Fructose-rich diet-induced abdominal adipose tissue endocrine dysfunction in normal male rats.

We have currently studied the changes induced by administration of a fructose-rich diet (FRD) to normal rats in the mass and the endocrine function of abdominal (omental) adipose tissue (AAT). Rats were fed ad libitum a standard commercial chow and tap water, either alone (control diet, CD) or containing fructose (10%, w/vol) (FRD). Three weeks after treatment, circulating metabolic markers and leptin release from adipocytes of AAT were measured. Plasma free fatty acids (FFAs), leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in FRD than in CD rats. AAT mass was greater in FRD than in CD rats and their adipocytes were larger, they secreted more leptin and showed impaired insulin sensitivity. While leptin mRNA expression increased in AAT from FRD rats, gene expression of insulin receptor substrate, IRS1 and IRS2 was significantly reduced. Our study demonstrates that administration of a FRD significantly affects insulin sensitivity and several AAT endocrine/metabolic functions. These alterations could be part of a network of interacting abnormalities triggered by FRD-induced oxidative stress at the AAT level. In view of the impaired glucose tolerance observed in FRD rats, these alterations could play a key role in both the development of metabolic syndrome (MS) and beta-cell failure.

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.

Vascular dysfunction in children conceived by assisted reproductive technologies: underlying mechanisms and future implications.

Epidemiological studies in humans have demonstrated a relationship between pathological events during fetal development and increased cardiovascular risk later in life and have led to the so called "Fetal programming of cardiovascular disease hypothesis". The recent observation of generalised vascular dysfunction in young apparently healthy children conceived by assisted reproductive technologies (ART) provides a novel and potentially very important example of this hypothesis. This review summarises recent data in ART children demonstrating premature subclinical atherosclerosis in the systemic circulation and pulmonary vascular dysfunction predisposing to exaggerated hypoxia-induced pulmonary hypertension. These problems appear to be related to the ART procedure per se. Studies in ART mice demonstrating premature vascular aging and arterial hypertension further demonstrate the potential of ART to increase cardiovascular risk and have allowed to unravel epigenetic alterations of the eNOS gene as an underpinning mechanism. The roughly 25% shortening of the life span in ART mice challenged with a western style high-fat-diet demonstrates the potential importance of these alterations for the long-term outcome. Given the young age of the ART population, data on cardiovascular endpoints will not be available before 20 to 30 years from now. However, already now cohort studies of the ART population are needed to early detect cardiovascular alterations with the aim to prevent or at least optimally treat cardiovascular complications. Finally, a debate needs to be engaged on the future of ART and the consequences of its exponential growth for public health.

Enhanced diastolic reflections on arterial pressure pulse during exercise recovery

RESUMEDurant la phase de récupération d'un exercice de course à pied d'intensité maximale ou submaximale, une augmentation de la pression artérielle systolique centrale (aortique) résultant de la réflexion des ondes de pouls sur l'arbre vasculaire est constatée chez l'individu en bonne santé. En diastole cependant, l'impact de la réflexion de ces ondes de pouls sur la pression centrale demeure inconnu durant la récupération d'un exercice.Nous avons évalué les ondes de pouls centrales systolique et diastolique chez onze athlètes d'endurance durant la phase de récupération d'un exercice de course à pied dans des conditions d'effort maximal (sur tapis de course) et lors d'un effort submaximal lors d'une course à pied de 4000 mètres en plein air sur terrain mixte.Pour chaque sujet et lors des deux exercices, l'onde de pouls a été mesurée au niveau radial par tonométrie d'aplanation durant une phase de repos précédant l'exercice, puis à 5, 15, 25, 35 et 45 minutes après la fin de l'exercice. En utilisant une fonction mathématique de transfert, l'onde de pouls centrale a été extrapolée à partir de l'onde de pouls radiale. En compilant la forme de l'onde de pouls centrale avec une mesure simultanée de la pression artérielle brachiale, un index d'augmentation de l'onde de pouls en systole (Alx) et en diastole (Als) peut être calculé, reflétant l'augmentation des pressions résultant de la réflexion des ondes sur l'arbre vasculaire périphérique.A 5 minutes de la fin de l'exercice, les deux index ont été mesurés moindres que ceux mesurés lors de la phase précédant celui-ci. Lors des mesures suivantes, Alx est resté bas, alors que Aid a progressivement augmenté pour finalement dépasser la valeur de repos après 45 minutes de récupération. Le même phénomène a été constaté pour les deux modalités d'exercice (maximal ou submaximal). Ainsi, au-delà de quelques minutes de récupération après un exercice de course d'intensité maximale ou submaximale, nous avons montré par ces investigations que les ondes de pouls réfléchies en périphérie augmentent de façon sélective la pression centrale en diastole chez l'athlète d'endurance.ABSTRACTDuring recovery from a maximal or submaximal aerobic exercise, augmentation of central (aortic) systolic pressure by reflected pressure waves is blunted in healthy humans. However, the extent to which reflected pressure waves modify the central pulse in diastole in these conditions remains unknown. We evaluated systolic and diastolic central reflected waves in 11 endurance-trained athletes on recovery from a maximal running test on a treadmill (treadmill-max) and a 4000m run in field conditions. On both occasions in each subject, the radial pulse was recorded with applanation tonometry in the resting preexercise state and then 5, 15, 25, 35, and 45 minutes after exercise termination. From the central waveform, as reconstructed by application of a generalized transfer function, we computed a systolic (Alx) and a diastolic index (Aid) of pressure augmentation by reflections. At 5 minutes, both indices were below preexercise. At further time-points, Alx remained low, while Aid progressively increased, to overshoot above preexercise at 45 minutes. The same behavior was observed with both exercise types. Beyond the first few minutes of recovery following either maximal or submaximal aerobic exercise, reflected waves selectively augment the central pressure pulse in diastole, at least in endurance- trained athletes.

Dysfunction of epithelial sodium transport: from human to mouse.

The highly amiloride-sensitive epithelial sodium channel (ENaC) is an apical membrane constituent of cells of many salt-absorbing epithelia. In the kidney, the functional relevance of ENaC expression has been well established. ENaC mediates the aldosterone-dependent sodium reabsorption in the distal nephron and is involved in the regulation of blood pressure. Mutations in genes encoding ENaC subunits are causative for two human inherited diseases: Liddle's syndrome, a severe form of hypertension associated with ENaC hyperfunction, and pseudohypoaldosteronism (PHA-1), a salt-wasting syndrome caused by decreased ENaC function. Transgenic mouse technologies provide a useful tool to study the role of ENaC in vivo. Different mouse lines have been established in which each of the ENaC subunits was affected. The phenotypes observed in these mice demonstrated that each subunit is essential for survival and for regulation of sodium transport in kidney and colon. Moreover, the alpha subunit plays a specific role in the control of fluid absorption in the airways at birth. Such mice can now be used to study the role of ENaC in various organs and can serve as models to understand the pathophysiology of these human diseases.

Disfunções orgânicas de pacientes internados em Unidades de Terapia Intensiva segundo o Logistic Organ Dysfunction System

Foi objetivo do estudo verificar as associações entre a probabilidade de morte, número e tipo de insuficiências orgânicas na admissão de pacientes na Unidade de Terapia Intensiva (UTI), segundo o Logistic Organ Dysfunction System (LODS), e as seguintes variáveis: tempo de internação, condição de saída e readmissão na unidade. Estudo prospectivo longitudinal de 600 pacientes adultos internados em UTI gerais de quatro hospitais do Município de São Paulo. Como resultados, a probabilidade de morte apresentou associação com as condições de saída da UTI (p<0,001). Também houve associação do número de insuficiências orgânicas com as condição de saída (p<0,001) e tempo de internação na UTI (p<0,001). Quanto ao tipo de insuficiências e tempo de internação na Unidade houve diferença apenas entre os pacientes com insuficiência neurológica (p<0,001), pulmonar (p<0,001) e renal (p=0,020). A readmissão dos pacientes na UTI não teve associação com nenhuma das variáveis estudadas.

Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.

During the initial phases of type 1 diabetes, pancreatic islets are invaded by immune cells, exposing β-cells to proinflammatory cytokines. This unfavorable environment results in gene expression modifications leading to loss of β-cell functions. To study the contribution of microRNAs (miRNAs) in this process, we used microarray analysis to search for changes in miRNA expression in prediabetic NOD mice islets. We found that the levels of miR-29a/b/c increased in islets of NOD mice during the phases preceding diabetes manifestation and in isolated mouse and human islets exposed to proinflammatory cytokines. Overexpression of miR-29a/b/c in MIN6 and dissociated islet cells led to impairment in glucose-induced insulin secretion. Defective insulin release was associated with diminished expression of the transcription factor Onecut2, and a consequent rise of granuphilin, an inhibitor of β-cell exocytosis. Overexpression of miR-29a/b/c also promoted apoptosis by decreasing the level of the antiapoptotic protein Mcl1. Indeed, a decoy molecule selectively masking the miR-29 binding site on Mcl1 mRNA protected insulin-secreting cells from apoptosis triggered by miR-29 or cytokines. Taken together, our findings suggest that changes in the level of miR-29 family members contribute to cytokine-mediated β-cell dysfunction occurring during the initial phases of type 1 diabetes.

Intrauterine growth restriction and absent or reverse end-diastolic blood flow in umbilical artery (Doppler class II or III): A retrospective study of short- and long-term fetal morbidity and mortality.

OBJECTIVE: Absent or reverse end-diastolic flow (Doppler II/III) in umbilical artery is correlated with poor perinatal outcome, particularly in intrauterine growth restricted (IUGR) fetuses. The optimal timing of delivery is still controversial. We studied the short- and long-term morbidity and mortality among these children associated with our defined management. STUDY DESIGN: Sixty-nine IUGR fetuses with umbilical Doppler II/III were divided into three groups; Group 1, severe early IUGR, no therapeutic intervention (n = 7); Group 2, fetuses with pathological biophysical profile, immediate delivery (n = 35); Group 3, fetuses for which expectant management had been decided (n = 27). RESULTS: In Group 1, stillbirth was observed after a mean delay of 6.3 days. Group 2 delivered at an average of 31.6 weeks and two died in the neonatal period (6%). In Group 3 after a mean delay of 8 days, average gestational age at delivery was 31.7 weeks; two intra uterine and four perinatal deaths were observed (22%). Long-term follow-up revealed no sequelae in 25/31 (81%) and 15/18 (83%), and major handicap occurred in 1 (3%) and 2 patients (11%), respectively, for Groups 2 and 3. CONCLUSION: Fetal mortality was observed in 22% of this high risk group. After a mean period of follow-up of 5 years, 82% of infants showed no sequelae. According to our management, IUGR associated with umbilical Doppler II or III does not show any benefit from an expectant management in term of long-term morbidity.

Endothelial dysfunction in systemic lupus erythematosus: evaluation with 13N-ammonia PET.

Systemic lupus erythematosus (SLE) affects multiple organs and systems, severely involving the cardiovascular system. The aim of this study was to evaluate the presence of endothelial dysfunction with N-13-ammonia PET in asymptomatic SLE patients. Methods: We enrolled 16 women with SLE and 16 healthy women. Myocardial blood flow (MBF) was quantified in a 64-slice PET/CT scanner at rest, during a cold pressor test (CPT), and during stress. Endothelium-dependent vasodilation index, %Delta MBF, and myocardial flow reserve (MFR) were calculated. Results: There were 16 women in the SLE group (mean age +/- SD, 31.4 +/- 8.3 y) and 16 women in the healthy control group (31.5 +/- 11.1 y). Mean endothelium-dependent vasodilatation index and %Delta MBF were significantly lower in SLE patients (1.18 +/- 0.55 vs. 1.63 +/- 0.65, P = 0.04, and 18 +/- 55 vs. 63 +/- 65, P = 0.04, respectively). MFR was also lower in the SLE group (2.41 +/- 0.59 vs. 2.73 +/- 0.77, P = 0.20). Conclusion: SLE patients who are free of active disease present abnormal coronary flow and endothelial dysfunction. It is necessary to develop and intensify treatment strategies directed to CAD in SLE patients.

Mutism and Amnesia following High-Voltage Electrical Injury: Psychogenic Symptomatology Triggered by Organic Dysfunction?

Background: Mutism and dense retrograde amnesia are found both in organic and dissociative contexts. Moreover, dissociative symptoms may be modulated by right prefrontal activity. A single case, M.R., developed left hemiparesis, mutism and retrograde amnesia after a high-voltage electric shock without evidence of lasting brain lesions. M.R. suddenly recovered from his mutism following a mild brain trauma 2 years later. Methods: M.R.'s neuropsychological pattern and anatomoclinical correlations were studied through (i) language and memory assessment to characterize his deficits, (ii) functional neuroimaging during a standard language paradigm, and (iii) assessment of frontal and left insular connectivity through diffusion tractography imaging and transcranial magnetic stimulation. A control evaluation was repeated after recovery. Findings: M.R. recovered from the left hemiparesis within 90 days of the accident, which indicated a transient right brain impairment. One year later, neurobehavioral, language and memory evaluations strongly suggested a dissociative component in the mutism and retrograde amnesia. Investigations (including MRI, fMRI, diffusion tensor imaging, EEG and r-TMS) were normal. Twenty-seven months after the electrical injury, M.R. had a very mild head injury which was followed by a rapid recovery of speech. However, the retrograde amnesia persisted. Discussion: This case indicates an interaction of both organic and dissociative mechanisms in order to explain the patient's symptoms. The study also illustrates dissociation in the time course of the two different dissociative symptoms in the same patient.

Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review.

IntroductionSeveral studies have reported the presence of electroencephalography (EEG) abnormalities or altered evoked potentials (EPs) during sepsis. However, the role of these tests in the diagnosis and prognostic assessment of sepsis-associated encephalopathy remains unclear.MethodsWe performed a systematic search for studies evaluating EEG and/or EPs in adult (¿18 years) patients with sepsis-associated encephalopathy. The following outcomes were extracted: a) incidence of EEG/EP abnormalities; b) diagnosis of sepsis-associated delirium or encephalopathy with EEG/EP; c) outcome.ResultsAmong 1976 citations, 17 articles met the inclusion criteria. The incidence of EEG abnormalities during sepsis ranged from 12% to 100% for background abnormality and 6% to 12% for presence of triphasic waves. Two studies found that epileptiform discharges and electrographic seizures were more common in critically ill patients with than without sepsis. In one study, EEG background abnormalities were related to the presence and the severity of encephalopathy. Background slowing or suppression and the presence of triphasic waves were also associated with higher mortality. A few studies demonstrated that quantitative EEG analysis and EP could show significant differences in patients with sepsis compared to controls but their association with encephalopathy and outcome was not evaluated.ConclusionsAbnormalities in EEG and EPs are present in the majority of septic patients. There is some evidence to support EEG use in the detection and prognostication of sepsis-associated encephalopathy, but further clinical investigation is needed to confirm this suggestion.

Profound impact of uncomplicated pregnancy on diastolic, but not systolic pulse contour of aortic pressure

RESUME: L'objectif de cette étude était de déterminer l'impact de la grossesse non compliquée sur l'onde de pouls de la pression aortique centrale. Méthode 66 femmes au total avec une grossesse simple ont été réparties en trois groupes selon le stade de leur gestation: premier trimestre (T1, n=22), deuxième trimestre (T2, n=20) et troisième trimestre (T3, n=24). Le groupe contrôle (C, n=21) était constitué de femmes non enceintes, en bonne santé habituelle, prenant une contraception oestroprogestative. La tonométrie d'aplanation a été utilisée pour l'acquisition des ondes de pouls centrale un appareil disponible dans le commerce (SphygmoCor) permet l'enregistrement de l'onde de pouls périphérique avec un tonomètre d'aplanation de l'artère radiale au niveau du poignet, puis effectue sa transformation en sa forme centrale, grâce à une analyse de Fourrier et une fonction de transfert. L'influence des ondes réfléchies sur l'onde de pouls a été déterminée non seulement pendant la systole (augmentation systolique), comme on procède habituellement dans l'analyse de l'onde de pouls, mais aussi pendant la diastole (augmentation diastolique). Résultats Au cours de la grossesse, les pressions centrales systolique et diastolique sont restées inchangées et comparables aux valeurs mesurées chez les femmes qui ne sont pas enceintes. Dans le groupe contrôle, l'augmentation systolique s'élevait à 8.1±7.5% de la pression de pouls ; il n'y avait pas de différence statistiquement significative avec les valeurs obtenues chez les femmes enceintes, et ce, à n'importe quel stade de la grossesse (T1 : 4.6±11.4%, T2: 5.0±9.3%, T3 : 4.7±8.1%). Par contre, l'amplitude de l'augmentation diastolique diminuait avec la progression de la grossesse (C 6.5±2.4%, T1 : 5.2±3.1%, T2 : 3.8±2.6%; P=0.002 versus C; T3 : 2.3±2.0%; P<0.0001 versus C et P=0.004 versus T 1). Conclusion La grossesse ne modifie pas la forme de l'onde de pouls systolique centrale, ce qui implique de la part du système cardiovasculaire une adaptation fine à la demande croissante de flux sanguin, et ce, à tous les stades de la grossesse. Par contre, l'amplitude de l'onde de réflexion atteignant l'aorte pendant la diastole diminue progressivement au cours de la grossesse. Perspectives De récentes études montrent qu'une valeur anormalement haute de l'augmentation systolique de la pression centrale, comme on peut la déterminer avec la tonométrie d'aplanation, pourrait être un indice de trouble hypertensif de la grossesse débutant. Cette technique simple pourrait être d'autant plus facile à mettre en oeuvre si les valeurs normales pour l'augmentation systolique étaient indépendantes du stade de la grossesse, comme le suggèrent nos résultats, du moins pour les mesures prises en position assise.

Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism.

Acute myocardial dysfunction is a typical manifestation of septic shock. Experimentally, the administration of endotoxin [lipopolysacharride (LPS)] to laboratory animals is frequently used to study such dysfunction. However, a majority of studies used load-dependent indexes of cardiac function [including ejection fraction (EF) and maximal systolic pressure increment (dP/dt(max))], which do not directly explore cardiac inotropism. Therefore, we evaluated the direct effects of LPS on myocardial contractility, using left ventricular (LV) pressure-volume catheters in mice. Male BALB/c mice received an intraperitoneal injection of E. coli LPS (1, 5, 10, or 20 mg/kg). After 2, 6, or 20 h, cardiac function was analyzed in anesthetized, mechanically ventilated mice. All doses of LPS induced a significant drop in LV stroke volume and a trend toward reduced cardiac output after 6 h. Concomitantly, there was a significant decrease of LV preload (LV end-diastolic volume), with no apparent change in LV afterload (evaluated by effective arterial elastance and systemic vascular resistance). Load-dependent indexes of LV function were markedly reduced at 6 h, including EF, stroke work, and dP/dt(max). In contrast, there was no reduction of load-independent indexes of LV contractility, including end-systolic elastance (ejection phase measure of contractility) and the ratio dP/dt(max)/end-diastolic volume (isovolumic phase measure of contractility), the latter showing instead a significant increase after 6 h. All changes were transient, returning to baseline values after 20 h. Therefore, the alterations of cardiac function induced by LPS are entirely due to altered loading conditions, but not to reduced contractility, which may instead be slightly increased.