Inactivity as a key factor inducting insulin resistance and metabolic syndrome

2009/2010Introduction. The metabolic syndrome is a cluster of alterations, including insulin resistance, dyslipidaemia, hypertension, hyperglycaemia, abdominal obesity, hyperhomocysteinemia, inflammation and oxidative stress, leading to type II diabetes and cardiovascular disease. The metabolic syndrome is usually associated with sedentary lifestyle and overweight, while regular physical activity and weight loss can counteract these alterations and prevent type II diabetes and cardiovascular disease. Aim of the Thesis. In order to define the net role of inactivity as key factor inducing insulin resistance and metabolic syndrome independently from changes in body fat we have investigated the net impact of experimental bed rest on human metabolism. Experimental bed rest in healthy, young, lean subjects represents a suitable model to determine the effects of inactivity on physiology, avoiding potential interferences and confounding effects of diseases, ageing, energy unbalance and excess body fat. We have focused on inactivity-related development of insulin resistance, dyslipidaemia, hypertension as well as inflammation and oxidative stress. These aspects have been investigated during four different experimental bed rest protocols, lasting 2 months (WISE-Toulouse, France) and 5 weeks (Valdoltra, Slovenia 2006–2007–2008). Energy requirements and intakes were strictly controlled to avoid changes in fat mass. Results and discussion. Muscle atrophy. Muscle atrophy was evidenced after three weeks of bed rest and was worsened by prolonged exposure to inactivity (WISE, Valdoltra studies). However, muscle loss rate was higher in the first 5 weeks of bed rest while it decreased in the second month of inactivity (WISE). Time-course analysis of insulin resistance development. Insulin resistance, measured by an oral glucose tolerance test, rapidly developed in the first week of inactivity and was maintained after 5 weeks of bed rest, as assessed by the ISI-Belfiore index of insulin sensitivity (Valdoltra 2008). Cardiovascular regulation. In the first week of bed rest, baroreflex sensitivity decreased indicating that, in an early phase, alterations in the sympatovagal balance paralleled changes in insulin resistance development. At the end of 5 week-bed rest, heart rate and heart rate variability as well as systolic blood pressure variability, indexes of cardiovascular regulation, were also impaired (Valdoltra 2008). Plasma lipids and lipid metabolism. Five weeks of bed rest induced a decrease in high-density lipoprotein (HDL) cholesterol. During inactivity, cholesteryl ester transfer protein (CETP), a key enzyme involved in HDL metabolism, was up-regulated and changes in CETP inversely correlated with changes in HDL-to-non-HDL cholesterol ratio. Conversely, changes in CETP and HDL were not directly correlated to insulin resistance (Valdoltra studies). Cell membrane lipids. Bed rest reduced monounsaturated FAs, enhanced n-6 polyunsaturated FA total contents and affected activities of both Δ-5 and Δ-9 desaturases, enzymes involved in FA metabolism. These data further support that membrane FA composition and activities of Δ-5 and Δ-9 desaturases are predictive indicators of metabolic syndrome development. Moreover, arachidonic-to-eicosapentaenoic acid ratio, reflecting the competitive role of these FAs in the modulation of inflammatory processes, was shifted towards pro-inflammatory state (Valdoltra studies). Oxidative stress and glutathione kinetics. Bed rest induced oxidative stress as showed by enhanced muscle protein carbonylation, a marker of tissue exposure to oxidative damage, and increased muscle glutathione absolute synthesis, as assessed by a new one-sample, double-isotope tracers infusion method (Valdoltra 2007). Homocysteinemia and homocysteine kinetics. Plasma homocysteine level was increased by bed rest, due to a decrease in homocysteine clearance related to remethylation (WISE). Hyperhomocysteinemia is a further evidence of inactivity-mediated oxidative stress and increased cardiovascular risk. Conclusions. Physical inactivity in healthy young subjects is a suitable model to define the net impact of physical inactivity on the development of metabolic alterations observed in patients with the metabolic syndrome. Our results indicate that inactivity is directly involved in insulin resistance development, low-grade systemic inflammation, dyslipidaemia, hyperhomocysteinemia, oxidative stress and autonomic-cardiovascular abnormalities.XXIII Ciclo198

White Matter Imaging Correlates of Early Cognitive Impairment Detected by the Montreal Cognitive Assessment after Transient Ischemic Attack and Minor Stroke

BACKGROUND AND PURPOSE:  Among screening tools for cognitive impairment in large cohorts, the Montreal Cognitive assessment (MoCA) appears to be more sensitive to early cognitive impairment than the Mini-Mental State Examination (MMSE), particularly after transient ischemic attack (TIA) or minor stroke. We reasoned that if MoCA-detected early cognitive impairment is pathologically significant, then it should be specifically associated with the presence of white matter hyperintensities (WMH) and reduced fractional anisotropy (FA) on MRI. METHODS: Consecutive eligible patients with TIA or minor stroke (Oxford Vascular Study) underwent MRI and cognitive assessment. We correlated MoCA and MMSE scores with WMH and FA, then specifically studied patients with low MoCA and normal MMSE. RESULTS: Among 400 patients, MoCA and MMSE scores were significantly correlated (all p<0.001) with WMH volumes (rMoCA=-0.336, rMMSE=-0.297) and FA (rMoCA=0.409, rMMSE=0.369), and -on voxel-wise analyses- with WMH in frontal white matter and reduced FA in almost all white matter tracts. However, only the MoCA was independently correlated with WMH volumes (r=-0.183, p<0.001), average FA values (r=0.218, p<0.001), and voxel-wise reduced FA in anterior tracts after controlling for the MMSE. In addition, patients with low MoCA but normal MMSE (N=57) had higher WMH volumes (t=3.1,p=0.002), lower average FA (t=-4.0,p<0.001), and lower voxel-wise FA in almost all white matter tracts than those with normal MoCA and MMSE (N=238). CONCLUSIONS: In patients with TIA or minor stroke, early cognitive impairment detected with the MoCA but not with the MMSE was independently associated with white matter damage on MRI, particularly reduced FA

Prehistoric pottery and the instrumental kit for its production. Description of the archaeological record of Coro Trasito (Tella-Sin, Huesca)

Resumen: En este artículo presentamos los instrumentos de trabajo relacionados con la producción cerámica. El punto de partida es una serie de programas experimentales que nos permiten definir la aparición y el desarrollo de los rastros de uso en las superficies de los distintos instrumentos relacionados con esa producción, una vez reconocidos a nivel arqueológico. Esto incluye el uso de instrumentos manufacturados en materias primas de distinto origen: minerales (lítico tallado, cantos y/o guijarros naturales, fragmentos de cerámica?), y materias duras de origen animal (espátulas/punzones de hueso, instrumentos de conchas?). Una vez definidos estos tipos de instrumentos de trabajo, aplicamos el estudio a un yacimiento arqueológico concreto. En este caso, describimos los instrumentos recuperados en Coro Trasito (Tella-Sin, Huesca) que tienen que ver con la producción y el mantenimiento de la cerámica, especialmente en un periodo cronológico relacionado con el Neolítico antiguoAbstract: In this work, we present the working tools related to pottery production. The starting point is a series of experimental programs that allow us to define the presence and development of usewear traces on the surfaces of the different instruments related to that production ?which were recognized in archaeological contexts. This includes the use of tools manufactured in raw materials of different origin: minerals (lithic knapped blanks, natural cobbles and/or pebbles, pottery sticks?), and hard materials of animal origin (bone spatulas/awls, shell tools?). Once these types of working tools have been defined, we bring the study to specific archaeological contexts. In this case, we describe the instruments recovered in Coro Trasito (Tella-Sin, Huesca) and how these tools relate to the production and upkeep of pottery vessels, especially during a chronological period related to the ancient Neolithic period

Coro Trasito (Tella-Sin, Huesca): una cueva redil del Neolítico Antiguo en la alta montaña

En este trabajo se presentan los resultados preliminares de las intervenciones arqueológicas llevadas a cabo en la Cueva de Coro Trasito, situada en el Pirineo central aragonés, dentro del municipio de Tella-Sin, Huesca. Estas intervenciones corresponden tanto a los sondeos llevados a cabo durante el 2011 y el 2013, como la excavación en extensión de la parte central de la cueva, aproximadamente de unos 70m2, durante las campañas de 2014 y 2015. Estos trabajos han permitido documentar una secuencia de ocupaciones neolíticas de la cueva datadas entre 5300 y 4600 cal ANE, sucedidas por una última fase prehistórica de mediados del II Milenio cal ANE. De esta forma, repasaremos los principales hallazgos que se han documentado en las diferentes campañas arqueológicas, materiales líticos, cerámicos, así como los diferentes estudios realizados sobre la fauna y la carpología provenientes del sondeo nº 3 (2013). Así mismo, presentaremos algunas de las características más relevantes de la excavación en extensión de la cueva, así como las diferentes estructuras documentadas asociadas al Neolítico Medio. Estas evidencias, junto con los estudios que se han llevado a cabo hasta este momento, nos hacen intuir que la ocupación de la cueva durante este periodo fue recurrente y con una economía plenamente neolítica.Peer Reviewe

Mountains, Herds and Crops : Notes on New Evidence from the Early Neolithic in the Southern Central Pyrenees

After years of intense fieldwork, our knowledge about the Neolithisation of the Pyrenees has considerably increased. In the southern central Pyrenees, some previously unknown Neolithic sites have been discovered at subalpine and alpine altitudes (1,000-1,500 m a.s.l.). One of them is Cueva Lóbrica, 1,170 m a.s.l., which has an occupation phase with impressed pottery dated ca. 5400 cal BCE. Another is Coro Trasito, 1,558 m a.s.l., a large rock shelter that preserves evidence of continuous occupations in the Early Neolithic, 5300-4600 cal BCE. Evidence of human occupation at higher altitudes has also been documented. In the Axial Pyrenees, at the Obagues de Ratera rock shelter, 2,345 m a.s.l., an occupation has been dated to around 5730-5600 cal BCE. At Cova del Sardo, in the Sant Nicolau Valley, at 1,780 m a.s.l., a series of occupations have been excavated, dated to ca. 5600-4500 cal BCE. These sites allow us to discuss patterns of occupation of the mountainous areas between the Late Mesolithic and Early Neolithic. Recent data suggest that the last hunter-gatherer occupied all altitudinal stages of the Pyrenees, both in the outer and inner ranges. A change in the settlement pattern seems to have occurred in the Early Neolithic, which consisted of a concentration of occupations in the valley bottom and mid-slopes, in biotopes favourable to both herding and agriculture

Effect of oral docosahexaenoic acid (DHA) supplementation on DHA levels and omega-3 index in red blood cell membranes of breast cancer patients

Rationale: Docosahexaenoic acid (DHA) in cell membrane may influence breast cancer (BC) patients' prognosis, affecting tumor cells sensitivity to chemo- and radio-therapy and likely modulating inflammation. The possibility of identifying BC patients presenting with low DHA levels and/or low ability of DHA incorporation into cell membrane might help to treat this condition. Methods: We enrolled BC patients and healthy controls, recording their seafood dietary intake. DHA in form of algal oil was administered for 10 consecutive days (2 g/day). Blood samples were collected at baseline (T0) and after 10 days of supplementation (T1) to assess DHA, omega-3 index, as the sum of DHA + eicosapentaenoic acid (EPA), in red blood cells (RBC) membranes and plasma tumor necrosis factor-alpha and interleukin-6 levels. Pre- and post-treatment fatty acid profiles were obtained by gas-chromatography. Parametric and non-parametric tests were performed, as appropriate, and P-value < 0.05 was considered statistically significant. Results: Forty-three women were studied, divided into 4 groups: 11 patients with BRCA1/2 gene mutation (M group), 12 patients with familiar positive history for BC (F group), 10 patients with sporadic BC (S group), and 10 healthy controls (C group). DHA and omega-3 index increased from T0 to T1 in the 3 groups of BC patients and in controls (P < 0.001). No difference was found in DHA incorporation between each group of BC patients and between patients and controls, except for M group, which incorporated higher DHA levels with respect to controls (\u3b2 = 0.42; P = 0.03). No association was documented between cytokines levels and DHA and omega-3 index at baseline and after DHA supplementation. Independent of the presence of BC, women considered as "good seafood consumers" showed at baseline DHA and omega-3 index higher with respect to "low seafood consumers" (P = 0.04; P = 0.007, respectively). After supplementation, the increase in DHA levels was greater in "low seafood consumers" with respect to "good seafood consumers" (P < 0.0001). Conclusion: DHA supplementation was associated with increased DHA levels and omega-3 index in RBC membranes of BC cancer patients, independent of the type of BC presentation, and in controls. BRCA1/2 mutation, as well as low seafood consuming habits in both BC patients and healthy controls, seem to be associated with greater ability of DHA incorporation. Larger samples of BC patients are necessary to confirm our observation

Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia

OBJECTIVE: The glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery. METHODS: We evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3\ub10.5 vs 6.5\ub10.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7\ub11.4 and 10.5\ub11.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT. RESULTS: Compared to CIT, IIT was associated with higher EGSR (2.70\ub10.51 versus 1.18\ub10.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2\ub10.2 versus 2.9\ub10.4 nmol/L). CONCLUSIONS: In patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress

Del territorio al asentamiento y del asentamiento al territorio: la investigación arqueológica en áreas de montaña y alta montaña en el Pirineo central

Aunque reciente en nuestra disciplina, la arqueología de las zonas de alta montaña poco a poco va consolidándose, generando corpus empíricos y procedimientos que en muchas ocasiones constituyen sus señas de identidad. Por encima de la diversidad de equipos y programas de investigación, algunos aspectos tienden a presentarse de forma recurrente. Uno es un cierto interés por las secuencias de larga duración. Otro lo constituye la mirada hacia un espacio amplio, que va mucho más allá del asentamiento. Este interés por el territorio o el paisaje, que en ocasiones se prefigura como un verdadero objeto de estudio, conlleva cambios en el diseño metodológico de la investigación. En este trabajo pretendemos recoger los ya casi veinte años de experiencia del Grupo de Arqueología de la Alta Montaña (GAAM) de la UAB y el CSIC para presentar una breve reflexión teórica sobre un aspecto que, a nuestro entender, es central en nuestra disciplina. La arqueología, en cuanto ciencia social, aborda una existencia humana colectiva que ocurre tanto en el tiempo como en el espacio. Por diversos motivos, la arqueología en áreas de alta montaña ha sido especialmente proclive a incorporar elementos metodológicos para tratar con el espacio también como instancia social. Quizás ha llegado el momento de empezar a evaluar los puntos fuertes de estas propuestas y tratar de identificar aquellas cuestiones que merecen mayor atención. En la parte final del artículo ilustramos, con un caso empírico, la pertinencia de la reflexión teórica planteada

Jaciments, ritmes i dinàmiques d'implantació i explotació del territori al neolític antic (5.500-4.500 cal BC) : el Pirineu i les serralades prepirinenques

La recerca sobre el neolític ha considerat fins fa relativament poc els Pirineus com un actor secundari en el procés d'introducció de les formes de vida agrícoles i ramaderes en contraposició a les serralades pre i litorals i de la depressió central. Els treballs realitzats en els darrers anys en aquests territoris, amb revisió de col·leccions antigues, excavacions preventives i nous projectes de recerca condueixen a obtenir una imatge molt més detallada i complexa del procés de neolitització de la preconcebuda. En aquest sentit els treballs duts a terme a l'alt Pirineu aporten dades d'un neolític incipient des del segon terç del vi mil·lenni cal BC en alçades properes als 2.000 metres, fet que obre una perspectiva de gran interès inèdita fa pocs anys. D'altra banda, projectes consolidats com el desenvolupat al jaciment de la Draga permeten proposar seqüenciacions regionals pel Prepirineu oriental per la introducció del neolític.Research on the Neolithic has until recently considered the Pyrenees as a secondary player in the process of introducing agricultural and livestock life forms as opposed to the pre- and coastal mountain ranges and the central depression. The work carried out in recent years in these territories, with a review of old collections, preventive excavations and new research projects, leads to a much more detailed and complex picture of the neolithic process of preconceived. In this sense, the work carried out in the high Pyrenees provides data from an incipient Neolithic since the second third of the sixth millennium cal BC at altitudes close to 2,000 meters, which opens a perspective of great interest unheard of a few years ago. On the other hand, consolidated projects such as the one developed at the Draga site make it possible to propose regional sequences for the eastern Pre-Pyrenees due to the introduction of the Neolithic

Des de la prehistòria fins a l'actualitat : les ocupacions de l'Abric de les Obagues de Ratera, al Parc Nacional d'Aigüestortes i Estany de Sant Maurici (Espot)

Actes de les Jornades d'Arqueologia i Paleontologia del Pirineu i Aran (2ones : 2019 ; Tremp)L'excavació de l'Abric de Les Obagues de Ratera, per sobre els 2300 m. d'altitud, ha permès documentar una extensa seqüència arqueològica. La sèrie de datacions radiocarbòniques efectuades ha precisat la cronologia d'aquestes ocupacions, que arrenquen a inicis de l'Holocé i s'estenen fins al s. XX, cobrint diversos períodes prehistòrics, de l'Edat Mitjana i d'època contemporània. L'anàlisi dels materials recuperats durant les excavacions complementa la imatge de l'abric com un lloc utilitzat de manera reiterada i canviant al llarg del temps. L'estudi d'aquest petit jaciment posa en valor els vestigis arqueològics de zones alpines i subalpines i referma el seu potencial per a l'estudi del passat.The excavation of the Las Obagues de Ratera Rockshelter, above 2300 m. of altitude, has allowed to document a large archaeological sequence. An intense radiocarbon dating defines the chronology of these occupations, which from the beginning of the Holocene and until the XXth century, covering different prehistoric and historic periods. The analysis of the materials recovered during excavations complements the image of this little rockshelter as a place used repeatedly but in changing ways over time. The study of this site highlights the archaeological remains of alpine and subalpine areas and reaffirms its potential for the study of the past