National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants.

BACKGROUND: Data for trends in glycaemia and diabetes prevalence are needed to understand the effects of diet and lifestyle within populations, assess the performance of interventions, and plan health services. No consistent and comparable global analysis of trends has been done. We estimated trends and their uncertainties in mean fasting plasma glucose (FPG) and diabetes prevalence for adults aged 25 years and older in 199 countries and territories. METHODS: We obtained data from health examination surveys and epidemiological studies (370 country-years and 2·7 million participants). We converted systematically between different glycaemic metrics. For each sex, we used a Bayesian hierarchical model to estimate mean FPG and its uncertainty by age, country, and year, accounting for whether a study was nationally, subnationally, or community representative. FINDINGS: In 2008, global age-standardised mean FPG was 5·50 mmol/L (95% uncertainty interval 5·37-5·63) for men and 5·42 mmol/L (5·29-5·54) for women, having risen by 0·07 mmol/L and 0·09 mmol/L per decade, respectively. Age-standardised adult diabetes prevalence was 9·8% (8·6-11·2) in men and 9·2% (8·0-10·5) in women in 2008, up from 8·3% (6·5-10·4) and 7·5% (5·8-9·6) in 1980. The number of people with diabetes increased from 153 (127-182) million in 1980, to 347 (314-382) million in 2008. We recorded almost no change in mean FPG in east and southeast Asia and central and eastern Europe. Oceania had the largest rise, and the highest mean FPG (6·09 mmol/L, 5·73-6·49 for men; 6·08 mmol/L, 5·72-6·46 for women) and diabetes prevalence (15·5%, 11·6-20·1 for men; and 15·9%, 12·1-20·5 for women) in 2008. Mean FPG and diabetes prevalence in 2008 were also high in south Asia, Latin America and the Caribbean, and central Asia, north Africa, and the Middle East. Mean FPG in 2008 was lowest in sub-Saharan Africa, east and southeast Asia, and high-income Asia-Pacific. In high-income subregions, western Europe had the smallest rise, 0·07 mmol/L per decade for men and 0·03 mmol/L per decade for women; North America had the largest rise, 0·18 mmol/L per decade for men and 0·14 mmol/L per decade for women. INTERPRETATION: Glycaemia and diabetes are rising globally, driven both by population growth and ageing and by increasing age-specific prevalences. Effective preventive interventions are needed, and health systems should prepare to detect and manage diabetes and its sequelae. FUNDING: Bill & Melinda Gates Foundation and WHO.

Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale: some case studies

Every year, debris flows cause huge damage in mountainous areas. Due to population pressure in hazardous zones, the socio-economic impact is much higher than in the past. Therefore, the development of indicative susceptibility hazard maps is of primary importance, particularly in developing countries. However, the complexity of the phenomenon and the variability of local controlling factors limit the use of processbased models for a first assessment. A debris flow model has been developed for regional susceptibility assessments using digital elevation model (DEM) with a GIS-based approach.. The automatic identification of source areas and the estimation of debris flow spreading, based on GIS tools, provide a substantial basis for a preliminary susceptibility assessment at a regional scale. One of the main advantages of this model is its workability. In fact, everything is open to the user, from the data choice to the selection of the algorithms and their parameters. The Flow-R model was tested in three different contexts: two in Switzerland and one in Pakistan, for indicative susceptibility hazard mapping. It was shown that the quality of the DEM is the most important parameter to obtain reliable results for propagation, but also to identify the potential debris flows sources.

Volemic status influences the response of plasma atrial natriuretic factor to positive airway pressure.

STUDY OBJECTIVE; To evaluate interactive effects of volemic status and positive end-expiratory pressure (PEEP) on the plasma levels of atrial natriuretic factor (ANF) in assist-controlled mechanical ventilation (MV). DESIGN: Three successive protocols applied in randomized order to each participant. SETTING: Clinical investigation laboratory. PARTICIPANTS: Twenty-one young, healthy adults. INTERVENTIONS: The three protocols were as follows: (1) MV+PEEP, normovolemia; (2) MV+PEEP, hypervolemia; and (3) spontaneous breathing (SB), hypervolemia. In protocols 1 and 2, a preliminary period of SB lasting 2 h was followed by MV alone (0.5 h), MV+20 cm H2O PEEP (1 h), and a recovery period of SB (1.5 h). Hypervolemia was induced by the continuous i.v. infusion of 3 L of 0.9% NaCl in 5 h (protocols 2 and 3). MEASUREMENTS AND RESULTS: Heart rate, BP, and the plasma levels of immunoreactive ANF and catecholamines were measured serially. During hypervolemia, ANF significantly decreased when PEEP was added to MV (protocol 2: from 31.1 +/- 2.7 to 20.7 +/- 1.5 fmol/mL; p < 0.01). This did not occur in normovolemia (protocol 1: from 20.0 +/- to 16.7 +/- 1.2 fmol/mL; p = NS). The different effects of MV+PEEP in normovolemia and hypervolemia were not related to differences in circulating catecholamine levels. CONCLUSIONS: These results demonstrate for the first time (to our knowledge) that volemic status modulates the response of plasma ANF to PEEP in humans. The role of ANF in the water and salt retention induced by MV with PEEP might be limited to hypervolemic conditions.

A flow cytometry based oligotrophic pollutant exposure test to detect bacterial growth inhibition and cell injury.

Toxicity of chemical pollutants in aquatic environments is often addressed by assays that inquire reproductive inhibition of test microorganisms, such as algae or bacteria. Those tests, however, assess growth of populations as a whole via macroscopic methods such as culture turbidity or colony-forming units. Here we use flow cytometry to interrogate the fate of individual cells in low-density populations of the bacterium Pseudomonas fluorescens SV3 exposed or not under oligotrophic conditions to a number of common pollutants, some of which derive from oil contamination. Cells were stained at regular time intervals during the exposure assay with fluorescent dyes that detect membrane injury (i.e., live-dead assay). Reduction of population growth rates was observed upon toxicant insult and depended on the type of toxicant. Modeling and cell staining indicate that population growth rate decrease is a combined effect of an increased number of injured cells that may or may not multiply, and live cells dividing at normal growth rates. The oligotrophic assay concept presented here could be a useful complement for existing biomarker assays in compliance with new regulations on chemical effect studies or, more specifically, for judging recovery after exposure to fluctuating toxicant conditions.

Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein.

The plasma concentrations of alpha 1-acid glycoprotein (AAG), albumin, triglycerides, cholesterol, and total proteins, as well as the plasma binding of racemic, d-methadone, and l-methadone were measured in 45 healthy subjects. The AAG phenotypes and the concentrations of AAG variants were also determined. The measured free fractions for racemic, d-methadone, and l-methadone were, respectively, 12.7% +/- 3.3%, 10.0% +/- 2.9%, and 14.2% +/- 3.2% (mean +/- SD). A significant correlation was obtained between the binding ratio (B/F) for dl-methadone and the total AAG concentration (r = 0.724; p less than 0.001). A multiple stepwise regression analysis showed that AAG was the main explanatory variable for the binding of the racemate. When concentrations of AAG variants were considered, a significant correlation was obtained between the binding ratio of dl-methadone and orosomucoid2 A concentration (r = 0.715; p less than 0.001), a weak correlation between dl-methadone and orosomucoid1 S concentration (r = 0.494; p less than 0.001), and no correlation between dl-methadone and orosomucoid1 F1 concentration (r = 0.049; not significant). Similar findings were obtained with the enantiomers. This study shows the importance of considering not only total AAG but also concentrations of AAG variants when measuring the binding of methadone and possibly of other drugs in plasma.

Low plasma lactate concentration as a biomarker of an incompetent brain-pull: a risk factor for weight gain in type 2 diabetes patients.

OBJECTIVE: Body weight development is closely regulated by central nervous mechanisms. As has been demonstrated recently, the capability of the brain to actively demand energy from the body (brain-pull) is indispensable for the maintenance of systemic homeostasis. A deficit in this brain-pull may result in compensatory ingestive behavior followed by weight gain in the medium or long term. The aim of this study was to establish a biomarker of such an incompetent brain-pull. Since lactate is an alternative cerebral energy substrate to glucose, we investigated whether low fasting plasma lactate concentrations are associated with weight gain and increased feelings of hunger in patients with type 2 diabetes over a 3-year period. METHODS: In a population based cohort study 134 type 2 diabetes patients were examined at baseline and 3-year follow-up. Plasma lactate concentrations and additional hormones associated with food intake such as e.g. insulin, or leptin, as well as psychological variables like hunger feelings before and after a standardized breakfast were measured. The relation between fasting plasma lactate concentrations and postprandial hunger as well as follow-up weight was analyzed. RESULTS: Low fasting plasma lactate concentrations predicted a higher 3-year follow-up weight (B=-1.268, SE=0.625, p=0.04). Moreover, low fasting plasma lactate concentrations were associated with more pronounced feelings of postprandial hunger (B=-0.406, SE=0.137, p<0.01). CONCLUSIONS: We conclude that low plasma lactate concentrations may represent a biomarker of an incompetent brain-pull, which is associated with weight gain and increased postprandial hunger in patients with type 2 diabetes mellitus. These results are in line with the view that plasma lactate can be used by the brain as an alternative energy substrate and thereby to some extent prevent overeating and obesity.

The sample processing time interval as an influential factor in flow cytometry analysis of lymphocyte subsets

The objective of this paper is to propose a protocol to analyze blood samples in yellow fever 17DD vaccinated which developed serious adverse events. We investigated whether or not the time between sample collection and sample processing could interfere in lymphocyte subset percentage, for it is often impossible to analyze blood samples immediately after collection due to transport delay from collection places to the flow cytometry facility. CD4+CD38+ T, CD8+CD38+ T, CD3+ T, CD19+ B lymphocyte subsets were analyzed by flow cytometry in nine healthy volunteers immediately after blood collection and after intervals of 24 and 48 h. The whole blood lysis method and gradient sedimentation by Histopaque were applied to isolate peripheral blood mononuclear cells for flow cytometry analyses. With the lysis method, there was no significant change in lymphocyte subset percentage between the two time intervals (24 and 48 h). In contrast, when blood samples were processed by Histopaque gradient sedimentation, time intervals for sample processing influenced the percentage in T lymphocyte subsets but not in B cells. From the results obtained, we could conclude that the whole blood lysis method is more appropriate than gradient sedimentation by Histopaque for immunophenotyping of blood samples collected after serious adverse events, due to less variation in the lymphocyte subset levels with respect to the time factor.

Effect of acute and chronic exercise on fat oxidation and hormonal and plasma metabolite kinetics in obese and severely obese men

Acute exercise increases energy expenditure (EE) during exercise and post-exercise recovery [excess post-exercise oxygen consumption (EPOC)] and therefore may be recommended as part of the multidisciplinary management of obesity. Moreover, chronic exercise (training) effectively promotes an increase in insulin sensitivity, which seems to be associated with increased fat oxidation rates (FORs). The main purpose of this thesis is to investigate 1) FORs and extra-muscular factors (hormones and plasma metabolites) that regulate fat metabolism during acute and chronic exercise; and 2) EPOC during acute post-exercise recovery in obese and severely obese men (class II and III). In the first study, we showed that obese and severely obese men present a lower exercise intensity (Fatmax) eliciting maximal fat oxidation and a lower reliance on fat oxidation at high, but not at low and moderate, exercise intensities compared to lean men. This was most likely related to an impaired muscular capacity to oxidize non-esterified fatty acids (NEFA) rather than decreased plasma NEFA availability or a change in the hormonal milieu during exercise. In the second study, we developed an accurate maximal incremental test to correctly and simultaneously evaluate aerobic fitness and fat oxidation kinetics during exercise in this population. This test may be used for the prescription of an appropriate exercise training intensity. In the third study, we demonstrated that only 2 wk of exercise training [continuous training at Fatmax and adapted high-intensity interval training (HIIT)], matched with respect to mechanical work, may be effective to improve aerobic fitness, FORs during exercise and insulin sensitivity, which suggest that FORs might be rapidly improved and that adapted HIIT is feasible in this population. The increased FORs concomitant with the lack of changes in lipolysis during exercise suggest an improvement in the mismatching between NEFA availability and oxidation, highlighting the importance of muscular (oxidative capacity) rather than extra-muscular (hormones and plasma metabolites) factors in the regulation of fat metabolism after a training program. In the fourth study, we observed a positive correlation between EE during exercise and EPOC, suggesting that a chronic increase in the volume or intensity of exercise may increase EE during exercise and during recovery. This may have an impact in weight management in obesity. In conclusion, these findings might have practical implications for exercise training prescriptions in order to improve the therapeutic approaches in obesity and severe obesity. -- L'exercice aigu augmente la dépense énergétique (DE) pendant l'exercice et la récupération post-exercice [excès de consommation d'oxygène post-exercise (EPOC)] et peut être utilisé dans la gestion multidisciplinaire de l'obésité. Quant à l'exercice chronique (entraînement), il est efficace pour augmenter la sensibilité à l'insuline, ce qui semble être associé à une amélioration du débit d'oxydation lipidique (DOL). Le but de cette thèse est d'étudier 1) le DOL et les facteurs extra-musculaires (hormones et métabolites plasmatiques) qui régulent le métabolisme lipidique pendant l'exercice aigu et chronique et 2) l'EPOC lors de la récupération aiguë post-exercice chez des hommes obèses et sévèrement obèses (classe II et III). Dans la première étude nous avons montré que les hommes obèses et sévèrement obèses présentent une plus basse intensité d'exercice (Fatmax) correspondant au débit d'oxydation lipidique maximale et un plus bas DOL à hautes, mais pas à faibles et modérées, intensités d'exercice comparé aux sujets normo-poids, ce qui est probablement lié à une incapacité musculaire à oxyder les acides gras non-estérifiés (AGNE) plutôt qu'à une diminution de leur disponibilité ou à un changement du milieu hormonal pendant l'exercice. Dans la deuxième étude nous avons développé un test maximal incrémental pour évaluer simultanément l'aptitude physique aérobie et la cinétique d'oxydation des lipides pendant l'exercice chez cette population. Dans la troisième étude nous avons montré que seulement deux semaines d'entraînement (continu à Fatmax et intermittent à haute intensité), appariés par la charge de travail, sont efficaces pour améliorer l'aptitude physique aérobie, le DOL pendant l'exercice et la sensibilité à l'insuline, ce qui suggère que le DOL peut être rapidement amélioré chez cette population. Ceci, en absence de changements de la lipolyse pendant l'exercice, suggère une amélioration de la balance entre la disponibilité et l'oxydation des AGNE, ce qui souligne l'importance des facteurs musculaires (capacité oxydative) plutôt que extra-musculaires (hormones et métabolites plasmatiques) dans la régulation du métabolisme lipidique après un entraînement. Dans la quatrième étude nous avons observé une corrélation positive entre la DE pendant l'exercice et l'EPOC, ce qui suggère qu'une augmentation chronique du volume ou de l'intensité de l'exercice pourrait augmenter la DE lors de l'exercice et lors de la récupération post-exercice. Ceci pourrait avoir un impact sur la gestion du poids chez cette population. En conclusion, ces résultats pourraient avoir des implications pratiques lors de la prescription des entraînements dans le but d'améliorer les approches thérapeutiques de l'obésité et de l'obésité sévère.

Enhancement by diuretics of the antihypertensive action of long-term angiotensin converting enzyme blockade

Thirty-nine patients with various types of hypertension were treated by chronic blockage of the angiotensin converting enzyme, i.e. by twice daily administration of captopril, 50 to 200 mg p.o. The blood pressure reduction observed 1 hour following administration of the inhibitor was directly related to the baseline plasma renin activity (r=- 0.67, p < 0.001). Whenever blockade of the renin system alone did not lower blood pressure to normal levels additional sodium subtraction brought it under control. With the renin system neutralized, blood pressure becomes exquisitely sensitive to changes in sodium balance. Diuretics seem to preserve optimal natriuretic efficacy despite blood pressure reduction, probably because aldosterone levels are reduced and renal blood flow increases. Blockade of the renin system together with individually tailored salt subtraction provides an attractive new approach to long-term treatment of clinical hypertension.

Plasma angiotensin-(1-8) octapeptide measurement to assess acute angiotensin-converting enzyme inhibition with captopril administered parenterally to normal subjects.

The blood pressure (BP), heart rate (HR), and humoral effects of single intravenous (i.v.) doses of the angiotensin-converting enzyme (ACE) inhibitor captopril was investigated in five normotensive healthy volunteers. Each subject received at 1-week intervals a bolus dose of either captopril (1, 5, and 25 mg) or its vehicle. The study was conducted in a single-blind fashion, and the order of treatment phases was randomized. The different doses of captopril had no acute effect on BP and HR. They induced a dose-dependent decrease in plasma ACE activity and plasma angiotensin II levels. The angiotensin-(1-8) octapeptide was isolated by solid-phase extraction and high-performance liquid chromatography (HPLC) prior to radioimmunoassay (RIA). All three doses of captopril reduced circulating angiotensin II levels within 15 min of drug administration. Only with the 25-mg dose was the angiotensin II concentration below the detection limit at 15 min and still significantly reduced 90 min after drug administration. Simultaneous and progressive decreases in plasma aldosterone levels were observed both with ACE inhibition and during vehicle injection, but the relative fall was more pronounced after captopril administration. No adverse reaction was noticed. These results demonstrate that captopril given parenterally blocks the renin-angiotensin system in a dose-dependent manner. Only with the dose of 25 mg was the inhibition of plasma-converting enzyme activity and the reduction of plasma angiotensin II sustained for at least 1 1/2 h.

Reconstituted human polyclonal plasma-derived secretory-like IgM and IgA maintain the barrier function of epithelial cells infected with an enteropathogen.

Intravenous administration of polyclonal and monoclonal antibodies has proven to be a clinically valid approach in the treatment, or at least relief, of many acute and chronic pathologies, such as infection, immunodeficiency, and a broad range of autoimmune conditions. Plasma-derived IgG or recombinant IgG are most frequently used for intravenous or subcutaneous administration, whereas a few IgM-based products are available as well. We have established recently that secretory-like IgA and IgM can be produced upon association of plasma-derived polymeric IgA and IgM with a recombinant secretory component. As a next step toward potential future mucosal administration, we sought to unravel the mechanisms by which these secretory Igs protect epithelial cells located at the interface between the environment and the inside of the body. By using polarized epithelial Caco-2 cell monolayers and Shigella flexneri as a model enteropathogen, we found that polyspecific plasma-derived SIgA and SIgM fulfill many protective functions, including dose-dependent recognition of the antigen via formation of aggregated immune complexes, reduction of bacterial infectivity, maintenance of epithelial cell integrity, and inhibition of proinflammatory cytokine/chemokine production by epithelial cells. In this in vitro model devoid of other cellular or molecular interfering partners, IgM and secretory IgM showed stronger bacterial neutralization than secretory IgA. Together, these data suggest that mucosally delivered antibody preparations may be most effective when combining both secretory-like IgA and IgM, which, together, play a crucial role in preserving several levels of epithelial cell integrity.

Using flow cytometry for in situ monitoring of antimicrobial compound production in the biocontrol bacterium Pseudomonas fluorescens CHA0.

Pseudomonas fluorescens strain CHA0 is able to protect plants against a variety of pathogens, notably by producing the two antimicrobial compounds 2,4-diacetylphloroglucinol (DAPG) and pyoluteorin (PLT). The regulation of the expression of these compounds is affected by many biotic factors, such as fungal pathogens, rhizosphere bacteria as well as plant species. Therefore, the influence of some plant phenolic compounds on the expression of DAPG and PLT biosynthetic genes has been tested using GFP-based reporter, monitored by standard fluometry and flow cytometry. In situ experiments were also performed with cucumber plants. We found that several plant metabolites such as IAA and umbelliferone are able to modify significantly the expression of DAPG and PLT. The use of flow cytometry with autofluorescents proteins seems to be a promising method to study rhizobacteria-plant interactions.

Artificial neural network study of whole-cell bacterial bioreporter response determined using fluorescence flow cytometry.

Genetically engineered bioreporters are an excellent complement to traditional methods of chemical analysis. The application of fluorescence flow cytometry to detection of bioreporter response enables rapid and efficient characterization of bacterial bioreporter population response on a single-cell basis. In the present study, intrapopulation response variability was used to obtain higher analytical sensitivity and precision. We have analyzed flow cytometric data for an arsenic-sensitive bacterial bioreporter using an artificial neural network-based adaptive clustering approach (a single-layer perceptron model). Results for this approach are far superior to other methods that we have applied to this fluorescent bioreporter (e.g., the arsenic detection limit is 0.01 microM, substantially lower than for other detection methods/algorithms). The approach is highly efficient computationally and can be implemented on a real-time basis, thus having potential for future development of high-throughput screening applications.

The role of platelet and plasma markers of antioxidant status and oxidative stress in thrombocytopenia among patients with vivax malaria

Malaria remains an important health problem in tropical countries like Brazil. Thrombocytopenia is the most common hematological disturbance seen in malarial infection. Oxidative stress (OS) has been implicated as a possible mediator of thrombocytopenia in patients with malaria. This study aimed to investigate the role of OS in the thrombocytopenia of Plasmodium vivax malaria through the measurement of oxidant and antioxidant biochemical markers in plasma and in isolated platelets. Eighty-six patients with P. vivax malaria were enrolled. Blood samples were analyzed for total antioxidant and oxidant status, albumin, total protein, uric acid, zinc, magnesium, bilirubin, total thiols, glutathione peroxidase (GPx), malondialdehyde (MDA), antibodies against mildly oxidized low-density lipoproteins (LDL-/nLDL ratio) and nitrite/nitrate levels in blood plasma and GPx and MDA in isolated platelets. Plasma MDA levels were higher in thrombocytopenic (TCP) (median 3.47; range 1.55-12.90 µmol/L) compared with the non-thrombocytopenic (NTCP) patients (median 2.57; range 1.95-8.60 µmol/L). Moreover, the LDL-/nLDL autoantibody ratio was lower in TCP (median 3.0; range 1.5-14.8) than in NTCP patients (median 4.0; range 1.9-35.5). Finally, GPx and MDA were higher in the platelets of TPC patients. These results suggest that oxidative damage of platelets might be important in the pathogenesis of thrombocytopenia found in P. vivax malaria as indicated by alterations of GPx and MDA.