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Total Entries: 10690
Title:
Milk fat biomarkers and cardiometabolic disease
Authors:
Risérus, Ulf; Marklund, Matti
Abstract:
PURPOSE OF REVIEW: Dairy is a major food group with potential impact on cardiometabolic health. Self-reported dairy intake has limitations that can partly be avoided by using biomarkers. This review aims to summarize the evidence of odd-chain saturated fatty acids (OCFAs), that is, pentadecanoic acid (C15 : 0) and heptadecanoic acid (17 : 0), as biomarkers of dairy fat intake. In addition, the associations of OCFA biomarkers with cardiometabolic disease will be overviewed. RECENT FINDINGS: Adipose tissue 15 : 0 is the preferred biomarker but also circulating 15 : 0, and to a weaker extent 17 : 0, reflects both habitual and changes in dairy intake. Whereas results from studies assessing cardiovascular outcomes are inconsistent, OCFA biomarkers are overall associated with lower diabetes risk. Residual confounding should however be considered until interventional data and mechanisms are available. Although OCFA biomarkers mainly reflect dairy fat intake, recently proposed endogenous synthesis and metabolism do motivate further research. SUMMARY: Taking into account the study population diet and limitations of OCFA biomarkers, both adipose and circulating levels of 15 : 0, in particular, are useful for estimating total dairy fat intake. OCFA biomarkers are overall not linked to cardiovascular disease risk, but a possible beneficial role of dairy foods in diabetes prevention warrant further study.
Published:
2017
Title:
Modeling tool for calculating dietary iron bioavailability in iron-sufficient adults
Authors:
Fairweather-Tait, Susan J.; Jennings, Amy; Harvey, Linda J.; Berry, Rachel; Walton, Janette; Dainty, Jack R.
Abstract:
Background: Values for dietary iron bioavailability are required for setting dietary reference values. These are estimated from predictive algorithms, nonheme iron absorption from meals, and models of iron intake, serum ferritin concentration, and iron requirements.Objective: We developed a new interactive tool to predict dietary iron bioavailability.Design: Iron intake and serum ferritin, a quantitative marker of body iron stores, from 2 nationally representative studies of adults in the United Kingdom and Ireland and a trial in elderly people in Norfolk, United Kingdom, were used to develop a model to predict dietary iron absorption at different serum ferritin concentrations. Individuals who had raised inflammatory markers or were taking iron-containing supplements were excluded.Results: Mean iron intakes were 13.6, 10.3, and 10.9 mg/d and mean serum ferritin concentrations were 140.7, 49.4, and 96.7 mg/L in men, premenopausal women, and postmenopausal women, respectively. The model predicted that at serum ferritin concentrations of 15, 30, and 60 mg/L, mean dietary iron absorption would be 22.3%, 16.3%, and 11.6%, respectively, in men; 27.2%, 17.2%, and 10.6%, respectively, in premenopausal women; and 18.4%, 12.7%, and 10.5%, respectively, in postmenopausal women.Conclusions: An interactive program for calculating dietary iron absorption at any concentration of serum ferritin is presented. Differences in iron status are partly explained by age but also by diet, with meat being a key determinant. The effect of the diet is more marked at lower serum ferritin concentrations. The model can be applied to any adult population in whom representative, good-quality data on iron intake and iron status have been collected. Values for dietary iron bioavailability can be derived for any target concentration of serum ferritin, thereby giving risk managers and public health professionals a flexible and transparent basis on which to base their dietary recommendations. This trial was registered at clinicaltrials.gov as NCT01754012.
Published:
2017
Title:
Mortality statistics and their contribution to improving the knowledge of rare diseases epidemiology: The example of hereditary ataxia in Europe
Authors:
Arias Merino, Greta; Sánchez Díaz, Germán; Villaverde-Hueso, Ana; Posada de la Paz, Manuel; Alonso Ferreira, Verónica
Abstract:
Official mortality statistics provide population-based data and serve to improve epidemiological knowledge of rare diseases (RDs), by helping with the description of the natural history of the disease. They are an important complement of registries and estimates of disease burden and costs. At the same time, they heighten both the visibility of these diseases and the interest in their study and the search for treatments that may increase survival. This chapter contains a European analysis of hereditary ataxia mortality, which considers the time trend in different countries and the geographical variability in risk of death. Despite the limitations of applying this data source to RDs, mortality statistics share criteria which facilitate international comparisons and are of great utility for obtaining sufficiently uniform and robust time series for analysis of low-prevalence diseases.
Published:
2017
Title:
Multi-parameter comparison of a standardized mixed meal tolerance test in healthy and type 2 diabetic subjects: the PhenFlex challenge
Authors:
Wopereis, Suzan; Stroeve, Johanna H. M.; Stafleu, Annette; Bakker, Gertruud C. M.; Burggraaf, Jacobus; van Erk, Marjan J.; Pellis, Linette; Boessen, Ruud; Kardinaal, Alwine A. F.; van Ommen, Ben
Abstract:
BACKGROUND: A key feature of metabolic health is the ability to adapt upon dietary perturbations. Recently, it was shown that metabolic challenge tests in combination with the new generation biomarkers allow the simultaneous quantification of major metabolic health processes. Currently, applied challenge tests are largely non-standardized. A systematic review defined an optimal nutritional challenge test, the "PhenFlex test" (PFT). This study aimed to prove that PFT modulates all relevant processes governing metabolic health thereby allowing to distinguish subjects with different metabolic health status. Therefore, 20 healthy and 20 type 2 diabetic (T2D) male subjects were challenged both by PFT and oral glucose tolerance test (OGTT). During the 8-h response time course, 132 parameters were quantified that report on 26 metabolic processes distributed over 7 organs (gut, liver, adipose, pancreas, vasculature, muscle, kidney) and systemic stress. RESULTS: In healthy subjects, 110 of the 132 parameters showed a time course response. Patients with T2D showed 18 parameters to be significantly different after overnight fasting compared to healthy subjects, while 58 parameters were different in the post-challenge time course after the PFT. This demonstrates the added value of PFT in distinguishing subjects with different health status. The OGTT and PFT response was highly comparable for glucose metabolism as identical amounts of glucose were present in both challenge tests. Yet the PFT reports on additional processes, including vasculature, systemic stress, and metabolic flexibility. CONCLUSION: The PFT enables the quantification of all relevant metabolic processes involved in maintaining or regaining homeostasis of metabolic health. Studying both healthy subjects and subjects with impaired metabolic health showed that the PFT revealed new processes laying underneath health. This study provides the first evidence towards adopting the PFT as gold standard in nutrition research.
Published:
2017
Title:
Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice
Authors:
Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Meng; Costyn, Leah; Beharry, Zanna; Bartlett, Michael G.; Cai, Houjian
Abstract:
Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression.
Published:
2017
Title:
Natural history, trial readiness and gene discovery: Advances in patient registries for neuromuscular disease
Authors:
Thompson, Rachel; Robertson, Agata; Lochmüller, Hanns
Abstract:
Inherited neuromuscular diseases (NMDs) are genetic disorders that affect the skeletal muscles or the nerves controlling muscle function. With a new generation of diagnostic options and recent advances in translational research improving the opportunities for therapy development for these rare conditions, capturing patient information in databases collecting a range of clinical and genetic data together with contact details has assumed an increasingly important role in trial planning and recruitment as well as natural history data collection. Here we provide an overview of a decade of patient registration activities in the NMD field, with a particular focus on patient registries set up with trial readiness in mind. A summary is provided of databases collecting precise genetic information focused on confirming the causative mutation and their evolution into registries that combine genetic data with additional clinical information useful for trial feasibility and recruitment. Use of these systems for a range of purposes beyond trial recruitment, including natural history assessment, care standards monitoring, genotypephenotype correlation and disease burden evaluation is also described within the context of research networks (TREAT-NMD) and European Reference Networks (ERN-EURO-NMD). New initiatives including registries using controlled vocabularies for computational accessibility that focus on phenotypic data capture for gene discovery are analysed, and examples of the lessons learned at every stage are provided in order to allow new patient registration initiatives to benefit from the extensive experience gained.
Published:
2017
Title:
Need for new review of article on ketogenic dietary regimes for cancer patients
Authors:
Klement, Rainer J.; Feinman, Richard D.; Gross, Elena C.; Champ, Colin E.; D'Agostino, Dominic P.; Fine, Eugene J.; Kämmerer, Ulrike; Poff, Angela; Rho, Jong M.; Seyfried, Thomas N.; Scheck, Adrienne C.
Abstract:
Published:
2017
Title:
Negative effects of restricted sleep on facial appearance and social appeal
Authors:
Sundelin, Tina; Lekander, Mats; Sorjonen, Kimmo; Axelsson, John
Abstract:
© 2017 The Authors. The importance of assessing evolutionarily relevant social cues suggests that humans should be sensitive to others' sleep history, as this may indicate something about their health as well as their capacity for social interaction. Recent findings show that acute sleep deprivation and looking tired are related to decreased attractiveness and health, as perceived by others. This suggests that one might also avoid contact with sleep-deprived, or sleepy-looking, individuals, as a strategy to reduce health risk and poor interactions. In this study, 25 participants (14 females, age range 18–47 years) were photographed after 2 days of sleep restriction and after normal sleep, in a balanced design. The photographs were rated by 122 raters (65 females, age range 18–65 years) on how much they would like to socialize with the participants. They also rated participants' attractiveness, health, sleepiness and trustworthiness. The results show that raters were less inclined to socialize with individuals who had gotten insufficient sleep. Furthermore, when sleep-restricted, participants were perceived as less attractive, less healthy and more sleepy. There was no difference in perceived trustworthiness. These findings suggest that naturalistic sleep loss can be detected in a face and that people are less inclined to interact with a sleep-deprived individual.
Published:
2017
Title:
New insights into the mechanisms of the ketogenic diet
Authors:
Boison, Detlev
Abstract:
PURPOSE OF REVIEW: High-fat, low-carbohydrate ketogenic diets have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of ketogenic diets has experienced a revival to include the treatment of adulthood epilepsies as well as conditions ranging from autism to chronic pain and cancer. Despite the ability of ketogenic diet therapy to suppress seizures refractory to antiepileptic drugs and reports of lasting seizure freedom, the underlying mechanisms are poorly understood. This review explores new insights into mechanisms mobilized by ketogenic diet therapies. RECENT FINDINGS: Ketogenic diets act through a combination of mechanisms, which are linked to the effects of ketones and glucose restriction, and to interactions with receptors, channels, and metabolic enzymes. Decanoic acid, a component of medium-chain triclycerides, contributes to seizure control through direct α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition, whereas drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway. Ketogenic diet therapy also affects DNA methylation, a novel epigenetic mechanism of the diet. SUMMARY: Ketogenic diet therapy combines several beneficial mechanisms that provide broad benefits for the treatment of epilepsy with the potential to not only suppress seizures but also to modify the course of the epilepsy.
Published:
2017
Title:
New therapeutic uses for existing drugs
Authors:
Austin, Bobbie Ann; Gadhia, Ami D.
Abstract:
Eighty percent of drugs that enter human clinical testing are never approved for use. This means that for every five drugs that make it into the clinic, there are four that failed to show effectiveness for treating the disease or condition the drug was designed to treat.This high failure rate means there are many existing, partially developed therapeutic candidates with known pharmacology, formulation, and potential toxicity. Finding new uses for existing experimental drugs or biologics "repositioning" builds upon previous research and development efforts, so new candidate therapies can be advanced to clinical trials for a new use more quickly than starting from scratch.Federal funding initiatives in the U.S. and UK started to support pre-clinical /or early stage trials for repositioning existing experimental drugs or biologics (therapies). This chapter covers some of the process issues that have been solved and the remaining challenges that are still in need of solutions. The chapter is primarily written from a U.S. federal funding perspective. The general concepts could be applied more globally to benefit rare and neglected disease populations. The drug development and process bottlenecks are the same for both rare and common disease.
Published:
2017
Title:
Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer
Authors:
Audet-Walsh, Étienne; Dufour, Catherine R.; Yee, Tracey; Zouanat, Fatima Z.; Yan, Ming; Kalloghlian, Georges; Vernier, Mathieu; Caron, Maxime; Bourque, Guillaume; Scarlata, Eleonora; Hamel, Lucie; Brimo, Fadi; Aprikian, Armen G.; Lapointe, Jacques; Chevalier, Simone; Giguère, Vincent
Abstract:
Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.
Published:
2017
Title:
Nutrigenomics in the modern era
Authors:
Mathers, John C.
Abstract:
The concept that interactions between nutrition and genetics determine phenotype was established by Garrod at the beginning of the 20th century through his ground-breaking work on inborn errors of metabolism. A century later, the science and technologies involved in sequencing of the human genome stimulated development of the scientific discipline which we now recognise as nutritional genomics (nutrigenomics). Much of the early hype around possible applications of this new science was unhelpful and raised expectations, which have not been realised as quickly as some would have hoped. However, major advances have been made in quantifying the contribution of genetic variation to a wide range of phenotypes and it is now clear that for nutrition-related phenotypes, such as obesity and common complex diseases, the genetic contribution made by SNP alone is often modest. There is much scope for innovative research to understand the roles of less well explored types of genomic structural variation, e.g. copy number variants, and of interactions between genotype and dietary factors, in phenotype determination. New tools and models, including stem cell-based approaches and genome editing, have huge potential to transform mechanistic nutrition research. Finally, the application of nutrigenomics research offers substantial potential to improve public health e.g. through the use of metabolomics approaches to identify novel biomarkers of food intake, which will lead to more objective and robust measures of dietary exposure. In addition, nutrigenomics may have applications in the development of personalised nutrition interventions, which may facilitate larger, more appropriate and sustained changes in eating (and other lifestyle) behaviours and help to reduce health inequalities.
Published:
2017
Title:
Nutrition, microRNAs, and Human Health
Authors:
Cui, Juan; Zhou, Beiyan; Ross, Sharon A.; Zempleni, Janos
Abstract:
MicroRNAs (miRs) hybridize with complementary sequences in mRNA and silence genes by destabilizing mRNA or preventing translation of mRNA. Over 60% of human protein-coding genes are regulated by miRs, and 1881 high-confidence miRs are encoded in the human genome. Evidence suggests that miRs not only are synthesized endogenously, but also might be obtained from dietary sources, and that food compounds alter the expression of endogenous miR genes. The main food matrices for studies of biological activity of dietary miRs include plant foods and cow milk. Encapsulation of miRs in exosomes and exosome-like particles confers protection against RNA degradation and creates a pathway for intestinal and vascular endothelial transport by endocytosis, as well as delivery to peripheral tissues. Evidence suggests that the amount of miRs absorbed from nutritionally relevant quantities of foods is sufficient to elicit biological effects, and that endogenous synthesis of miRs is insufficient to compensate for dietary miR depletion and rescue wild-type phenotypes. In addition, nutrition alters the expression of endogenous miR genes, thereby compounding the effects of nutrition-miR interactions in gene regulation and disease diagnosis in liquid biopsies. For example, food components and dietary preferences may modulate serum miR profiles that may influence biological processes. The complex crosstalk between nutrition, miRs, and gene targets poses a challenge to gene network analysis and studies of human disease. Novel pipelines and databases have been developed recently, including a dietary miR database for archiving reported miRs in 15 dietary resources. miRs derived from diet and endogenous synthesis have been implicated in physiologic and pathologic conditions, including those linked with nutrition and metabolism. In fact, several miRs are actively regulated in response to overnutrition and tissue inflammation, and are involved in facilitating the development of chronic inflammation by modulating tissue-infiltrated immune cell function.
Published:
2017
Title:
Nutritional Renaissance and Public Health Policy
Authors:
Campbell, T. C.
Abstract:
The science of nutrition has long been entrapped in reductionist interpretation of details, a source of great confusion. However, if nutrition is defined as the integration of countless nutrient factors, metabolic reactions and outcomes, biologically orchestrated as in symphony, its relevance for personal and public health would be less confusing and more productive. This more wholistic interpretation may be observed at the cellular and physiological levels and may be described, in part, by the concept of pleiotropy (multiple cell-based effects from one nutrient source), together with its more expansive cousin, epitropy (multiple cell-based effects from multiple nutrients). There are many consequences. First, wholistic interpretation helps to explain the profound but little-known health benefits of whole plant-based foods (not vegan or vegetarian) when compared with whole animal-based foods and/or with the nutritionally variable convenience foods (generally high in fat, salt, refined carbohydrates and low in complex carbohydrates). Second, wholistic interpretation explains why the U.S. Dietary Guidelines and related public policies, which are primarily conceived from reductionist reasoning, serve political agendas so effectively. If diet and health advisories were to acknowledge the biological complexity of nutrition, then make greater use of deductive (top down) instead of inductive (bottom up) reasoning, there would be less confusion. Third, wholistic nutrition, if acknowledged, could greatly help to resolve the highly-polarized, virtually intractable political debate on health care. And fourth, this definition tells why nutrition is rarely if ever offered in medical school training, is not one of the 130 or so medical specialties, and does not have a dedicated research institute at U.S. National Institutes of Health. Nutrition is a wholistic science whereas medical practice is reductionist, a serious mismatch that causes biased judgement of nutrition. But this dichotomy would not exist if the medical practice profession were to understand and adopt wholistic interpretation. Reductionist research, however, is crucially important because its findings provide the granular structure for wholistic interpretation-these two philosophies are inescapably interdependent. Evidence obtained in this manner lends strong support to the suggestion that nutrition is more efficacious and far more affordable in maintaining and restoring (treating) health than all the pills and procedures combined. Admittedly, this is a challenging paradigm for the domain of medical science itself.
Published:
2017
Title:
O-GlcNAcylation and cardiovascular disease
Authors:
Wright, JaLessa N.; Collins, Helen E.; Wende, Adam R.; Chatham, John C.
Abstract:
The post-translational modification of serine and threonine residues of proteins found in numerous subcellular locations by O-linked N-acetylglucosamine (O-GlcNAc) is emerging as a key mediator of many cardiovascular pathophysiological processes. Early studies implicated increased protein O-GlcNAcylation as contributing to the cardiovascular complications associated with diabetes, whereas subsequent studies demonstrated that acute increases in O-GlcNAc levels were protective against ischemia/reperfusion injury. There is now a growing understanding that O-GlcNAc modification of proteins influences numerous cellular functions, including transcription, protein turnover, calcium handling, and bioenergetics. As a result, a more nuanced view of the role of protein O-GlcNAcylation in the cardiovascular system is emerging along with the recognition that it is required for normal cellular function and homeostasis. Consequently, the impact of changes in O-GlcNAc cycling due to stress or disease on the heart is complex and highly dependent on the specific context of these events. The goal of this review is to provide an overview of some of the more recent advances in our understanding of the role O-GlcNAcylation plays in mediating cardiovascular function and disease.
Published:
2017
Title:
Omega-3 fatty acids promote fatty acid utilization and production of pro-resolving lipid mediators in alternatively activated adipose tissue macrophages
Authors:
Rombaldova, Martina; Janovska, Petra; Kopecky, Jan; Kuda, Ondrej
Abstract:
It is becoming increasingly apparent that mutual interactions between adipocytes and immune cells are key to the integrated control of adipose tissue inflammation and lipid metabolism in obesity, but little is known about the non-inflammatory functions of adipose tissue macrophages (ATMs) and how they might be impacted by neighboring adipocytes. In the current study we used metabolipidomic analysis to examine the adaptations to lipid overload of M1 or M2 polarized macrophages co-incubated with adipocytes and explored potential benefits of omega-3 polyunsaturated fatty acids (PUFA). Macrophages adjust their metabolism to process excess lipids and M2 macrophages in turn modulate lipolysis and fatty acids (FA) re-esterification of adipocytes. While M1 macrophages tend to store surplus FA as triacylglycerols and cholesteryl esters in lipid droplets, M2 macrophages channel FA toward re-esterification and β-oxidation. Dietary omega-3 PUFA enhance β-oxidation in both M1 and M2. Our data document that ATMs contribute to lipid trafficking in adipose tissue and that omega-3 PUFA could modulate FA metabolism of ATMs.
Published:
2017
Title:
Operationalising the health aspects of sustainable diets: a review
Authors:
Mertens, Elly; Van't Veer, Pieter; Hiddink, Gerrit J.; Steijns, Jan Mjm; Kuijsten, Anneleen
Abstract:
OBJECTIVE: Shifting towards a more sustainable food consumption pattern is an important strategy to mitigate climate change. In the past decade, various studies have optimised environmentally sustainable diets using different methodological approaches. The aim of the present review was to categorise and summarise the different approaches to operationalise the health aspects of environmentally sustainable diets. DESIGN: Conventional keyword and reference searches were conducted in PubMed, Scopus, Web of Knowledge and CAB Abstracts. Inclusion criteria were: (i) English-language publication; (ii) published between 2005 and October 2015; (iii) dietary data collected for the diet as a whole at the national, household or individual level; (iv) comparison of the current diet with dietary scenarios; and (v) for results to consider the health aspect in some way. SETTING: Consumer diets. SUBJECTS: Adult population. RESULTS: We reviewed forty-nine studies that combined the health and environmental aspects of consumer diets. Hereby, five approaches to operationalise the health aspect of the diet were identified: (i) food item replacements; (ii) dietary guidelines; (iii) dietary quality scores; (iv) diet modelling techniques; and (v) diet-related health impact analysis. CONCLUSIONS: Although the sustainability concept is increasingly popular and widely advocated by nutritional and environmental scientists, the journey towards designing sustainable diets for consumers has only just begun. In the context of operationalising the health aspects, diet modelling might be considered the preferred approach since it captures the complexity of the diet as a whole. For the future, we propose SHARP diets: environmentally Sustainable (S), Healthy (H), Affordable (A), Reliable (R) and Preferred from the consumer's perspective (P).
Published:
2017
Title:
Organoids model distinct Vitamin E effects at different stages of prostate cancer evolution
Authors:
Njoroge, Rose N.; Unno, Kenji; Zhao, Jonathan C.; Naseem, Anum F.; Anker, Jonathan F.; McGee, Warren A.; Nonn, Larisa; Abdulkadir, Sarki A.
Abstract:
Vitamin E increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) through unknown mechanisms while Selenium showed no efficacy. We determined the effects of the SELECT supplements on benign (primary), premalignant ( RWPE-1) and malignant (LNCaP) prostate epithelial organoids. While the supplements decreased proliferation and induced cell death in cancer organoids, they had no effect on the benign organoids. In contrast, Vitamin E enhanced cell proliferation and survival in the premalignant organoids in a manner that recapitulated the SELECT results. Indeed, while Vitamin E induced a pro-proliferative gene expression signature, Selenium alone or combined with Vitamin E produced an anti-proliferative signature. The premalignant organoids also displayed significant downregulation of glucose transporter and glycolytic gene expression pointing to metabolic alterations. Detached RWPE-1 cells had low ATP levels due to diminished glucose uptake and glycolysis which was rescued by Vitamin E through the activation of fatty acid oxidation (FAO). FAO inhibition abrogated the ATP rescue, diminished survival of the inner matrix detached cells, restoring the normal hollow lumen morphology in Vitamin E treated organoids. Organoid models therefore clarify the paradoxical findings from SELECT and demonstrate that Vitamin E promotes tumorigenesis in the early stages of prostate cancer evolution.
Published:
2017
Title:
Oxidative and anti-oxidative status in muscle of young rats in response to six protein diets
Authors:
Zhu, J.; Li, X.; Qi, H.; Gu, Z.; Song, S.; Yang, X.; Zhou, G.; Li, C.
Abstract:
We investigated the impact of six protein diets on oxidation and anti-oxidation status in the muscle of young rats. Rats were fed six protein diets for 14 days, including casein (control), and proteins isolated from soy, fish, chicken, pork and beef. Grx1, Trx1 and other oxidative metabolic indices in muscle were quantified. Compared with the casein diet, the soy protein diet had a similar oxidation level, but higher GSH and lower SOD activities. The chicken and fish protein groups had lower GSH and higher SOD activities, the pork protein group showed lower Grx1 levels than the casein group and the beef protein group showed the highest GSH, Grx1 and Trx1 levels as reflected by RT-PCR, Western blotting and immunohistochemistry analyses. Intake of meat proteins showed higher ROS and T-AOC but lower MDA levels than non-meat proteins, which may be due to the increase in Grx1 and Trx1 expression and other antioxidants. Meat proteins are more conducive to muscle of growing rats. © 2017 The Author(s).
Published:
2017
Title:
PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro
Authors:
Martinez-Marin, Dalia; Jarvis, Courtney; Nelius, Thomas; de Riese, Werner; Volpert, Olga V.; Filleur, Stéphanie
Abstract:
BACKGROUND: Although inflammation and prostate cancer (PCa) have been linked, the molecular interactions between macrophages and PCa cells are poorly explored. Pigment Epithelium-Derived Factor (PEDF) is an anti-angiogenic and anti-tumor factor. We previously showed that PEDF induces macrophages recruitment in vitro, correlates with macrophages density in human prostate, and stimulates macrophages polarization towards the classically activated pathway. Here, we demonstrate that PEDF modulates the interaction between macrophages and PCa cells through a bidirectional signalling leading to tumor cell apoptosis and phagocytosis. METHODS: RAW 264.7 and THP-1 cells, and BMDMs were grown in vitro as mono- or co-cultures with PC3 or CL1 tumor cells. The effects of PEDF and its derived P18 peptide were measured on macrophages differentiation, migration, and superoxide production, and tumor cell apoptosis and phagocytosis. PEDF receptors (ATP5B, PNPLA2, and LRP6) and CD47 mRNA and protein expression were quantified in macrophages and tumor cells by quantitative RT-PCR, western blot, immunofluorescence and flow cytometry. RESULTS: We found that PEDF induced the migration of macrophages towards tumor 3D spheroids and 2D cultures. In co-culture, PEDF increased PCa cells phagocytosis through an indirect apoptosis-dependent mechanism. Moreover, PEDF stimulated the production of superoxide by macrophages. Conditioned media from macrophages exposed to PEDF induced tumor cells apoptosis in contrast to control conditioned media suggesting that ROS may be involved in tumor cells apoptosis. ATP5B and PNPLA2 PEDF receptors on macrophages and CD47 on tumor cells were respectively up- and down-regulated by PEDF. As PEDF, blocking CD47 induced phagocytosis. Inhibiting ATP5B reduced phagocytosis. Inversely, PNPLA2 inhibition blocks differentiation but maintains phagocytosis. CD47-induced phagocytosis was partially reverted by ATP5B inhibition suggesting a complementary action. Similar effects were observed with P18 PEDF-derived peptide. CONCLUSIONS: These data established that modulating the molecular interactions between macrophages and PCa cells using PEDF may be a promising strategy for PCa treatment.
Published:
2017
Title:
Patient Empowerment and Involvement in Research
Authors:
Perestelo-Pérez, Lilisbeth; Rivero-Santana, Amado; Abt-Sacks, Analia; Toledo-Chavarri, Ana; Brito, Noe; Álvarez-Pérez, Yolanda; González-Hernández, Nerea; Serrano-Aguilar, Pedro
Abstract:
Published:
2017
Title:
Personalized medicine: What's in it for rare diseases?
Authors:
Schee Genannt Halfmann, Sebastian; Mählmann, Laura; Leyens, Lada; Reumann, Matthias; Brand, Angela
Abstract:
Personalised Medicine has become a reality over the last years. The emergence of ‘omics' and big data has started revolutionizing healthcare. New ‘omics' technologies lead to a better molecular characterization of diseases and a new understanding of the complexity of diseases. The approach of PM is already successfully applied in different healthcare areas such as oncology, cardiology, nutrition and for rare diseases. However, health systems across the EU are often still promoting the ‘one-size fits all' approach, even if it is known that patients do greatly vary in their molecular characteristics and response to drugs and other interventions. To make use of the full potentials of PM in the next years ahead several challenges need to be addressed such as the integration of big data, patient empowerment, translation of basic to clinical research, bringing the innovation to the market and shaping sustainable healthcare systems.
Published:
2017
Title:
Plant based diet in the prevention of civilization diseases
Authors:
Křivohlavá, L.
Abstract:
Exercise and plant based diet can reduce the risk for diabetes, cancer and cardiovascular disease. An underlying cause of these diseases is chronic inflammation. American Study (2011) demonstrated that non-smoking adult men and women whose lifestyles were most consistent with the 2006 American Cancer Society (ACS) cancer prevention guidelines for weight control, diet, physical activity, and alcohol had a significantly lower risk of dying from cancer and cardiovascular disease. Two of recommendations (ACS) for individual choices are: consume a healthy diet, with an emphasis on plant foods and limit consumption of processed meat and red meat. A Mediterranean diet is associated with lower levels of some important biomarkers of inflammation (such as C-reactive protein (CRP), interleukin-6 and fibrinogen) thus suggesting an anti-inflammatory action of its main food components.
Published:
2017
Title:
Plant-Based Nutrition: An Essential Component of Cardiovascular Disease Prevention and Management
Authors:
Patel, Hena; Chandra, Sonal; Alexander, Sarah; Soble, Jeffrey; Williams, Kim Allan
Abstract:
PURPOSE OF REVIEW: This review aims to summarize and discuss the role of plant-based nutrition as an adjunct to the management of cardiovascular disease (CVD). Discussion of nutrition and the benefits of a plant-based diet should be highlighted during healthcare provider visits as an essential part of the overall CVD prevention and management care plan. RECENT FINDINGS: Evidence from prospective cohort studies indicates that a high consumption of predominantly plant-based foods, such as fruit and vegetables, nuts, and whole grains, is associated with a significantly lower risk of CVD. The protective effects of these foods are likely mediated through their multiple beneficial nutrients, including mono- and polyunsaturated fatty acids, omega-3 fatty acids, antioxidant vitamins, minerals, phytochemicals, fiber, and plant protein. In addition, minimizing intake of animal proteins has been shown to decrease the prevalence of CVD risk factors. Substantial evidence indicates that plant-based diets can play an important role in preventing and treating CVD and its risk factors. Such diets deserve more emphasis in dietary recommendations.
Published:
2017
Title:
Post-approval studies for rare disease treatments and orphan drugs
Authors:
Maier, William C.; Christensen, Ronald A.; Anderson, Patricia
Abstract:
Drug development involves a multi-stage process of drug discovery, animal studies and human clinical trials to assess the safety and efficacy of new medications. Rare disease drug development involves a much smaller number of affected patients, a predominance of pediatric patients and more complicated disease presentation. Post-approval studies are designed to address several limitations associated with the rare disease clinical trials.National and international regulatory agencies in the US and Europe have adopted similar approaches to requirements post-approval data for rare diseases and orphan drug indications. The US FDA published guidance in 2011 and the European Medicines Agency in 2015.Post-approval studies for rare diseases include observational studies, pragmatic trials and randomized controlled studies. Observational studies include both original data collection studies and the use of secondary data (retrospective studies). Original data collection can address limitations of retrospective studies resulting from incomplete information in secondary data sources. Disease registries focus on detail about a broad range of patients with a rare disease while product-related registries focus on specific health care outcomes associated with a single product and may incorporate a comparator of an alternative therapy or therapies.Rare disease patients can be difficult to find and enroll in a registry using conventional physician based driven recruitment. The study process also needs to recognize changes in the patient's disease and lifestyle and adapt both the study design and methods over time. Many rare diseases have strong patient advocacy groups that can in aid the design and execution of rare disease registries.
Published:
2017
Title:
Potential health hazards of eating red meat
Authors:
Wolk, A.
Abstract:
Red meat (beef, veal, pork, lamb and mutton) consumption contributes several important nutrients to the diet, for example essential amino acids, vitamins (including B12) and minerals (including iron and zinc). Processed red meat (ham, sausages, bacon, frankfurters, salami, etc.) undergoes treatment (curing, smoking, salting or the use of chemical preservatives and additives) to improve its shelf life and/or taste. During recent decades, consumption of red meat has been increasing globally, especially in developing countries. At the same time, there has been growing evidence that high consumption of red meat, especially of processed meat, may be associated with an increased risk of several major chronic diseases. Here, a comprehensive summary is provided of the accumulated evidence based on prospective cohort studies regarding the potential adverse health effects of red meat consumption on major chronic diseases, such as diabetes, coronary heart disease, heart failure, stroke and cancer at several sites, and mortality. Risk estimates from pooled analyses and meta-analyses are presented together with recently published findings. Based on at least six cohorts, summary results for the consumption of unprocessed red meat of 100 g day−1 varied from nonsignificant to statistically significantly increased risk (11% for stroke and for breast cancer, 15% for cardiovascular mortality, 17% for colorectal and 19% for advanced prostate cancer); for the consumption of 50 g day−1 processed meat, the risks were statistically significantly increased for most of the studied diseases (4% for total prostate cancer, 8% for cancer mortality, 9% for breast, 18% for colorectal and 19% for pancreatic cancer, 13% for stroke, 22% for total and 24% for cardiovascular mortality and 32% for diabetes). Potential biological mechanisms underlying the observed risks and the environmental impact of red meat production are also discussed. The evidence-based integrated message is that it is plausible to conclude that high consumption of red meat, and especially processed meat, is associated with an increased risk of several major chronic diseases and preterm mortality. Production of red meat involves an environmental burden. Therefore, some European countries have already integrated these two issues, human health and the ‘health of the planet’, into new dietary guidelines and recommended limiting consumption of red meat.
Published:
2017
Title:
Predicting cardiovascular events in familial hypercholesterolemia: The SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study)
Authors:
Pérez De Isla, Leopoldo; Alonso, Rodrigo; Mata, Nelva; Fernández-Pérez, Cristina; Muñiz, Ovidio; Díaz-Díaz, José Luis; Saltijeral, Adriana; Fuentes-Jiménez, Francisco; De Andrés, Raimundo; Zambón, Daniel; Piedecausa, Mar; Cepeda, José María; Mauri, Marta; Galiana, Jesús; Brea, Ángel; Sanchez Muñoz-Torrero, Juan Francisco; Padró, Teresa; Argueso, Rosa; Miramontes-González, José Pablo; Badimón, Lina; Santos, Raúl D.; Watts, Gerald F.; Mata, Pedro
Abstract:
BACKGROUND-: Although risk factors for atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia (FH) have been described, models for predicting incident ASCVD have not been reported. Our aim was to utilise the SAFEHEART registry to define key risk factors for predicting incident ASCVD in patients with FH. METHODS-: SAFEHEART is a multicentre, nationwide, long-term prospective cohort study of a molecularly-defined population with FH, with or without previous ASCVD. Analysis to define risk factors and to build a risk prediction equation were developed and tested for its ability to discriminate patients who experience incident ASCVD from those who did not over time. RESULTS-: We recruited 2404 adult patients with FH who were followed-up for a mean period 5.5 years (SD 3.2), during which 12 (0.5%) and 122 (5.1%) suffered fatal and non-fatal incident ASCVD respectively. Age, male gender, history of previous ASCVD, high blood pressure, increased body mass index, active smoking, and LDL-C and Lp(a) levels were independent predictors of incident ASCVD from which a risk equation (SAFEHEART-RE) with a Harrell's C index 0.85 was derived. The bootstrap resampling (100 randomized samples) of the original set for internal validation showed a degree of overoptimism of 0.003. Individual risk was estimated for each person without an established diagnosis of ASCVD before enrolment in the registry by using the SAFEHEART-RE, the modified Framingham's risk equation and the ACC/AHA ASCVD Pooled Cohort Risk Equations. Harrell's C index for these models were 0.81, 0.78 and 0.8 respectively and differences between the SAFEHEART-RE and the other two were significant (p=0.023 and p=0.045). CONCLUSIONS-: The risk of incident ASCVD may be estimated in FH patients using simple clinical predictors. This finding may improve risk stratification and could be utilized to guide therapy in patients with FH. CLINICAL TRIAL REGISTRATION-: https://clinicaltrials.gov Unique Identifier: NCT02693548, Copyright © 2017 by the American College of Cardiology Foundation and the American Heart Association, Inc.
Published:
2017
Title:
Preparing data at the source to foster interoperability across rare disease resources
Authors:
Roos, Marco; Martin López, Estrella; Wilkinson, Mark D.
Abstract:
The ability to combine heterogeneous data distributed across the globe is critically important to boost research on rare diseases, but it presents a number of methodological, representational and automation challenges. In this scenario, biomedical ontologies are of critical importance for enabling computers to aid in information retrieval and analysis across data collections. This chapter presents an approach to preparing rare disease data for integration through the application of a global standard for computer-readable data and knowledge. This includes the use of common data elements, ontological codes and computer-readable data. This approach was developed under a number of domain-relevant requirements, such as controlled access to data, independence of the original sources, and the desire to combining the data sources with other computational workflows and data platforms.
Published:
2017
Title:
Preparing for the future of rare diseases
Authors:
Groft, Stephen C.; Posada de la Paz, Manuel
Abstract:
Members of the rare disease community have devoted significant financial and personnel resources to address the numerous issues surrounding rare diseases. The past has been devoted to developing an emphasis on rare diseases including an emphasis on research studies or locating information on rare diseases and the requirements and limitations of conducting clinical trials with small patient populations. The expanded role of patient advocacy organizations and patient engagement in all aspects of clinical research continues to gain acceptance within the research community. The future will require a greater understanding and interpretation of available information from multiple sources including electronic health records and big data sources. The pipeline of potential orphan products continues to grow significantly and holds great promise for novel interventions due to advances in clinical trial design and data analyses. Expanding diagnostic procedures with improved sequencing methods will speed up the diagnosis or rare diseases. Accepting agreed upon nomenclature and codification of rare diseases will assist in differentiating diseases and identifying selected sub-populations of rare diseases. Improvements in patient recruitment and increased flexibility in the product review and approval procedures by regulatory agencies will facilitate product approvals. Children particularly will need help and assistance dealing with feelings of isolation from their peers due to their rare disease. During the transition from childhood to adolescence to adult, difficulties of fitting in with peers and not wanting to be different are a major concern. In response to increasing costs of treatments, Value-Based Care is gaining greater acceptance by the reimbursement and the payer community as a basis for payment for interventions. Mobile Health (M-health) Technologies have the potential to revolutionize how clinical research is conducted in the future. Wearable devices, remote sensors, and the development of mobile device applications (apps) will all assist in constant monitoring of patients for safety and efficacy of approved and investigational compounds. Tele Health and Tele Medicine may provide the necessary access to expert clinicians with a better understanding of individual rare diseases. The future promises great advances and even greater personalized treatments with the introduction of novel treatments and approaches to care.
Published:
2017
Title:
Primary prevention of congenital anomalies: Special focus on environmental chemicals and other toxicants, maternal health and health services and infectious diseases
Authors:
Taruscio, Domenica; Baldi, Francesca; Carbone, Pietro; Neville, Amanda J.; Rezza, Giovanni; Rizzo, Caterina; Mantovani, Alberto
Abstract:
© Springer International Publishing AG 2017. Congenital anomalies (CA) represent an important fraction of rare diseases, due to the critical role of non-genetic factors in their pathogenesis. CA are the main group of rare diseases in which primary prevention measures will have a beneficial impact. Indeed, since 2013 the European Union has endorsed a body of evidence-based recommendations for CA primary prevention; the recommendations aim at facilitating the inclusion of primary prevention actions the National Rare Disease Plans of EU Member States and encompass different public health fields, from environment through to maternal diseases and lifestyles. The chapter overviews and discusses the assessment of main risk factors for CA, such as environmental toxicants, maternal health and lifestyles and infections, with a special attention to issues that are emerging or need more knowledge. Overall, the availability of CA registries is important for estimating the health burden of CA, identifying possible hotspots, assessing the impact of interventions and addressing further, fit-to-purpose research. The integration of relevant public health actions that are already in place (e.g., control of noxious chemicals, vaccination programmes, public health services addressing chronic maternal conditions) can increase the affordability and sustainability of CA primary prevention. In developing countries with less primary prevention in place and limited overall resources, a first recognition phase may be pivotal in order to identify priority targets. In the meanwhile, policy makers should be made aware that primary prevention of RD supports publicly endorsed societal values like the knowledge-based promotion of health, empowerment, equity and social inclusiveness.
Published:
2017
Title:
Prospects of pluripotent and adult stem cells for rare diseases
Authors:
García-Castro, Javier; Singeç, Ilyas
Abstract:
© Springer International Publishing AG 2017. Rare diseases are highly diverse and complex regarding molecular underpinning and clinical manifestation and afflict millions of patients worldwide. The lack of appropriate model systems with face and construct validity and the limited availability of live tissues and cells from patients has largely hampered the understanding of underlying disease mechanisms. As a consequence, there are no adequate treatment options available for the vast majority of rare diseases. Over the last decade, remarkable progress in pluripotent and adult stem cell biology and the advent of powerful genomic technologies opened up exciting new avenues for the investigation, diagnosis, and personalized therapy of intractable human diseases. Utilizing the entire range of available stem cell types will continue to cross-fertilize different research areas and leverage the investigation of rare diseases based on evidence-based medicine. Standardized cell engineering and manufacturing from inexhaustible stem cell sources should lay the foundation for next-generation drug discovery and cell therapies that are broadly applicable in regenerative medicine. In this chapter we discuss how patient- and disease-specific iPS cells as well as adult stem cells are changing the pace of biomedical research and the translational landscape.
Published:
2017
Title:
Prostate-specific IL-6 transgene autonomously induce prostate neoplasm through amplifying inflammation in the prostate and peri-prostatic adipose tissue
Authors:
Liu, Gang; Zhang, Jinyu; Frey, Lewis; Gang, Xiao; Wu, Kongming; Liu, Qian; Lilly, Michael; Wu, Jennifer
Abstract:
BACKGROUND: The causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level. However, whether and how IL-6 may play a role in prostate cancer risk and development is not well defined. One limitation factor to acquiring this knowledge is the lack of appropriate animal models. METHODS: We generated a novel line of prostate-specific IL-6 transgenic mouse model. We compared the prostate pathology, tumorigenic signaling components, and prostate tumor microenvironment of the IL-6 transgenic mice with wild type littermates. RESULTS: With this model, we demonstrate that IL-6 induces prostate neoplasm autonomously. We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways, induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue, upregulates paracrine insulin-like growth factor (IGF) signaling axis, reprograms prostate oncogenic gene expression, and more intriguingly, amplifies inflammation in the prostate and peri-prostatic adipose tissue. CONCLUSIONS: The pro-inflammatory IL-6 is autonomous oncogene for the prostate. IL-6 induces prostate oncogenesis through amplifying local inflammation. We also presented a valuable animal model to study inflammation and prostate cancer development.
Published:
2017
Title:
Putative model for heat shock protein 70 complexation with receptor of advanced glycation end products through fluorescence proximity assays and normal mode analyses
Authors:
Grunwald, M.S.; Ligabue-Braun, R.; Souza, C.S.; Heimfarth, L.; Verli, H.; Gelain, D.P.; Moreira, J.C.F.
Abstract:
Extracellular heat shock protein 70 (HSP70) is recognized by receptors on the plasma membrane, such as Toll-like receptor 4 (TLR4), TLR2, CD14, and CD40. This leads to activation of nuclear factor-kappa B (NF-κB), release of pro-inflammatory cytokines, enhancement of the phagocytic activity of innate immune cells, and stimulation of antigen-specific responses. However, the specific characteristics of HSP70 binding are still unknown, and all HSP70 receptors have not yet been described. Putative models for HSP70 complexation to the receptor for advanced glycation endproducts (RAGEs), considering both ADP- and ATP-bound states of HSP70, were obtained through molecular docking and interaction energy calculations. This interaction was detected and visualized by a proximity fluorescence-based assay in A549 cells and further analyzed by normal mode analyses of the docking complexes. The interacting energy of the complexes showed that the most favored docking situation occurs between HSP70 ATP-bound and RAGE in its monomeric state. The fluorescence proximity assay presented a higher number of detected spots in the HSP70 ATP treatment, corroborating with the computational result. Normal-mode analyses showed no conformational deformability in the interacting interface of the complexes. Results were compared with previous findings in which oxidized HSP70 was shown to be responsible for the differential modulation of macrophage activation, which could result from a signaling pathway triggered by RAGE binding. Our data provide important insights into the characteristics of HSP70 binding and receptor interactions, as well as putative models with conserved residues on the interface area, which could be useful for future site-directed mutagenesis studies. © 2016, Cell Stress Society International.
Published:
2017
Title:
Rabbits as Food at the end of the Upper Palaeolithic at Molí del Salt (Catalonia, Spain)
Authors:
Martínez‐Polanco, M. F.; Blasco, R.; Rosell, J.; Ibañez, N.; Vaquero, M.
Abstract:
Many factors have been causally linked to the diversification of hunting during the European Palaeolithic: declining supplies of high-ranked prey, considerable human demographic growth, reduced residential mobility, larger populations of ubiquitous small mammals and significant technological developments. However, small prey exploitation was not uniform: the European rabbit (Oryctolagus cuniculus) is the most frequent species in the Upper Palaeolithic archaeological record of the Iberian Peninsula – south and Mediterranean area – and Southern France. This is demonstrated at Molí del Salt, an Upper Palaeolithic site located at Vimbodí (Catalonia, Spain), whose mammal fauna stands out for the predominance of rabbits [91% of minimum number of individuals (n = 136)]. We analysed the faunal remains from one level [Asup (c. 12 700–13 000 cal BP)] in order to identify the agent responsible for the faunal accumulation, and to reconstruct aspects of procurement and consumption that shed light on Palaeolithic subsistence strategies in the Northeast Iberian Peninsula. Our results indicate that human agency rather than carnivore activity was responsible for the bone accumulation at Molí del Salt. We identified all the stages in the consumption sequence from skinning to ingestion. We argue that the rabbits were mostly harvested during summer or winter or both seasons. Clearly, the European rabbit was a target species for the human groups which lived at Molí del Salt providing meat, and skin. Copyright © 2016 John Wiley & Sons, Ltd.
Published:
2017
Title:
Randomized controlled trial on the impact of early-life intervention with bifidobacteria on the healthy infant fecal microbiota and metabolome
Authors:
Bazanella, Monika; Maier, Tanja V.; Clavel, Thomas; Lagkouvardos, Ilias; Lucio, Marianna; Maldonado-Gòmez, Maria X.; Autran, Chloe; Walter, Jens; Bode, Lars; Schmitt-Kopplin, Philippe; Haller, Dirk
Abstract:
Background: Early-life colonization of the intestinal tract is a dynamic process influenced by numerous factors. The impact of probiotic- supplemented infant formula on the composition and function of the infant gut microbiota is not well defined. Objective: We sought to determine the effects of a bifidobacteria- containing formula on the healthy human intestinal microbiome during the first year of life. Design: A double-blind, randomized, placebo-controlled study of newborn infants assigned to a standard whey-based formula containing a total of 107 colony-forming units (CFU)/g of Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, B. longum subspecies infantis (intervention), or to a control formula without bifidobacteria (placebo). Breastfed controls were included. Diversity and composition of fecal microbiota were determined by 16S ribosomal RNA gene amplicon sequencing, and metabolite profiles were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry over a period of 2 y. Results: Infants (n = 106) were randomly assigned to either the interventional (n = 48) or placebo (n = 49) group; 9 infants were exclusively breastfed throughout the entire intervention period of 12 mo. Infants exposed to bifidobacteria-supplemented formula showed decreased occurrence of Bacteroides and Blautia spp. associated with changes in lipids and unknown metabolites at month 1. Microbiota and metabolite profiles of intervention and placebo groups converged during the study period, and long-term colonization (24 mo) of the supplemented Bifidobacterium strains was not detected. Significant differences in microbiota and metabolites were detected between infants fed breast milk and those fed formula (P < 0.005) and between infants birthed vaginally and those birthed by cesarean delivery (P 0.05). Conclusion: The supplementation of bifidobacteria to infant diet can modulate the occurrence of specific bacteria and metabolites during early life with no detectable long-term effects. This trial was registered at germanctr.de as DRKS00003660.
Published:
2017
Title:
Rare Diseases Epidemiology: Update and Overview
Authors:
Posada De La Paz, Manuel; Taruscio, Domenica; Groft, Stephen C
Abstract:
This second edition of the book about Rare Diseases Epidemiology aims to highlight the progress of rare diseases research and related activities since the first volume published. As with the previous book, this update provides a comprehensive list of issues and adds new authors who are leaders in their different areas of expertise related to rare diseases at national and international levels. Rare diseases and orphan drugs are challenges for patients and families but also for physicians, researchers, and policy-makers in both the public and private sectors. This book aims to help all of them to address topics like health care policies, societal issues and clinical and experimental research. Readers will discover methods and procedures to address a variety of questions like cases of undiagnosed rare diseases, patient registries and biobanks, health care and public health approach to rare diseases, orphan drugs and new therapies, cost-effectiveness analyses, prevention, clinical and epidemiology of individual and groups of related rare diseases, novel advances in study design and data analyses, national and international policies and social issues. Within each one of these general issues, advances, new challenges and opportunities to address significant health care issues are described across thirty-two chapters. Editors and all authors providing chapters include globally recognized experts in different areas of rare diseases, including epidemiology, public health, health economics and pharmacology, statistics, and basic, clinical and translational research. People engaged in policy formulation decisions on rare diseases as well as patient representatives relate their own point of view about social constraints they live under on a daily basis. Renowned research investigators, highly-skilled clinicians, and recognized patient leaders are included as contributing authors to this new book about rare diseases. In fact, two of the editors are the current President and President Elect of the International Conference on Rare Diseases and Orphan Drugs and the third one is a board member of this society. The book has been written for all stakeholders but mainly for those involved in the many issues related to rare diseases. They can discover new ways for dealing with important matters related to the prevention, diagnosis, natural history, treatments, and research of rare diseases and the development of orphan products.
Published:
2017
Title:
Rare disease biospecimens and patient registries: Interoperability for research promotion, a European example: EuroBioBank and SpainRDR-BioNER
Authors:
Rubinstein, Yaffa R.; Posada De La Paz, Manuel; Mora, Marina
Abstract:
Well-annotated and properly preserved specimens are crucial both for diagnostic purposes and for use in basic and pre-clinical research, and are especially important for rare disease (RD) studies. Several consortia have been established in the recent years in order to facilitate research and to maximise access to rare biological samples and data stored in rare disease biobanks and registries, among them the EuroBioBank network and the Spain National Rare Disease Registry (RDR) and Biobank (BioNER). EuroBioBank, established in 2001, was the first network of RD biobanks to operate in Europe as a service distributing human DNA, cells, and tissue to the scientific community conducting research on rare diseases. The Spanish RDR and BioNER were created for facilitating rare disease research and health-related matters. The coordination of these two bodies represents an example of great scientific value as biological samples donated by patients at BioNER are linked to clinical information collected in the RDR. Rare disease biobanks and registries will need for the future to increase their effort to improve interconnection so to enable investigators to better locate samples and associated data, while protecting security of the data and privacy of the participants and adhering to international ethical and legal requirements.
Published:
2017
Title:
Rare diseases: Joining mainstream research and treatment based on reliable epidemiological data
Authors:
Groft, Stephen C.; Posada De La Paz, Manuel
Abstract:
© Springer International Publishing AG 2017. Despite growing acceptance of patient registries and natural history studies to provide useful information, the rare disease community suffers from the absence of reliable epidemiological data on the prevalence and incidence of most rare diseases in national and global populations. Likewise, the patients and health care providers lack adequate information on the pathophysiology of rare diseases and expected outcomes of these disorders. The rare diseases community includes all of the stakeholders involved in the research and development and dissemination of products and information for the diagnosis, prevention or treatment of rare diseases or conditions. To replace many of the perceptions with realities, several global efforts have been implemented to sustain and increase the reported progress with the thousands of rare diseases. The first efforts is to develop a global research infrastructure of qualified investigators to stimulate and coordinate research efforts by seeking ways to provide access to clinical trials at multi-national research sites with common protocols and multi-disciplinary research teams. Next, is the continued identification and expansion of worldwide partnerships and collaborations of Patient Advocacy Groups (PAGs), research investigators, the biopharmaceutical and medical devices industries, and the government research and regulatory agencies for a specific rare disease or group of related diseases. Gaining access to information about rare diseases, patient advocacy groups, ongoing and planned research studies and products in research protocols continue to improve the lives of patients and their families. Many basic, clinical and translational research investigators, public and private sector funding organizations, patient advocacy groups, foundations, and the pharmaceutical, biotechnology, and medical devices industries are committed to translating research discoveries that will be useful in the treatment and care of patients with rare diseases over their lifespan. Evidence from well-constructed epidemiological studies will provide the evidence that point to the value of additional clinical studies to increase the understanding of rare diseases.
Published:
2017
Title:
Rare neurodegenerative diseases: Clinical and genetic update
Authors:
Matilla-Dueñas, Antoni; Corral-Juan, Marc; Rodríguez-Palmero Seuma, Agustí; Vilas, Dolores; Ispierto, Lourdes; Morais, Sara; Sequeiros, Jorge; Alonso, Isabel; Volpini, Víctor; Serrano-Munuera, Carmen; Pintos-Morell, Guillem; Álvarez, Ramiro; Sánchez, Ivelisse
Abstract:
More than 600 human disorders afflict the nervous system. Of these, neurodegenerative diseases are usually characterised by onset in late adulthood, progressive clinical course, and neuronal loss with regional specificity in the central nervous system. They include Alzheimer's disease and other less frequent dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and Prion diseases, among others. Neurodegeneration usually affects, but is not limited to, the cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum. Although the majority of neurodegenerative diseases are sporadic, Mendelian inheritance is well documented. Intriguingly, the clinical presentations and neuropathological findingsin inherited neurodegenerative forms are often indistinguishable from those of sporadic cases, suggesting that converging genomic signatures and pathophysiologic mechanisms underlie both hereditary and sporadic neurodegenerative diseases. Unfortunately, effective therapies for these diseases are scarce to non-existent. In this chapter, we highlight the clinical and genetic features associated with the rare inherited forms of neurodegenerative diseases, including ataxias, multiple system atrophy, spastic paraplegias, Parkinson's disease, dementias, motor neuron diseases, and rare metabolic disorders.
Published:
2017
Title:
Relationship among age, insulin resistance, and blood pressure
Authors:
Jung, Chan Hee; Jung, Sang Hee; Lee, Bora; Rosenberg, Melanie; Reaven, Gerald M.; Kim, Sun H.
Abstract:
The effect of age to modify the relationship between insulin resistance and hypertension is unclear. In this retrospective, cross-sectional study, median age was used to create two age groups (\textless52 vs. ≥52 years), and comparisons were made of metabolic characteristics, including steady-state plasma glucose (SSPG) concentrations measured during the insulin suppression test to quantify insulin resistance. Individuals were stratified into SSPG tertiles and categorized as having normal blood pressure (BP), prehypertension, or hypertension. SSPG concentrations were similar in the two age groups (161 vs. 164 mg/dL). In the most insulin-resistant tertile, distribution of normal BP, prehypertension, and hypertension was equal in those aged \textless52 years, whereas in those aged ≥52 years, prevalence of hypertension was increased approximately fivefold compared with those with normal BP. Multivariate regression analysis demonstrated significant interaction between age and SSPG in predicting systolic BP (P =.023). In stratified analysis, SSPG, but not age, was an independent predictor of systolic BP and diastolic BP in ≥52 years group, whereas the reverse was true in the younger group. The adverse impact of insulin resistance on BP was accentuated in older individuals and may have a greater impact than further aging.
Published:
2017
Title:
Relationship between simple markers of insulin resistance and coronary artery calcification
Authors:
Reaven, Gerald M.; Knowles, Joshua W.; Leonard, David; Barlow, Carolyn E.; Willis, Benjamin L.; Haskell, William L.; Maron, David J.
Abstract:
Background Insulin resistance in apparently healthy persons is associated with a cluster of metabolic abnormalities that promote coronary atherosclerosis. Identifying these individuals before manifest disease would provide useful clinical information. Objective We hypothesized that combining 2 simple markers of insulin resistance, prediabetes (PreDM) and triglyceride (TG) concentration ≥150 mg/dL, would identify apparently healthy persons with adverse cardiometabolic risk profiles and increased coronary artery calcium (CAC) compared with those with neither or only 1 abnormality. Methods A cross-sectional analysis was performed using data from 25,886 apparently healthy individuals (18,453 men and 7433 women) evaluated at the Cooper Clinic from 1998 to 2015. Participants were divided into those with a normal fasting glucose concentrations (\textless100 mg/dL = normal fasting glucose) or PreDM (fasting plasma glucose ≥100 and \textless126 mg/dL) and further subdivided into those with a plasma TG concentration \textless150 or ≥150 mg/dL. These 4 groups were compared on the basis of multiple coronary artery disease risk factors and the presence of CAC determined during their evaluation. Results Participants with PreDM and a TG concentration ≥150 mg/dL had a significantly more adverse coronary artery disease risk profile than individuals with either abnormality or only 1 abnormality (PreDM or TG concentration ≥150 mg/dL). Furthermore, the odds of detectable CAC were higher in participants with PreDM and a TG ≥ 150 mg/dL than in participants with neither or only 1 abnormality. Conclusion The presence of 2 markers of insulin resistance, PreDM and TG concentration ≥150 mg/dL, is associated with increased cardiometabolic risk and detectable CAC within a population of apparently healthy individuals.
Published:
2017
Title:
Rethinking the role of fat oxidation: Substrate utilisation during high-intensity interval training in well-trained and recreationally trained runners
Authors:
Hetlelid, Ken J.; Plews, Daniel J.; Herold, Eva; Laursen, Paul B.; Seiler, Stephen
Abstract:
Background: Although carbohydrate is the predominant fuel source supporting high-intensity exercise workloads, the role of fat oxidation, and the degree to which it may be altered by training status, is less certain. Methods: We compared substrate oxidation rates, using indirect calorimetry, during a high-intensity interval training (HIT) session in well-trained (WT) and recreationally trained (RT) runners. Following preliminary testing, 9 WT (VO2max 71±5 mL/min/kg) and 9 RT (VO2max 55±5 mL/min/kg) male runners performed a self-paced HIT sequence consisting of six, 4 min work bouts separated by 2 min recovery periods on a motorised treadmill set at a 5% gradient. Results: WT and RT runners performed the HIT session with the same perceived effort (rating of perceived exertion (RPE) =18.3±0.7 vs 18.2±1.1, respectively), blood lactate (6.4±2.1 vs 6.2±2.5 mmol/L) and estimated carbohydrate oxidation rates (4.2±0.29 vs 4.4±0.45 g/min; effect size (ES) 90% confidence limits (CL)=−0.19±0.85). Fat oxidation (0.64±0.13 vs 0.22±0.16 g/min for WT and RT, respectively) accounted for 33±6% of the total energy expenditure in WT vs 16±6% in RT most likely very large difference in fat oxidation (ES 90% CL=1.74±0.83) runners. Higher rates of fat oxidation had a very large correlation with VO2max (r=0.86; 90% CI (0.7 to 0.94). Conclusions: Despite similar RPE, blood lactate and carbohydrate oxidation rates, the better performance by the WT group was explained by their nearly threefold higher rates of fat oxidation at high intensity.
Published:
2017
Title:
Risk score model of type 2 diabetes prediction for rural Chinese adults: the Rural Deqing Cohort Study
Authors:
Chen, X.; Wu, Z.; Chen, Y.; Wang, X.; Zhu, J.; Wang, N.; Jiang, Q.; Fu, C.
Abstract:
Objective: Risk score (RS) model is a cost-effective tool to identify adults who are at high risk for diabetes. This study was to develop an RS model of type 2 diabetes (T2DM) prediction specifically for rural Chinese adults. Methods: A prospective whole cohort study (n = 28,251) and a sub-cohort study (n = 3043) were conducted from 2006–2014 and 2006–2008 to 2015 in rural Deqing, China. All participants were free of T2DM at baseline. Incident T2DM cases were identified through electronic health records, self-reported and fasting plasma glucose testing for the sub-cohort, respectively. RS models were constructed with coefficients (β) of Cox regression. Receiver-operating characteristic curves were plotted and the area under the curve (AUC) reflected the discriminating accuracy of an RS model. Results: By 2015, the incidence of T2DM was 3.3 and 7.7 per 1000 person-years in the whole cohort and the sub-cohort, respectively. Based on data from the whole cohort, the non-invasive RS model included age (4 points), overweight (2 points), obesity (4 points), family history of T2DM (3 points), meat diet (3 points), and hypertension (2 points). The plus-fasting plasma glucose (FPG) model added impaired fasting glucose (4 points). The AUC was 0.705 with a positive predictive value of 2.5% for the non-invasive model, and for the plus-FPG model the AUC was 0.754 with a positive predictive value of 2.5%. These models performed better as compared with 12 existing RS models for the study population. Conclusions: Our non-invasive RS model can be used to identify individuals who are at high risk of T2DM as a simple, fast, and cost-effective tool for rural Chinese adults. © 2017, Italian Society of Endocrinology (SIE).
Published:
2017
Title:
Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions
Authors:
Malhotra, Aseem; Redberg, Rita F; Meier, Pascal
Abstract:
Coronary artery disease pathogenesis and treatment urgently requires a paradigm shift. Despite popular belief among doctors and the public, the conceptual model of dietary saturated fat clogging a pipe is just plain wrong. A landmark systematic review and meta-analysis of observational studies showed no association between saturated fat consumption and (1) all-cause mortality, (2) coronary heart disease (CHD), (3) CHD mortality, (4) ischaemic stroke or (5) type 2 diabetes in healthy adults.1 Similarly in the secondary prevention of CHD there is no benefit from reduced fat, including saturated fat, on myocardial infarction, cardiovascular or all-cause mortality.2 It is instructive to note that in an angiographic study of postmenopausal women with CHD, greater intake of saturated fat was associated with less progression of atherosclerosis whereas carbohydrate and polyunsaturated fat intake were associated with greater progression.3 The inflammatory processes that contribute to cholesterol deposition within the artery wall and subsequent plaque formation (atherosclerosis), more closely resembles a ‘pimple' (figure 1). Most cardiac events occur at sites with \textless70% coronary artery obstruction and these do not \ldots
Published:
2017
Title:
Sauna Bathing and Incident Hypertension: A Prospective Cohort Study
Authors:
Zaccardi, Francesco; Laukkanen, Tanjaniina; Willeit, Peter; Kunutsor, Setor K.; Kauhanen, Jussi; Laukkanen, Jari A.
Abstract:
© American Journal of Hypertension, Ltd 2017. All rights reserved. BACKGROUND Sauna bathing is associated with reduced cardiovascular risk, but the mechanisms underlying this beneficial effect are not entirely understood. We aimed to assess the relationship between sauna bathing and risk of incident hypertension. METHODS Frequency of sauna bathing was ascertained using questionnaires in the Kuopio Ischemic Heart Disease Study, a prospective cohort study conducted in Eastern Finland that comprised a population-based sample of 1,621 men aged 42 to 60 years without hypertension at baseline. The incidence of hypertension was defined as a physician diagnosis of hypertension, systolic blood pressure (SBP) \textgreater 140 mm Hg, diastolic blood pressure \textgreater 90 mm Hg, or use of antihypertensive medication. RESULTS During a median follow-up of 24.7 years, 251 incident cases (15.5%) were recorded. In Cox regression analysis adjusted for baseline age, smoking, body mass index, and SBP; compared to participants reporting 1 sauna session per week, the hazard ratio for incident hypertension in participants reporting 2 to 3 sessions and 4 to 7 sessions was 0.76 (95% confidence interval: 0.57-1.02) and 0.54 (0.32-0.91), respectively. The corresponding hazard ratios were similar after further adjustment for glucose, creatinine, alcohol consumption, heart rate, family history of hypertension, socioeconomic status, and cardiorespiratory fitness: 0.83 (95% confidence interval: 0.59-1.18) and 0.53 (0.28-0.98), respectively. CONCLUSIONS Regular sauna bathing is associated with reduced risk of hypertension, which may be a mechanism underlying the decreased cardiovascular risk associated with sauna use. Further epidemiological and experimental studies could help elucidate the effects of sauna bathing on cardiovascular function.
Published:
2017
Title:
Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged Finnish men
Authors:
Laukkanen, Tanjaniina; Kunutsor, Setor; Kauhanen, Jussi; Laukkanen, Jari Antero
Abstract:
© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. Background: there are no previous studies linking repeated heat exposure of sauna and the risk of memory diseases. We aimed to investigate whether frequency of sauna bathing is associated with risk of dementia and Alzheimer's disease. Setting: prospective population-based study. Methods: the frequency of sauna bathing was assessed at baseline in the Kuopio Ischaemic Heart Disease populationbased prospective cohort study of 2,315 apparently healthy men aged 42-60 years at baseline, with baseline examinations conducted between 1984 and 1989. Hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia and Alzheimer's disease were ascertained using Cox-regression modelling with adjustment for potential confounders. Results: during a median follow-up of 20.7 (interquartile range 18.1-22.6) years, a total of 204 and 123 diagnosed cases of dementia and Alzheimer's disease were respectively recorded. In analysis adjusted for age, alcohol consumption, body mass index, systolic blood pressure, smoking status, Type 2 diabetes, previous myocardial infarction, resting heart rate and serum lowdensity lipoprotein cholesterol, compared with men with only 1 sauna bathing session per week, the HR for dementia was 0.78 (95% CI: 0.57-1.06) for 2-3 sauna bathing sessions per week and 0.34 (95% CI: 0.16-0.71) for 4-7 sauna bathing sessions per week. The corresponding HRs for Alzheimer's disease were 0.80 (95% CI: 0.53-1.20) and 0.35 (95% CI: 0.14-0.90). Conclusion: in this male population, moderate to high frequency of sauna bathing was associated with lowered risks of dementia and Alzheimer's disease. Further studies are warranted to establish the potential mechanisms linking sauna bathing and memory diseases.
Published:
2017
Title:
Selection in Europeans on Fatty Acid Desaturases Associated with Dietary Changes
Authors:
Buckley, Matthew T.; Racimo, Fernando; Allentoft, Morten E.; Jensen, Majken K.; Jonsson, Anna; Huang, Hongyan; Hormozdiari, Farhad; Sikora, Martin; Marnetto, Davide; Eskin, Eleazar; Jørgensen, Marit E.; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Kraft, Peter; Willerslev, Eske; Nielsen, Rasmus
Abstract:
FADS genes encode fatty acid desaturases that are important for the conversion of short chain polyunsaturated fatty acids (PUFAs) to long chain fatty acids. Prior studies indicate that the FADS genes have been subjected to strong positive selection in Africa, South Asia, Greenland, and Europe. By comparing FADS sequencing data from present-day and Bronze Age (5-3k years ago) Europeans, we identify possible targets of selection in the European population, which suggest that selection has targeted different alleles in the FADS genes in Europe than it has in South Asia or Greenland. The alleles showing the strongest changes in allele frequency since the Bronze Age show associations with expression changes and multiple lipid-related phenotypes. Furthermore, the selected alleles are associated with a decrease in linoleic acid and an increase in arachidonic and eicosapentaenoic acids among Europeans; this is an opposite effect of that observed for selected alleles in Inuit from Greenland. We show that multiple SNPs in the region affect expression levels and PUFA synthesis. Additionally, we find evidence for a gene-environment interaction influencing low-density lipoprotein (LDL) levels between alleles affecting PUFA synthesis and PUFA dietary intake: carriers of the derived allele display lower LDL cholesterol levels with a higher intake of PUFAs. We hypothesize that the selective patterns observed in Europeans were driven by a change in dietary composition of fatty acids following the transition to agriculture, resulting in a lower intake of arachidonic acid and eicosapentaenoic acid, but a higher intake of linoleic acid and α-linolenic acid.
Published:
2017
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