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Title:
Guide for Current Nutrigenetic, Nutrigenomic, and Nutriepigenetic Approaches for Precision Nutrition Involving the Prevention and Management of Chronic Diseases Associated with Obesity
Authors:
Ramos-Lopez, Omar; Milagro, Fermín I.; Allayee, Hooman; Chmurzynska, Agata; Choi, Myung Sook; Curi, Rui; De Caterina, Raffaele; Ferguson, Lynnette R.; Goni, Leticia; Kang, Jing X.; Kohlmeier, Martin; Marti, Amelia; Moreno, Luis A.; Pérusse, Louis; Prasad, Chandan; Qi, Lu; Reifen, Ram; Riezu-Boj, Jose I.; San-Cristobal, Rodrigo; Santos, Jose Luis; Martínez, J. Alfredo
Abstract:
Chronic diseases, including obesity, are major causes of morbidity and mortality in most countries. The adverse impacts of obesity and associated comorbidities on health remain a major concern due to the lack of effective interventions for prevention and management. Precision nutrition is an emerging therapeutic approach that takes into account an individual's genetic and epigenetic information, as well as age, gender, or particular physiopathological status. Advances in genomic sciences are contributing to a better understanding of the role of genetic variants and epigenetic signatures as well as gene expression patterns in the development of diverse chronic conditions, and how they may modify therapeutic responses. This knowledge has led to the search for genetic and epigenetic biomarkers to predict the risk of developing chronic diseases and personalizing their prevention and treatment. Additionally, original nutritional interventions based on nutrients and bioactive dietary compounds that can modify epigenetic marks and gene expression have been implemented. Although caution must be exercised, these scientific insights are paving the way for the design of innovative strategies for the control of chronic diseases accompanying obesity. This document provides a number of examples of the huge potential of understanding nutrigenetic, nutrigenomic, and nutriepigenetic roles in precision nutrition.
Published:
2017
Title:
Hair chemical element contents and influence factors of reproductive-age women in the West Ujimqin Banner, Inner Mongolia, China
Authors:
Zhou, S.; Yuan, H.; Ma, X.; Liu, Y.
Abstract:
Women have an increased risk for chemical element deficiencies during reproductive age, particularly due to higher chemical element requirements and poor diets. Twenty-one chemical elements (Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Pb, Se, Si, Sn, Sr, Ti, V and Zn) in hair samples, which were collected from 71 non-pregnant and 236 pregnant women living in the West Ujimqin Banner, central Inner Mongolia, China, were measured, and the environment, dietary habits and ethnic group influence factors associated with the biomarker were analyzed. The results indicated that the average values of the chemical element contents from hair were greatly different compared to those from other areas, especially the Al, Cd, Pb, Ca and Sr contents. There was no significant difference among the three ethnicities for any element except Mn and Ti in non-pregnant women. Compared to non-pregnant women, in the first trimester group, the levels of nine chemical elements (Ba, Cd, Cu, Pb, Se, Si, Sn and Ti) decreased, while the others increased, and the contents of all of the chemical elements decreased in the second trimester group, while in the third trimester, there was a slight increase. Three chemical elements (Cu, Mn and Zn) displayed a synergistic correlation between each other in the third trimester group, which may protect the placenta from some oxidant damage. The high levels of Cd and Pb in hair likely originate from house renovations and traffic pollution. This study provided basic and useful information on the levels of chemical elements in reproductive-age women, and the results of this study are helpful to control the contents and improve the health of pregnant and non-pregnant women. © 2016 Elsevier Ltd
Published:
2017
Title:
Health systems sustainability and rare diseases
Authors:
Ferrelli, Rita Maria; De Santis, Marta; Egle Gentile, Amalia; Taruscio, Domenica
Abstract:
© Springer International Publishing AG 2017. The paper is addressing aspects of health system sustainability for rare diseases in relation to the current economic crisis and equity concerns. It takes into account the results of the narrative review carried out in the framework of the Joint Action for Rare Diseases (Joint RD-Action) “Promoting Implementation of Recommendations on Policy, Information and Data for Rare Diseases”, that identified networks as key factors for health systems sustainability for rare diseases. The legal framework of European Reference Networks and their added value is also presented. Networks play a relevant role for health systems sustainability, since they are based upon, pay special attention to and can intervene on health systems knowledge development, partnership, organizational structure, resources, leadership and governance. Moreover, sustainability of health systems can not be separated from the analysis of the context and the action on it, including fiscal equity. As a result of the financial crisis of 2008, cuts of public health-care budgets jeopardized health equity, since the least wealthy suffered from the greatest health effects. Moreover, austerity policies affected economic growth much more adversely than previously believed. Therefore, reducing public health expenditure not only is going to jeopardise citizens' health, but also to hamper fair and sustainable development.
Published:
2017
Title:
Health technology assessment and appraisal of therapies for rare diseases
Authors:
Iskrov, Georgi; Miteva-Katrandzhieva, Tsonka; Stefanov, Rumen
Abstract:
© Springer International Publishing AG 2017. Innovative rare disease therapies and health technology assessment (HTA) share a lot of similarities. Both represent cases of interaction of epidemiology and health economics. Both are relatively new topics in public health practice. And both pose a lot of challenges to rare disease stakeholders who are currently looking for tools to support the timely access to innovative treatments while putting budget spending in order. This is why optimisation of assessment and appraisal of new rare disease therapies is a fundamental issue in rare disease health policy. Rare disease patients and caregivers expect prolonged life expectancy and improved quality of life and they perceive innovative health technologies as a rightful way to achieve these objectives. Multi-criteria decision analysis (MCDA) provides a structured, transparent approach to identify preferred alternatives by means of combined calculation of relative importance of different criteria and performance of the alternatives on these criteria. The labyrinth of competing interests and numerous stakeholders involved is why innovative rare disease health technologies make an excellent case study of the integration between HTA and MCDA. This kind of formalisation of decision-making is perceived as fair and legitimate, leading to a balance and agreement. MCDA provides a stage for a debate of policy priorities, health system specifics and societal attitudes, while also addressing the impact of rarity on all criteria and considerations.
Published:
2017
Title:
Herring and chicken/pork meals lead to differences in plasma levels of TCA intermediates and arginine metabolites in overweight and obese men and women
Authors:
Vincent, A.; Savolainen, O.I.; Sen, P.; Carlsson, N.-G.; Almgren, A.; Lindqvist, H.; Lind, M.V.; Undeland, I.; Sandberg, A.-S.; Ross, A.B.
Abstract:
Scope: What effect does replacing chicken or pork with herring as the main dietary source of protein have on the human plasma metabolome?. Method and results: A randomised crossover trial with 15 healthy obese men and women (age 24–70 years). Subjects were randomly assigned to four weeks of herring diet or a reference diet of chicken and lean pork, five meals per week, followed by a washout and the other intervention arm. Fasting blood serum metabolites were analysed at 0, 2 and 4 weeks for eleven subjects with available samples, using GC-MS based metabolomics. The herring diet decreased plasma citrate, fumarate, isocitrate, glycolate, oxalate, agmatine and methyhistidine and increased asparagine, ornithine, glutamine and the hexosamine glucosamine. Modelling found that the tricarboxylic acid cycle, glyoxylate, and arginine metabolism were affected by the intervention. The effect on arginine metabolism was supported by an increase in blood nitric oxide in males on the herring diet. Conclusion: The results suggest that eating herring instead of chicken and lean pork leads to important metabolic effects, particularly on energy and amino acid metabolism. Our findings support the hypothesis that there are metabolic effects of herring intake unrelated to the long chain n-3 polyunsaturated fatty acid content. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Published:
2017
Title:
High-Fat Diet in the Absence of Obesity Does Not Aggravate Surgically Induced Lymphoedema in Mice
Authors:
Gousopoulos, Epameinondas; Karaman, Sinem; Proulx, Steven T.; Leu, Kristin; Buschle, Dorina; Detmar, Michael
Abstract:
BACKGROUND Lymphoedema represents the cardinal manifestation of lymphatic dysfunction and is associated with expansion of the adipose tissue in the affected limb. In mice, high-fat diet (HFD)-induced obesity was associated with impaired collecting lymphatic vessel function, and adiposity aggravated surgery-induced lymphoedema in a mouse model. The aim of the current study was to investigate whether adiposity is necessary to impair lymphatic function or whether increased lipid exposure alone might be sufficient in a surgical lymphoedema model. METHODS To investigate the role of increased lipid exposure in lymphoedema development we used a well-established mouse tail lymphoedema model. Female mice were subjected to a short-term (6 weeks) HFD, without development of obesity, before surgical induction of lymphedema. Lymphoedema was followed over a period of 6 weeks measuring oedema, evaluating tissue histology and lymphatic vascular function. RESULTS HFD increased baseline angiogenesis and average lymphatic vessel size in comparison to the chow control group. Upon induction of lymphedema, HFD-treated mice did not exhibit aggravated oedema and no morphological differences were observed in the blood and lymphatic vasculature. Importantly, the levels of fibro-adipose tissue deposition were comparable between the 2 groups and lymphatic vessel function was not impaired as a result of the HFD. Although the net immune cell infiltration was comparable, the HFD group displayed an increased infiltration of macrophages, which exhibited an M2 polarization phenotype. CONCLUSIONS These results indicate that increased adiposity rather than dietary influences determines predisposition to or severity of lymphedema.
Published:
2017
Title:
High-Intensity Interval Training in Patients with Heart Failure with Reduced Ejection Fraction
Authors:
Ellingsen, Øyvind; Halle, Martin; Conraads, Viviane; Støylen, Asbjørn; Dalen, H\aavard; Delagardelle, Charles; Larsen, Alf Inge; Hole, Torstein; Mezzani, Alessandro; Van Craenenbroeck, Emeline M.; Videm, Vibeke; Beckers, Paul; Christle, Jeffrey W.; Winzer, Ephraim; Mangner, Norman; Woitek, Felix; Höllriegel, Robert; Pressler, Axel; Monk-Hansen, Tea; Snoer, Martin; Feiereisen, Patrick; Valborgland, Torstein; Kjekshus, John; Hambrecht, Rainer; Gielen, Stephan; Karlsen, Trine; Prescott, Eva; Linke, Axel
Abstract:
BACKGROUND Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). METHODS Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. RESULTS Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. CONCLUSIONS HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.
Published:
2017
Title:
Hladik, C. M
Authors:
Chivers, David J.
Abstract:
Marcel Hladik pioneered multidisciplinary, intercontinental research into primate feeding behavior in primates, principally in Gabon, Panama, and Sri Lanka, with detailed studies of gut anatomy and food composition and availability.
Published:
2017
Title:
Human tear proteomics and peptidomics in ophthalmology: Toward the translation of proteomic biomarkers into clinical practice
Authors:
Azkargorta, Mikel; Soria, Javier; Acera, Arantxa; Iloro, Ibon; Elortza, Felix
Abstract:
Tears are a complex biological mixture containing electrolytes, metabolites, lipids, mucins, some small organic molecules, and proteins. The tear film has various roles in the lubrication, protection from the external environment, and nutrition of the cornea; it is also involved in the modulation of the optical properties of the eye. Tear composition reflects the physiological condition of the underlying tissues. Therefore, the tear fluid is useful in the evaluation of health and disease states and it is a valuable source of biomarkers for objective analysis of ocular and systemic diseases. The relatively high protein concentration of this fluid and the ease of noninvasive sample collection make it suitable for diagnostic and prognostic purposes. Efforts in proteomics research have positively affected to the field of ophthalmology, and the knowledge on the tear proteome has expanded considerably in the last few years. Nevertheless, despite a large amount of available data and the many biomarkers proposed for several eye and systemic diseases, the extent of translation to well-characterized and clinically useful tools has been largely insufficient. As for most of other biofluids, the road from discovery to clinical application is still long and full of pitfalls. In this review, we discuss the proteomic approaches used in the characterization of tear protein and peptide content, recapitulating the main studies and the progress done. We also present a brief summary of the path from discovery to clinical application of tear protein markers, with some representative examples of translation from the bench to the bedside. SIGNIFICANCE: In this review we cover the most relevant proteomic approaches used in the characterization of the tear proteome, and for the first time we also focus in advances performed in the nowadays emerging peptide content characterization. In this context, we recapitulate on the main studies and the progresses done in this field. We also present a concise overview of the course that may be happen from discovery to clinical application for tear protein markers. Finally we include some representative examples of translation from the bench to the bedside.
Published:
2017
Title:
Humans as Agents in the Termination of the African Humid Period
Authors:
Wright, David K.
Abstract:
There is great uncertainty over the timing and magnitude of the termination of the African Humid Period (AHP). Spanning from the early to middle Holocene, the AHP was a period of enhanced moisture over most of northern and eastern Africa. However, beginning 8000 years ago the moisture balance shifted due to changing orbital precession and vegetation feedbacks. Some proxy records indicate a rapid transition from wet to dry conditions, while others indicate a more gradual changeover. Heretofore, humans have been viewed as passive agents in the termination of the AHP, responding to changing climatic conditions by adopting animal husbandry and spreading an agricultural lifestyle across the African continent. This paper explores scenarios whereby humans could be viewed as active agents in landscape denudation. During the period when agriculture was adopted in northern Africa, the regions where it was occurring were at the precipice of ecological regime shifts. Pastoralism, in particular, is argued to enhance devegetation and regime shifts in unbalanced ecosystems. Threshold crossing events were documented in the historical records of New Zealand and western North America due to the introduction of livestock. In looking at temporally correlated archaeological and paleoenvironmental records of northern Africa, similar landscape dynamics from the historical precedents are observed: reduction in net primary productivity, homogenization of the flora, transformation of the landscape into a shrub-dominated biozone and increasing xerophylic vegetation overall. Although human agents are not seen as the only forces inducing regime change during the termination of the AHP, their potential role in inducing large-scale landscape change must be properly contextualized against other global occurrences of neolithization.
Published:
2017
Title:
Identifying and targeting cancer stem cells in the treatment of gastric cancer
Authors:
Bekaii-Saab, T.; El-Rayes, B.
Abstract:
Current treatment regimens for gastric cancer are not adequate. Cancer stem cells (CSCs) may be a key driving factor for growth and metastasis of this tumor type. In contrast to the conventional clonal evolution hypothesis, CSCs can initiate tumor formation, self-renew, and differentiate into tumor-propagating cells. Because gastric cancer can originate from CSCs, it is necessary to review current targets of signaling pathways for CSCs in gastric cancer that are being studied in clinical trials. These pathways are known to regulate the self-renewal and differentiation process in gastric CSCs. A better understanding of the clinical results of trials that target gastric CSCs will lead to better outcomes for patients with gastric cancer. Cancer 2017;123:1303–1312. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Published:
2017
Title:
Immunological rare diseases
Authors:
Baldovino, Simone; Menegatti, Elisa; Roccatello, Dario; Sciascia, Savino
Abstract:
© Springer International Publishing AG 2017. The immune system is delegated to defend the body from attacks from outside or inside. Many diseases can affect immune system reducing its ability to defend self or inducing an abnormal response against external or internal antigens. Rare diseases affecting immune system present some issue in common with other rare diseases and some peculiarities due to the huge variability in the disease's expression. However, a correct estimation of the epidemiology of rare disorders is necessary for evaluating the prognosis and the responses to new therapies, for planning proper public health services, and finally to establish fair and sustainable prices for innovative medicines. Due to the enormous number of different rare immunological diseases, in this chapter we are going to analyse some of them that can be considered paradigmatic of the various expressions of disease.
Published:
2017
Title:
Impact of intermittent fasting on health and disease processes.
Authors:
Mattson, Mark P; Longo, Valter D; Harvie, Michelle
Abstract:
Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16–48 h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer's disease Parkinson's disease and stroke. Studies of IF (e.g., 60% energy restriction on 2 days per week or every other day), PF (e.g., a 5 day diet providing 750–1100 kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8 h or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging.
Published:
2017
Title:
Impact of red meat consumption on the metabolome of rats
Authors:
Jakobsen, L.M.A.; Yde, C.C.; Van Hecke, T.; Jessen, R.; Young, J.F.; De Smet, S.; Bertram, H.C.
Abstract:
Scope: The scope of the present study was to investigate the effects of red versus white meat intake on the metabolome of rats. Methods and results: Twenty-four male Sprague–Dawley rats were randomly assigned to 15 days of ad libitum feeding of one of four experimental diets: (i) lean chicken, (ii) chicken with lard, (iii) lean beef, and (iv) beef with lard. Urine, feces, plasma, and colon tissue samples were analyzed using 1H NMR-based metabolomics and real-time PCR was performed on colon tissue to examine the expression of specific genes. Urinary excretion of acetate and anserine was higher after chicken intake, while carnosine, fumarate, and trimethylamine N-oxide excretion were higher after beef intake. In colon tissue, higher choline levels and lower lipid levels were found after intake of chicken compared to beef. Expression of the apc gene was higher in response to the lean chicken and beef with lard diets. Correlation analysis revealed that intestinal apc gene expression was correlated with fecal lactate content (R2 = 0.65). Conclusion: This study is the first to identify specific differences in the metabolome related to the intake of red and white meat. These differences may reflect perturbations in endogenous metabolism that can be linked to the proposed harmful effects associated with intake of red meat. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Published:
2017
Title:
Improved diagnosis and care for rare diseases through implementation of precision public health framework
Authors:
Baynam, Gareth; Bowman, Faye; Lister, Karla; Walker, Caroline E.; Pachter, Nicholas; Goldblatt, Jack; Boycott, Kym M.; Gahl, William A.; Kosaki, Kenjiro; Adachi, Takeya; Ishii, Ken; Mahede, Trinity; McKenzie, Fiona; Townshend, Sharron; Slee, Jennie; Kiraly-Borri, Cathy; Vasudevan, Anand; Hawkins, Anne; Broley, Stephanie; Schofield, Lyn; Verhoef, Hedwig; Groza, Tudor; Zankl, Andreas; Robinson, Peter N.; Haendel, Melissa; Brudno, Michael; Mattick, John S.; Dinger, Marcel E.; Roscioli, Tony; Cowley, Mark J.; Olry, Annie; Hanauer, Marc; Alkuraya, Fowzan S.; Taruscio, Domenica; Posada De La Paz, Manuel; Lochmüller, Hanns; Bushby, Kate; Thompson, Rachel; Hedley, Victoria; Lasko, Paul; Mina, Kym; Beilby, John; Tifft, Cynthia; Davis, Mark; Laing, Nigel G.; Julkowska, Daria; Le Cam, Yann; Terry, Sharon F.; Kaufmann, Petra; Eerola, Iiro; Norstedt, Irene; Rath, Ana; Suematsu, Makoto; Groft, Stephen C.; Austin, Christopher P.; Draghia-Akli, Ruxandra; Weeramanthri, Tarun S.; Molster, Caron; Dawkins, Hugh J.S.
Abstract:
Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the ‘person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards ‘precision public health'. Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 20152018 (RD Framework) and Australian government health briefings on the need for a National plan. The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population. Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging ‘precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families. The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.
Published:
2017
Title:
Incentivizing orphan product development: United States food and drug administration orphan incentive programs
Authors:
Le, Tran T.
Abstract:
Over 30 years ago, the United States (US) Congress passed the Orphan Drug Act (ODA) to encourage the development of products for rare diseases or conditions (“orphan products”). The Act provided incentives to sponsors for developing products with orphan designation and established a grant program to fund studies of orphan products. Since its enactment in 1983, the ODA has been credited for bringing more than 590 orphan drugs to the market, inspiring the implementation of orphan legislation globally, and enabling the creation of other programs that extend existing knowledge of the natural history of rare diseases and stimulate the development of medical devices for children and patients with rare diseases. This chapter provides a brief overview of the main features and successes of 5 of the orphan incentive programs administered by the US Food and Drug Administration (FDA): the Orphan Drug Designation Program, the Humanitarian Use Device (HUD) Designation Program, the Orphan Products Clinical Trials Grants Program, the Pediatric Device Consortia (PDC) Grant Program, and the Orphan Products Natural History Grants Program.
Published:
2017
Title:
Indigenous genetics and rare diseases: Harmony, diversity and equity
Authors:
Baynam, Gareth; Molster, Caron; Bauskis, Alicia; Kowal, Emma; Savarirayan, Ravi; Kelaher, Margaret; Easteal, Simon; Massey, Libby; Garvey, Gail; Goldblatt, Jack; Pachter, Nicholas; Weeramanthri, Tarun S.; Dawkins, Hugh J.S.
Abstract:
Advances in our understanding of genetic and rare diseases are changing the face of healthcare. Crucially, the global community must implement these advances equitably to reduce health disparities, including between Indigenous and non-Indigenous peoples. We take an Australian perspective to illustrate some key areas that are fundamental to the equitable translation of new knowledge for the improved diagnosis of genetic and rare diseases for Indigenous people. Specifically, we focus on inequalities in access to clinical genetics services and the lack of genetic and phenomic reference data to inform diagnoses. We provide examples of ways in which these inequities are being addressed through Australian partnerships to support a harmonious and inclusive approach to ensure that benefits from traditional wisdom, community knowledge and shared experiences are interwoven to support and inform implementation of new knowledge from genomics and precision public health. This will serve to deliver benefits to all of our diverse citizens, including Indigenous populations.
Published:
2017
Title:
Influence of Diet on the Course of Inflammatory Bowel Disease
Authors:
Tasson, L.; Canova, C.; Vettorato, M.G.; Savarino, E.; Zanotti, R.
Abstract:
Background: While the importance of diet in the pathogenesis of inflammatory bowel disease (IBD) is generally recognized, influence of food on the course of IBD is little understood. Aim: The purpose of this study was to assess the association between food intake and course of disease in patients with IBD. Methods: We performed a cross-sectional study on 103 adult patients (50 with active disease and 53 in remission, divided by their calprotectin level), who completed a food frequency questionnaire on their intake of several foods over 1 year. Diet, as assessed using a 146-item self-administered food frequency questionnaire, was correlated with objective evidence of disease based on fecal calprotectin levels. Results: Legumes and potato were inversely associated with disease relapse (p value for trend 0.023) with patients in the highest quartile for legume and potato consumption carrying a 79% lower risk of active disease (adjusted OR 0.21, 95% CI 0.57–0.81). A positive association emerged between meat intake and disease relapse, the highest quartile for meat consumption coinciding with a higher risk of active disease (OR 3.61, 95% CI 1.15–11.38), though this was not significant in the adjusted analysis. No statistically significant associations were found between disease relapse and the intake of vegetables, cereals, dairy products, or fish. Conclusions: Our results suggest a potentially protective role of legumes and potato and a detrimental influence of meat in maintaining clinical remission in IBD patients. These findings have important public health implications, but further interventional studies will be needed to demonstrate these associations. © 2017, Springer Science+Business Media New York.
Published:
2017
Title:
Intellectual disability & rare disorders: A diagnostic challenge
Authors:
Kvarnung, Malin; Nordgren, Ann
Abstract:
Rare disorders constitute a large and heterogeneous group of diagnoses of which many cause chronic disabilities with significant impact on the lives of affected individuals and their families as well as on the health-care system. Each individual disorder is rare, but when considered as a group, rare disorders are common with a total prevalence of approximately 6-8%. The clinical presentation of these disorders includes a broad diversity of symptoms and signs, often involving the nervous system and resulting in symptoms such as intellectual disability, neuropsychiatric disorders, epilepsy and motor dysfunction. The methods for establishing an etiological diagnosis in patients with rare disorders have improved dramatically during recent years. With the introduction of genomic screening methods, it has been shown that the cause is genetic in the majority of the patients and many will receive an etiological diagnosis in a clinical setting. However, there are a lot of challenges in diagnosing these disorders and despite recent years' advances, a large number of patients with rare disorders still go without an etiological diagnosis. In this chapter we will review the etiology of rare disorders with focus on intellectual disability and what has been learned from massive parallel sequencing studies in deciphering the genetic basis. Furthermore, we will discuss challenges in the etiological diagnostics of these disorders including issues that regard interpretation of the numerous genetic variants detected by genomic screening methods and challenges in the translation of massive parallel sequencing technologies into clinical practice.
Published:
2017
Title:
Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs
Authors:
Zanoni, Ivan; Granucci, Francesca; Broggi, Achille
Abstract:
Type III interferons (IFNs) (or IFN-λ) are the latest addition to the interferon family. Even though they share little protein homology with type I interferon, both exhibit remarkable functional similarities: each can be induced in response to viral infections, and both lead to Janus Kinases (JAKs) and signal transducer and activator of transcription (STATs) activation. The JAK/STAT pathway induces antiviral responses and interferon-stimulated gene (ISG) transcription. However, despite the similarities in their effector functions with type I interferons, IFN-λ also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-λ rather than type I interferons; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-λ, is highly expressed on cells of epithelial lineage. Thus far, IFN-λ has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-λ. Moreover, in many in vivo models, IFN-λ modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here we critically review the recent literature on immune modulatory roles for IFN-λ, and distinguish between the direct and indirect effects of this interferon on immune cell functions in different inflammatory settings.
Published:
2017
Title:
Interferon-λs: Front-Line Guardians of Immunity and Homeostasis in the Respiratory Tract
Authors:
Andreakos, Evangelos; Salagianni, Maria; Galani, Ioanna E.; Koltsida, Ourania
Abstract:
Type III interferons (IFNs), also termed lambda IFNs (IFNLs) or interleukins-28-29, constitute a new addition to the interferon family. They are induced upon infection and are particularly abundant at barrier surfaces such as the respiratory and gastrointestinal tracts. Although they signal through a unique heterodimeric receptor complex comprising IFNLRα and IL-10Rβ, they activate a downstream signaling pathway remarkably similar to that of type I IFNs and share many functions with them. Yet, they also have important differences which are only now starting to unfold. Here, we review the current literature implicating type III IFNs in the regulation of immunity and homeostasis in the respiratory tract. We survey the common and unique characteristics of type III IFNs in terms of expression patterns, cellular targets and biological activities, and discuss their emerging role in first line defenses against respiratory viral infections. We further explore their immune modulatory functions and their involvement in the regulation of inflammatory responses during chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease. Type III IFNs are therefore arising as front line guardians of immune defenses in the respiratory tract, fine tuning inflammation, and as potential novel therapeutics for the treatment of diverse respiratory diseases including influenza virus infection and asthma.
Published:
2017
Title:
Interweaving Ideas and Patchwork Programmes: Nutrition Projects in Colonial Fiji, 1945–60
Authors:
Hartley, Sarah Clare
Abstract:
The influence of a range of actors is discernible in nutrition projects during the period after the Second World War in the South Pacific. Influences include: international trends in nutritional science, changing ideas within the British establishment about state responsibility for the welfare of its citizens and the responsibility of the British Empire for its subjects; the mixture of outside scrutiny and support for projects from post-war international and multi-governmental organisations, such as the South Pacific Commission. Nutrition research and projects conducted in Fiji for the colonial South Pacific Health Service and the colonial government also sought to address territory-specific socio-political issues, especially Fiji’s complex ethnic poli,tics. This study examines the subtle ways in which nutrition studies and policies reflected and reinforced these wider socio-political trends. It suggests that historians should approach health research and policy as a patchwork of territorial, international, and regional ideas and priorities, rather than looking for a single causality.
Published:
2017
Title:
Invited Review: Measurable biomarkers linked to meat quality from different pig production systems
Authors:
Te Pas, M.F.W.; Lebret, B.; Oksbjerg, N.
Abstract:
Biological processes underlie all livestock traits, including post-mortem meat quality traits. Biomarkers are molecular components of the biological processes showing differential expression associated with the phenotype of the trait. The phenotypes of the meat quality traits are determined by the animal's genotype interacting with the environment affecting the expression of the genome. The omics technologies enable measuring the expression of the genome at all levels: Transcriptome, proteome, and metabolome. Associations between the phenotype of the traits and expressions measured with the omics techniques are a first step in developing biomarkers. Biomarkers enable the monitoring, diagnosis, and prediction of changes in meat quality related to external (environmental, e.g. feed and animal management conditions) stimuli and interactions with the genotype. In this paper we review the development of biomarkers for meat quality of pigs in diverse pig breeds, environments, and pork production chains.
Published:
2017
Title:
Is Salt a Culprit or an Innocent Bystander in Hypertension? A Hypothesis Challenging the Ancient Paradigm
Authors:
DiNicolantonio, James J.; Mehta, Varshil; O'Keefe, James H.
Abstract:
For decades the notion that an excessive consumption of salt (NaCl) leads to hypertension has persisted. However, this idea is based on opinion, not scientific proof. Despite this, every health organization, agency, and clinicians around the world have been advising salt restriction, especially to hypertensive patients. The present review article suggests that the consumption of a high-salt diet is not the cause of hypertension and that there are other factors, such as added sugars, which are causative for inducing hypertension and cardiovascular disease.
Published:
2017
Title:
Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution
Authors:
Hu, Wen-Yang; Hu, Dan-Ping; Xie, Lishi; Li, Ye; Majumdar, Shyama; Nonn, Larisa; Hu, Hong; Shioda, Toshi; Prins, Gail S.
Abstract:
Using primary cultures of normal human prostate epithelial cells, we developed a novel prostasphere-based, label-retention assay that permits identification and isolation of stem cells at a single cell level. Their bona fide stem cell nature was corroborated using in vitro and in vivo regenerative assays and documentation of symmetric/asymmetric division. Robust WNT10B and KRT13 levels without E-cadherin or KRT14 staining distinguished individual stem cells from daughter progenitors in spheroids. Following FACS to isolate label-retaining stem cells from label-free progenitors, RNA-seq identified unique gene signatures for the separate populations which may serve as useful biomarkers. Knockdown of KRT13 or PRAC1 reduced sphere formation and symmetric self-renewal highlighting their role in stem cell maintenance. Pathways analysis identified ribosome biogenesis and membrane estrogen-receptor signaling enriched in stem cells with NF-ĸB signaling enriched in progenitors; activities that were biologically confirmed. Further, bioassays identified heightened autophagy flux and reduced metabolism in stem cells relative to progenitors. These approaches similarly identified stem-like cells from prostate cancer specimens and prostate, breast and colon cancer cell lines suggesting wide applicability. Together, the present studies isolate and identify unique characteristics of normal human prostate stem cells and uncover processes that maintain stem cell homeostasis in the prostate gland.
Published:
2017
Title:
Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: A positron emission tomography study
Authors:
Gormsen, Lars C.; Svart, Mads; Thomsen, Henrik Holm; Søndergaard, Esben; Vendelbo, Mikkel H.; Christensen, Nana; Tolbod, Lars Poulsen; Harms, Hendrik Johannes; Nielsen, Roni; Wiggers, Henrik; Jessen, Niels; Hansen, Jakob; Bøtker, Hans Erik; Møller, Niels
Abstract:
BACKGROUND High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and-most recently-treatment with sodium-glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow. METHODS AND RESULTS Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na-3-hydroxybutyrate (KETONE) or (2) during 390 minutes infusion of saline (SALINE), together with a concomitant low-dose hyperinsulinemic-euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by (15)O-H2O positron emission tomography/computed tomography, myocardial fatty acid metabolism by (11)C-palmitate positron emission tomography/computed tomography and MGU by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na-3-hydroxybutyrate infusion increased circulating Na-3-hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia (MGU [nmol/g per minute]: 304±97 [SALINE] versus 156±62 [KETONE], P\textless0.01), whereas no effects were observed on palmitate uptake oxidation or esterification. Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%. CONCLUSIONS Ketone bodies displace MGU and increase myocardial blood flow in healthy humans; these novel observations suggest that ketone bodies are important cardiac fuels and vasodilators, which may have therapeutic potentials.
Published:
2017
Title:
Landscape scale heterogeneity in the East Turkana ecosystem during the Okote Member (1.56-1.38 Ma)
Authors:
Patterson, D. B.; Braun, D. R.; Behrensmeyer, A. K.; Lehmann, S. B.; Merritt, S. R.; Reeves, J. S.; Wood, B. A.; Bobe, R.
Abstract:
Placing the biological adaptations of Pleistocene hominins within a well-resolved ecological framework has been a longstanding goal of paleoanthropology. This effort, however, has been challenging due to the discontinuous nature of paleoecological data spanning many important periods in hominin evolution. Sediments from the Upper Burgi (1.98-1.87 Ma), KBS (1.87-1.56 Ma) and Okote (1.56-1.38 Ma) members of the Koobi Fora Formation at East Turkana in northern Kenya document an important time interval in the evolutionary history of the hominin genera Homo and Paranthropus. Although much attention has been paid to Upper Burgi and KBS member deposits, far less is known regarding the East Turkana paleoecosystem during Okote Member times. This study pairs spatially-resolved faunal abundance data with stable isotope geochemistry from mammalian enamel to investigate landscape-scale ecosystem variability during Okote Member times. We find that during this period 1) taxa within the East Turkana large mammal community were distributed heterogeneously across space, 2) the abundance of C3 and C4 vegetation varied between East Turkana subregions, and 3) the Karari subregion, an area with abundant evidence of hominin stone tool manufacture, had significantly more C3 vegetation than regions closer to the central axis of the Turkana Basin (i.e., Ileret and Koobi Fora). These findings indicate that the East Turkana paleoecosystem during the Okote Member was highly variable across space and provided a complex adaptive landscape for Pleistocene hominins.
Published:
2017
Title:
Lipoprotein insulin resistance score and risk of incident diabetes during extended follow-up of 20 years: The Women's Health Study
Authors:
Harada, Paulo H.N.; Demler, Olga V.; Dugani, Sagar B.; Akinkuolie, Akintunde O.; Moorthy, Manickavasagar V.; Ridker, Paul M.; Cook, Nancy R.; Pradhan, Aruna D.; Mora, Samia
Abstract:
Background Type II diabetes (T2D) is preceded by prolonged insulin resistance and relative insulin deficiency incompletely captured by glucose metabolism parameters, high-density lipoprotein (HDL) cholesterol and triglycerides. Objective Whether lipoprotein insulin resistance (LPIR) score, a metabolomic marker, is associated with incident diabetes and improves risk reclassification over traditional markers on extended follow-up. Methods Among 25,925 nondiabetic women aged 45 years or older, LPIR was measured by nuclear magnetic resonance spectroscopy as a weighted score of very low density lipoprotein, low-density lipoprotein, and HDL particle sizes, and their subsets concentrations. We run adjusted cox regression models for LPIR with incident T2D (20.4 years median follow-up). Results Adjusting for demographics, body mass index, life style factors, blood pressure, and T2D family history, the LPIR hazard ratio for T2D (hazard ratio [HR] per standard deviation, 95% confidence interval) was 1.95 (1.85, 2.06). Further adjusting for HbA1c, C-reactive protein, triglycerides, HDL and low-density lipoprotein cholesterol, LPIR HR was attenuated to 1.41 (1.31, 1.53) and had the strongest association with T2D after HbA1C in mutually adjusted models. The association persisted even in those with optimal clinical profiles, adjusted HR per standard deviation 1.91 (1.17, 3.13). In participants deemed at intermediate T2D risk by the Framingham Offspring T2D score, LPIR led to a net reclassification of 0.145 (0.117, 0.175). Conclusion In middle-aged or older healthy women followed prospectively for over 20 years, LPIR was robustly associated with incident T2D, including among those with an optimal clinical metabolic profile. LPIR improved T2D risk classification and may guide early and targeted prevention strategies.
Published:
2017
Title:
Loss of ABHD5 promotes the aggressiveness of prostate cancer cells
Authors:
Chen, Guohua; Zhou, Guoli; Aras, Siddhesh; He, Zhenhui; Lucas, Stephanie; Podgorski, Izabela; Skar, Wael; Granneman, James G.; Wang, Jian
Abstract:
The accumulation of neutral lipids in intracellular lipid droplets has been associated with the formation and progression of many cancers, including prostate cancer (PCa). Alpha-beta Hydrolase Domain Containing 5 (ABHD5) is a key regulator of intracellular neutral lipids that has been recently identified as a tumor suppressor in colorectal cancer, yet its potential role in PCa has not been investigated. Through mining publicly accessible PCa gene expression datasets, we found that ABHD5 gene expression is markedly decreased in metastatic castration-resistant PCa (mCRPC) samples. We further demonstrated that RNAi-mediated ABHD5 silencing promotes, whereas ectopic ABHD5 overexpression inhibits, the invasion and proliferation of PCa cells. Mechanistically, we found that ABHD5 knockdown induces epithelial to mesenchymal transition, increasing aerobic glycolysis by upregulating the glycolytic enzymes hexokinase 2 and phosphofrucokinase, while decreasing mitochondrial respiration by downregulating respiratory chain complexes I and III. Interestingly, knockdown of ATGL, the best-known molecular target of ABHD5, impeded the proliferation and invasion, suggesting an ATGL-independent role of ABHD5 in modulating PCa aggressiveness. Collectively, these results provide evidence that ABHD5 acts as a metabolic tumor suppressor in PCa that prevents EMT and the Warburg effect, and indicates that ABHD5 is a potential therapeutic target against mCRPC, the deadly aggressive PCa.
Published:
2017
Title:
Mass spectrometric based approaches in urine metabolomics and biomarker discovery
Authors:
Khamis, Mona M.; Adamko, Darryl J.; El-Aneed, Anas
Abstract:
Urine metabolomics has recently emerged as a prominent field for the discovery of non-invasive biomarkers that can detect subtle metabolic discrepancies in response to a specific disease or therapeutic intervention. Urine, compared to other biofluids, is characterized by its ease of collection, richness in metabolites and its ability to reflect imbalances of all biochemical pathways within the body. Following urine collection for metabolomic analysis, samples must be immediately frozen to quench any biogenic and/or non-biogenic chemical reactions. According to the aim of the experiment; sample preparation can vary from simple procedures such as filtration to more specific extraction protocols such as liquid-liquid extraction. Due to the lack of comprehensive studies on urine metabolome stability, higher storage temperatures (i.e. 4°C) and repetitive freeze-thaw cycles should be avoided. To date, among all analytical techniques, mass spectrometry (MS) provides the best sensitivity, selectivity and identification capabilities to analyze the majority of the metabolite composition in the urine. Combined with the qualitative and quantitative capabilities of MS, and due to the continuous improvements in its related technologies (i.e. ultra high-performance liquid chromatography [UPLC] and hydrophilic interaction liquid chromatography [HILIC]), liquid chromatography (LC)-MS is unequivocally the most utilized and the most informative analytical tool employed in urine metabolomics. Furthermore, differential isotope tagging techniques has provided a solution to ion suppression from urine matrix thus allowing for quantitative analysis. In addition to LC-MS, other MS-based technologies have been utilized in urine metabolomics. These include direct injection (infusion)-MS, capillary electrophoresis-MS and gas chromatography-MS. In this article, the current progresses of different MS-based techniques in exploring the urine metabolome as well as the recent findings in providing potentially diagnostic urinary biomarkers are discussed. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:115-134, 2017.
Published:
2017
Title:
Meal Frequency and Timing Are Associated with Changes in Body Mass Index in Adventist Health Study 2
Authors:
Kahleova, Hana; Lloren, Jan Irene; Mashchak, Andrew; Hill, Martin; Fraser, Gary E.
Abstract:
Background: Scientific evidence for the optimal number, timing, and size of meals is lacking.Objective: We investigated the relation between meal frequency and timing and changes in body mass index (BMI) in the Adventist Health Study 2 (AHS-2), a relatively healthy North American cohort.Methods: The analysis used data from 50,660 adult members aged ≥30 y of Seventh-day Adventist churches in the United States and Canada (mean ± SD follow-up: 7.42 ± 1.23 y). The number of meals per day, length of overnight fast, consumption of breakfast, and timing of the largest meal were exposure variables. The primary outcome was change in BMI per year. Linear regression analyses (stratified on baseline BMI) were adjusted for important demographic and lifestyle factors.Results: Subjects who ate 1 or 2 meals/d had a reduction in BMI per year (in kg · m-2 · y-1) (-0.035; 95% CI: -0.065, -0.004 and -0.029; 95% CI: -0.041, -0.017, respectively) compared with those who ate 3 meals/d. On the other hand, eating >3 meals/d (snacking) was associated with a relative increase in BMI (P < 0.001). Correspondingly, the BMI of subjects who had a long overnight fast (≥18 h) decreased compared with those who had a medium overnight fast (12-17 h) (P < 0.001). Breakfast eaters (-0.029; 95% CI: -0.047, -0.012; P
Published:
2017
Title:
Meat and Nicotinamide: A Causal Role in Human Evolution, History, and Demographics
Authors:
Williams, Adrian C.; Hill, Lisa J.
Abstract:
Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B3 /nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the ‘de novo’ tryptophan-to-kynurenine-nicotinamide ‘immune tolerance’ pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital.
Published:
2017
Title:
Meat consumption reduction in Italian regions: Health co-benefits and decreases in GHG emissions
Authors:
Farchi, Sara; De Sario, Manuela; Lapucci, Enrica; Davoli, Marina; Michelozzi, Paola
Abstract:
INTRODUCTION: Animal agriculture has exponentially grown in recent decades in response to the rise in global demand for meat, even in countries like Italy that traditionally eat a Mediterranean, plant-based diet. Globalization related dietary changes are contributing to the epidemic of non-communicable diseases and to the global climate crisis, and are associated with huge carbon and water footprints. The objective of the study is to assess inequalities in health impacts and in attributable greenhouse gases-GHG emissions in Italy by hypothesizing different scenarios of reduction in red and processed meat consumption towards healthier consumption patterns more compliant with the recommendations of the Mediterranean food pyramid. METHODS: We used demographic and food consumption patterns from national surveys and risk relationships between meat intake and cardiovascular and colorectal cancer mortality from IARC and other meta-analyses. From the baseline data (year 2005-2006, average 406 gr/week beef and 245 gr/week processed meat), we considered hypothetical meat reduction scenarios according to international dietary guidelines such as the Mediterranean pyramid targets. For each geographical area (Northwest, Northeast, Centre, and South) and gender, we calculated the number of avoidable deaths from colorectal cancer, and cardiovascular disease among the adult population. Moreover, years of life gained by the adult population from 2012 to 2030 and changes in life expectancy of the 2012 birth cohort were quantified using gender-specific life tables. GHG emission reductions under Mediterranean scenario were estimated only for beef by applying the Global Warming Potential (GWP) coefficient to total consumption and to a low carbon food substitution in adult diet. RESULTS: The deaths avoidable (as percentage change compared to baseline) according to the three reduction scenarios for beef consumption were between 2.3% and 4.5% for colorectal cancer, and between 2.1% and 4.0% for cardiovascular disease; higher benefits would be observed in Northwestern areas and among males. In parallel, 5% and 6.4% of colorectal cancer and CVD deaths would be avoided if the Italian population ate the advised quantity of processed meat. Life table analysis suggests that the scenario that is fully compliant with the Mediterranean diet model would save 5 million years of life lost prematurely among men and women over the next 18 years and would increase average life expectancy of future generations by over 7 months. Considering the environmental impact, emissions associated with the actual total intake of beef range from 12,900 to 21,800 Gg CO2 eq; emissions saved according to the Mediterranean scenario are in the range 8000-14000 Gg CO2 eq per year. The per capita reduction is 263 KgCO2eq/year/person with higher reductions in Northwestern and Central areas. CONCLUSIONS: In Italy, scenarios for reducing beef consumption are consistent with significant health and environmental co-benefits on current and future generations. Results support introducing policies to promote healthier behavior towards red and processed meat in the adult population within an overall balanced and healthy dietary pattern. Interventions should address gender, vulnerable population groups, and geographical differences in order to be more effective.
Published:
2017
Title:
Meditation and cardiovascular risk reduction a scientific statement from the American Heart Association
Authors:
Levine, Glenn N.; Lange, Richard A.; Bairey-Merz, C. Noel; Davidson, Richard J.; Jamerson, Kenneth; Mehta, Puja K.; Michos, Erin D.; Norris, Keith; Ray, Indranill Basu; Saban, Karen L.; Shah, Tina; Stein, Richard; Smith, Sidney C.
Abstract:
Despite numerous advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains a leading cause of morbidity and mortality. Novel and inexpensive interventions that can contribute to the primary and secondary prevention of cardiovascular disease are of interest. Numerous studies have reported on the benefits of meditation. Meditation instruction and practice is widely accessible and inexpensive and may thus be a potential attractive cost-effective adjunct to more traditional medical therapies. Accordingly, this American Heart Association scientific statement systematically reviewed the data on the potential benefits of meditation on cardiovascular risk. Neurophysiological and neuroanatomical studies demonstrate that meditation can have long-standing effects on the brain, which provide some biological plausibility for beneficial consequences on the physiological basal state and on cardiovascular risk. Studies of the effects of meditation on cardiovascular risk have included those investigating physiological response to stress, smoking cessation, blood pressure reduction, insulin resistance and metabolic syndrome, endothelial function, inducible myocardial ischemia, and primary and secondary prevention of cardiovascular disease. Overall, studies of meditation suggest a possible benefit on cardiovascular risk, although the overall quality and, in some cases, quantity of study data are modest. Given the low costs and low risks of this intervention, meditation may be considered as an adjunct to guideline-directed cardiovascular risk reduction by those interested in this lifestyle modification, with the understanding that the benefits of such intervention remain to be better established. Further research on meditation and cardiovascular risk is warranted. Such studies, to the degree possible, should utilize randomized study design, be adequately powered to meet the primary study outcome, strive to achieve low drop-out rates, include long-term follow-up, and be performed by those without inherent bias in outcome.
Published:
2017
Title:
Melatonin Natural Health Products and Supplements: Presence of serotonin and significant variability of melatonin content
Authors:
Erland, Lauren A.E.; Saxena, Praveen K.
Abstract:
STUDY OBJECTIVES Melatonin is an important neurohormone, which mediates circadian rhythms and the sleep cycle. As such, it is a popular and readily available supplement for the treatment and prevention of sleep-related disorders including insomnia and jet lag. This study quantified melatonin in 30 commercial supplements, comprising different brands and forms and screened supplements for the presence of serotonin. METHODS A total of 31 supplements were analyzed by ultraperformance liquid chromatography with electrochemical detection for quantification of melatonin and serotonin. Presence of serotonin was confirmed through analysis by ultraperformance liquid chromatography with mass spectrometry detection. RESULTS Melatonin content was found to range from -83% to +478% of the labelled content. Additionally, lot-to-lot variable within a particular product varied by as much as 465%. This variability did not appear to be correlated with manufacturer or product type. Furthermore, serotonin (5-hydroxytryptamine), a related indoleamine and controlled substance used in the treatment of several neurological disorders, was identified in eight of the supplements at levels of 1 to 75 μg. CONCLUSIONS Melatonin content did not meet label within a 10% margin of the label claim in more than 71% of supplements and an additional 26% were found to contain serotonin. It is important that clinicians and patients have confidence in the quality of supplements used in the treatment of sleep disorders. To address this, manufacturers require increased controls to ensure melatonin supplements meet both their label claim, and also are free from contaminants, such as serotonin. COMMENTARY A commentary on this article appears in this issue on page 163.
Published:
2017
Title:
Mercury exposure and risk of cardiovascular disease: a nested case-control study in the PREDIMED (PREvention with MEDiterranean Diet) study
Authors:
Downer, Mary K.; Martínez-González, Miguel A.; Gea, Alfredo; Stampfer, Meir; Warnberg, Julia; Ruiz-Canela, Miguel; Salas-Salvadó, Jordi; Corella, Dolores; Ros, Emilio; Fitó, Montse; Estruch, Ramon; Arós, Fernando; Fiol, Miquel; Lapetra, José; Serra-Majem, Lluís; Bullo, Monica; Sorli, Jose V.; Muñoz, Miguel A.; García-Rodriguez, Antonio; Gutierrez-Bedmar, Mario; Gómez-Gracia, Enrique; PREDIMED Study Investigators
Abstract:
BACKGROUND: Substantial evidence suggests that consuming 1-2 servings of fish per week, particularly oily fish (e.g., salmon, herring, sardines) is beneficial for cardiovascular health due to its high n-3 polyunsaturated fatty acid content. However, there is some concern that the mercury content in fish may increase cardiovascular disease risk, but this relationship remains unclear. METHODS: The PREDIMED trial included 7477 participants who were at high risk for cardiovascular disease at baseline. In this study, we evaluated associations between mercury exposure, fish consumption and cardiovascular disease. We randomly selected 147 of the 288 cases diagnosed with cardiovascular disease during follow-up and matched them on age and sex to 267 controls. Instrumental neutron activation analysis was used to assess toenail mercury concentration. In-person interviews, medical record reviews and validated questionnaires were used to assess fish consumption and other covariates. Information was collected at baseline and updated yearly during follow-up. We used conditional logistic regression to evaluate associations in the total nested case-control study, and unconditional logistic regression for population subsets. RESULTS: Mean (±SD) toenail mercury concentrations (μg per gram) did not significantly differ between cases (0.63 (±0.53)) and controls (0.67 (±0.49)). Mercury concentration was not associated with cardiovascular disease in any analysis, and neither was fish consumption or n-3 fatty acids. The fully-adjusted relative risks for the highest versus lowest quartile of mercury concentration were 0.71 (95% Confidence Interval [CI], 0.34, 1.14; ptrend = 0.37) for the nested case-control study, 0.74 (95% CI, 0.32, 1.76; ptrend = 0.43) within the Mediterranean diet intervention group, and 0.50 (95% CI, 0.13, 1.96; ptrend = 0.41) within the control arm of the trial. Associations remained null when mercury was jointly assessed with fish consumption at baseline and during follow-up. Results were similar in different sensitivity analyses. CONCLUSIONS: We found no evidence that mercury exposure from regular fish consumption increases cardiovascular disease risk in a population of Spanish adults with high cardiovascular disease risk and high fish consumption. This implies that the mercury content in fish does not detract from the already established cardiovascular benefits of fish consumption. TRIAL REGISTRATION: ISRCTN35739639 .
Published:
2017
Title:
Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches
Authors:
Cheng, Ning; Rho, Jong M.; Masino, Susan A.
Abstract:
Autism spectrum disorder (ASD) is characterized by deficits in sociability and communication, and increased repetitive and/or restrictive behaviors. While the etio-pathogenesis of ASD is unknown, clinical manifestations are diverse and many possible genetic and environmental factors have been implicated. As such, it has been a great challenge to identify key neurobiological mechanisms and to develop effective treatments. Current therapies focus on co-morbid conditions (such as epileptic seizures and sleep disturbances) and there is no cure for the core symptoms. Recent studies have increasingly implicated mitochondrial dysfunction in ASD. The fact that mitochondria are an integral part of diverse cellular functions and are susceptible to many insults could explain how a wide range of factors can contribute to a consistent behavioral phenotype in ASD. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), used for nearly a century to treat medically intractable epilepsy, has been shown to enhance mitochondrial function through a multiplicity of mechanisms and affect additional molecular targets that may address symptoms and comorbidities of ASD. Here, we review the evidence for the use of metabolism-based therapies such as the KD in the treatment of ASD as well as emerging co-morbid models of epilepsy and autism. Future research directions aimed at validating such therapeutic approaches and identifying additional and novel mechanistic targets are also discussed.
Published:
2017
Title:
Metabolic Inputs into the Epigenome
Authors:
Sharma, Upasna; Rando, Oliver J.
Abstract:
A number of molecular pathways play key roles in transmitting information in addition to the genomic sequence-epigenetic information-from one generation to the next. However, so-called epigenetic marks also impact an enormous variety of physiological processes, even under circumstances that do not result in heritable consequences. Perhaps inevitably, the epigenetic regulatory machinery is highly responsive to metabolic cues, as, for example, central metabolites are the substrates for the enzymes that catalyze the deposition of covalent modifications on histones, DNA, and RNA. Interestingly, in addition to the effects that metabolites exert over biological regulation in somatic cells, over the past decade multiple studies have shown that ancestral nutrition can alter the metabolic phenotype of offspring, raising the question of how metabolism regulates the epigenome of germ cells. Here, we review the widespread links between metabolism and epigenetic modifications, both in somatic cells and in the germline.
Published:
2017
Title:
Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development
Authors:
Wilde, Lindsay; Roche, Megan; Domingo-Vidal, Marina; Tanson, Katherina; Philp, Nancy; Curry, Joseph; Martinez-Outschoorn, Ubaldo
Abstract:
Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation, and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate, and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism, are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.
Published:
2017
Title:
Metabolic profiles from two different breakfast meals characterized by 1H NMR-based metabolomics
Authors:
Rådjursöga, M.; Karlsson, G.B.; Lindqvist, H.M.; Pedersen, A.; Persson, C.; Pinto, R.C.; Ellegård, L.; Winkvist, A.
Abstract:
It is challenging to measure dietary exposure with techniques that are both accurate and applicable to free-living individuals. We performed a cross-over intervention, with 24 healthy individuals, to capture the acute metabolic response of a cereal breakfast (CB) and an egg and ham breakfast (EHB). Fasting and postprandial urine samples were analyzed using 1H nuclear magnetic resonance (NMR) spectroscopy and multivariate data analysis. Metabolic profiles were distinguished in relation to ingestion of either CB or EHB. Phosphocreatine/creatine and citrate were identified at higher concentrations after consumption of EHB. Beverage consumption (i.e., tea or coffee) could clearly be seen in the data. 2-furoylglycine and 5-hydroxymethyl-2-furoic acid – potential biomarkers for coffee consumption were identified at higher concentrations in coffee drinkers. Thus 1H NMR urine metabolomics is applicable in the characterization of acute metabolic fingerprints from meal consumption and in the identification of metabolites that may serve as potential biomarkers. © 2017 Elsevier Ltd
Published:
2017
Title:
Metabolic reprogramming is associated with flavopiridol resistance in prostate cancer DU145 cells
Authors:
Li, Xiaoran; Lu, Jie; Kan, Quancheng; Li, Xiaoli; Fan, Qiong; Li, Yaqing; Huang, Ruixia; Slipicevic, Ana; Dong, Hiep Phuc; Eide, Lars; Wang, Junbai; Zhang, Hongquan; Berge, Viktor; Goscinski, Mariusz Adam; Kvalheim, Gunnar; Nesland, Jahn M.; Suo, Zhenhe
Abstract:
Flavopiridol (FP) is a pan-cyclin dependent kinase inhibitor, which shows strong efficacy in inducing cancer cell apoptosis. Although FP is potent against most cancer cells in vitro, unfortunately it proved less efficacious in clinical trials in various aggressive cancers. To date, the molecular mechanisms of the FP resistance are mostly unknown. Here, we report that a small fraction human prostate cancer DU145 cells can survive long-term FP treatment and emerge as FP-resistant cells (DU145FP). These DU145FP cells show accumulated mitochondrial lesions with stronger glycolytic features, and they proliferate in slow-cycling and behave highly migratory with strong anti-apoptotic potential. In addition, the cells are less sensitive to cisplatin and docetaxel-induced apoptotic pressure, and over-express multiple stem cell associated biomarkers. Our studies collectively uncover for the first time that FP-resistant prostate cancer cells show metabolic remodeling, and the metabolic plasticity might be required for the FP resistance-associated cancer cell stemness up-regulation.
Published:
2017
Title:
Metabolomic profiling as a possible reverse engineering tool for estimating processing conditions of dry-cured hams
Authors:
Sugimoto, M.; Obiya, S.; Kaneko, M.; Enomoto, A.; Honma, M.; Wakayama, M.; Soga, T.; Tomita, M.
Abstract:
Dry-cured hams are popular among consumers. To increase the attractiveness of the product, objective analytical methods and algorithms to evaluate the relationship between observable properties and consumer acceptability are required. In this study, metabolomics, which is used for quantitative profiling of hundreds of small molecules, was applied to 12 kinds of drycured hams from Japan and Europe. In total, 203 charged metabolites, including amino acids, organic acids, nucleotides, and peptides, were successfully identified and quantified. Metabolite profiles were compared for the samples with different countries of origin and processing methods (e.g., smoking or use of a starter culture). Principal component analysis of the metabolite profiles with sensory properties revealed significant correlations for redness, homogeneity, and fat whiteness. This approach could be used to design new ham products by objective evaluation of various features. © 2016 American Chemical Society.
Published:
2017
Title:
Metabolomics and Metabolic Diseases: Where Do We Stand?
Authors:
Newgard, Christopher B.
Abstract:
Metabolomics, or the comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, has undergone a rapid technological evolution in the past two decades. These advances have led to the application of metabolomics to defining predictive biomarkers for incident cardiometabolic diseases and, increasingly, as a blueprint for understanding those diseases' pathophysiologic mechanisms. Progress in this area and challenges for the future are reviewed here.
Published:
2017
Title:
MicroRNAs and Their Impact on Breast Cancer, the Tumor Microenvironment, and Disparities
Authors:
Evans-Knowell, A.; LaRue, A.C.; Findlay, V.J.
Abstract:
Published:
2017
Title:
Microbiome and metabolome data integration provides insight into health and disease
Authors:
Shaffer, Michael; Armstrong, Abigail J. S.; Phelan, Vanessa V.; Reisdorph, Nichole; Lozupone, Catherine A.
Abstract:
For much of our history, the most basic information about the microbial world has evaded characterization. Next-generation sequencing has led to a rapid increase in understanding of the structure and function of host-associated microbial communities in diverse diseases ranging from obesity to autism. Through experimental systems such as gnotobiotic mice only colonized with known microbes, a causal relationship between microbial communities and disease phenotypes has been supported. Now, microbiome research must move beyond correlations and general demonstration of causality to develop mechanistic understandings of microbial influence, including through their metabolic activities. Similar to the microbiome field, advances in technologies for cataloguing small molecules have broadened our understanding of the metabolites that populate our bodies. Integration of microbial and metabolomics data paired with experimental validation has promise for identifying microbial influence on host physiology through production, modification, or degradation of bioactive metabolites. Realization of microbial metabolic activities that affect health is hampered by gaps in our understanding of (1) biological properties of microbes and metabolites, (2) which microbial enzymes/pathways produce which metabolites, and (3) the effects of metabolites on hosts. Capitalizing on known mechanistic relationships and filling gaps in our understanding has the potential to enable translational microbiome research across disease contexts.
Published:
2017
Title:
Microphysiological systems (tissue chips) and their utility for rare disease research
Authors:
Low, Lucie A.; Tagle, Danilo A.
Abstract:
© Springer International Publishing AG 2017. The scientific and technological development of microphysiological systems (MPS) modeling organs-on-chips, or “tissue chips” (TCs), has progressed rapidly over the past decade. Stem cell research and microfluidic concepts have combined to lead to the development of microphysiological platforms representing an ever-expanding list of different human organ systems. In the context of rare diseases, these bioengineered microfluidics platforms hold promise for modeling of disorders and could prove useful in the screening and efficacy testing of existing therapeutics. Additionally, they have the potential for replacing and refining animal use for new drugs and clinical treatments, or could even act as surrogate human systems for testing of new therapeutics in the future, which could be particularly useful in populations of rare disease sufferers. This chapter will discuss the current state of tissue chip research, and challenges facing the field. Additionally, we will discuss how these devices are being used to model basic cellular and molecular phenotypes of rare diseases, holding promise to provide new tools for understanding of disease pathologies and screening and efficacy testing of potential therapeutics for drug discovery.
Published:
2017
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