Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Organic complexation of U(VI) in reducing soils at a natural analogue site: Implications for uranium transport.

Understanding the long-term fate, stability, and bioavailability of uranium (U) in the environment is important for the management of nuclear legacy sites and radioactive wastes. Analysis of U behavior at natural analogue sites permits evaluation of U biogeochemistry under conditions more representative of long-term equilibrium. Here, we have used bulk geochemical and microbial community analysis of soils, coupled with X-ray absorption spectroscopy and µ-focus X-ray fluorescence mapping, to gain a mechanistic understanding of the fate of U transported into an organic-rich soil from a pitchblende vein at the UK Needle's Eye Natural Analogue site. U is highly enriched in the Needle's Eye soils (∼1600 mg kg-1). We show that this enrichment is largely controlled by U(VI) complexation with soil organic matter and not U(VI) bioreduction. Instead, organic-associated U(VI) seems to remain stable under microbially-mediated Fe(III)-reducing conditions. U(IV) (as non-crystalline U(IV)) was only observed at greater depths at the site (>25 cm); the soil here was comparatively mineral-rich, organic-poor, and sulfate-reducing/methanogenic. Furthermore, nanocrystalline UO2, an alternative product of U(VI) reduction in soils, was not observed at the site, and U did not appear to be associated with Fe-bearing minerals. Organic-rich soils appear to have the potential to impede U groundwater transport, irrespective of ambient redox conditions.

Beyond N and P: The impact of Ni on crude oil biodegradation.

N and P are the key limiting nutrients considered most important for the stimulation of crude oil degradation but other trace nutrients may also be important. Experimental soil microcosms were setup to investigate crude oil degradation in the context of Ni amendments. Amended Nickel as NiO, NiCl2, or, a porphyrin complex either inhibited, had no effect, or, enhanced aerobic hydrocarbon degradation in an oil-contaminated soil. Biodegradation was significantly (95% confidence) enhanced (70%) with low levels of Ni-Porph (12 mg/kg) relative to an oil-only control; whereas, NiO (200 and 350 mg/kg) significantly inhibited (36 and 87%) biodegradation consistent with oxide particle induced reactive oxygen stress. Microbial community compositions were also significantly affected by Ni. In 16S rRNA sequence libraries, the enriched hydrocarbon degrading genus, Rhodococcus, was partially replaced by a Nocardia sp. in the presence of low levels of NiO (12 and 50 mg/kg). In contrast, the highest relative and absolute Rhodococcus abundances were coincident with the maximal rates of oil degradation observed in the Ni-Porph-amended soils. Growth dependent constitutive requirements for Ni-dependent urease or perhaps Ni-dependent superoxide dismutase enzymes (found in Rhodococcus genomes) provided a mechanistic explanation for stimulation. These results suggest biostimulation technologies, in addition to N and P, should also consider trace nutrients such as Ni tacitly considered adequately supplied and available in a typical soil.

Assessment of Breast Milk Iodine Concentrations in Lactating Women in Western Australia.

Breast-fed infants may depend solely on an adequate supply of iodine in breast milk for the synthesis of thyroid hormones which are essential for optimal growth and cognitive development. This is the first study to measure breast milk iodine concentration (BMIC) among lactating women in Western Australian (n = 55). Breast milk samples were collected between 2014 and 2015 at a mean (±SD) of 38.5 (±5.5) days post-partum. The samples were analysed to determine median BMIC and the percentage of samples with a BMIC < 100 µg/L, a level considered adequate for breast-fed infants. The influence of (a) iodine-containing supplements and iodised salt use and (b) consumption of key iodine-containing foods on BMIC was also examined. The median (p25, p75) BMIC was 167 (99, 248) µg/L and 26% of samples had a BMIC < 100 µg/L. Overall, BMIC tended to be higher with iodine-containing supplement usage (ratio 1.33, 95% confidence interval (CI) (1.04, 1.70), p = 0.030), cow's milk consumption (ratio 1.66, 95% CI (1.23, 2.23), p = 0.002) and lower for Caucasians (ratio 0.61, 95% CI (0.45, 0.83), p = 0.002), and those with secondary school only education (ratio 0.66, 95% CI (0.46, 0.96), p = 0.030). For most women, BMIC was adequate to meet the iodine requirements of their breast-fed infants. However, some women may require the use of iodine-containing supplements or iodised salt to increase BMIC to adequate levels for optimal infant nutrition.

First trimester screening cut-offs for noninvasive prenatal testing as a contingent screen: Balancing detection and screen-positive rates for trisomy 21.

OBJECTIVE: To provide data on how screen-positive and detection rates of first trimester prenatal screening for fetal Down syndrome vary with changes in the risk cut-off and maternal age to inform contingency criteria for publicly funded noninvasive prenatal testing. MATERIALS AND METHODS: First trimester screening and diagnostic data were collected for all women attending for first trimester fetal aneuploidy screening in Western Australia between 2005 and 2009. Prenatal screening and diagnostic data were linked to pregnancy outcomes, including data from the Midwives' Notification System and the Western Australian Registry of Developmental Anomalies. The prevalence of Down syndrome and performance of screening by risk cut-off and/or for women >35 years were analysed. RESULTS: The current screening risk cut-off of 1:300 has screen-positive and detection rates of 3.5% and 82%. The screen-positive rate increases by 0.7-0.8% for each 100 point change in risk, up to 19.2% at 1:2500 (96% detection rate). Including all women >35 years as screen positive would increase the screen-positive rate and detection rates to 30.2% and 97.2%. CONCLUSION: Variation in screening risk cut-off and the use of maternal age to assess eligibility for noninvasive testing could significantly impact the demand for, and cost of, the test. A contingent first trimester screening approach for risk assessment is superior to the use of a combination of screening and maternal age alone. These data will inform decisions regarding the criteria used to determine eligibility for publicly funded noninvasive prenatal testing.

Folate status in Aboriginal people before and after mandatory fortification of flour for bread-making in Australia.

BACKGROUND: Mandatory fortification of wheat flour for bread-making was introduced in Australia in September 2009, to assist in the prevention of neural tube defects (NTD). NTD are twice as common in Aboriginal compared with non-Aboriginal infants, and folate levels are lower in the Aboriginal population. AIMS: This study was undertaken to compare folate status and NTD in the Aboriginal population before and after fortification. METHODS: Postfortification, 95 Aboriginal men and nonpregnant women aged 16-44 years in metropolitan and regional Western Australia (WA) completed a rapid dietary assessment tool and had blood taken to measure red cell folate. Measures were compared with prefortification values obtained in an earlier study using the same methods. Data on NTD in Aboriginal infants were obtained from the WA Register of Developmental Anomalies. RESULTS: No participant was folate deficient. The mean red cell folate increased after fortification to 443 ng/mL for males and 567 ng/mL for females. The mean difference between red cell folate after fortification compared with before was 129 ng/mL for males (95% CI 81-177); t = 5.4; P < 0.0001) and 186 ng/mL for females (95% CI 139-233); t = 7.9; P < 0.0001). Most participants ate fortified shop-bought bread at least weekly, resulting in an estimated additional folate intake per day of 178 (males) and 145 (females) dietary folate equivalents. NTD prevalence fell by 68% following fortification (prevalence ratio 0.32 (CI 0.15-0.69)). CONCLUSIONS: The population health intervention of mandatory fortification of wheat flour for bread-making has had the desired effect of increasing folate status and reducing NTD in the Australian Aboriginal population.

The Australian primary healthcare experiment: a national survey of Medicare Locals.

OBJECTIVE: The objectives of this study are to evaluate the development and implementation of Medicare Locals as new primary care organisations and consider the implications of these findings for the wider challenge of strengthening primary healthcare in Australia and internationally. DESIGN: National survey of Medicare Locals which involved the use of content analysis and a descriptive survey tool. SETTING: 61 Medicare Locals in Australia. PARTICIPANTS: The survey was distributed electronically to all 61 Medicare Local Chief Executive Officers (CEOs) between October and December 2013. MAIN OUTCOME MEASURES: The research was interested in exploring the following areas; the form and function of Medicare Locals; the confidence and capacity of Medicare Locals to perform against their objectives around population planning and system integration; their ability to engage relevant stakeholder groups; and the barriers and facilitators to reform. RESULTS: A total of 43 (70%) of Medicare Locals completed the survey with representation from six of the eight Australian states and Territories. Results suggest differences in the form and function of the Medicare Local organisations and considerable diversity in the implementation of Medicare Local organisations across Australia. This diversity and lack of guidance from government impacted on the overall success of the reform. Other barriers to reform included difficulties in stakeholder relationships and limited incentives (financial and other) to drive and influence change. CONCLUSIONS: Findings from this study produce important insights for primary care reform in Australia; and internationally it adds to the growing body of knowledge around primary care reform.

Baseline investigations of folate status in Aboriginal and non-Aboriginal West Australians prior to the introduction of mandatory fortification.

OBJECTIVE: In September 2009, Australia implemented mandatory folic acid fortification of wheat flour for bread-making to reduce the incidence of neural tube defects. Our study aimed to establish baseline folate status data in Aboriginal and non-Aboriginal Western Australians. METHODS: Patients who presented at a health service or collection centre for blood tests were invited to participate. One hundred and ninety-one Aboriginals and 159 non-Aboriginals were recruited between April 2008 and September 2009. Participants completed a five-minute questionnaire and had blood taken for red blood cell (RBC) folate and serum vitamin B12. Data were analysed using SPSS (version 17.0.2, SPSS Inc., Chicago, IL, USA). RESULTS: Ten per cent (95% confidence intervals (CI): 5, 19) of the Aboriginal women participants and 26% (95% CI: 16, 40) of men had RBC folate concentrations below 250 ng/mL, the cut-off associated with folate deficiency. None of the non-Aboriginal women (95% CI: 0, 4) and 4% of the non-Aboriginal men (95% CI: 2, 12) had RBC folate concentrations below 250 ng/mL. All participants were vitamin B12 replete. None of the 96 Aboriginal and 8% of non-Aboriginal women aged 16-44 reported consumption of supplements with a daily intake of >400 µg folic acid during the previous week. CONCLUSIONS AND IMPLICATIONS: This study established a baseline of RBC folate, folate consumption and supplement use in Aboriginal and non-Aboriginal groups. We identified 10% of Aboriginal women and none of non-Aboriginal women participants with low folate concentrations. The higher prevalence of folate deficiency in Aboriginal participants suggests they are more likely to benefit from a universal program of folate fortification.

A new model of care for familial hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology.

Familial hypercholesterolaemia (FH) is the most common monogenic cause of premature coronary artery disease. FH remains underdiagnosed and inadequately treated, with no national strategies for dealing with the problem. We report an executive summary of a comprehensive model of care for FH developed in Western Australia.

A survey of folate knowledge and consumer behaviours in Western Australia prior to the introduction of mandatory food fortification.

OBJECTIVES: Prior to the introduction of mandatory folic acid fortification in September 2009, this study collected baseline data on folate awareness, knowledge of pregnancy-relevant public health messages and consumer behaviours in Western Australia. METHODS: One thousand residents aged 18 years or older participated in a cross sectional telephone survey in September 2006. Respondents were recruited randomly from the electronic residential telephone directory. RESULTS: Most respondents reported knowing little or nothing about folate (86%). Women of childbearing age were more likely than other adults to know the association between folate intake and birth defects (82% v 56%) but 41% did not know that folate should be consumed periconceptionally to reduce the risk of spina bifida. Overall, half the respondents did not take supplements and two-thirds did not know if the food products they ate were fortified with folic acid. Associations were detected between knowledge, consumer behaviours and socio-economic indicators such as age, income, highest level of education, area of residence and parental status. IMPLICATIONS: A mix of public health strategies that includes mandatory fortification and the promotion of supplement use should improve the timely and sufficient intake of folate across all socio-economic strata of the Australian population. Strategies that support the introduction of mandatory fortification, such as awareness and education campaigns should be built on a solid understanding of the drivers and barriers to knowledge acquisition and desired consumer behaviours.

Australian survey on community knowledge and attitudes regarding the fortification of food with folic acid.

BACKGROUND: In response to the proposal that mandatory fortification be introduced in Australia to reduce the incidence of NTDs, the purpose of this study was to establish, for the adult community, baseline data on knowledge, attitudes, and behaviors towards the fortification of foods with folic acid. METHODS: A cross-sectional, Computer Assisted Telephone Interviewing survey with respondents recruited randomly from the electronic version of the Western Australian telephone directory was used. One thousand members of the community aged 18 years or older were interviewed for the study. RESULTS: Interviews were conducted in September 2006, with a response rate of 76%. Half the respondents were aware folate is currently added to some breakfast cereals (59%) and some breads (53%), but awareness of other food types that may be voluntarily fortified with folate was much lower. Only 13% of respondents were concerned about folate being added to bread, 10% believed folate should not be added to foods, and 9% said they would avoid foods with added folate. Generally, around half the respondents were uncertain about the benefits of fortifying foods with folate and around a quarter were uncertain about any risks or concerns with this practice. CONCLUSIONS: The community appears no more concerned about the fortification of bread with folate than they are about other existing fortification programs in Australia, and appear more likely to support rather than oppose the fortification of foods with folate, particularly if they are informed of the benefits of such a program.

Selenium bioavailability from buckwheat bran in rats fed a modified AIN-93G torula yeast-based diet.

Selenium (Se) is an essential nutrient for humans and animals. The Se RDA for adult humans is 55 mug/d; however, dietary amounts as high as 200 mug/d in the highly available form of selenomethionine in yeast were shown to reduce the incidence of certain cancers. A number of natural foods contain relatively high amounts of Se; for the most part, however, the availability of food Se for absorption and utilization is unknown. This experiment was conducted to determine the bioavailability of Se from a high-protein, high-fiber bran-isolate of buckwheat groats that contains Se. The method used was based on the ability of Se from buckwheat bran to restore Se-dependent enzyme activities and tissue Se concentrations in Se-deficient rats. The responses produced from buckwheat bran Se were compared with a standard response curve generated by feeding graded amounts of Se as sodium selenite (Na(2)SeO(3); Na selenite) or selenomethionine (SeMet) in a newly reformulated AIN-93G-Torula yeast diet with a more balanced nutrient composition than older diets of this nature. Relative bioavailability was determined by using the slope-ratio assay method for enzyme data, or the parallel lines assay method for tissue Se concentration data. Results showed that Se availability from buckwheat bran based on the restoration of plasma Se was 70-80% as high as Na selenite or SeMet. However, when based on the restoration of muscle Se, buckwheat bran was 90% as high as Na selenite, but only 60% as high as SeMet. When using the ability of dietary Se to restore whole blood and liver glutathione peroxidase activity, buckwheat bran Se was 75-80% as high as Na selenite or SeMet. However, for the restoration of liver thioredoxin reductase, buckwheat bran Se was only 40% as high as Na selenite and 70% as high as SeMet. The relative bioavailability of Se from buckwheat bran with all variables considered was approximately 73% whether measured against Na selenite or SeMet. Although some variables indicated low bioavailability of Se from buckwheat bran, other factors such as Se speciation in the bran, digestibility of the bran, the cooking process, and combinations with other foods in the diet should be considered and analyzed before firm conclusions can be reached.