Skeletal muscle reactive oxygen species: a target of good cop/bad cop for exercise and disease

Metabolic stresses associated with disease, ageing, and exercise increase the levels of reactive oxygen species (ROS) in skeletal muscle. These ROS have been linked mechanistically to adaptations in skeletal muscle that can be favourable (i.e. in response to exercise) or detrimental (i.e. in response to disease). The magnitude, duration (acute versus chronic), and cellular origin of the ROS are important underlying factors in determining the metabolic perturbations associated with the ROS produced in skeletal muscle. In particular, insulin resistance has been linked to excess ROS production in skeletal muscle mitochondria. A chronic excess of mitochondrial ROS can impair normal insulin signalling pathways and glucose disposal in skeletal muscle. In contrast, ROS produced in skeletal muscle in response to exercise has been linked to beneficial metabolic adaptations including mitochondrial biogenesis and muscle hypertrophy. Moreover, unlike insulin resistance, exercise-induced ROS appears to be primarily of non-mitochondrial origin. The present review summarizes the diverse ROS-targeted metabolic outcomes associated with insulin resistance versus exercise in skeletal muscle, thus, presenting two contrasting perspectives of pathologically harmful versus physiologically beneficial ROS. Here, we discuss the key sites of ROS production during exercise and the effect of ROS in skeletal muscle of people with type 2 diabetes.

A telephone support program to reduce costs and hospital admissions for patients at risk of readmissions: lessons from an evaluation of a complex health intervention

This study aimed to evaluate the effectiveness of a telephone health coaching and support service provided to members of an Australian private health insurance fund-Telephonic Complex Care Program (TCCP)-on hospital use and associated costs. A case-control pre-post study design was employed using propensity score matching. Private health insurance members (n=273) who participated in TCCP between April and December 2012 (cases) were matched (1:1) to members who had not previously been enrolled in the program or any other disease management programs offered by the insurer (n=232). Eligible members were community dwelling, aged ≥65 years, and had 2 or more hospital admissions in the 12 months prior to program enrollment. Preprogram variables that estimated the propensity score included: participant demographics, diagnoses, and hospital use in the 12 months prior to program enrollment. TCCP participants received one-to-one telephone support, personalized care plan, and referral to community-based services. Control participants continued to access usual health care services. Primary outcomes were number of hospital admission claims and total benefits paid for all health care utilizations in the 12 months following program enrollment. Secondary outcomes included change in total benefits paid, hospital benefits paid, ancillary benefits paid, and total hospital bed days over the 12 months post enrollment. Compared with matched controls, TCCP did not appear to reduce health care utilization or benefits paid in the 12 months following program enrollment. However, program characteristics and implementation may have impacted its effectiveness. In addition, challenges related to evaluating complex health interventions such as TCCP are discussed.

Regulators of mitochondrial complex I activity: a review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.

Blaming the target of sexual harrassment: impact of gender role, sexist attitudes and work role.

This study was conducted to examine factors associated with blaming the target of sexual harassment. Participants' experiences of sexual harassment, sexist attitudes, gender, gender role identity, age, worker or student status, and belief in a just world were included as independent variables. Level of blame was evaluated using a series of 12 vignettes that manipulated the gender of the target and harasser as well as the seriousness of the harassing behavior. The sample comprised 30 female and 32 male workers from two workplaces, whose ages ranged from 18 to 65 (M = 35) years, and 102 female and 18 male university students whose ages ranged from 17 to 40 (M = 21) years. Approximately 70% of the sample were from Anglo Australian background, and 30% from European, Middle Eastern or Asian background. Females experienced more sexual harassment than males did, although the male rate was higher than expected. Although the majority of subjects attributed little blame to the target, males blamed the target of sexual harassment more than females did, and workers blamed the target of harassment more than university students did. Worker status, sexist attitudes, and gender significantly predicted blame for the total sample. Gender-typing increased the blame of the target by males but not by females. Attribution of blame was significantly influenced by worker versus student status, which supports the social psychological perspective that gender-related behavior is context dependent. The findings from this study suggest that organisational culture and environment influence respondents' attitudes to sexually harassing behavior.

Plasma phospholipid and dietary fatty acids as predictors of type 2 diabetes: interpreting the role of linoleic acid 1-3

Background: Dietary fatty acids may be associated with diabetes but are difficult to measure accurately.

Objective: We aimed to investigate the associations of fatty acids in plasma and diet with diabetes incidence.

Design: This was a prospective case-cohort study of 3737 adults aged 36-72 y. Fatty acid intake (/kJ) and plasma phospholipid fatty acids (%) were measured at baseline, and diabetes incidence was assessed by self-report 4 y later. Logistic regression excluding (model 1) and including (model 2) body mass index and waist-hip ratio was used to calculate odds ratios (ORs) for plasma phospholipid and dietary fatty acids.

Results: In plasma phospholipid, positive associations with diabetes were seen for stearic acid [OR model 1, highest versus lowest quintile: 4.14 (95% CI: 2.65, 6.49), P for trend < 0.0001] and total saturated fatty acids [OR model 1: 3.76 (2.43, 5.81), P for trend < 0.0001], whereas an inverse association was seen for linoleic acid [OR model 1: 0.22 (0.14, 0.36), P for trend < 0.0001]. Dietary linoleic [OR model 1: 1.77 (1.19, 2.64), P for trend = 0.002], palmitic [OR model 1: 1.65 (1.12, 2.43), P for trend = 0.012], and stearic [OR model 1: 1.46 (1.00, 2.14), P for trend = 0.030] acids were positively associated with diabetes incidence before adjustment for body size. Within each quintile of linoleic acid intake, cases had lower baseline plasma phospholipid linoleic acid proportions than did controls.

Conclusions: Dietary saturated fat intake is inversely associated with diabetes risk. More research is required to determine whether linoleic acid is an appropriate dietary substitute.

The occurrence of trans-18:1 isomers in plasma lipids classes in humans

Objective: The aim of this study was to examine the distribution of trans fatty acids (TFA) in plasma lipid classes and the relationship with dietary intake of TFA.

Design: After a 2 week baseline (habitual) diet, all subjects consumed a moderate fat (MF) diet for 3 weeks with the fat being derived mainly from margarine and the rest from lean beef, and then a very low fat (VLF) diet for 3 weeks with the TFA being derived only from the lean beef. Blood samples were collected 2 days prior to the end and also on the last day of each dietary period.

Setting: Deakin Institute of Human Nutrition, Deakin University, Geelong, Australia.

Subjects: Ten free-living mildly hypercholesterolaemic subjects aged 22-66 were recruited in Geelong.

Outcome measures: TFA intake was calculated from analyses of Australian margarines, butter, lean meat and animal fat. The TFA in plasma lipid fractions were separated by AgNO3 thin-layer chromatography and quantitated by capillary gas-liquid chromatography using internal standards.

Results: The phospholipid (PL) fraction contained more than 60% of the trans-18:1 isomers in the plasma lipids in all subjects. On the baseline diet, the predominant positional isomer of trans-18:1 in PL was Delta11, whereas in the other lipid classes it was the Delta9 isomer. The concentration of the Delta9 isomer increased on the MF diet, particularly in the PL fraction, while the concentration of the Delta11 isomer decreased in all fractions. On the VLF diet, the total TFA level decreased by approximately 50%, mainly due to decreases in the TFA isomers in the PL and TG fractions. Changes in plasma total and PL TFA, PL Delta9, Delta10 and Delta11 were strongly correlated with dietary TFA intake (P<0.0001). There were also significant association between dietary TFA intake and PL Delta12 (P=0.003), triacylglycerol Delta9 (P=0.009), Delta11 (P=0.0005), total triacylglycerol (P=0.023) and free fatty acid TFA (P=0.042).

Conclusions: The results suggest that the measurement of trans-18:1 in plasma PL and TAG, and plasma total TFA could be used to estimate the intake of TFA.

Source of Bet v 1 loaded inhalable particles from birch revealed

Allergenic proteins present in pollen grains, when inhaled, interact with the airways to cause an attack of asthma in susceptible humans. In one system, grass pollen grains rupture osmotically in rainfall, releasing allergen-containing inhalable particles into the atmosphere. In contrast, birch tree pollen grains do not rupture under these conditions, yet the major allergen, Bet v 1, has been detected in the atmosphere in inhalable particles of unknown origin. It is possible that Bet v 1 may diffuse from intact settled pollen grains and the allergenic material may again become airborne, interacting with settled fine particles from other sources prior to resuspension. This study investigates the mechanism for the release of birch pollen allergen-containing inhalable particles from pollen grains. We propose the hypothesis that (1) airborne birch pollen grains settle on nearby leaf surfaces; (2) then, following light rainfall, the grains germinate and, (3) later, pollen tubes burst, releasing inhalable particles carrying Bet v 1 into the atmospheric aerosol.   We used microscopic analyses of pollen behaviour following anther opening, a Burkard volumetric trap for pollen counts and a high volume air sampler with a two-stage cascade impactor for quantitative immunochemical analyses of Bet v 1. On dry days of high birch pollen count (48 grains/m3, 1.5 ng/m3 of Bet v 1), we found that the surfaces of birch leaves became coated with pollen. This ”pollen rain” is a source of secondary emission of allergens into the atmosphere. We observed that following light rainfall (<1 mm per day), about 80% of the birch pollen grains germinated, producing pollen tubes, especially in the sticky surface secretions of leaf glands. These pollen tubes may grow up to 300 μm in length prior to rupturing, each releasing about 400 starch granules coated with allergen molecules that may, after drying, be dispersed into the aerosol. On these days following light rainfall, the highest atmospheric levels of Bet v 1 (1.18 ng/m3) are associated with inhalable particles. Following heavy rainfall, both pollen and inhalable particles are washed from the atmosphere. Immunoprinting studies show that Bet v 1 is associated with starch granules rather than the smaller orbicules. Bet v 1 is present in the atmosphere in large particles, i.e. in particular pollen grains and in inhalable particles, i.e. in particular starch granules.

Alteration of the proline at position 7 of the HIV-1 spacer peptide p1 suppresses viral infectivity in a strain dependent manner

The HIV-1 spacer peptide p1 is located in the C-terminus of the Gag polyprotein and separates the nucleocapsid (NC) and p6(Gag). Research centered on p1 has been limited and as yet no function has been ascribed to this spacer peptide. We have previously found that the conserved p1 proline residues (position 7 and 13) are critical for replication in the HIV-1 strain HXB2-BH10. In this study we have focused on the proline rich p1-p6(Gag) C-terminus of HIV-1. We individually examined the role of p1 proline's in multiple strains of HIV-1 and investigated the role of three proline residues in p6(Gag) (P24, P25 and P30). Assessment of the HXB2-BH10 based mutants revealed that Gag-Pol incorporation relative to Gag decreased in the p1 mutant virions, with the double proline mutant the most impaired. Mutating both p1 proline residues was found to abolish infectivity in multiple strains of HIV-1. Independent mutation of the p1 proline at position 7 resulted in a strain-dependent suppression of viral infectivity. This defect correlates with the presence of a tyrosine residue at position 9 of p1 and occurs in the early phase of the HIV-1 replication cycle. The p1 proline residues were found to be functionally distinct from P24, P25 and P30 in p6(Gag). This work affords novel insights into our understanding of the role of p1 in HIV-1 replication.

The packaging and maturation of the HIV-1 Pol proteins

The Pol protein of human immunodeficiency virus type 1 (HIV-1) harbours the viral enzymes critical for viral replication; protease (PR), reverse transcriptase (RT), and integrase (IN). PR, RT and IN are not functional in their monomeric forms and must come together as either dimers (PR), heterodimers (RT) or tetramers (IN) to be catalytically active. Our knowledge of the tertiary structures of the functional enzymes is well advanced, and substantial progress has recently been made towards understanding the precise steps leading from Pol protein synthesis through viral assembly to the release of active viral enzymes. This review will summarise our current understanding of how the Pol proteins, which are initially expressed as a Gag-Pol fusion product, are packaged into the assembling virion and discuss the maturation process that results in the release of the viral enzymes in their active forms. Our discussion will focus on the relationship between structure and function for each of the viral enzymes. This review will also provide an overview of the current status of inhibitors against the HIV-1 Pol proteins. Effective inhibitors of PR and RT are well established and we will discuss the next generation inhibitors of these enzymes as well recent investigations that have highlighted the potential of IN and RNase H as antiretroviral targets.