Do Fructose-Containing Sugars Lead to Adverse Health Consequences? Results of Recent Systematic Reviews and Meta-analyses

Sugars have replaced fat as the dominant public health nutrition concern. A fructose-centric view of cardiometabolic disease has emerged whereby fructose-containing sugars are thought to have deleterious effects on body weight, fasting and postprandial blood lipids, glycemia, blood pressure, uric acid, and markers of nonalcoholic fatty liver disease. Long-term prospective cohort studies have not supported these associations when assessing the relation between total fructose-containing sugars at any amount of intake and incident cardiometabolic disease. Conversely, a consistent signal for harm has been reported for sugary beverages when comparing the highest with the lowest intakes. These associations, however, do not hold at moderate intakes, which are more reflective of real-world intakes, are subject to important collinearity effects, and have small risk estimates with modest population-attributable risk fractions. Higher-level evidence from controlled feeding trials shows that fructose-containing sugars in either liquid or solid form have adverse cardiometabolic effects only when they supplement diets with excess calories compared with the same diets without the excess calories. In the absence of harm when fructose-containing sugars are exchanged for other sources of carbohydrate under energy-matched conditions, excess calories appear to be the dominant consideration. Like with the earlier fat story, it is difficult to separate the contribution of fructose-containing sugars from that of other sources of excess calories in the epidemic of obesity and cardiometabolic disease. Attention needs to remain focused on reducing the overconsumption of all caloric foods associated with obesity and cardiometabolic disease, including sugary beverages and foods, and promoting greater physical activity.     

Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres

The selective 5-HT? receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5-HT? receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca2? transients. Pre-application of the 5-HT? antagonist GR 127935 or the selective 5-HT(1D) antagonist BRL 15572 prevented inhibition while the selective 5-HT(1B) antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT(1D) receptor subtype. Sumatriptan inhibition of the action potential evoked Ca2? signaling was mediated selectively through N-type Ca2? channels. Although the T-type Ca2? channel accounted for a greater proportion of the Ca2? signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca2? channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5-HT? receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.     

Biodegradable microspheres: polyacryl starch microparticles as a delivery system for the antileishmanial drug, sodium stibogluconate

Liver parasite burdens of Leishmania donovani in the mouse have been determined after treatment with intravenous administration of sodium stibogluconate in the free or carrier form. The carrier form, in which the drug was covalently bound to polyacryl starch microparticles, was up to 100x more effective than the free form in this murine model of visceral leishmaniasis. Empty microparticles had no effect on liver parasite burdens and the enhanced in-vivo antileishmanial activity of the carrier form of the drug was apparently due to passive drug delivery to the infected liver.     

The structure of alcohol dependence in the community

BACKGROUND: Although dependence on alcohol appears to be a reliable unitary construct, abuse has not found a similar level of support as a separate construct. This paper describes a confirmatory factor analysis of the DSM-IV alcohol abuse and dependence criteria in a general population sample. METHODS: Data from alcohol drinkers (n = 7746) were obtained from a cross-sectional study of a large, representative sample of the Australian general population. One- and two-factor solutions for the DSM-IV criteria for abuse and dependence (assessed by CIDI-Auto) were compared using confirmatory factor analysis. RESULTS: Approximately 74% of Australians had used alcohol 12 or more times in the past year and 19% met at least one DSM-IV alcohol abuse or dependence criterion. Overall 6% met criteria for an alcohol use disorder (1.9% abuse, 4.1% dependence). More men than women met criteria for an alcohol use disorder and the prevalence of alcohol use disorders decreased with increasing age. Both one- and two-factor solutions from the confirmatory factor analyses provided an adequate fit to the data for the overall sample. The correlation between the abuse and dependence factors in the two-factor model was extremely high (0.95). CONCLUSION: Alcohol abuse and dependence criteria were most parsimoniously described by a single continuous construct incorporating all eleven abuse and dependence criteria.     

Analysis of peptide mimotopes of Burkholderia pseudomallei exopolysaccharide

Previously two capsule-specific monoclonal antibodies (4VA5 and 3VIE5) were identified as protective against Burkholderia pseudomallei in passive transfer experiments. Panning these antibodies against evolutionary phage libraries identified reactive peptides capable of inhibiting its parent monoclonal from binding to B. pseudomallei. Mice immunized with peptide conjugated to thyroglobulin developed serum antibodies capable of recognizing the immunizing peptide of which a subset recognized exopolysaccharide in the context of whole B. pseudomallei cells. These serum antibodies recognized protease treated B. pseudomallei but not B. thailandensis suggesting that these peptides are mimotopes of the B. pseudomallei capsular exopolysaccharide. In a murine model of acute melioidosis, immunization with the mimotope of the 4VA5 binding site extended the mean time to death to 8.00 days over the 2.18 days afforded by immunization with thyroglobulin alone. This mimotope may be of use in developing an antibody response against B. pseudomallei exopolysaccharide.     

Metabolic activation of a pyrazinone-containing thrombin inhibitor. Evidence for novel biotransformation involving pyrazinone ring oxidation,rearrangement, and covalent binding to proteins

Compound I, (2-[3-[(2,2-difluoro-2(2-pyridyl)ethyl)amino]-6-methyl-2-oxohydropyrazinyl]-N-[(3-fluoro(2-pyridyl))methyl]acetamide, is a potent competitive inhibitor of thrombin that reacts stoichiometrically with the protease. Compounds of this class possess therapeutic potential as anticoagulation agents. During the metabolic characterization of compound I, evidence was obtained for extensive metabolic activation of the pyrazinone ring system. Following administration of (14)C-labeled I to rats, significant levels of irreversibly bound radioactivity to proteins were detected in rat plasma and liver. LC/MS/MS analysis of metabolites formed in rat and human liver microsomes fortified with glutathione (GSH) revealed the presence of two structurally distinct GSH adducts. It is proposed that the first of these GSH conjugates derives from a two electron oxidation of the 6-methyl-2-oxo-3-aminopyrazinone moiety to afford an electrophilic imine-methide intermediate, while the second is formed by addition of GSH to an epoxide formed by P-450-mediated oxidation of the double bond at the 5-6 position of the pyrazinone ring. The addition of GSH to the proposed epoxide facilitates opening of the pyrazinone ring and a rearrangement to afford a stable, rearranged imidazole-containing metabolite. Elucidation of the metabolic activation pathways of I provides structural guidance for the design of thrombin inhibitors with decreased potential for the generation of chemically reactive intermediates.     

Co-immunisation with a plasmid DNA cocktail primes mice against anthrax and plague

The protective antigen (PA) of Bacillus anthracis and the V antigen of Yersinia pestis are potent immunogens and candidate vaccine sub-units. When plasmid DNA encoding either PA or V antigen was used to immunise the Balb/c mouse, a low serum IgG titre was detected (log (10)1.0 or less) which was slightly increased by boosting with plasmid DNA. However, when mice immunised with plasmid DNA were later boosted with the respective recombinant protein, a significant increase in titre (up to 100-fold) was observed. Mice primed with a combination of each plasmid and boosted with a combination of the recombinant proteins, were fully protected (6/6) against challenge with Y. pestis. This compared favourably with mice primed only with plasmid DNA encoding the V antigen and boosted with rV, which were partially protected (3/6) against homologous challenge or with mice primed and boosted with plasmid DNA encoding the V antigen which were poorly protected (1/6). Combined immunisation with the two plasmid DNA constructs followed by boosting with a combination of the encoded recombinant proteins enhanced the protective immune response to Y. pestis compared with priming only with plasmid DNA encoding the V antigen and boosting with rV. This enhancement may be due to the effect of CpG motifs known to be present in the plasmid DNA construct encoding PA.     

Association of Preference-Based Health-Related Quality of Life with Weight Loss in Obese Adults

Background

The obesity epidemic is linked to substantial health care resource use, reduction in workforce and home productivity, and poor health-related quality of life (HRQOL). Changes in body mass index (BMI) are associated with improvements in HRQOL; the nature of this relationship, however, has not been reliably described.