The interaction of aluminum with catecholamine-based neurotransmitters: Can the formation of these species be considered a potential risk factor for neurodegenerative diseases?

The potential neurotoxic role of Al(iii) and its proposed link with the insurgence of Alzheimer's Disease (AD) have attracted increasing interest towards the determination of the nature of bioligands that are propitious to interact with aluminum. Among them, catecholamine-based neurotransmitters have been proposed to be sensitive to the presence of this non-essential metal ion in the brain. In the present work, we characterize several aluminum-catecholamine complexes in various stoichiometries, determining their structure and thermodynamics of formation. For this purpose, we apply a recently validated computational protocol with results that show a remarkably good agreement with the available experimental data. In particular, we employ Density Functional Theory (DFT) in conjunction with continuum solvation models to calculate complexation energies of aluminum for a set of four important catecholamines: l-DOPA, dopamine, noradrenaline and adrenaline. In addition, by means of the Quantum Theory of Atoms in Molecules (QTAIM) and Energy Decomposition Analysis (EDA) we assessed the nature of the Al-ligand interactions, finding mainly ionic bonds with an important degree of covalent character. Our results point at the possibility of the formation of aluminum-catecholamine complexes with favorable formation energies, even when proton/aluminum competition is taken into account. Indeed, we found that these catecholamines are better aluminum binders than catechol at physiological pH, because of the electron withdrawing effect of the positively-charged amine that decreases their deprotonation penalty with respect to catechol. However, overall, our results show that, in an open biological environment, the formation of Al-catecholamine complexes is not thermodynamically competitive when compared with the formation of other aluminum species in solution such as Al-hydroxide, or when considering other endogenous/exogenous Al(iii) ligands such as citrate, deferiprone and EDTA. In summary, we rule out the possibility, suggested by some authors, that the formation of Al-catecholamine complexes in solution might be behind some of the toxic roles attributed to aluminum in the brain. An up-to-date view of the catecholamine biosynthesis pathway with sites of aluminum interference (according to the current literature) is presented. Alternative mechanisms that might explain the deleterious effects of this metal on the catecholamine route are thoroughly discussed, and new hypotheses that should be investigated in future are proposed

Impact of prior accumulated work and intensity on power output in elite/international level road cyclists—a pilot study

Background. This study aimed to investigate the impact of the intensity of prior accumulated work on the decline in power output in elite/international level road cyclists, comparing the effects of prior continuous moderate intensity versus intermittent high intensity cycling.Methods. Nine elite/international level road cyclists (age 26.2 +/- 4.0 years; body mass: 66.6 +/- 5.5 kg; height: 176 +/- 0.4 cm) conducted a 12-min field test (12 min(fresh)) during two consecutive training camps. Participants then performed both a 150-min moderate intensity continuous (MIC) work bout or a 150-min high intensity intermittent (HII) race simulation in randomized order, cross-over design. After each condition a 12-min field test (12 min(fatigue)) was completed.Results. Absolute and relative 12min(fresh) power output were not significantly different between training camps (p>0.05). The 12 min(fatigue) power after HII was significantly lower than 12min(fatigue) after MIC (Delta=14W; p=0.014). Participants recorded more percentage time (%Time) in heart rate (HR) zone 3 (Delta=9.2%; p=0.003) and power output band between 5.0-7.9W.kg(-1) (Delta=8.9%; p=0.002) as well as higher total work (Delta=237 kJ; p <= 0.001) during HII.Conclusion. These findings reveal that the decline in power output is higher after HII compared to MIC cycling work bouts. This suggests that the quantification of total work and intensity should be used in conjunction to predict a distinctive decline in power output. Future research is required to better understand the mechanisms of endurance "durability" in elite/international level road cyclists

Effects of Bed Rest on Physical Performance in Athletes: A Systematic and Narrative Review.

BACKGROUND: Athletes can face scenarios in which they are confined to bed rest (e.g., due to injury or illness). Existing research in otherwise healthy individuals indicates that those entering bed rest with the greatest physical performance level might experience the greatest performance decrements, which indirectly suggests that athletes might be more susceptible to the detrimental consequences of bed rest than general populations. Therefore, a comprehensive understanding of the effects of bed rest might help guide the medical care of athletes during and following bed rest. OBJECTIVE: This systematic and narrative review aimed to (1) establish the evidence for the effects of bed rest on physical performance in athletes; (2) discuss potential countermeasures to offset these negative consequences; and (3) identify the time-course of recovery following bed rest to guide return-to-sport rehabilitation. METHODS: This review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four databases were searched (SPORTDiscus, Web of Science, Scopus, and MEDLINE/PubMed) in October of 2022, and studies were included if they were peer-reviewed investigations, written in English, and investigated the effects of horizontal bed rest on changes in physical capacities and qualities in athletes (defined as Tier 3-5 participants). The reporting quality of the research was assessed using a modified version of the Downs & Black checklist. Furthermore, findings from studies that involved participants in Tiers 1-2 were presented and synthesized using a narrative approach. RESULTS: Our systematic review of the literature using a rigorous criterion of 'athletes' revealed zero scientific publications. Nevertheless, as a by-product of our search, seven studies were identified that involved apparently healthy individuals who performed specific exercise training prior to bed rest. CONCLUSIONS: Based on the limited evidence from studies involving non-athletes who were otherwise healthy prior to bed rest, we generally conclude that (1) bed rest rapidly (within 3 days) decreases upright endurance exercise performance, likely due to a rapid loss in plasma volume; whereas strength is reduced within 5 days, likely due to neural factors as well as muscle atrophy; (2) fluid/salt supplementation may be an effective countermeasure to protect against decrements in endurance performance during bed rest; while a broader array of potentially effective countermeasures exists, the efficacy of these countermeasures for previously exercise-trained individuals requires further study; and (3) athletes likely require at least 2-4 weeks of progressive rehabilitation following bed rest of ≤ 28 days, although the timeline of recovery might need to be extended depending on the underlying reason for bed rest (e.g., injury or illness). Despite these general conclusions from studies involving non-athletes, our primary conclusion is that substantial effort and research is still required to quantify the effects of bed rest on physical performance, identify effective countermeasures, and provide return-to-sport timelines in bona fide athletes. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: Registration ID: osf.io/d3aew; Date: October 24, 2022

SEOM clinical guideline for the management of cutaneous melanoma (2020)

Tractament adjuvant; Melanoma; EscenificacióAdjuvant treatment; Melanoma; StagingTratamiento adyuvante; Melanoma; EscenificaciónMelanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I–III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available

Different Psychophysiological Responses to a High-intensity Repetition Session Performed Alone or in a Group by Elite Middle-distance Runners

Internal training load refers to the degree of disturbance in psychophysiological homeostasis provoked by a training session and has been traditionally measured through session-RPE, which is the product of the session Rate of Perceived Exertion (RPE) and the duration. External training load refers to the actual physical work completed, and depends on session volume, intensity, frequency and density. Drafting, which is achieved by running closely behind another runner has been demonstrated to reduce the energy cost of running at a fixed speed and to improve performance. Therefore, it is hypothesized that psychophysiological responses might reflect different levels of internal load if training is performed individually or collectively. 16 elite middle-distance runners performed two high-intensity training sessions consisting of 4 repetitions of 500 m separated by 3 minutes of active recovery. Sessions were performed individually and collectively. Times for each repetition, RPE, core affect (valence and felt arousal) and blood lactate concentrations [BLa] were measured after each repetition. Main time effect was significant and increased across repetitions for [BLa] and RPE (p <0.001), and decreased for valence (p =0.001). Main group effect was significant and values were higher when training individually for [BLa] (p =0.003) and RPE (p =0.001), and lower for valence (p =0.001). No differential responses were found between conditions in terms of repeat time or felt arousal. Findings demonstrate that elite middle-distance athletes running collectively display lower levels of internal training load compared to running alone, despite external training load being similar

Aluminum's preferential binding site in proteins: sidechain of amino acids versus backbone interactions

The interaction of aluminum ion Al(III) with polypeptides is a subject of paramount importance, since it is a central feature to understand its deleterious effects in biological systems. Various drastic effects have been attributed to aluminum in its interaction with polypeptides and proteins. These interactions are thought to be established mainly through the binding of aluminum to phosphorylated and non-phosphorylated amino acid sidechains. However, a new structural paradigm has recently been proposed, in which aluminum interacts directly with the backbone of the proteins, provoking drastic changes in their secondary structure and leading ultimately to their denaturation. In the present paper, we use computational methods to discuss the possibility of aluminum to interact with the backbone of peptides and compare it with the known ability of aluminum to interact with amino acid sidechains. To do so, we compare the thermodynamics of formation of prototype aluminum-backbone structures with prototype aluminum-sidechain structures, and compare these results with previous data generated in our group in which aluminum interacts with various types of polypeptides and known aluminum biochelators. Our results clearly points to a preference of aluminum towards amino acid sidechains, rather than towards the peptide backbone. Thus, structures in which aluminum is interacting with the carbonyl group are only slightly exothermic, and they become even less favorable if the interaction implies additionally the peptide nitrogen. However, structures in which aluminum is interacting with negatively-charged sidechains like aspartic acid, or phosphorylated serines are highly favored thermodynamically.Technical and human support was provided by SGI/IZO (SGIker) of UPV/EHU and European funding (ERDF and ESF). Financial support comes from UPV/EHU (PES14/35), Eusko Jaurlaritza (IT588-13) and the Spanish Ministerio de Ciencia e Innovación (MINECO/FEDER) (CTQ2015-67608-P). GdT thanks the European Union for a Ph.D. grant inside the ITN-TCCM-642294 program

Screening young athletes for prevention of sudden cardiac death: Practical recommendations for sports physicians

Regular intensive exercise in athletes increases the relative risk of sudden cardiac death (SCD) compared with the relatively sedentary population. Most cases of SCD are due to silent cardiovascular diseases, and preparticipation screening of athletes at risk of SCD is thus of major importance. However, medical guidelines and recommendations differ widely between countries. In Italy, the National Health System recommends preparticipation screening for all competitive athletes including personal and family history, a physical examination, and a resting 12-lead electrocardiogram (ECG). In the United States, the American College of Cardiology and the American Heart Association recommend a preparticipation screening program limited to the use of specific questionnaires and a clinical examination. The value of a 12-lead ECG is debated based on issues surrounding cost-efficiency and feasibility. The aim of this review was to focus on (i) the incidence rate of cardiac diseases in relation to SCD; (ii) the value of conducting a questionnaire and a physical examination; (iii) the value of a 12-lead resting ECG; (iv) the importance of other cardiac evaluations in the prevention of SCD; and (v) the best practice for pre-participation screening

Utilización de microhilos magnéticos para promover la muerte de células de osteosarcoma mediante hipertermia magnética in vitro

Los tratamientos para el cáncer que se llevan a cabo actualmente tienen una serie de limitaciones que, unido a que se trata de técnicas invasivas, hace que se tienda a buscar nuevas alternativas. Una de ellas es la hipertermia dirigida, cuyo objetivo son las células cancerígenas. Se trata de una técnica relativamente nueva, por lo que aún no se ha estudiado en profundidad. En este trabajo, se han utilizado microhilos magnéticos amorfos recubiertos de vidrio para calentar células de osteosarcoma aplicando un campo magnético alterno. De acuerdo con los resultados obtenidos de los ensayos realizados “in vitro”, se puede confirmar que la utilización de estos microhilos magnéticos reduce la proliferación de células cancerígenas dando lugar finalmente a la muerte celular. Además, esta técnica es un proceso mucho menos invasivo que los utilizados actualmente y que requiere exposiciones breves a campos magnéticos débiles. Por todo esto, la hipertermia dirigida se presenta como una alternativa efectiva para el tratamiento de osteosarcoma.Por último, agradecer a Tamag Ibérica S.L. por proporcionarnos los microhilos magnéticos para poder llevar a cabo este estudio y a Fomento de San Sebastián por financiar el proyecto de investigació

Diabetes self-management arrangements in Europe: a realist review to facilitate a project implemented in six countries

Background: Self-management of long term conditions can promote quality of life whilst delivering benefits to the financing of health care systems. However, rarely are the meso-level influences, likely to be of direct relevance to these desired outcomes, systematically explored. No specific international guidelines exist suggesting the features of the most appropriate structure and organisation of health care systems within which to situate self-management approaches and practices. This review aimed to identify the quantitative literature with regard to diabetes self-management arrangements currently in place within the health care systems of six countries (The United Kingdom, The Netherlands, Norway, Spain, Bulgaria, and Greece) and explore how these are integrated into the broader health care and welfare systems in each country. Methods: The methodology for a realist review was followed. Publications of interest dating from 2000 to 2013 were identified through appropriate MeSH terms by a systematic search in six bibliographic databases. A search diary was maintained and the studies were assessed for their quality and risk of bias. Results: Following the multi-step search strategy, 56 studies were included in the final review (the majority from the UK) reporting design methods and findings on 21 interventions and programmes for diabetes and chronic disease self-management. Most (11/21, 52%) of the interventions were designed to fit within the context of primary care. The majority (11/21, 52%) highlighted behavioural change as an important goal. Finally, some (5/21, 24%) referred explicitly to Internet-based tools. Conclusions: This review is based on results which are derived from a total of at least 5,500 individuals residing in the six participating countries. It indicates a policy shift towards patient-centred self-management of diabetes in a primary care context. The professional role of diabetes specialist nurses, the need for multidisciplinary approaches and a focus on patient education emerge as fundamental principles in the design of relevant programmes. Socio-economic circumstances are relevant to the capacity to self-manage and suggest that any gains and progress will be hard to maintain during economic austerity. This realist review should be interpreted within the wider context of a whole systems approach regarding self-care support and chronic illness management

Quantum mechanics/molecular mechanics simulations identify the ring-opening mechanism of creatininase

Creatininase catalyzes the conversion of creatinine (a biosensor for kidney function) to creatine via a two-step mechanism: water addition followed by ring opening. Water addition is common to other known cyclic amidohydrolases, but the precise mechanism for ring opening is still under debate. The proton donor in this step is either His178 or a water molecule bound to one of the metal ions, and the roles of His178 and Glu122 are unclear. Here, the two possible reaction pathways have been fully examined by means of combined quantum mechanics/molecular mechanics simulations at the SCC-DFTB/CHARMM22 level of theory. The results indicate that His178 is the main catalytic residue for the whole reaction and explain its role as proton shuttle during the ring-opening step. In the first step, His178 provides electrostatic stabilization to the <i>gem-diolate</i> tetrahedral intermediate. In the second step, His178 abstracts the hydroxyl proton of the intermediate and delivers it to the cyclic amide nitrogen, leading to ring opening. The latter is the rate-limiting step with a free energy barrier of 18.5 kcal/mol, in agreement with the experiment. We find that Glu122 must be protonated during the enzyme reaction, so that it can form a stable hydrogen bond with its neighboring water molecule. Simulations of the E122Q mutant showed that this replacement disrupts the H-bond network formed by three conserved residues (Glu34, Ser78, and Glu122) and water, increasing the energy barrier. Our computational studies provide a comprehensive explanation for previous structural and kinetic observations, including why the H178A mutation causes a complete loss of activity but the E122Q mutation does not