Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease

Objectives In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. Methods 20 patients with NAFLD (mean±SD body mass index (BMI) 34.1±6.7 kg/m2) and 15 healthy controls (BMI 23.4±2.7 kg/m2) were assessed. Respiratory quotient (RQ), whole-body fat (Fatox) and carbohydrate (CHOox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic–euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fatox). Severity of disease and steatosis were determined by liver histology, hepatic Fatox from plasma β-hydroxybutyrate concentrations, aerobic fitness expressed as , and visceral adipose tissue (VAT) measured by computed tomography. Results Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fatox to energy expenditure) in patients with NAFLD activity score (NAS) ≥5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fatox (1.2±0.3 vs 1.5±0.4 mg/kgFFM/min, p=0.024) and lower basal hepatic Fatox (ie, β-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fatox (2.5±1.4 vs. 5.8±3.7 mg/kgFFM/min, p=0.002) and lower (p<0.001) than controls. Fatox during exercise was not associated with disease severity (p=0.79). Conclusions Overweight/obese patients with NAFLD had reduced hepatic Fatox and reduced whole-body Fatox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS

Akt, AS160, metabolic risk factors and aerobic fitness in middle-aged women

Aims: This study investigated the association between the basal (rest) insulin-signaling proteins, Akt, and the Akt substrate AS160, metabolic risk factors, inflammatory markers and aerobic fitness, in middle-aged women with varying numbers of metabolic risk factors for type 2 diabetes. Methods: Sixteen women (n = 16) aged 51.3+/-5.1 (mean +/-SD) years provided muscle biopsies and blood samples at rest. In addition, anthropometric characteristics and aerobic power were assessed and the number of metabolic risk factors for each participant was determined (IDF criteria). Results: The mean number of metabolic risk factors was 1.6+/-1.2. Total Akt was negatively correlated with IL-1 beta (r = -0.45, p = 0.046), IL-6 (r = -0.44, p = 0.052) and TNF-alpha (r = -0.51, p = 0.025). Phosphorylated AS160 was positively correlated with HDL (r = 0.58, p = 0.024) and aerobic fitness (r = 0.51, p = 0.047). Furthermore, a multiple regression analysis revealed that both HDL (t = 2.5, p = 0.032) and VO(2peak) (t = 2.4, p = 0.037) were better predictors for phosphorylated AS160 than TNF-alpha or IL-6 (p>0.05). Conclusions: Elevated inflammatory markers and increased metabolic risk factors may inhibit insulin-signaling protein phosphorylation in middle-aged women, thereby increasing insulin resistance under basal conditions. Furthermore, higher HDL and fitness levels are associated with an increased AS160 phosphorylation, which may in turn reduce insulin resistance.

A dual-polarized microstrip antenna array with port decoupling for MIMO systems

Utilization of multiport-antennas represents an appropriate way for the mitigation of multi-path fading in wireless communication systems. However, to obtain low correlation between the signals from different antenna ports and to prevent gain reduction by cross-talk, large antenna elements spacing is expected. Polarization diversity allows signal separation even with small antenna spacing. Although it is effective, polarization diversity alone does not suffice once the number of antennas exceeds the number of orthogonal polarizations. This paper presents an approach which combines a novel array concept with the use of dual polarization. The theory is verified by a compact dual polarized patch antenna array, which consists of four elements and a decoupling network.

The psychometric properties of the Spanish version of the Foot Health Status Questionnaire

Purpose: Clinical studies suggest that foot pain may be problematic in one-third of patients in early disease. The Foot Health Status Questionnaire (FHSQ) was developed and validated to evaluate the effectiveness of conservative (orthoses, taping, stretching) and surgery interventions. Despite this fact, there are few validated instruments that measure foot health status in Spanish. Thus, the primary aim of the current study was to translate and evaluate psychometrically a Spanish version of FHSQ. Methods: A cross-sectional study was designed in a university community-based podiatric clinic located in south of Spain. All participants (n = 107) recruited consecutively completed a Spanish version of FHSQ and EuroQoL Health Questionnaire 5 dimensions, and 29 participants repeated these same measures 48 h later. Data analysis included test–retest reliability, construct and criterion-related validity and factor analyses. Results: Construct validity was appropriate with moderate-to-high corrected item–subscale correlations (α = ≥0.739) for all subscales. Test–retest reliability was satisfactory (ICC > 0.932). Factor analysis revealed four dimensions with 86.6 % of the common variance explained. The confirmatory factor analysis findings demonstrated that the proposed structure was well supported (comparative fit index = 0.92, standardized root mean square = 0.09). The Spanish EuroQoL 5D score negatively correlated with the FHSQ pain (r = −0.445) and positively with general foot health and function (r = 0.261 − 0.579), confirming criterion-related validity. Conclusion: The clinimetric properties of the Spanish version of FHSQ were satisfactory.

Retinal and choroidal thickness in myopic anisometropia

PURPOSE: To examine the foveal retinal thickness (RT) and subfoveal choroidal thickness (ChT) between the fellow eyes of myopic anisometropes. METHODS: Twenty-two young (mean age 23 ± 5 years), healthy myopic anisometropes (≥ 1 D spherical equivalent [SEq] anisometropia) without amblyopia or strabismus were recruited. Spectral domain optical coherence tomography (SD-OCT) was used to capture images of the retina and choroid. Customised software was used to register, align and average multiple foveal OCT B-Scan images from each subject in order to enhance image quality. Two independent masked observers then manually determined the RT and ChT at the centre of the fovea from each SD-OCT image, which were then averaged. Axial length was measured using optical low coherence biometry during relaxed accommodation. RESULTS: The mean absolute SEq anisometropia was 1.74 ± 0.95 D and the mean interocular difference in axial length was 0.58 ± 0.41 mm. There was a strong correlation between SEq anisometropia and the interocular difference in axial length (r = 0.90, p < 0.001). Measures of RT and ChT were highly correlated between the two observers (r = 0.99 and 0.97 respectively) and in close agreement (mean inter-observer difference: RT 1.3 ± 2.2 µm, ChT 1.5 ± 13.7 µm). There was no significant difference in RT between the more (218 ± 18 µm) and less myopic eyes (215 ± 18 µm) (p > 0.05). However, the mean subfoveal ChT was significantly thinner in the more myopic eye (252 ± 46 µm) compared to the fellow, less myopic eye (286 ± 58 µm) (p < 0.001). There was a moderate correlation between the interocular difference in ChT and the interocular difference in axial length (r = -0.50, p < 0.01). CONCLUSIONS: Foveal RT was similar between the fellow eyes of myopic anisometropes; however, the subfoveal choroid was significantly thinner in the more myopic (longer) eye of our anisometropic cohort. The interocular difference in ChT correlated with the magnitude of axial anisometropia.

The effect of exercise on sleep quality in heart failure

Purpose The primary objective of this study was to examine the effect of exercise on subjective sleep quality in heart failure patients. Methods This study used a randomised, controlled trial design with blinded end-point analysis. Participants were randomly assigned to a 12-week programme of education and self-management support (control) or to the same programme with the addition of a tailored physical activity programme designed and supervised by an exercise specialist (intervention). The intervention consisted of 1 hour of aerobic and resistance exercise twice a week. Participants included 108 patients referred to three hospital heart failure services in Queensland, Australia. Results Patients who participated in supervised exercise classes showed significant improvement in subjective sleep quality, sleep latency, sleep disturbance and global sleep quality scores after 12 weeks of supervised hospital based exercise. Secondary analysis showed that improvements in sleep quality were correlated with improvements in geriatric depression score (p=0.00) and exercise performance (p=0.03). General linear models were used to examine whether the changes in sleep quality following intervention occurred independently of changes in depression, exercise performance and weight. Separate models adjusting for each covariate were performed. Results suggest that exercise significantly improved sleep quality independent of changes in depression, exercise performance and weight. Conclusion This study supports the hypothesis that a 12 week program of aerobic and resistance exercise improves subjective sleep quality in patients with heart failure. This is the first randomised controlled trial to examine the role of exercise in the improvement of sleep quality for patients with this disease. While this study establishes exercise as a therapy for poor sleep quality, further research is needed to investigate exercise as a treatment for other parameters of sleep in this population. Study investigators plan to undertake a more in-depth examination within the next 12 months

Food consumption of Sri Lankan adults : an appraisal of serving characteristics

Objective The main aim of the present study was to identify food consumption in Sri Lankan adults based on serving characteristics. Design Cross-sectional study. Fruits, vegetables, starch, meat, pulses, dairy products and added sugars in the diet were assessed with portion sizes estimated using standard methods. Setting Twelve randomly selected clusters from the Sri Lanka Diabetes and Cardiovascular Study. Subjects Six hundred non-institutionalized adults. Results The daily intake of fruit (0·43), vegetable (1·73) and dairy (0·39) portions were well below national recommendations. Only 3·5 % of adults consumed the recommended 5 portions of fruits and vegetables/d; over a third of the population consumed no dairy products and fewer than 1 % of adults consumed 2 portions/d. In contrast, Sri Lankan adults consumed over 14 portions of starch and 3·5 portions of added sugars daily. Almost 70 % of those studied exceeded the upper limit of the recommendations for starch intake. The total daily number of meat and pulse portions was 2·78. Conclusions Dietary guidelines emphasize the importance of a balanced and varied diet; however, a substantial proportion of the Sri Lankan population studied failed to achieve such a recommendation. Nutrition-related diseases in the country may be closely correlated with unhealthy eating habits.

Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand

Overexpression of the receptor tyrosine kinase EphB4 is common in epithelial cancers and linked to tumor progression by promoting angiogenesis, increasing survival and facilitating invasion and migration. However, other studies have reported loss of EphB4 suggesting a tumor suppressor function in some cancers. These opposing roles may be regulated by (i) the presence of the primary ligand ephrin-B2 that regulates pathways involved in tumor suppression or (ii) the absence of ephrin-B2 that allows EphB4 signaling via ligand-independent pathways that contribute to tumor promotion. To explore this theory, EphB4 was overexpressed in the prostate cancer cell line 22Rv1 and the mammary epithelial cell line MCF-10A. Overexpressed EphB4 localized to lipid-rich regions of the plasma membrane and confirmed to be ligand-responsive as demonstrated by increased phosphorylation of ERK1/2 and internalization. EphB4 overexpressing cells demonstrated enhanced anchorage-independent growth, migration and invasion, all characteristics associated with an aggressive phenotype, and therefore supporting the hypothesis that overexpressed EphB4 facilitates tumor promotion. Importantly, these effects were reversed in the presence of ephrin-B2 which led to a reduction in EphB4 protein levels, demonstrating that ligand-dependent signaling is tumor suppressive. Furthermore, extended ligand stimulation caused a significant decrease in proliferation that correlated with a rise in caspase-3/7 and -8 activities. Together, these results demonstrate that overexpression of EphB4 confers a transformed phenotype in the case of MCF-10A cells and an increased metastatic phenotype in the case of 22Rv1 cancer cells and that both phenotypes can be restrained by stimulation with ephrin-B2, in part by reducing EphB4 levels.

Expression of PTRF in PC3 cells modulates cholesterol dynamics and the actin cytoskeleton impacting secretion pathways

Expression of caveolin-1 is up-regulated in prostate cancer metastasis and is associated with aggressive recurrence of the disease. Intriguingly, caveolin-1 is also secreted from prostate cancer cell lines and has been identified in secreted prostasomes. Caveolin-1 is the major structural component of the plasma membrane invaginations called caveolae. Co-expression of the coat protein Polymerase I and transcript release factor (PTRF) is required for caveolae formation. We recently found that expression of caveolin-1 in the aggressive prostate cancer cell line PC-3 is not accompanied by PTRF, leading to noncaveolar caveolin-1 lipid rafts. Moreover, ectopic expression of PTRF in PC-3 cells sequesters caveolin-1 into caveolae. Here we quantitatively analyzed the effect of PTRF expression on the PC-3 proteome using stable isotope labeling by amino acids in culture and subcellular proteomics. We show that PTRF reduced the secretion of a subset of proteins including secreted proteases, cytokines, and growth regulatory proteins, partly via a reduction in prostasome secretion. To determine the cellular mechanism accounting for the observed reduction in secreted proteins we analyzed total membrane and the detergent-resistant membrane fractions. Our data show that PTRF expression selectively impaired the recruitment of actin cytoskeletal proteins to the detergent-resistant membrane, which correlated with altered cholesterol distribution in PC-3 cells expressing PTRF. Consistent with this, modulating cellular cholesterol altered the actin cytoskeleton and protein secretion in PC-3 cells. Intriguingly, several proteins that function in ER to Golgi trafficking were reduced by PTRF expression. Taken together, these results suggest that the noncaveolar caveolin-1 found in prostate cancer cells generates a lipid raft microenvironment that accentuates secretion pathways, possibly at the step of ER sorting/exit. Importantly, these effects could be modulated by PTRF expression.

Accident risk identification and its impact analyses for strategic construction safety management

The study presented in this paper reviewed 9,358 accidents which occurred in the U.S. construction industry between 2002 and 2011, in order to understand the relationships between the risk factors and injury severity (e.g. fatalities, hospitalized injuries, or non-hospitalized injuries) and to develop a strategic prevention plan to reduce the likelihood of fatalities where an accident is unavoidable. The study specifically aims to: (1) verify the relationships among risk factors, accident types, and injury severity, (2) determine significant risk factors associated with each accident type that are highly correlated to injury severity, and (3) analyze the impact of the identified key factors on accident and fatality occurrence. The analysis results explained that safety managers’ roles are critical to reducing human-related risks—particularly misjudgement of hazardous situations—through safety training and education, appropriate use of safety devices and proper safety inspection. However, for environment-related factors, the dominant risk factors were different depending on the different accident types. The outcomes of this study will assist safety managers to understand the nature of construction accidents and plan for strategic risk mitigation by prioritizing high frequency risk factors to effectively control accident occurrence and manage the likelihood of fatal injuries on construction sites.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Weight gain and nutritional intake in obese pregnant women : some clues for intervention

Aim:  Maternal obesity is associated with increased risk of adverse outcomes for mothers and offspring. Strategies to better manage maternal obesity are urgently needed; however, there is little evidence to assist the development of nutrition interventions during antenatal care. The present study aimed to assess maternal weight gain and dietary intakes of overweight and obese women participating in an exercise trial. Results will assist the development of interventions for the management of maternal overweight and obesity. Methods:  Fifty overweight and obese pregnant women receiving antenatal care were recruited and provided dietary and weight data at baseline (12 weeks), 28 weeks, 36 weeks gestation and 6 weeks post-partum. Data collected were compared with current nutritional and weight gain recommendations. Associations used Pearson's correlation coefficient, and ANOVA assessed dietary changes over time, P < 0.05. Results:  Mean prepregnancy body mass index was 34.4 ± 6.6 kg/m2. Gestational weight gain was 10.6 ± 6 kg with a wide range (−4.1 to 23.0 kg). 52% of women gained excessive weight (>11.5 kg for overweight and >9 kg for obese women). Gestational weight gain correlated with post-partum weight retention (P < 0.001). Dietary intakes did not change significantly during pregnancy. No women achieved dietary fat or dietary iron recommendations, only 11% achieved adequate dietary folate, and 38% achieved adequate dietary calcium. Very few women achieved recommended food group servings for pregnancy, with 83% consuming excess servings of non-core foods. Conclusion:  Results provide evidence that early intervention and personalised support for obese pregnant women may help achieve individualised goals for maternal weight gain and dietary adequacy, but this needs to be tested in a clinical setting.

Spatial and temporal distribution of falciparum malaria in China

Background: Falciparum malaria is the most deadly among the four main types of human malaria. Although great success has been achieved since the launch of the National Malaria Control Programme in 1955, malaria remains a serious public health problem in China. This paper aimed to analyse the geographic distribution, demographic patterns and time trends of falciparum malaria in China. Methods: The annual numbers of falciparum malaria cases during 1992–2003 and the individual case reports of each clinical falciparum malaria during 2004–2005 were extracted from communicable disease information systems in China Center for Diseases Control and Prevention. The annual number of cases and the annual incidence were mapped by matching them to corresponding province- and county-level administrative units in a geographic information system. The distribution of falciparum malaria by age, gender and origin of infection was analysed. Time-series analysis was conducted to investigate the relationship between the falciparum malaria in the endemic provinces and the imported falciparum malaria in non-endemic provinces. Results: Falciparum malaria was endemic in two provinces of China during 2004–05. Imported malaria was reported in 26 non-endemic provinces. Annual incidence of falciparum malaria was mapped at county level in the two endemic provinces of China: Yunnan and Hainan. The sex ratio (male vs. female) for the number of cases in Yunnan was 1.6 in the children of 0–15 years and it reached 5.7 in the adults over 15 years of age. The number of malaria cases in Yunnan was positively correlated with the imported malaria of concurrent months in the non-endemic provinces. Conclusion: The endemic area of falciparum malaria in China has remained restricted to two provinces, Yunnan and Hainan. Stable transmission occurs in the bordering region of Yunnan and the hilly-forested south of Hainan. The age and gender distribution in the endemic area is characterized by the predominance of adult men cases. Imported falciparum malaria in the non-endemic area of China, affected mainly by the malaria transmission in Yunnan, has increased both spatially and temporally. Specific intervention measures targeted at the mobile population groups are warranted.

The evolutionary value of recombination is constrained by genome modularity

Genetic recombination is a fundamental evolutionary mechanism promoting biological adaptation. Using engineered recombinants of the small single-stranded DNA plant virus, Maize streak virus (MSV), we experimentally demonstrate that fragments of genetic material only function optimally if they reside within genomes similar to those in which they evolved. The degree of similarity necessary for optimal functionality is correlated with the complexity of intragenomic interaction networks within which genome fragments must function. There is a striking correlation between our experimental results and the types of MSV recombinants that are detectable in nature, indicating that obligatory maintenance of intragenome interaction networks strongly constrains the evolutionary value of recombination for this virus and probably for genomes in general.

High level protein expression in plants through the use of a novel autonomously replicating geminivirus shuttle vector

We constructed a novel autonomously replicating gene expression shuttle vector, with the aim of developing a system for transiently expressing proteins at levels useful for commercial production of vaccines and other proteins in plants. The vector, pRIC, is based on the mild strain of the geminivirus Bean yellow dwarf virus (BeYDV-m) and is replicationally released into plant cells from a recombinant Agrobacterium tumefaciens Ti plasmid. pRIC differs from most other geminivirus-based vectors in that the BeYDV replication-associated elements were included in cis rather than from a co-transfected plasmid, while the BeYDV capsid protein (CP) and movement protein (MP) genes were replaced by an antigen encoding transgene expression cassette derived from the non-replicating A. tumefaciens vector, pTRAc. We tested vector efficacy in Nicotiana benthamiana by comparing transient cytoplasmic expression between pRIC and pTRAc constructs encoding either enhanced green fluorescent protein (EGFP) or the subunit vaccine antigens, human papillomavirus subtype 16 (HPV-16) major CP L1 and human immunodeficiency virus subtype C p24 antigen. The pRIC constructs were amplified in planta by up to two orders of magnitude by replication, while 50% more HPV-16 L1 and three- to seven-fold more EGFP and HIV-1 p24 were expressed from pRIC than from pTRAc. Vector replication was shown to be correlated with increased protein expression. We anticipate that this new high-yielding plant expression vector will contribute towards the development of a viable plant production platform for vaccine candidates and other pharmaceuticals. © 2009 Blackwell Publishing Ltd.