Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study.

OBJECTIVES: To analyze the effect of tight glycemic control with the use of intensive insulin therapy on cerebral glucose metabolism in patients with severe brain injury. DESIGN: Retrospective analysis of a prospective observational cohort. SETTING: University hospital neurologic intensive care unit. PATIENTS: Twenty patients (median age 59 yrs) monitored with cerebral microdialysis as part of their clinical care. INTERVENTIONS: Intensive insulin therapy (systemic glucose target: 4.4-6.7 mmol/L [80-120 mg/dL]). MEASUREMENTS AND MAIN RESULTS: Brain tissue markers of glucose metabolism (cerebral microdialysis glucose and lactate/pyruvate ratio) and systemic glucose were collected hourly. Systemic glucose levels were categorized as within the target "tight" (4.4-6.7 mmol/L [80-120 mg/dL]) vs. "intermediate" (6.8-10.0 mmol/L [121-180 mg/dL]) range. Brain energy crisis was defined as a cerebral microdialysis glucose <0.7 mmol/L with a lactate/pyruvate ratio >40. We analyzed 2131 cerebral microdialysis samples: tight systemic glucose levels were associated with a greater prevalence of low cerebral microdialysis glucose (65% vs. 36%, p < 0.01) and brain energy crisis (25% vs.17%, p < 0.01) than intermediate levels. Using multivariable analysis, and adjusting for intracranial pressure and cerebral perfusion pressure, systemic glucose concentration (adjusted odds ratio 1.23, 95% confidence interval [CI] 1.10-1.37, for each 1 mmol/L decrease, p < 0.001) and insulin dose (adjusted odds ratio 1.10, 95% CI 1.04-1.17, for each 1 U/hr increase, p = 0.02) independently predicted brain energy crisis. Cerebral microdialysis glucose was lower in nonsurvivors than in survivors (0.46 +/- 0.23 vs. 1.04 +/- 0.56 mmol/L, p < 0.05). Brain energy crisis was associated with increased mortality at hospital discharge (adjusted odds ratio 7.36, 95% CI 1.37-39.51, p = 0.02). CONCLUSIONS: In patients with severe brain injury, tight systemic glucose control is associated with reduced cerebral extracellular glucose availability and increased prevalence of brain energy crisis, which in turn correlates with increased mortality. Intensive insulin therapy may impair cerebral glucose metabolism after severe brain injury.

Effects of dietary protein on lipid metabolism in high fructose fed humans.

BACKGROUND & AIMS: It has been reported that a high protein diet improves insulin sensitivity and reduces ectopic lipids in animals and humans with the metabolic syndrome. We therefore tested the hypothesis that a high dietary protein content may stimulate whole body lipid oxidation and alter post-prandial triglyceride (TG) after fructose ingestion. METHODS: The post-prandial metabolism of 8 young males was studied after two 6-day periods of hyper-energetic, high fructose diet (HiFruD), and after two 6-day periods of hyper-energetic high fructose high protein diet (HiFruHiProD). The order with which these periods were applied was randomized. At the end of each period, either a low protein, (13)C fructose test meal (Fru meal) or a high protein, (13)C fructose test meal (HiPro Fru meal) was administered. This resulted in the monitoring of metabolic parameters at 4 occasions in random order: a) with Fru meal ingested after HiFruD, b) with HiPro Fru meal ingested after HiFruD, c) with Fru meal ingested after HiFruHiProD or d) with HiPro Fru meal ingested after HiFruHiProD. On each occasion, post-prandial TG concentrations were monitored, energy expenditure and substrate metabolism were measured by indirect calorimetry, and fructose-induced gluconeogenesis was evaluated by measuring plasma (13)C-labeled glucose. RESULTS: TG responses to fructose ingestion were significantly higher after a hyper-energetic HiFruHiProD and after HiPro Fru meals than after a Fru meal ingested after a hyper-energetic HiFruD. Compared to low protein meals, high protein meals increased post-prandial energy expenditure, inhibited post-prandial lipid oxidation, and enhanced fructose-induced gluconeogenesis. These effects were similar with HiFruD and HiFruHiProD. CONCLUSIONS: Dietary proteins did not increase lipid oxidation and increased fructose-induced post-prandial TG in healthy humans fed an hyper-energetic, high fructose diet.

Use of phycoerythrin and allophycocyanin for fluorescence resonance energy transfer analyzed by flow cytometry: advantages and limitations.

BACKGROUND: This study validates the use of phycoerythrin (PE) and allophycocyanin (APC) for fluorescence energy transfer (FRET) analyzed by flow cytometry. METHODS: FRET was detected when a pair of antibody conjugates directed against two noncompetitive epitopes on the same CD8alpha chain was used. FRET was also detected between antibody conjugate pairs specific for the two chains of the heterodimeric alpha (4)beta(1) integrin. Similarly, the association of T-cell receptor (TCR) with a soluble antigen ligand was detected by FRET when anti-TCR antibody and MHC class I/peptide complexes (&lt;&lt;tetramers&gt;&gt;) were used. RESULTS: FRET efficiency was always less than 10%, probably because of steric effects associated with the size and structure of PE and APC. Some suggestions are given to take into account this and other effects (e.g., donor and acceptor concentrations) for a better interpretation of FRET results obtained with this pair of fluorochromes. CONCLUSIONS: We conclude that FRET assays can be carried out easily with commercially available antibodies and flow cytometers to study arrays of multimolecular complexes.

Dynamic Modelling of Material Flows and Sustainable Resource Use: Case Studies in Regional Metabolism and Space Life Support Systems

Sustainable resource use is one of the most important environmental issues of our times. It is closely related to discussions on the 'peaking' of various natural resources serving as energy sources, agricultural nutrients, or metals indispensable in high-technology applications. Although the peaking theory remains controversial, it is commonly recognized that a more sustainable use of resources would alleviate negative environmental impacts related to resource use. In this thesis, sustainable resource use is analysed from a practical standpoint, through several different case studies. Four of these case studies relate to resource metabolism in the Canton of Geneva in Switzerland: the aim was to model the evolution of chosen resource stocks and flows in the coming decades. The studied resources were copper (a bulk metal), phosphorus (a vital agricultural nutrient), and wood (a renewable resource). In addition, the case of lithium (a critical metal) was analysed briefly in a qualitative manner and in an electric mobility perspective. In addition to the Geneva case studies, this thesis includes a case study on the sustainability of space life support systems. Space life support systems are systems whose aim is to provide the crew of a spacecraft with the necessary metabolic consumables over the course of a mission. Sustainability was again analysed from a resource use perspective. In this case study, the functioning of two different types of life support systems, ARES and BIORAT, were evaluated and compared; these systems represent, respectively, physico-chemical and biological life support systems. Space life support systems could in fact be used as a kind of 'laboratory of sustainability' given that they represent closed and relatively simple systems compared to complex and open terrestrial systems such as the Canton of Geneva. The chosen analysis method used in the Geneva case studies was dynamic material flow analysis: dynamic material flow models were constructed for the resources copper, phosphorus, and wood. Besides a baseline scenario, various alternative scenarios (notably involving increased recycling) were also examined. In the case of space life support systems, the methodology of material flow analysis was also employed, but as the data available on the dynamic behaviour of the systems was insufficient, only static simulations could be performed. The results of the case studies in the Canton of Geneva show the following: were resource use to follow population growth, resource consumption would be multiplied by nearly 1.2 by 2030 and by 1.5 by 2080. A complete transition to electric mobility would be expected to only slightly (+5%) increase the copper consumption per capita while the lithium demand in cars would increase 350 fold. For example, phosphorus imports could be decreased by recycling sewage sludge or human urine; however, the health and environmental impacts of these options have yet to be studied. Increasing the wood production in the Canton would not significantly decrease the dependence on wood imports as the Canton's production represents only 5% of total consumption. In the comparison of space life support systems ARES and BIORAT, BIORAT outperforms ARES in resource use but not in energy use. However, as the systems are dimensioned very differently, it remains questionable whether they can be compared outright. In conclusion, the use of dynamic material flow analysis can provide useful information for policy makers and strategic decision-making; however, uncertainty in reference data greatly influences the precision of the results. Space life support systems constitute an extreme case of resource-using systems; nevertheless, it is not clear how their example could be of immediate use to terrestrial systems.

Nitrogen metabolism in Zucker rats is affected by moderate reduction, but not by moderate incerase in dietary protein

Marked changes in the content of protein in the diet affects the rat"s pattern of growth, but there is not any data on the effects to moderate changes. Here we used a genetically obese rat strain (Zucker) to examine the metabolic modifications induced to moderate changes in the content of protein of diets, doubling (high-protein (HP): 30%) or halving (low-protein (LP): 8%) the content of protein of reference diet (RD: 16%). Nitrogen, energy balances, and amino acid levels were determined in lean (L) and obese (O) animals after 30 days on each diet. Lean HP (LHP) animals showed higher energy efficiency and amino acid catabolism but maintained similar amino acid accrual rates to the lean RD (LRD) group. Conversely, the lean LP (LLP) group showed a lower growth rate, which was compensated by a relative increase in fat mass. Furthermore, these animals showed greater efficiency accruing amino acids. Obesity increased amino acid catabolism as a result of massive amino acid intake; however, obese rats maintained protein accretion rates, which, in the OHP group, implied a normalization of energy efficiency. Nonetheless, the obese OLP group showed the same protein accretion pattern as in lean animals (LLP). In the base of our data, concluded that the Zucker rats accommodate their metabolism to support moderates increases in the content of protein in the diet, but do not adjust in the same way to a 50% decrease in content of protein, as shown by an index of growth reduced, both in lean and obese rats.

Feasibility of direct mapping of cerebral fluorodeoxy-D-glucose metabolism in situ at subcellular resolution using soft X-ray fluorescence.

Glucose metabolism is difficult to image with cellular resolution in mammalian brain tissue, particularly with (18) fluorodeoxy-D-glucose (FDG) positron emission tomography (PET). To this end, we explored the potential of synchrotron-based low-energy X-ray fluorescence (LEXRF) to image the stable isotope of fluorine (F) in phosphorylated FDG (DG-6P) at 1 μm(2) spatial resolution in 3-μm-thick brain slices. The excitation-dependent fluorescence F signal at 676 eV varied linearly with FDG concentration between 0.5 and 10 mM, whereas the endogenous background F signal was undetectable in brain. To validate LEXRF mapping of fluorine, FDG was administered in vitro and in vivo, and the fluorine LEXRF signal from intracellular trapped FDG-6P over selected brain areas rich in radial glia was spectrally quantitated at 1 μm(2) resolution. The subsequent generation of spatial LEXRF maps of F reproduced the expected localization and gradients of glucose metabolism in retinal Müller glia. In addition, FDG uptake was localized to periventricular hypothalamic tanycytes, whose morphological features were imaged simultaneously by X-ray absorption. We conclude that the high specificity of photon emission from F and its spatial mapping at ≤1 μm resolution demonstrates the ability to identify glucose uptake at subcellular resolution and holds remarkable potential for imaging glucose metabolism in biological tissue. © 2012 Wiley Periodicals, Inc.

City Energy Management Program A Regional Energy Manager Approach, May 2014

Through the City Energy Management Program, energy managers will directly work with up to 20 municipalities in Iowa to help identify opportunities to reduce energy costs in city-owned buildings, exterior lighting, and water/wastewater facilities. This assistance will be provided to the selected municipalities who will provide an in-kind match to achieve energy efficiency within their community. Power Point of theses resources.

Disturbance of wildlife by outdoor winter recreation: allostatic stress response and altered activity-energy budgets

Anthropogenic disturbance of wildlife is of growing conservation concern, but we lack comprehensive approaches of its multiple negative effects. We investigated several effects of disturbance by winter outdoor sports on free-ranging alpine Black Grouse by simultaneously measuring their physiological and behavioral responses. We experimentally flushed radio-tagged Black Grouse from their snow burrows, once a day, during several successive days, and quantified their stress hormone levels (corticosterone metabolites in feces [FCM] collected from individual snow burrows). We also measured feeding time allocation (activity budgets reconstructed from radio-emitted signals) in response to anthropogenic disturbance. Finally, we estimated the related extra energy expenditure that may be incurred: based on activity budgets, energy expenditure was modeled from measures of metabolism obtained from captive birds subjected to different ambient temperatures. The pattern of FCM excretion indicated the existence of a funneling effect as predicted by the allostatic theory of stress: initial stress hormone concentrations showed a wide inter-individual variation, which decreased during experimental flushing. Individuals with low initial pre-flushing FCM values augmented their concentration, while individuals with high initial FCM values lowered it. Experimental disturbance resulted in an extension of feeding duration during the following evening foraging bout, confirming the prediction that Black Grouse must compensate for the extra energy expenditure elicited by human disturbance. Birds with low initial baseline FCM concentrations were those that spent more time foraging. These FCM excretion and foraging patterns suggest that birds with high initial FCM concentrations might have been experiencing a situation of allostatic overload. The energetic model provides quantitative estimates of extra energy expenditure. A longer exposure to ambient temperatures outside the shelter of snow burrows, following disturbance, could increase the daily energy expenditure by >10%, depending principally on ambient temperature and duration of exposure. This study confirms the predictions of allostatic theory and, to the best of our knowledge, constitutes the first demonstration of a funneling effect. It further establishes that winter recreation activities incur costly allostatic behavioral and energetic adjustments, which call for the creation of winter refuge areas together with the implementation of visitor-steering measures for sensitive wildlife.

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions.

ABSTRACT: A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

Erreurs innées du métabolisme: transition enfant-adulte [Inborn errors of metabolism: transition from childhood to adulthood].

Les erreurs innées du métabolisme (EIM) sont dues à des mutations de gènes codant pour des enzymes du métabolisme et sont classées selon trois grands groupes de maladies: 1) intoxications; 2) déficit énergétique et 3) déficit de synthèse ou catabolisme des maladies complexes. Le progrès thérapeutique des vingt dernières années a permis d'améliorer le pronostic des enfants atteints d'EIM. Ces enfants grandissent et doivent être pris en charge à l'adolescence et à l'âge adulte par des équipes spécialisées. Cette médecine métabolique pour adultes est une discipline relativement nouvelle avec une information limitée chez l'adulte. Les recommandations pédiatriques sont extrapolées à la prise en charge des adultes tout en intégrant les différentes étapes de vie (indépendance sociale, grossesse, vieillissement et éventuelles complications tardives). Inborn errors of metabolism (IEM) are due to mutations of genes coding for enzymes of intermediary metabolism and are classified into 3 broad categories: 1) intoxication, 2) energy defect and 3) cellular organelles synthesis or catabolism defect. Improvements of therapy over these last 20 years has improved prognosis of children with IEM. These children grow up and should have their transition to specialized adult care. Adult patients with IEM are a relatively new phenomenon with currently only limited knowledge. Extrapolated pediatric guidelines are applied to the adult population taking into account adult life stages (social independence, pregnancy, aging process and potential long-term complications).

Cerebral Lactate Metabolism After Traumatic Brain Injury.

Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome.

Effects of Weight Loss on Adipose Tissue, Liver and Heart Metabolism in Humans

Obesity has become the leading cause of many chronic diseases, such as type 2 diabetes and cardiovascular diseases. The prevalence of obesity is high in developed countries and it is also a major cause of the use of health services. Ectopic fat accumulation in organs may lead to metabolic disturbances, such as insulin resistance.Weight loss with very-low-energy diet is known to be safe and efficient. Weight loss improves whole body insulin sensitivity, but its effects on tissue and organ level in vivo are not well known. The aims of the studies were to investigate possible changes of weight loss in glucose and fatty acid uptake and perfusion and fat distribution at tissue and organ level using positron emission tomography and magnetic resonance imaging and spectroscopy in 34 healthy obese subjects. The results showed that whole-body insulin sensitivity increased after weight loss with very-low-energy diet and this is associated with improved skeletal muscle insulin-stimulated glucose uptake, but not with adipose tissue, liver or heart glucose uptake. Liver insulin resistance decreased after weight loss. Liver and heart free fatty acid uptakes decreased concomitantly with liver and heart triglyceride content. Adipose tissue and myocardial perfusion decreased. In conclusion, enhanced skeletal muscle glucose uptake leads to increase in whole-body insulin sensitivity when glucose uptake is preserved in other organs studied. These findings suggest that lipid accumulation found in the liver and the heart in obese subjects without co-morbidies is in part reversible by reduced free fatty acid uptake after weight loss. Reduced lipid accumulation in organs may improve metabolic disturbances, e.g. decrease liver insulin resistance. Keywords: Obesity, weight loss, very-low-energy diet, adipose tissue metabolism, liver metabolism, heart metabolism, positron emission tomography

Foliar photochemical processes and carbon metabolism under favourable and adverse winter conditions in a Mediterranean mixed forest, Catalonia (Spain)

Evergreen trees in the Mediterranean region must cope with a wide range of environmental stresses from summer drought to winter cold. The mildness of Mediterranean winters can periodically lead to favourable environmental conditions above the threshold for a positive carbon balance, benefitting evergreen woody species more than deciduous ones. The comparatively lower solar energy input in winter decreases the foliar light saturation point. This leads to a higher susceptibility to photoinhibitory stress especially when chilly (< 12 C) or freezing temperatures (< 0 C) coincide with clear skies and relatively high solar irradiances. Nonetheless, the advantage of evergreen species that are able to photosynthesize all year round where a significant fraction can be attributed to winter months, compensates for the lower carbon uptake during spring and summer in comparison to deciduous species. We investigated the ecophysiological behaviour of three co-occurring mature evergreen tree species (Quercus ilex L., Pinus halepensis Mill., and Arbutus unedo L.). Therefore, we collected twigs from the field during a period of mild winter conditions and after a sudden cold period. After both periods, the state of the photosynthetic machinery was tested in the laboratory by estimating the foliar photosynthetic potential with CO2 response curves in parallel with chlorophyll fluorescence measurements. The studied evergreen tree species benefited strongly from mild winter conditions by exhibiting extraordinarily high photosynthetic potentials. A sudden period of frost, however, negatively affected the photosynthetic apparatus, leading to significant decreases in key physiological parameters such as the maximum carboxylation velocity (Vc,max), the maximum photosynthetic electron transport rate (Jmax), and the optimal fluorometric quantum yield of photosystem II (Fv/Fm). The responses of Vc,max and Jmax were highly species specific, with Q. ilex exhibiting the highest and P. halepensis the lowest reductions. In contrast, the optimal fluorometric quantum yield of photosystem II (Fv/Fm) was significantly lower in A. unedo after the cold period. The leaf position played an important role in Q. ilex showing a stronger winter effect on sunlit leaves in comparison to shaded leaves. Our results generally agreed with the previous classifications of photoinhibition-tolerant (P. halepensis) and photoinhibitionavoiding (Q. ilex) species on the basis of their susceptibility to dynamic photoinhibition, whereas A. unedo was the least tolerant to photoinhibition, which was chronic in this species. Q. ilex and P. halepensis seem to follow contrasting photoprotective strategies. However, they seemed equally successful under the prevailing conditions exhibiting an adaptive advantage over A. unedo. These results show that our understanding of the dynamics of interspecific competition in Mediterranean ecosystems requires consideration of the physiological behaviour during winter which may have important implications for long-term carbon budgets and growth trends.

Cyanobacteria from the Baltic Sea and Finnish lakes as an energy source and modulators of bioenergetic pathways

Cyanobacteria are a diverse group of oxygenic photosynthetic bacteria that inhabit in a wide range of environments. They are versatile and multifaceted organisms with great possibilities for different biotechnological applications. For example, cyanobacteria produce molecular hydrogen (H2), which is one of the most important alternatives for clean and sustainable energy. Apart from being beneficial, cyanobacteria also possess harmful characteristics and may become a source of threat to human health and other living organisms, as they are able to form surface blooms that are producing a variety of toxic or bioactive compounds. The University of Helsinki Culture Collection (UHCC) maintains around 1,000 cyanobacterial strains representing a large number of genera and species isolated from the Baltic Sea and Finnish lakes. The culture collection covers different life forms such as unicellular and filamentous, N2-fixing and non-N2-fixing strains, and planktonic and benthic cyanobacteria. In this thesis, the UHCC has been screened to identify potential strains for sustainable biohydrogen production and also for strains that produce compounds modifying the bioenergetic pathways of other cyanobacteria or terrestrial plants. Among the 400 cyanobacterial strains screened so far, ten were identified as high H2-producing strains. The enzyme systems involved in H2 metabolism of cyanobacteria were analyzed using the Southern hybridization approach. This revealed the presence of the enzyme nitrogenase in all strains tested, while none of them are likely to have contained alternative nitrogenases. All the strains tested, except for two Calothrix strains, XSPORK 36C and XSPORK 11A, were suggested to contain both uptake and bidirectional hydrogenases. Moreover, 55 methanol extracts of various cyanobacterial strains were screened to identify potent bioactive compounds affecting the photosynthetic apparatus of the model cyanobacterium, Synechocystis PCC 6803. The extract from Nostoc XPORK 14A was the only one that modified the photosynthetic machinery and dark respiration. The compound responsible for this effect was identified, purified, and named M22. M22 demonstrated a dual-action mechanism: production of reactive oxygen species (ROS) under illumination and an unknown mechanism that also prevailed in the dark. During summer, the Baltic Sea is occupied by toxic blooms of Nodularia spumigena (hereafter referred to as N. spumigena), which produces a hepatotoxin called nodularin. Long-term exposure of the terrestrial plant spinach to nodularin was studied. Such treatment resulted in inhibition of growth and chlorosis of the leaves. Moreover, the activity and amount of mitochondrial electron transfer complexes increased in the leaves exposed to nodularin-containing extract, indicating upregulation of respiratory reactions, whereas no marked changes were detected in the structure or function of the photosynthetic machinery. Nodularin-exposed plants suffered from oxidative stress, evidenced by oxidative modifications of various proteins. Plants initiated strategies to combat the stress by increasing the levels of alpha-tocopherol, mitochondrial alternative oxidase (AOX), and mitochondrial ascorbate peroxidase (mAPX).