A Wide Range of 3243A>G/tRNALeu(UUR) (MELAS) Mutation Loads May Segregate in Offspring through the Female Germline Bottleneck

Segregation of mutant mtDNA in human tissues and through the germline is debated, with no consensus about the nature and size of the bottleneck hypothesized to explain rapid generational shifts in mutant loads. We investigated two maternal lineages with an apparently different inheritance pattern of the same pathogenic mtDNA 3243A>G/tRNALeu(UUR) (MELAS) mutation. We collected blood cells, muscle biopsies, urinary epithelium and hair follicles from 20 individuals, as well as oocytes and an ovarian biopsy from one female mutation carrier, all belonging to the two maternal lineages to assess mutant mtDNA load, and calculated the theoretical germline bottleneck size (number of segregating units). We also evaluated “mother-to-offspring” segregations from the literature, for which heteroplasmy assessment was available in at least three siblings besides the proband. Our results showed that mutation load was prevalent in skeletal muscle and urinary epithelium, whereas in blood cells there was an inverse correlation with age, as previously reported. The histoenzymatic staining of the ovarian biopsy failed to show any cytochrome-c-oxidase defective oocyte. Analysis of four oocytes and one offspring from the same unaffected mother of the first family showed intermediate heteroplasmic mutant loads (10% to 75%), whereas very skewed loads of mutant mtDNA (0% or 81%) were detected in five offspring of another unaffected mother from the second family. Bottleneck size was 89 segregating units for the first mother and 84 for the second. This was remarkably close to 88, the number of “segregating units” in the “mother-to-offspring” segregations retrieved from literature. In conclusion, a wide range of mutant loads may be found in offspring tissues and oocytes, resulting from a similar theoretical bottleneck size

Development of an Implementation Intervention Using Intervention Mapping to Increase Mammography Among Low Income Women

Background: Although much work has begun to elucidate contextual factors influencing implementation, the specific processes that facilitate and hinder adoption, implementation, and maintenance of evidence-based interventions (EBIs) in clinical settings remains poorly understood. Intervention Mapping (IM) is a systematic process that facilitates planning and design for dissemination, implementation and maintenance of EBIs in practice. IM has been used to guide the design of many health interventions, focusing on program implementation. Less studied is its use to adapt and scale screening interventions within the healthcare clinic setting. This paper describes the development of an implementation intervention using IM to facilitate the adoption, implementation, and maintenance of an EBI designed to increase mammography adherence in healthcare clinics, the adapted Peace of Mind Program (PMP).Methods: IM framework, Step 5, was used to guide the implementation intervention planning. IM guided identification of specific adoption, implementation, and maintenance performance objectives. We formed an implementation intervention planning group consisting of members of the academic team, our community partner and community health workers (CHWs) with substantial experience working on mammography screening programs in federally qualified health centers (FQHCs) and charity clinics.Results: Results are presented by Intervention Mapping task for Step 5 (Program Implementation Plan). We describe how the consolidated framework for implementation research (CFIR) informed the selection of performance objectives, determinants, methods, and practical applications in the final implementation intervention.Conclusions: This paper provides an example of the use of Intervention Mapping Step 5 and CFIR to create an implementation intervention to support EBI scale up of an evidence-based mammography intervention within a specific setting.Clinical trials registration number: NCT0229617

Safety evaluation of substituted thiophenes used as flavoring ingredients

AbstractThis publication is the second in a series by the Expert Panel of the Flavor and Extract Manufacturers Association summarizing the conclusions of its third systematic re-evaluation of the safety of flavorings previously considered to be generally recognized as safe (GRAS) under conditions of intended use. Re-evaluation of GRAS status for flavorings is based on updated considerations of exposure, structural analogy, metabolism, pharmacokinetics and toxicology and includes a comprehensive review of the scientific information on the flavorings and structurally related substances. Of the 12 substituted thiophenes reviewed here, 11 were reaffirmed as GRAS based on their rapid absorption, metabolism and excretion in humans and animals; the low estimated dietary exposure from flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels; and the lack of significant genotoxic and mutagenic potential. For one of the substituted thiophenes, 3-acetyl-2,5-dimethylthiophene, it was concluded that more detailed exposure information, comparative metabolism studies and comprehensive toxicity data, including an in-depth evaluation of the mechanism of action for any adverse effects observed, are required for continuation of its FEMA GRAS™ status. In the absence of these data, the compound was removed from the FEMA GRAS list

Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost

Detection and quantification of mammaglobin in the blood of breast cancer patients: can it be useful as a potential clinical marker? Preliminary results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients. PATIENTS AND METHODS: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay. RESULTS: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P <0.05). None of the samples from peripheral blood of 35 healthy female individuals were positive for MGB1 transcript. In contrast MGB1 mRNA expression was detected in three of 36 (8%) peripheral blood of BC patients. CONCLUSIONS: Our preliminary results demonstrate that the detection of MGB1 transcript in peripheral blood of BC patients was specific but with low sensitivity. MGB1 overexpression by itself or in combination with Ki67 might be considered an index of BC progression

High-Fat Diet with Acyl-Ghrelin Treatment Leads to Weight Gain with Low Inflammation, High Oxidative Capacity and Normal Triglycerides in Rat Muscle

Obesity is associated with muscle lipid accumulation. Experimental models suggest that inflammatory cytokines, low mitochondrial oxidative capacity and paradoxically high insulin signaling activation favor this alteration. The gastric orexigenic hormone acylated ghrelin (A-Ghr) has antiinflammatory effects in vitro and it lowers muscle triglycerides while modulating mitochondrial oxidative capacity in lean rodents. We tested the hypothesis that A-Ghr treatment in high-fat feeding results in a model of weight gain characterized by low muscle inflammation and triglycerides with high muscle mitochondrial oxidative capacity. A-Ghr at a non-orexigenic dose (HFG: twice-daily 200-µg s.c.) or saline (HF) were administered for 4 days to rats fed a high-fat diet for one month. Compared to lean control (C) HF had higher body weight and plasma free fatty acids (FFA), and HFG partially prevented FFA elevation (P<0.05). HFG also had the lowest muscle inflammation (nuclear NFkB, tissue TNF-alpha) with mitochondrial enzyme activities higher than C (P<0.05 vs C, P = NS vs HF). Under these conditions HFG prevented the HF-associated muscle triglyceride accumulation (P<0.05). The above effects were independent of changes in redox state (total-oxidized glutathione, glutathione peroxidase activity) and were not associated with changes in phosphorylation of AKT and selected AKT targets. Ghrelin administration following high-fat feeding results in a novel model of weight gain with low inflammation, high mitochondrial enzyme activities and normalized triglycerides in skeletal muscle. These effects are independent of changes in tissue redox state and insulin signaling, and they suggest a potential positive metabolic impact of ghrelin in fat-induced obesity

First Report of Circulating MicroRNAs in Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention

A comprehensive framework for assessing the accuracy and uncertainty of global above-ground biomass maps

Over the past decade, several global maps of above-ground biomass (AGB) have been produced, but they exhibit significant differences that reduce their value for climate and carbon cycle modelling, and also for national estimates of forest carbon stocks and their changes. The number of such maps is anticipated to increase because of new satellite missions dedicated to measuring AGB. Objective and consistent methods to estimate the accuracy and uncertainty of AGB maps are therefore urgently needed. This paper develops and demonstrates a framework aimed at achieving this. The framework provides a means to compare AGB maps with AGB estimates from a global collection of National Forest Inventories and research plots that accounts for the uncertainty of plot AGB errors. This uncertainty depends strongly on plot size, and is dominated by the combined errors from tree measurements and allometric models (inter-quartile range of their standard deviation (SD) = 30–151 Mg ha−1). Estimates of sampling errors are also important, especially in the most common case where plots are smaller than map pixels (SD = 16–44 Mg ha−1). Plot uncertainty estimates are used to calculate the minimum-variance linear unbiased estimates of the mean forest AGB when averaged to 0.1∘. These are used to assess four AGB maps: Baccini (2000), GEOCARBON (2008), GlobBiomass (2010) and CCI Biomass (2017). Map bias, estimated using the differences between the plot and 0.1∘ map averages, is modelled using random forest regression driven by variables shown to affect the map estimates. The bias model is particularly sensitive to the map estimate of AGB and tree cover, and exhibits strong regional biases. Variograms indicate that AGB map errors have map-specific spatial correlation up to a range of 50–104 km, which increases the variance of spatially aggregated AGB map estimates compared to when pixel errors are independent. After bias adjustment, total pantropical AGB and its associated SD are derived for the four map epochs. This total becomes closer to the value estimated by the Forest Resources Assessment after every epoch and shows a similar decrease. The framework is applicable to both local and global-scale analysis, and is available at https://github.com/arnanaraza/PlotToMap. Our study therefore constitutes a major step towards improved AGB map validation and improvement

A comprehensive framework for assessing the accuracy and uncertainty of global above-ground biomass maps

International audienceOver the past decade, several global maps of above-ground biomass (AGB) have been produced, but they exhibit significant differences that reduce their value for climate and carbon cycle modelling, and also for national estimates of forest carbon stocks and their changes. The number of such maps is anticipated to increase because of new satellite missions dedicated to measuring AGB. Objective and consistent methods to estimate the accuracy and uncertainty of AGB maps are therefore urgently needed. This paper develops and demonstrates a framework aimed at achieving this. The framework provides a means to compare AGB maps with AGB estimates from a global collection of National Forest Inventories and research plots that accounts for the uncertainty of plot AGB errors. This uncertainty depends strongly on plot size, and is dominated by the combined errors from tree measurements and allometric models (inter-quartile range of their standard deviation (SD) = 30–151 Mg ha−1). Estimates of sampling errors are also important, especially in the most common case where plots are smaller than map pixels (SD = 16–44 Mg ha−1). Plot uncertainty estimates are used to calculate the minimum-variance linear unbiased estimates of the mean forest AGB when averaged to 0.1∘. These are used to assess four AGB maps: Baccini (2000), GEOCARBON (2008), GlobBiomass (2010) and CCI Biomass (2017). Map bias, estimated using the differences between the plot and 0.1∘ map averages, is modelled using random forest regression driven by variables shown to affect the map estimates. The bias model is particularly sensitive to the map estimate of AGB and tree cover, and exhibits strong regional biases. Variograms indicate that AGB map errors have map-specific spatial correlation up to a range of 50–104 km, which increases the variance of spatially aggregated AGB map estimates compared to when pixel errors are independent. After bias adjustment, total pantropical AGB and its associated SD are derived for the four map epochs. This total becomes closer to the value estimated by the Forest Resources Assessment after every epoch and shows a similar decrease. The framework is applicable to both local and global-scale analysis, and is available at https://github.com/arnanaraza/PlotToMap. Our study therefore constitutes a major step towards improved AGB map validation and improvement