Mycotoxins have been suggested to contribute to a spectrum of adverse health effects in humans, including at low concentrations. The recognition of these food contaminants being carcinogenic, as ...co-occurring rather than as singularly present, has emerged from recent research. The aim of this study was to assess the potential associations of single and multiple mycotoxin exposures with renal cell carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Food questionnaire data from the EPIC cohort were matched to mycotoxin food occurrence data compiled by the European Food Safety Authority (EFSA) from European Member States to assess long-term dietary mycotoxin exposures, and to associate these with the risk of renal cell carcinoma (RCC,
= 911 cases) in 450,112 EPIC participants. Potential confounding factors were taken into account. Analyses were conducted using Cox's proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) with mycotoxin exposures expressed as µg/kg body weight/day.
Demographic characteristics differed between the RCC cases and non-cases for body mass index, age, alcohol intake at recruitment, and other dietary factors. In addition, the mycotoxin exposure distributions showed that a large proportion of the EPIC population was exposed to some of the main mycotoxins present in European foods such as deoxynivalenol (DON) and derivatives, fumonisins,
toxins,
toxins, and total mycotoxins. Nevertheless, no statistically significant associations were observed between the studied mycotoxins and mycotoxin groups, and the risk of RCC development.
These results show an absence of statistically significant associations between long-term dietary mycotoxin exposures and RCC risk. However, these results need to be validated in other cohorts and preferably using repeated dietary exposure measurements. In addition, more occurrence data of, e.g., citrinin and fumonisins in different food commodities and countries in the EFSA database are a prerequisite to establish a greater degree of certainty.
•Non-Hispanic Asians had lower levels of adiposity compared to other race/ethnicities.•Non-Hispanic Asians had similar adjusted levels of hypertension and LDL cholesterol.•Body mass index levels in ...Asians can underestimate cardiometabolic disease risk.
Asians develop diabetes at lower levels of adiposity than people of other race/ethnicities. However, there is limited data investigating the health of US Asians with diabetes. We compared cardiovascular risk factors in US Asians to other race/ethnicities stratified by diabetes status.
Among 4645 adults in the 2011–2014 National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey of the US population, odds ratios were calculated for obesity, hypertension, and elevated low-density lipoprotein (LDL) cholesterol associated with race/ethnicity after adjustment for age, sex, income, education, smoking, alcohol consumption, and health insurance.
Overall and stratified by diabetes status, non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans were significantly more likely to be obese compared to non-Hispanic Asians after adjustment. Overall and stratified by diabetes status, adjusted levels of hypertension compared to non-Hispanic Asians was generally similar for non-Hispanic whites and Mexican-Americans and generally more common among non-Hispanic blacks; among those with diagnosed diabetes, the adjusted odds ratios (95% confidence interval) were 1.48 (0.79–2.77), 2.54 (1.49–4.30), and 1.38 (0.73–2.60) for non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans, respectively. Overall and stratified by diabetes status, elevated LDL cholesterol levels were generally similar between non-Hispanic Asians and other race/ethnicities; among those with diagnosed diabetes, the adjusted odds ratios (95% confidence interval) were 0.88 (0.32–2.43), 0.58 (0.24–1.42), and 1.15 (0.29–4.58) for non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans, respectively.
Although non-Hispanic Asians had lower levels of adiposity compared to other race/ethnicities with diabetes, their adjusted levels of hypertension and LDL cholesterol were generally more comparable.
Purpose of Review
The purposes of this study were to describe how medication prices are established, to explain why antihyperglycemic medications have become so expensive, to show trends in ...expenditures for antihyperglycemic medications, and to highlight strategies to control expenditures in the USA.
Recent Findings
In the U.S., pharmaceutical manufacturers set the prices for new products. Between 2002 and 2012, expenditures for antihyperglycemic medications increased from $10 billion to $22 billion. This increase was primarily driven by expenditures for insulin which increased sixfold. The increase in insulin expenditures may be attributed to several factors: the shift from inexpensive beef and pork insulins to more expensive genetically engineered human insulins and insulin analogs, dramatic price increases for the available insulins, physician prescribing practices, policies that limit payers’ abilities to negotiate prices, and nontransparent negotiation of rebates and discounts.
Summary
The costs of antihyperglycemic medications, especially insulin, have become a barrier to diabetes treatment. While clinical interventions to shift physician prescribing practices towards lower cost drugs may provide some relief, we will ultimately need policy interventions such as more stringent requirements for patent exclusivity, greater transparency in medication pricing, greater opportunities for price negotiation, and outcomes-based pricing models to control the costs of antihyperglycemic medications.
ABSTRACT
We present isochrone ages and initial bulk metallicities ($\rm Fe/H_{bulk}$, by accounting for diffusion) of 163 722 stars from the GALAH Data Release 2, mainly composed of main-sequence ...turn-off stars and subgiants ($7000\, \mathrm{ K}> T_{\mathrm{ eff}}> 4000\, \mathrm{ K}$ and $\log g>3$ dex). The local age–metallicity relationship (AMR) is nearly flat but with significant scatter at all ages; the scatter is even higher when considering the observed surface abundances. After correcting for selection effects, the AMR appears to have intrinsic structures indicative of two star formation events, which we speculate are connected to the thin and thick discs in the solar neighbourhood. We also present abundance ratio trends for 16 elements as a function of age, across different $\rm Fe/H_{bulk}$ bins. In general, we find the trends in terms of X/Fe versus age from our far larger sample to be compatible with studies based on small (∼100 stars) samples of solar twins, but we now extend them to both sub- and supersolar metallicities. The α-elements show differing behaviour: the hydrostatic α-elements O and Mg show a steady decline with time for all metallicities, while the explosive α-elements Si, Ca, and Ti are nearly constant during the thin-disc epoch (ages $\lesssim \! 12$ Gyr). The s-process elements Y and Ba show increasing X/Fe with time while the r-process element Eu has the opposite trend, thus favouring a primary production from sources with a short time delay such as core-collapse supernovae over long-delay events such as neutron star mergers.
Accurate and precise radius estimates of transiting exoplanets are critical for understanding their compositions and formation mechanisms. To know the planet, we must know the host star in as much ...detail as possible. We present first results from the K2-HERMES project, which uses the HERMES multi-object spectrograph on the Anglo-Australian Telescope to obtain R ∼ 28000 spectra of up to 360 stars in one exposure. This ongoing project aims to derive self-consistent spectroscopic parameters for about half of K2 target stars. We present complete stellar parameters and isochrone-derived masses and radii for 46 stars hosting 57 K2 candidate planets in Campaigns 1-3. Our revised host-star radii cast severe doubt on three candidate planets: EPIC 201407812.01, EPIC 203070421.01, and EPIC 202843107.01, all of which now have inferred radii well in excess of the largest known inflated Jovian planets.
Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, ...the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties. Notably, ClogP was found to directly correlate with pIC50 in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC50: 4.17 μM, solubility: 477 μM, mouse hepatocyte T 1/2 > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.
US Trends for Diabetes Prevalence Among Adults--Reply Menke, Andy; Casagrande, Sarah; Cowie, Catherine C
JAMA : the journal of the American Medical Association,
2016-Feb-16, Letnik:
315, Številka:
7
Journal Article
Mastoparan, and structurally-related amphipathic peptides, may induce cell death by augmentation of necrotic and/or apoptotic pathways. To more precisely delineate cytotoxic mechanisms, we determined ...that Lys
5,8Aib
10mastoparan (mitoparan) specifically induces apoptosis of U373MG and ECV304 cells, as demonstrated by endonuclease and caspase-3 activation and phosphatidylserine translocation. Live cell imaging confirmed that, following translocation of the plasma membrane, mitoparan specifically co-localizes with mitochondria. Complementary studies indicated that mitoparan induces swelling and permeabilization of isolated mitochondria, through cooperation with a protein of the permeability transition pore complex VDAC, leading to the release of the apoptogenic factor, cytochrome
c. N-terminal acylation of mitoparan facilitated the synthesis of chimeric peptides that incorporated target-specific address motifs including an integrin-specific RGD sequence and a Fas ligand mimetic. Significantly, these sychnologically-organised peptides demonstrated further enhanced cytotoxic potencies. We conclude that the cell penetrant, mitochondriotoxic and apoptogenic properties of mitoparan, and its chimeric analogues, offer new insights to the study and therapeutic induction of apoptosis.
Previous evidence suggests that heart rate (HR) is a prognostic factor for cardiovascular disease, for which persons with diabetes are at increased risk. We examined the association between heart ...rate and levels of glycemia in a nationally representative sample of U.S. adults.
This study included 27,602 adults age ≥20 years from the 2011-2014 National Health and Nutrition Examination Surveys. Levels of glycemia were defined as: diagnosed diabetes (self-report); undiagnosed diabetes fasting plasma glucose (FPG) ≥126mg/dL or A1c ≥6.5%; prediabetes (FPG 100-125mg/dL or A1c 5.7%-6.4%); normoglycemia (FPG <100mg/dL and A1c <5.7%). Predictive margins regression was used to determine mean HR by participant characteristics and glycemic status; and among those with diagnosed diabetes, by participant characteristics and A1c level. Mean HR was adjusted for age, sex, race/ethnicity, education, poverty income ratio, health insurance, smoking status, body mass index, history of cardiovascular disease, kidney disease, and antihypertensive medications; models by A1c level were additionally adjusted for oral antidiabetic medications. Mean HR was significantly higher for those with diagnosed and undiagnosed diabetes compared to those with normoglycemia (74 bpm vs. 72 bpm, p<0.05, for both). In the fully adjusted model, mean HR remained significantly higher for those with diagnosed (76 bpm) and undiagnosed diabetes (75 bpm) compared to those with normoglycemia (71 bpm, p<0.05 for both). Among persons with diagnosed diabetes, there was a positive association between HR and glycemic levels as measured by A1c (72 bpm, 75 bpm, 77 bpm, and 81 bpm for A1c <7.0%, 7.0%- <9.0%, 9.0%- <11.0%, and A1c ≥11.0%, respectively, p<0.001), and this association remained after adjustment for risk factors.
In conclusion, mean HR was higher among persons with diabetes and increased glycemia, which may reflect subtle autonomic and/or myocardial dysfunction among those with diabetes.
Disclosure
S. Casagrande: None. C.C. Cowie: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen Inc., Fresenius SE & Co. KGaA, General Electric, Johnson & Johnson, Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc. J.M. Sosenko: None. K.R. Mizokami-Stout: None. A.J. Boulton: None. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
Using GALAH (GALactic Archaeology with HERMES) survey data of nearby stars, we look at how structure in the planar (u, v) velocity distribution depends on metallicity and on viewing ...direction within the Galaxy. In nearby stars with distance $d \lesssim 1$ kpc, the Hercules stream is most strongly seen in higher metallicity stars Fe/H > 0.2. The Hercules stream peak v value depends on viewed galactic longitude, which we interpret as due to the gap between the stellar stream and more circular orbits being associated with a specific angular momentum value of about 1640 km s−1 kpc. The association of the gap with a particular angular momentum value supports a bar resonant model for the Hercules stream. Moving groups previously identified in Hipparcos(HIgh Precision Parallax COllecting Satellite) observations are easiest to see in stars nearer than 250 pc, and their visibility and peak velocities in the velocity distributions depends on both viewing direction (galactic longitude and hemisphere) and metallicity. We infer that there is fine structure in local velocity distributions that varies over distances of a few hundred pc in the Galaxy.
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