Fat oxidation kinetics during exercise in obese individuals.

Introduction An impaired ability to oxidize fat may be a factor in the obesity's aetiology (3). Moreover, the exercise intensity (Fatmax) eliciting the maximal fat oxidation rate (MFO) was lower in obese (O) compared with lean (L) individuals (4). However, difference in fat oxidation rate (FOR) during exercise between O and L remains equivocal and little is known about FORs during high intensities (>60% ) in O compared with L. This study aimed to characterize fat oxidation kinetics over a large range of intensities in L and O. Methods 12 healthy L [body mass index (BMI): 22.8±0.4] and 16 healthy O men (BMI: 38.9±1.4) performed submaximal incremental test (Incr) to determine whole-body fat oxidation kinetics using indirect calorimetry. After a 15-min resting period (Rest) and 10-min warm-up at 20% of maximal power output (MPO, determined by a maximal incremental test), the power output was increased by 7.5% MPO every 6-min until respiratory exchange ratio reached 1.0. Venous lactate and glucose and plasma concentration of epinephrine (E), norepinephrine (NE), insulin and non-esterified fatty acid (NEFA) were assessed at each step. A mathematical model (SIN) (1), including three variables (dilatation, symmetry, translation), was used to characterize fat oxidation (normalized by fat-free mass) kinetics and to determine Fatmax and MFO. Results FOR at Rest and MFO were not significantly different between groups (p≥0.1). FORs were similar from 20-60% (p≥0.1) and significantly lower from 65-85% in O than in L (p≤0.04). Fatmax was significantly lower in O than in L (46.5±2.5 vs 56.7±1.9 % respectively; p=0.005). Fat oxidation kinetics was characterized by similar translation (p=0.2), significantly lower dilatation (p=0.001) and tended to a left-shift symmetry in O compared with L (p=0.09). Plasma E, insulin and NEFA were significantly higher in L compared to O (p≤0.04). There were no significant differences in glucose, lactate and plasma NE between groups (p≥0.2). Conclusion The study showed that O presented a lower Fatmax and a lower reliance on fat oxidation at high, but not at moderate, intensities. This may be linked to a: i) higher levels of insulin and lower E concentrations in O, which may induce blunted lipolysis; ii) higher percentage of type II and a lower percentage of type I fibres (5), and iii) decreased mitochondrial content (2), which may reduce FORs at high intensities and Fatmax. These findings may have implications for an appropriate exercise intensity prescription for optimize fat oxidation in O. References 1. Cheneviere et al. Med Sci Sports Exerc. 2009 2. Holloway et al. Am J Clin Nutr. 2009 3. Kelley et al. Am J Physiol. 1999 4. Perez-Martin et al. Diabetes Metab. 2001 5. Tanner et al. Am J Physiol Endocrinol Metab. 2002

New approach for weight reduction by a combination of diet, light resistance exercise and the timing of ingesting a protein supplement.

We have reported that ingesting a meal immediately after exercise increased skeletal muscle accretion and less adipose tissue accumulation in rats employed in a 10 week resistance exercise program. We hypothesized that a possible increase in the resting metabolic rate (RMR) as a result of the larger skeletal muscle mass might be responsible for the less adipose deposition. Therefore, the effect of the timing of a protein supplement after resistance exercise on body composition and the RMR was investigated in 17 slightly overweight men. The subjects participated in a 12-week weight reduction program consisting of mild energy restriction (17% energy intake reduction) and a light resistance exercise using a pair of dumbbells (3-5 kg). The subjects were assigned to two groups. Group S ingested a protein supplement (10 g protein, 7 g carbohydrate, 3.3 g fat and one-third of recommended daily allowance (RDA) of vitamins and minerals) immediately after exercise. Group C did not ingest the supplement. Daily intake of both energy and protein was equal between the two groups and the protein intake met the RDA. After 12 weeks, the bodyweight, skinfold thickness, girth of waist and hip and percentage bodyfat significantly decreased in the both groups, however, no significant differences were observed between the groups. The fat-free mass significantly decreased in C, whereas its decrease in S was not significant. The RMR and post-meal total energy output significantly increased in S, while these variables did not change in C. In addition, the urinary nitrogen excretion tended to increase in C but not in S. These results suggest that the RMR increase observed in S might be associated with an increase in body protein synthesis.

Impact of global warming on potato late blight : risk, yield loss and control

Selostus: Ilmaston lämpenemisen vaikutus perunaruttoon

Recovery of postoperative visual loss following treatment of severe anaemia.

A 29-year-old pregnant woman noted acute visual loss following emergent Caesarean section complicated by excessive uterine bleeding. Postoperative visual acuity was count fingers in both eyes. Funduscopic changes were consistent with a diagnosis of anaemia-associated ischaemic optic neuropathy and retinopathy. One month later, because of persistent anaemia and poor visual recovery, blood transfusion was given. Following transfusion, the patient's vision improved over the next 6 months. In an otherwise healthy patient, visual loss associated with postoperative blood loss may still be partially reversible with correction of the anaemia, even after a delayed period of time.

Protein turnover, ureagenesis and gluconeogenesis.

The major processes discussed below are protein turnover (degradation and synthesis), degradation into urea, or conversion into glucose (gluconeogenesis, Figure 1). Daily protein turnover is a dynamic process characterized by a double flux of amino acids: the amino acids released by endogenous (body) protein breakdown can be reutilized and reconverted to protein synthesis, with very little loss. Daily rates of protein turnover in humans (300 to 400 g per day) are largely in excess of the level of protein intake (50 to 80 g per day). A fast growing rate, as in premature babies or in children recovering from malnutrition, leads to a high protein turnover rate and a high protein and energy requirement. Protein metabolism (synthesis and breakdown) is an energy-requiring process, dependent upon endogenous ATP supply. The contribution made by whole-body protein turnover to the resting metabolic rate is important: it represents about 20 % in adults and more in growing children. Metabolism of proteins cannot be disconnected from that of energy since energy balance influences net protein utilization, and since protein intake has an important effect on postprandial thermogenesis - more important than that of fats or carbohydrates. The metabolic need for amino acids is essentially to maintain stores of endogenous tissue proteins within an appropriate range, allowing protein homeostasis to be maintained. Thanks to a dynamic, free amino acid pool, this demand for amino acids can be continuously supplied. The size of the free amino acid pool remains limited and is regulated within narrow limits. The supply of amino acids to cover physiological needs can be derived from 3 sources: 1. Exogenous proteins that release amino acids after digestion and absorption 2. Tissue protein breakdown during protein turnover 3. De novo synthesis, including amino acids (as well as ammonia) derived from the process of urea salvage, following hydrolysis and microflora metabolism in the hind gut. When protein intake surpasses the physiological needs of amino acids, the excess amino acids are disposed of by three major processes: 1. Increased oxidation, with terminal end products such as CO₂ and ammonia 2. Enhanced ureagenesis i. e. synthesis of urea linked to protein oxidation eliminates the nitrogen radical 3. Gluconeogenesis, i. e. de novo synthesis of glucose. Most of the amino groups of the excess amino acids are converted into urea through the urea cycle, whereas their carbon skeletons are transformed into other intermediates, mostly glucose. This is one of the mechanisms, essential for life, developed by the body to maintain blood glucose within a narrow range, (i. e. glucose homeostasis). It includes the process of gluconeogenesis, i. e. de novo synthesis of glucose from non-glycogenic precursors; in particular certain specific amino acids (for example, alanine), as well as glycerol (derived from fat breakdown) and lactate (derived from muscles). The gluconeogenetic pathway progressively takes over when the supply of glucose from exogenous or endogenous sources (glycogenolysis) becomes insufficient. This process becomes vital during periods of metabolic stress, such as starvation.

The role of microRNAs in the development of type 2 diabets

Pancreatic ß cells are highly specialized endocrine cells located within the islets of Langerhans in the pancreas. Their main role is to produce and secrete insulin, the hormone essential for the regulation of glucose homeostasis and body's metabolism. Diabetes mellitus develops when the amount of insulin released by ß cells is not sufficient to cover the metabolic demand. In type 1 diabetes (5-10% of diagnoses) insulin deficiency is caused by the autoimmune destruction of pancreatic ß cells. Type 2 diabetes (90% of diagnoses) results from a genetic predisposition and from the presence of adverse environmental conditions. The combination of these factors reduces insulin sensitivity of peripheral target tissues, causes impairment in ß-cell function and can lead to partial loss of ß cells. The development of novel therapeutic strategies for the treatment of diabetes necessitates the comprehension of the cellular processes involved in dysfunction and loss of ß cells. My thesis was focused on the involvement in the physiopathological processes leading to the development of diabetes of a class of small regulatory RNA molecules, called microRNAs (miRNAs) that post- transcriptionally regulate gene expression. Global miRNA profiling in pancreatic islets of two animal models of diabetes, the db/db mice and mice that were fed a high fat diet (HFD), characterized by obesity and insulin resistance, led us to identify two groups of miRNAs displaying expression changes under pre-diabetic and diabetic conditions. Among the miRNAs already upregulated in pre-diabetic db/db mice and HFD mice, miR- 132 was found to have beneficial effects on pancreatic ß cell function and survival. Indeed, mimicking the upregulation of miR-132 in primary pancreatic islet cells and ß-cell lines improved glucose- induced insulin secretion and favored survival of the cells upon exposure to pro-apoptotic stimuli such as palmitate and cytokines. MiR-132 was found to exert its action by enhancing the expression of MafA, a transcription factor essential for ß-cell function, survival and identity. On the other hand, up-regulation of miR-199a-5p and miR-199a-3p was detectable only in the islets of diabetic db/db mice and resulted in impaired insulin secretion and sensitization of the cells to apoptosis. MiR-199a- 5p was found to decrease insulin secretion by inducing the expression of granuphilin, a potent inhibitor of ß cell exocytosis. In contrast, miR-199a-3p was demonstrated to directly target and reduce the expression of two key ß-cell genes, mTOR and cMET, resulting in impaired ß-cell adaptation to metabolic demands and loss by apoptosis. Our findings suggest that miRNAs are important players in the onset of type 2 diabetes. MiRNA expression is adjusted in pancreatic ß cells exposed to a diabetogenic environment. These changes initially concern miRNAs responsible for adaptive processes aimed at compensating the onset of insulin resistance, but later such changes can be overlapped by modifications in the level of several additional miRNAs that favor ß-cell failure and the onset of type 2 diabetes.

On the problematic of reserving and stochastic loss models

Abstract Traditionally, the common reserving methods used by the non-life actuaries are based on the assumption that future claims are going to behave in the same way as they did in the past. There are two main sources of variability in the processus of development of the claims: the variability of the speed with which the claims are settled and the variability between the severity of the claims from different accident years. High changes in these processes will generate distortions in the estimation of the claims reserves. The main objective of this thesis is to provide an indicator which firstly identifies and quantifies these two influences and secondly to determine which model is adequate for a specific situation. Two stochastic models were analysed and the predictive distributions of the future claims were obtained. The main advantage of the stochastic models is that they provide measures of variability of the reserves estimates. The first model (PDM) combines one conjugate family Dirichlet - Multinomial with the Poisson distribution. The second model (NBDM) improves the first one by combining two conjugate families Poisson -Gamma (for distribution of the ultimate amounts) and Dirichlet Multinomial (for distribution of the incremental claims payments). It was found that the second model allows to find the speed variability in the reporting process and development of the claims severity as function of two above mentioned distributions' parameters. These are the shape parameter of the Gamma distribution and the Dirichlet parameter. Depending on the relation between them we can decide on the adequacy of the claims reserve estimation method. The parameters have been estimated by the Methods of Moments and Maximum Likelihood. The results were tested using chosen simulation data and then using real data originating from the three lines of business: Property/Casualty, General Liability, and Accident Insurance. These data include different developments and specificities. The outcome of the thesis shows that when the Dirichlet parameter is greater than the shape parameter of the Gamma, resulting in a model with positive correlation between the past and future claims payments, suggests the Chain-Ladder method as appropriate for the claims reserve estimation. In terms of claims reserves, if the cumulated payments are high the positive correlation will imply high expectations for the future payments resulting in high claims reserves estimates. The negative correlation appears when the Dirichlet parameter is lower than the shape parameter of the Gamma, meaning low expected future payments for the same high observed cumulated payments. This corresponds to the situation when claims are reported rapidly and fewer claims remain expected subsequently. The extreme case appears in the situation when all claims are reported at the same time leading to expectations for the future payments of zero or equal to the aggregated amount of the ultimate paid claims. For this latter case, the Chain-Ladder is not recommended.

Cherenkov mesons as in-medium quark energy loss

We recently showed that a heavy quark moving su ciently fast through a quark-gluon plasma may lose energy by Cherenkov-radiating mesons [1]. Here we review our previous holographic calculation of the energy loss in N = 4 Super Yang-Mills and extend it to longitudinal vector mesons and scalar mesons. We also discuss phenomenological implications for heavy-ion collision experiments. Although the Cherenkov energy loss is an O(1=Nc) effect, a ballpark estimate yields a value of dE/dx for Nc = 3 which is comparable to that of other mechanisms.

Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice.

Mitochondrial dysfunction is one of the possible mechanisms by which azole resistance can occur in Candida glabrata. Cells with mitochondrial DNA deficiency (so-called "petite mutants") upregulate ATP binding cassette (ABC) transporter genes and thus display increased resistance to azoles. Isolation of such C. glabrata mutants from patients receiving antifungal therapy or prophylaxis has been rarely reported. In this study, we characterized two sequential and related C. glabrata isolates recovered from the same patient undergoing azole therapy. The first isolate (BPY40) was azole susceptible (fluconazole MIC, 4 μg/ml), and the second (BPY41) was azole resistant (fluconazole MIC, >256 μg/ml). BPY41 exhibited mitochondrial dysfunction and upregulation of the ABC transporter genes C. glabrata CDR1 (CgCDR1), CgCDR2, and CgSNQ2. We next assessed whether mitochondrial dysfunction conferred a selective advantage during host infection by testing the virulence of BPY40 and BPY41 in mice. Surprisingly, even with in vitro growth deficiency compared to BPY40, BPY41 was more virulent (as judged by mortality and fungal tissue burden) than BPY40 in both systemic and vaginal murine infection models. The increased virulence of the petite mutant correlated with a drastic gain of fitness in mice compared to that of its parental isolate. To understand this unexpected feature, genome-wide changes in gene expression driven by the petite mutation were analyzed by use of microarrays during in vitro growth. Enrichment of specific biological processes (oxido-reductive metabolism and the stress response) was observed in BPY41, all of which was consistent with mitochondrial dysfunction. Finally, some genes involved in cell wall remodelling were upregulated in BPY41 compared to BPY40, which may partially explain the enhanced virulence of BPY41. In conclusion, this study shows for the first time that mitochondrial dysfunction selected in vivo under azole therapy, even if strongly affecting in vitro growth characteristics, can confer a selective advantage under host conditions, allowing the C. glabrata mutant to be more virulent than wild-type isolates.

LOSS OF EXTRACTION CAPACITY OF MEHLICH-1 AND MONOCALCIUM PHOSPHATE AS A VARIABLE OF REMAINING P AND ITS RELATIONSHIP TO CRITICAL LEVELS OF SOIL PHOSPHORUS AND SULFUR

The Mehlich-1 (M-1) extractant and Monocalcium Phosphate in acetic acid (MCPa) have mechanisms for extraction of available P and S in acidity and in ligand exchange, whether of the sulfate of the extractant by the phosphate of the soil, or of the phosphate of the extractant by the sulfate of the soil. In clayey soils, with greater P adsorption capacity, or lower remaining P (Rem-P) value, which corresponds to soils with greater Phosphate Buffer Capacity (PBC), more buffered for acidity, the initially low pH of the extractants increases over their time of contact with the soil in the direction of the pH of the soil; and the sulfate of the M-1 or the phosphate of the MCPa is adsorbed by adsorption sites occupied by these anions or not. This situation makes the extractant lose its extraction capacity, a phenomenon known as loss of extraction capacity or consumption of the extractant, the object of this study. Twenty soil samples were chosen so as to cover the range of Rem-P (0 to 60 mg L-1). Rem-P was used as a measure of the PBC. The P and S contents available from the soil samples through M-1 and MCPa, and the contents of other nutrients and of organic matter were determined. For determination of loss of extraction capacity, after the rest period, the pH and the P and S contents were measured in both the extracts-soils. Although significant, the loss of extraction capacity of the acidity of the M-1 and MCPa extractants with reduction in the Rem-P value did not have a very expressive effect. A “linear plateau” model was observed for the M-1 for discontinuous loss of extraction capacity of the P content in accordance with reduction in the concentration of the Rem-P or increase in the PBC, suggesting that a discontinuous model should also be adopted for interpretation of available P of soils with different Rem-P values. In contrast, a continuous linear response was observed between the P variables in the extract-soil and Rem-P for the MCPa extractor, which shows increasing loss of extraction capacity of this extractor with an increase in the PBC of the soil, indicating the validity of the linear relationship between the available S of the soil and the PBC, estimated by Rem-P, as currently adopted.

Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice.

The transcription factor serum response factor (SRF) plays a crucial role in the development of several organs. However, its role in the skin has not been explored. Here, we show that keratinocytes in normal human and mouse skin expressed high levels of SRF but that SRF expression was strongly downregulated in the hyperproliferative epidermis of wounded and psoriatic skin. Keratinocyte-specific deletion within the mouse SRF locus during embryonic development caused edema and skin blistering, and all animals died in utero. Postnatal loss of mouse SRF in keratinocytes resulted in the development of psoriasis-like skin lesions. These lesions were characterized by inflammation, hyperproliferation, and abnormal differentiation of keratinocytes as well as by disruption of the actin cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-cell and cell-matrix contacts and loss of cell compaction in all epidermal layers. siRNA-mediated knockdown of SRF in primary human keratinocytes revealed that the cytoskeletal abnormalities and adhesion defects were a direct consequence of the loss of SRF. In contrast, the hyperproliferation observed in vivo was an indirect effect that was most likely a consequence of the inflammation. These results reveal that loss of SRF disrupts epidermal homeostasis and strongly suggest its involvement in the pathogenesis of hyperproliferative skin diseases, including psoriasis.

SPATIAL UNCERTAINTY OF NUTRIENT LOSS BY EROSION IN SUGARCANE HARVESTING SCENARIOS

The assessment of spatial uncertainty in the prediction of nutrient losses by erosion associated with landscape models is an important tool for soil conservation planning. The purpose of this study was to evaluate the spatial and local uncertainty in predicting depletion rates of soil nutrients (P, K, Ca, and Mg) by soil erosion from green and burnt sugarcane harvesting scenarios, using sequential Gaussian simulation (SGS). A regular grid with equidistant intervals of 50 m (626 points) was established in the 200-ha study area, in Tabapuã, São Paulo, Brazil. The rate of soil depletion (SD) was calculated from the relation between the nutrient concentration in the sediments and the chemical properties in the original soil for all grid points. The data were subjected to descriptive statistical and geostatistical analysis. The mean SD rate for all nutrients was higher in the slash-and-burn than the green cane harvest scenario (Student’s t-test, p<0.05). In both scenarios, nutrient loss followed the order: Ca>Mg>K>P. The SD rate was highest in areas with greater slope. Lower uncertainties were associated to the areas with higher SD and steeper slopes. Spatial uncertainties were highest for areas of transition between concave and convex landforms.

NITROGEN LOSS BY EROSION FROM MECHANICALLY TILLED AND UNTILLED SOIL UNDER SUCCESSIVE SIMULATED RAINFALLS

The description of the fate of fertilizer-derived nitrogen (N) in agricultural systems is an essential tool to enhance management practices that maximize nutrient use by crops and minimize losses. Soil erosion causes loss of nutrients such as N, causing negative effects on surface and ground water quality, aside from losses in agricultural productivity by soil depletion. Studies correlating the percentage of fertilizer-derived N (FDN) with soil erosion rates and the factors involved in this process are scarce. The losses of soil and fertilizer-derived N by water erosion in soil under conventional tillage and no tillage under different rainfall intensities were quantified, identifying the intervening factors that increase loss. The experiment was carried out on plots (3.5 × 11 m) with two treatments and three replications, under simulated rainfall. The treatments consisted of soil with and soil without tillage. Three successive rainfalls were applied in intervals of 24 h, at intensities of 30 mm/h, 30 mm/h and 70 mm/h. The applied N fertilizer was isotopically labeled (15N) and incorporated into the soil in a line perpendicular to the plot length. Tillage absence resulted in higher soil losses and higher total nitrogen losses (TN) by erosion induced by the rainfalls. The FDN losses followed another pattern, since FDN contributions were highest from tilled plots, even when soil and TN losses were lowest, i.e., the smaller the amount of eroded sediment, the greater the percentage of FDN associated with these. Rain intensity did not affect the FDN loss, and losses were greatest after less intense rainfalls in both treatments.

Loss of glucose-induced insulin secretion and GLUT2 expression in transplanted beta-cells.

Either 200 or 400 syngeneic islets were transplanted under the kidney capsule of normal or streptozocin-induced diabetic B6/AF1 mice. The diabetic mice with 400 islets became normoglycemic, but those with 200 islets, an insufficient number, were still diabetic after the transplantation (Tx). Two weeks after Tx, GLUT2 expression in the islet grafts was evaluated by immunofluorescence and Western blots, and graft function was examined by perfusion of the graft-bearing kidney. Immunofluorescence for GLUT2 was dramatically reduced in the beta-cells of grafts with 200 islets exposed to hyperglycemia. However, it was plentiful in grafts with 400 islets in a normoglycemic environment. Densitometric analysis of Western blots on graft homogenates demonstrated that GLUT2 protein levels in the islets, when exposed to chronic hyperglycemia for 2 weeks, were decreased to 16% of those of normal recipients. Moreover, these grafts had defective glucose-induced insulin secretion, while the effects of arginine were preserved. We conclude that GLUT2 expression in normal beta-cells is promptly down-regulated during exposure to hyperglycemia and may contribute to the loss of glucose-induced secretion of diabetes.

Seasonal changes in 24-h and basal energy expenditures in rural Gambian men as measured in a respiration chamber.

Adaptation of 24-h energy expenditure (24-h EE) to seasonal variations in food availability was studied, by using a respiration chamber, in 18 rural Gambian men on three occasions: period 1--at the end of the rainy season, which is characterized by low food availability; period 2--during the nutritionally favorable dry season; and period 3--at the onset of the following rainy season. From periods 1 to 2 body weight increased by 2.8 +/- 0.4 kg, and a rise in 24-h EE was observed (from 8556 +/- 212 kJ/d to 9166 +/- 224 kJ/d), which was correlated to weight change (r = 0.73, P less than 0.001). During period 3, 24-h EE averaged 8740 +/- 194 kJ/d. Diet-induced thermogenesis increased significantly from periods 1 to 2 (5.9 +/- 0.5% to 8.2 +/- 0.8%) and subsequently decreased to 3.6 +/- 0.6% during period 3. In rural Gambian men, metabolic adaptations in response to seasonal changes in food availability are reflected by a decrease in body weight, mainly manifested by a loss of fat-free mass accompanied by a decreased 24-h EE and a lowered diet-induced thermogenesis.