convergence ratio and the robustness of hot-spot formation during ICF implosions.

Indefinite loss: the experiences of carers of a spouse with cancer.

Cancer trajectories now follow a jagged path based on multiple probabilities. Thus, uncertainty now typifies cancer caregiving. What impact does uncertainty have on cancer carer grief? This article explores cancer carers' experiences of loss, based on qualitative interviews with 32 Australian carers of a spouse with cancer. Findings suggest that in addition to conventional and anticipatory grief, many carers experience indefinite loss. Indefinite loss characterised the experiences of spouses caregiving outside of the terminal stage. They experienced the current loss of a taken-for-granted certain future, but the future loss of their spouse remained uncertain. They described a heightened awareness of mortality, and an inability to plan for the future. Losses that are uncertain and potential are largely neglected within the grief literature. In this article, I offer the concept indefinite loss and extend health professionals' understanding of cancer carer loss.

A time-sovereignty approach to understanding carers of cancer patients' experiences and support preferences.

Much of the literature on informal carers of cancer patients is quantitative and psycho-oncology based. This literature has established that cancer carers experience higher rates of stress, depression and anxiety than their non-caregiving counterparts, with younger female carers reporting higher rates of burden and unmet needs. The reasons behind this variation and variations in support preferences are poorly understood: some carers prefer support groups and others prefer practical support. This study takes a sociological approach to exploring carers' varied experiences. Longitudinal interviews were conducted with 32 carers of a spouse with cancers of varying stages and diagnoses in the Australian Capital Territory. Analysis, informed by the discretionary time literature, shows time-sovereignty illuminates much of the variation in carers' emotional experiences and support preferences. Carers with few competing commitments and less onerous caregiving responsibilities had time to experience and unpack the range of emotions associated with cancer, and reconnect with their spouse. These carers preferred emotion-focused support. In contrast, carers with multiple commitments had little time to themselves and viewed emotions as an indulgence. These carers preferred practical support. A time-sovereignty framework offers health and support professionals a means of understanding carers' varying needs and tailoring support services.

Assembly of high-areal-density deuterium-tritium fuel from indirectly driven cryogenic implosions.

The National Ignition Facility has been used to compress deuterium-tritium to an average areal density of ~1.0±0.1 g cm(-2), which is 67% of the ignition requirement. These conditions were obtained using 192 laser beams with total energy of 1-1.6 MJ and peak power up to 420 TW to create a hohlraum drive with a shaped power profile, peaking at a soft x-ray radiation temperature of 275-300 eV. This pulse delivered a series of shocks that compressed a capsule containing cryogenic deuterium-tritium to a radius of 25-35 µm. Neutron images of the implosion were used to estimate a fuel density of 500-800 g cm(-3).

Observation of high soft x-ray drive in large-scale hohlraums at the National Ignition Facility.

The first soft x-ray radiation flux measurements from hohlraums using both a 96 and a 192 beam configuration at the National Ignition Facility have shown high x-ray conversion efficiencies of ∼85%-90%. These experiments employed gold vacuum hohlraums, 6.4 mm long and 3.55 mm in diameter, heated with laser energies between 150-635 kJ. The hohlraums reached radiation temperatures of up to 340 eV. These hohlraums for the first time reached coronal plasma conditions sufficient for two-electron processes and coronal heat conduction to be important for determining the radiation drive.

Triply differential single ionization of argon: charge effects for positron and electron impact.

Triply differential single ionization of Ar by 200 eV positron and electron impact is measured and calculated. For an unequivocal test of kinematic differences, fully differential ejected electron angular distributions are measured using the same experimental apparatus and conditions for both positron and electron impact. The binary/recoil intensity ratios are shown to significantly differ for the two projectiles. These data are used to test theoretical calculations.

Observation of persistent species temperature separation in inertial confinement fusion mixtures.

The injection and mixing of contaminant mass into the fuel in inertial confinement fusion (ICF) implosions is a primary factor preventing ignition. ICF experiments have recently achieved an alpha-heating regime, in which fusion self-heating is the dominant source of yield, by reducing the susceptibility of implosions to instabilities that inject this mass. We report the results of unique separated reactants implosion experiments studying pre-mixed contaminant as well as detailed high-resolution three-dimensional simulations that are in good agreement with experiments. At conditions relevant to mixing regions in high-yield implosions, we observe persistent chunks of contaminant that do not achieve thermal equilibrium with the fuel throughout the burn phase. The assumption of thermal equilibrium is made in nearly all computational ICF modeling and methods used to infer levels of contaminant from experiments. We estimate that these methods may underestimate the amount of contaminant by a factor of two or more.

Monosodium glutamate: feeding of large amounts in man and gerbils.

Oral administration of large amounts of glutamic acid to adult humans and animals in a formula diet appeared to cause no clinical pathological changes. The only biochemically demonstrable effect was a decrease in serum cholesterol and associated beta lipoproteins.

The role of multiple ionization of H2O in heavy ion collisions.

Collisional ionization processes involving H2O molecules and C6+, O8+, Si13+ ions are studied by means of the classical trajectory Monte Carlo method using molecular orbital calculations to define the ionization stages of the water molecule. Net total and single-differential cross sections in energy and angle are obtained by using a newly developed model that goes beyond the commonly applied one-active electron approximation. This model allows us to access the fraction of electron emission arising from single and multiple electron ionization. Calculated cross sections are contrasted and benchmarked against available experimental data at impact energies in the MeV/u range. The present results highlight the important role of multiple ionization in the emission of electrons where we find the majority of electrons emitted with energies greater than ~50 eV arise from multiple ionization collisions.

Effects of dietary cholesterol and fatty acids on plasma lipoproteins.

The effects of dietary cholesterol and fatty acids on low density and high density lipoproteins (LDL and HDL) were studied in 20 young men. After 2-3 wk of evaluations on ad lib. diets, basal diets, which consisted of 15% protein, 45% carbohydrates, 40% fat, and 300 mg/day of cholesterol, were given for 4-5 wk (Basal). The ratio of dietary polyunsaturated to saturated fatty acids (P/S) for different groups of subjects were 0.25, 0.4, 0.8, or 2.5. 750 and 1,500 mg/d of cholesterol were added to the basal diets as 3 and 6 eggs, respectively. Total cholesterol and LDL cholesterol were lower in all subjects on the basal diets than on the ad lib. diets. Addition of 750 mg cholesterol to the diet with P/S = 0.25-0.4 raised LDL cholesterol by 16 +/- 14 mg/dl to 115% of basal diet values (n = 11, P less than 0.01); 1,500 mg increased LDL cholesterol by 25 +/- 19 mg/dl to 125% (n = 9, P less than 0.01). On the diet with P/S = 0.8, 750 mg produced insignificant increases in LDL cholesterol, but 1,500 mg produced increases of 17 +/- 22 mg/dl to 115% of basal (n = 6, P less than 0.02). On the P/S = 2.5 diet, neither 750 nor 1,500 mg produced significant changes. Thus, both the cholesterol contents and P/S ratios of diets were important in determining LDL levels. The lipid and apoprotein compositions, flotation rates, molecular weights, and binding by cellular receptors of LDL were virtually unchanged by the addition of cholesterol to the diets high in saturated fat. These diets, therefore, caused an increase in the number of LDL particles of virtually unchanged physical and biological properties. On the diet with low P/S ratio, HDL2 rose, whereas this effect was absent on diets with high P/S ratios. The response of LDL to dietary manipulations is consonant with epidemiologic data relating diets high in cholesterol and saturated fat to atherogenesis. The response of HDL2, however, is opposite to that of its putative role as a negative risk factor. Further work is needed to clarify this interesting paradox.

Localization of the menaquinone-0 alkylating enzyme in the smooth reticulum of chicken liver microsomes.

The alkylation of menaquinone-0 to menaquinones occurs in the microsomal fraction of chick and rat liver. Subfractionation of chick microsomes into smooth and rough reticulum was achieved by density gradient centrifugation. The alkylation enzyme was localized in the smooth reticulum with an activity of 155 pmol/mg per h, about 50-fold greater than that in the rough reticulum. The membrane-bound alkylating enzyme system requires reduced menaquinone-0 and is phospholipid-dependent.

A critique of the report of the National Institutes of Health Expert Panel on detection, evaluation, and treatment of high blood cholesterol.

In summary, I think the National Cholesterol Education Program could be strengthened if more realistic values for normal and abnormal serum cholesterol levels were adopted, if lipoprotein typing were recommended as an early step in the screening process, if modification of other risk factors were attempted, and if intervention with diet were avoided for persons without other risk factors whose cholesterol levels are below 6.21 mmol/L. A more flexible program of diet therapy should be offered to those persons with serum cholesterol values over 6.21 mmol/L, which should include not only the "prudent diet" but also other dietary regimens with proven benefits. All physicians should make an attempt to carry out this program of preventive cardiology as a long-term clinical investigation to determine the extent to which modification of serum lipid levels in large outpatient populations influences the prognosis for CHD.

Aspartame use by persons with diabetes.

Sixty-two subjects having either insulin-dependent or non-insulin-dependent diabetes completed a randomized, double-blind study comparing effects of aspartame or a placebo on blood glucose control. Twenty-nine subjects consumed 2.7 g aspartame per day for 18 wk, given as aspartame-containing capsules with meals, while 33 subjects took identical appearing placebo capsules. After 18 wk, no changes were seen in fasting or 2-h postprandial blood glucose levels or glycohemoglobin levels in either the aspartame- or placebo-treated groups. Adverse reactions were no more common in the group taking aspartame. We conclude that use of aspartame as a low-calorie sweetener does not adversely affect glycemic control of persons with diabetes.

Introductory remarks: nutrient, hormone, enzyme interactions.

Homeostasis of the internal environment in mammals is accomplished by a series of feedback mechanisms in a variety of tissues. Homeostasis of cell structure and function during marked changes in the environment is equally important. Both types of homeostasis are dependent on adjustments in endocrine function and changes in enzyme activity. In some instances the intracellular servomechanisms required for homeostasis match in vigor and range the perturbations of the external environment. The regulation of cell metabolism is accomplished by enzymatic, membranous and genetic mechanisms. Most peptide hormones act by combining with a specific receptor in the membrane of sensitive cells, which activates adenyl cyclase to produce cyclic AMP which in turn has selective second messenger functions. Insulin and somatotropin appear to be exceptions and may act via cyclic GMP. Steroid hormones, on the other hand, pass through the cell membrane and combine with a specific receptor protein in the cytoplasm of sensitive cells. This receptor then serves as a transport system for movement of the hormone to the nucleus where it stimulates specific protein synthesis. Nutritional effects on enzyme synthesis are partially direct and partially mediated by the endocrine system. Trace nutrients, especially the fat-soluble vitamins, appear to act directly to modify specific protein syntheses, whereas the bulkier constituents of the diet (carbohydrate, fat protein) exert their effects principally through altered rates of secretion of insulin, glucagon, and the glucocortioids. Protein-calorie malnutrition is the result of a massive assault on homeostatic and adaptive mechanisms designed to conserve nutrients and preserve life. The pathogenesis of marasmus and kwashiorkor is discussed in the light of these adaptive mechanisms.

Defective local leukocyte mobilization in children with kwashiorkor.

The Rebuck window technique was used to determine the functional integrity of the inflammatory response in nine children with kwashiorkor. The total numbers of leukocytes mobilized into skin abrasions were similar between kwashiorkor and control patients. However, children with kwashiorkor showed significantly delayed and decreased macrophage migration and increased polymorphonuclear leukocyte migration. These defects of leukocyte mobilization were corrected with nutritional repair.

Changes in the red blood cell membrane in protein-calorie malnutrition.

Ten children with protein-calorie malnutrition (five with kwashiorkor, three with marasmus, and two with marasmic-kwashiorkor) were studied at hospital admission and during recovery for evidence of changes in red blood cell lipids, osmotic fragility, and chromium survival. On admission, the children had significantly higher-than-normal red blood cell membrane cholesterol and phospholipid, and an elevated cholesterol:phospholipid ratio. Both red blood cell osmotic fragility and red cell survivals were depressed. These measurements returned to normal limits with recovery.

Plasma vitamin A, retinol-binding protein and prealbumin concentrations in protein-calorie malnutrition. III. Response to varying dietary treatments.

Plasma vitamin A, retinol-binding protein, and prealbumin concentrations have been studied in 38 northern Thai children with protein-calorie malnutrition (PCM). The 4-week study period consisted of 1 week of stabilization followed by 3 weeks of treatment with formula diets varying in their protein and calorie content. The stabilization period comprised 7 days of initial treatment with fluids, antibiotics, and a gradually increasing intake of protein and calories to a final level of 1 g protein and 100 kcal/kg of body weight. During this period vitamin A, retinol-binding protein and prealbumin levels all showed significant increases compared to admission values, whereas plasma albumin and total protein did not change. During the subsequent 3 weeks, the effects of four different dietary regimens, with daily calorie and protein intakes of 100 or 175 kcal/kg and 1 or 4 g/kg, respectively, were studied. Significant increases in plasma total protein concentration were seen in each of the four test groups, and increases in plasma albumin and prealbumin were also seen in three of the four test groups, and increases in plasma albumin and prealbumin were also seen in three of the four test groups (all but the 175 kcal-1 g protein group). Significant increases in plasma vitamin A levels were not seen in any of the groups. The higher protein regimens (4 g/kg per day) resulted in much greater increases in plasma albumin and total protein levels than did the lower protein regimens. No significant differences in the changes in retinol-binding protein or vitamin A levels were apparent between the test groups. Sixteen additional children with both clinical vitamin A deficiency and protein-calorie malnutrition showed significant increases in total plasma vitamin A concentrations 24 hours after the intramuscular injection of 100,000 IU water-miscible vitamin A palmitate, without a change in plasma retinol-binding protein concentrations. These studies demonstrate that plasma retinol-binding protein and prealbumin concentrations are more rapidly responsive and sensitive to dietary protein intake than is plasma albumin concentration. Furthermore, the absence of a 24-hour rise in plasma retinol-binding protein after parenteral vitamin A provides further evidence that hepatic retinol-binding protein synthesis is impaired in protein-calorie malnutrition.

Immunoglobulins and antibody response in children with protein-calorie malnutrition.

The immunoglobulin levels (IgG, IgA, IgM, IgD, and IgE) were studied in 28 Northern Thai children with protein-calorie malnutrition (PCM). Of these 14 had marasmus, 7 had marasmus-kwashiorkor, and 7 had kwashiorkor. The immunoglobulin levels were measured on admission and serially during 12 weeks of treatment leading to recovery. All immunoglobulin fractions either equalled or exceeded levels seen in well-nourished urban and rural Thai children, with or without infection. There was no difference in levels of IgG, IgM, IgA, or IgD in children with marasmus when compared with those who had marasmus-kwashiokor or kwashiorkor. IgA levels were higher in malnourished than control children and returned to normal with treatment. Eighty percent of the children with PCM had detectable IgD levels while 64% had detectable IgE levels as compared to none in the control groups. Ten additional children admitted with PCM and 10 who had recovered from PCM were immunized with intradermal typhoid antigen. Within 8 days a significant increase in typhoid H antibody appeared in the recovered group, while the malnourished group demonstrated no significant increase in H antibody titer.

Progress towards testing the amyloid hypothesis: inhibitors of APP processing.

Alzheimer's disease is the most common form of dementia and a major public health problem. The amyloid hypothesis suggests that Alzheimer's disease is due to the abnormal accumulation of amyloid-beta protein (A beta) in affected brain regions. Rational therapies aimed at reducing amyloid burden in brain are currently being pursued in preclinical and early clinical development. This review summarizes recent progress in understanding the beta- and gamma-secretase activities required for the formation of A beta peptide and discusses therapeutic strategies aimed at inhibiting these activities. Recent progress in the identification of small molecule inhibitors of these secretases is also reviewed.