1,721,079 research outputs found
Thalassemia. A few new tiles in a large mosaic
No full textThalassemia is considered the most common genetic
disorder worldwide. In Europe the disease is particularly
prevalent in inhabitants of Italy and Greece. It is also
common in South East Asia and in the Middle East,
where it represents an important economic and social
burden. In North America more than 800 patients are
included in the Registry of the National Institutes of
Health-sponsored Thalassemia Clinical Research
Network.1 Thalassemia major used to be a rapidly fatal
disease and the results obtained in terms of survival
have been striking in the more industrialized parts of
the world, while they remain disappointing in lowincome
countries.
In this issue of the journal there is one article reporting
the results, in terms of survival, in the Greek Cypriot
population,2 and two articles evaluating new approaches
to the therapy of thalassemia
Metabolic Flexibility for Metabolic Health: Role of Nutrition and Nutraceuticals
No full textBoth lifespan and health span are influenced by nutrition, with nutritional interventions proving to be robust across a wide range of species. However, mechanisms by which nutrients and nutritional status may affect health span are not fully understood. Both health span and life span are closely linked to metabolic health and this condition mainly depends on metabolic flexibility. Metabolic flexibility is a term coined by Kelley et al. [1], and is conceptually defined as the ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, in response to availability and requirement of nutrients as well as by physical activity. In health conditions, metabolic flexibility, i.e. metabolic plasticity, is essential to maintain energy homeostasis. As example, skeletal muscle of lean or physically active individuals showed a remarkable ability to adapt fuel preference to nutrient supply and was therefore designated as metabolically flexible. Upon consumption of a high-fat diet, lean subjects were able to increase Fatty Acid Oxidation (FAO) at the expense of glucose, whereas obese individuals were not [2]. Lean or physically active individuals also showed an increased expression of genes involved in fatty acid transport and oxidation compared with little or no change in their obese counterparts [3]. The ability to shift fuel source oxidation from carbohydrates to fats is generally related to metabolic health. Studies on mice showed that metabolic flexibility correlates with a healthy Respiratory Exchange Ratio (RER) resulting from the circadian shift between carbohydrate (value of 1.0) to lipid metabolism (value of 0.7) [4]. Mitochondrial dysfunction lead to a cellular shift toward a glycolytic phenotype, which is intimately linked, to a sedentary lifestyle and senescence. Metabolic flexibility is negatively correlated with aging and is disrupted in some pathological conditions, as in ectopic lipid accumulation which is causally linked to insulin resistance, in the context of obesity and metabolic syndrome [5]. Insulin-resistant obese patients manifest a lesser reliance on fatty acid oxidation compared with lean individuals and do not show increased fatty acid oxidation after fasting or reduced fatty acid oxidation after insulin infusion. Because of their inadequate responses to metabolic challenges, these patients are named “metabolically inflexible” [6]. Metabolic inflexibility is a hallmark of many age-related metabolic diseases but also plays a central role in, for instance, cancer and immune metabolism diseases. Conversely, metabolic flexibility is enhanced by lifestyle interventions including exercise training and controlled Calorie Restriction (CR), which are able to reduce obesity, visceral fat deposit and ectopic lipid accumulation [7]. Exercise, in particular, is a principal preventive strategy to improve metabolic flexibility at all ages and prolong healthy aging [8]. These interventions are able to favor mitochondrial function and improve substrate switching and metabolic health. Molecular and signaling pathways drive metabolic flexibility and often serve as metabolic sensors able to respond to different nutritional conditions or exercise. Pathways involved in metabolic flexibility are those mediated by Mammalian Target of Rapamycin (mTOR) and insulin/insulin-like Growth Factor-1 (IGF-1) which are generally stimulated in fed conditions, and by pathways activated by fasting, involving AMP-Activated Protein Kinase (AMPK), NAD+- dependent sirtuin (SIRT) deacetylases and PPARγ coactivator 1-a PGC1a) (see ref 11 for a review). Main sensor of low energy levels is AMPK, which mediates one of the “chief” step of metabolic flexibility represented by “glucose-fatty acid cycle” [9]. This step states that high glucose availability suppresses oxidation of fatty acids and vice versa [5]. In particular, during CR, the rise in AMP/ATP activates AMPK, which inhibits Acetyl-Coenzyme a Carboxylase (ACC), thus stimulating fatty acid uptake by the mitochondria via Carnitine- Palmitoyl Transferase 1 (CPT-1) and increasing FAO. In parallel, during CR, the increase of NAD+ concentrations stimulates nuclear/ cytoplasmic-localized SIRT1 and mitochondrial SIRT3 activity and leads to protein deacetylation and improved mitochondrial function. There is a reciprocal interplay between AMPK and SIRT, which contributes to metabolic adaptations during fasting conditions [10] as well as during aerobic exercise. This interplay leads to increased transcription, translation, and activity of the transcriptional coactivator PGC1a which is a main mediator of mitochondrial biogenesis and regulator of exercise-induced adaptations in the capacity of oxidative phosphorylation in skeletal muscle [11,12]. In the last years many food-derived natural compounds, also named nutraceuticals have been investigated in relation to their effects on most of the nutrient sensing pathways activated by CR and physical exercise, and potentially related to longevity and health span [13- 15]. However, in our opinion there are only few controlled studies on the effects of single dietary components on biochemical pathways and enzymes able to improve metabolic flexibility. As example, one relevant aspect might be related to prevention of ectopic intracellular lipid accumulation. At this purpose biochemical studies on nutritional modulation of enzymes involved in substrate switching such as Pyruvate Dehydrogenase (PDH) and PDH kinase 4 (PDK4) as well as in pathways leading to cytosolic acetyl-coenzyme A (acetyl-CoA) accumulation could be of great interest. Nucleo-cytosolic acetyl-CoA has emerged as a central signaling node used to coordinate metabolic flexibility in response to a changing of nutritional status. In fact, cells utilize acetyl-CoA levels to integrate nutrient status with energy levels to ensure the proper funneling of substrate toward energy production or storage. In cytosol acetyl-CoA is generated by the enzyme ATP Citrate Lyase (ACLY) which catalyzes the cleavage of citrate to oxaloacetate and acetyl-CoA, a critical reaction linking cellular glucose metabolism and lipogenesis. Accumulation of acetyl-CoA in cytosol also favors protein acetylation and inhibits autophagy with a negative impact for metabolic health. Recently the involvement of ACLY in the progression and development of various chronic diseases has been comprehensively described [16]. Preclinical studies and clinical randomized trials showed the importance of ACLY activity in metabolism, supporting its inhibition as a potential therapeutic approach to treat atherosclerotic cardiovascular disease, nonalcoholic fatty liver disease and other metabolic disorders [17]. Among nutraceuticals Garcinia cambogia, which contains Hydroxycitric Acid (HCA) has been reported to play a role in inhibiting the enzyme ACLY [14]. However, the safety of this plant extract has been highly questioned [18]. In our opinion further studies are needed that address more exhaustive role of nutrition and nutraceuticals on pathways involved in regulation of metabolic flexibility as well as on any other process affecting cellular metabolic health
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Molecular mechanisms linking nutrition to metabolic homeostasis: An overview picture of current understanding
No full textIncreasing evidence supports the notion that in humans many pathological conditions including obesity, metabolic syndrome, and type 2 diabetes are closely related to the amount and quality of each nutritional component and to an impairment of the metabolic homeostatic mechanisms of their utilization. Cell signaling pathways that sense the availability of nutrients and the energy status of the cells communicate with signaling pahways triggered by hormones and growth factors to coordinately regulate whole-body metabolic homeostasis. The aim of this review is to provide an overview picture of current knowledge about the main molecular mechanisms that connect nutritional status, hormones, and nutrient levels with gene expression, metabolic homeostasis, and nutrient sensing. We recapitulate molecular mechanisms governing fuel selection between glucose and fatty acids in different nutritional conditions, highlighting metabolic flexibility as mechanism to ensure metabolic health. Disrupted metabolic flexibility, or metabolic inflexibility, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. We also describe how macronutrients that can be used as energy sources may reciprocally modulate their own metabolism as well as directly interact with transcriptional factors, nutrient sensors and nutrient sensing pathways in order to achieve metabolic homeostasis
Nutrients and pathways that regulate health span and life span
Full text linkBoth life span and health span are influenced by genetic, environmental and lifestyle factors. With the genetic influence on human life span estimated to be about 20–25%, epigenetic changes play an important role in modulating individual health status and aging. Thus, a main part of life expectance and healthy aging is determined by dietary habits and nutritional factors. Excessive or restricted food consumption have direct effects on health status. Moreover, some dietary interventions including a reduced intake of dietary calories without malnutrition, or a restriction of specific dietary component may promote health benefits and decrease the incidence of aging-related comorbidities, thus representing intriguing potential approaches to improve healthy aging. However, the relationship between nutrition, health and aging is still not fully understood as well as the mechanisms by which nutrients and nutritional status may affect health span and longevity in model organisms. The broad effect of different nutritional conditions on health span and longevity occurs through multiple mechanisms that involve evolutionary conserved nutrient-sensing pathways in tissues and organs. These pathways interacting each other include the evolutionary conserved key regulators mammalian target of rapamycin, AMP-activated protein kinase, insulin/insulin-like growth factor 1 pathway and sirtuins. In this review we provide a summary of the main molecular mechanisms by which different nutritional conditions, i.e., specific nutrient abundance or restriction, may affect health span and life span
Treatment of chronic childhood immune thrombocytopenic purpura with intramuscular anti-D immunoglobulins
No full textSeven patients with chronic immune thrombocytopenic purpura (ITP) were treated with intramuscular anti-D (anti-D IgG) five times, on an alternate-day basis, or until a platelet count of 100 x 109/l was achieved, and, subsequently, when necessary to maintain platelet counts above 50 x 109/l. Five patients responded to therapy, two of whom entered long-term remission. Although signs of haemolysis were present in all patients, anaemia was never a problem. No patient developed haematomas at the site of injection. We suggest that intramuscular anti-D represent a safe and relatively inexpensive alternative to intravenous gamma globulin (IVGG) for children with severe chronic ITP
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Cholostase recurrente benigne
No full textA 14-year-old girl with recurrent episodes of cholestatic jaundice since 7 years of age is presented. Absence of extrahepatic obstruction, recurrent character of jaundice and liver biopsy pattern suggest the diagnosis of benign recurrent cholestasis. Spontaneous variations in the clinical course of the illness make it difficult to evaluate the therapeutic value of drug
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