Acute post-exercise oxygen uptake, hormone and plasma metabolite response in obese men.

This study aimed to compare oxygen uptake (  V˙O2), hormone and plasma metabolite responses during the 30 min after submaximal incremental exercise (Incr) performed at the same relative/absolute exercise intensity and duration in lean (L) and obese (O) men. Eight L and 8 O men (BMI: 22.9±0.4; 37.2±1.8 kg · m(-2)) completed Incr and were then seated for 30 min.   V˙O2 was monitored during the first 10 min and from the 25-30(th) minutes of recovery. Blood samples were drawn for the determination of hormone (catecholamines, insulin) and plasma metabolite (NEFA, glycerol) concentrations. Excess post-exercise oxygen consumption (EPOC) magnitude during the first 10 min was similar in O and in L (3.5±0.4; 3.4±0.3 liters, respectively, p=0.86). When normalized to percent change (  V˙O2END=100%), %   V˙O2END during recovery was significantly higher from 90-120 s in O than in L (p≤0.04). There were no significant differences in catecholamines (p≥0.24), whereas insulin was significantly higher in O than in L during recovery (p=0.01). The time-course of glycerol was similar from 10-30 min of recovery (-42% for L; -41% for O, p=0.85), whereas significantly different patterns of NEFA were found from 10-30 min of recovery between groups (-18% for L; +8% for O, p=0.03). Despite similar EPOC, a difference in   V˙O2 modulation between groups was observed, likely due to faster initial rates of   V˙O2 decline in L than in O. The different patterns of NEFA between groups may suggest a lower NEFA reesterification during recovery in O, which was not involved in the rapid EPOC component.

Effect of hormone replacement therapy on vasomotor function of the coronary microcirculation in post-menopausal women with medically treated cardiovascular risk factors.

Aims The aim of this study was to evaluate the effect of hormone replacement therapy (HRT) on coronary vasomotor function in post-menopausal women (PM) with medically treated cardiovascular risk factors (RFs) in a cross-sectional and a longitudinal follow-up (FU) study. Methods and results Myocardial blood flow (MBF) response to cold pressor testing (CPT) and during pharmacologically induced hyperaemia was measured with positron emission tomography in pre-menopausal women (CON), in PM with HRT and without HRT, and repeated in PM after a mean FU of 24 +/- 14 months. When compared with CON at baseline, the endothelium-related change in MBF (DeltaMBF) to CPT progressively declined in PM with HRT and without HRT (0.35 +/- 0.23 vs. 0.24 +/- 0.20 and 0.16 +/- 0.12 mL/g/min; P = 0.171 and P = 0.021). In PM without HRT and in those with HRT at baseline but with discontinuation of HRT during FU, the endothelium-related DeltaMBF to CPT was significantly less at FU than at baseline (0.05 +/- 0.19 vs. 0.16 +/- 0.12 and -0.03 +/- 0.14 vs. 0.25 +/- 0.18 mL/g/min; P = 0.023 and P = 0.001), whereas no significant change was observed in PM with HRT (0.19 +/- 0.22 vs. 0.23 +/- 0.22 mL/g/min; P = 0.453). Impaired hyperaemic MBFs when compared with CON were not significantly altered from those at baseline exam. Conclusion Long-term administration of oestrogen may contribute to maintain endothelium-dependent coronary function in PM with medically treated cardiovascular RFs.

Inappropriate antidiuretic hormone secretion: long-term successful urea treatment.

Hyponatremia is the main complication of inappropriate antidiuretic hormone secretion (SIADH), sometimes fatal. Treatment strategy depends on the cause and the severity of the hyponatremia. Recent studies have shown the efficacy of urea in treating acute hyponatremia secondary to SIADH, by inducing an osmotic water drive. We describe an infant with chronic hyponatremia secondary to SIADH in which the long-term oral treatment with urea was successful and well tolerated. The aim of this paper is to highlight the potential benefits of urea treatment in case of chronic hyponatremia secondary to SIADH. CONCLUSION: Chronic oral urea treatment in children with SIADH allows an easy and safe water and sodium control and may permit a decrease in fluid restriction in this situation.

Meta-analysis : subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

Rapport de synthèse : Description : ce travail de thèse évalue de façon systématique les études sur l'association entre les dysfonctions thyroïdiennes infracliniques d'une part, et la maladie coronarienne et la mortalité d'autre part. Les hypothyroïdies infracliniques affectent environ 4-5% de la population adulte alors que la prévalence de l'hyperthyroïdie infraclinique est inférieure (environ 1%). L'éventuelle association entre elles pourrait justifier un dépistage systématique des dysfonctions thyroïdiennes infracliniques. Les précédentes études sur l'association entre l'hypothyroïdie infraclinique et la maladie coronarienne ont donné des résultats conflictuels. La parution de nouveaux articles récents basés sur de grandes cohortes prospectives nous a permis d'effectuer une méta-analyse basée uniquement sur des études de cohorte prospectives, augmentant ainsi la validité des résultats. Résultats: 10 des 12 études identifiées pour notre revue systématique sont basées sur des cohortes issues de la population générale («population-based »), regroupant en tout 14 449 participants. Ces 10 études examinent toutes le risque associé à l'hypothyroïdie infraclinique (avec 2134 événements coronariens et 2822 décès), alors que 5 étudient également le risque associé à l'hyperthyroïdie infraclinique (avec 1392 événements coronariens et 1993 décès). En utilisant un modèle statistique de type random-effect model, le risque relatif [RR] lié à l'hypothyroïdie infraclinique pour la maladie coronarienne est de 1.20 (intervalle de confiance [IC] de 95%, 0.97 à 1.49). Le risque diminue lorsque l'on regroupe uniquement les études de meilleure qualité (RR compris entre 1.02 et 1.08). Il est plus élevé parmi les participants de moins de 65 ans (RR, 1.51 [IC, 1.09 à 2.09] et 1.05 [IC, 0.90 à 1.22] pour les études dont l'âge moyen des participants est >_ 65 ans). Le RR de la mortalité cardiovasculaire est de 1.18 (IC, 0.98 à 1.42) et de 1.12 (IC, 0.99 à 1.26) pour la mortalité totale. En cas d'hyperthyroïdie infraclinique, les RR de la maladie coronarienne sont de 1.21 (IC, 0.88 à 1.68), de 1.19 (IC, 0.81 à 1.76) pour la mortalité cardiovasculaire, et de 1.12 (IC, 0.89 à 1.42) pour la mortalité totale. Conclusions et perspectives : nos résultats montrent que les dysfonctions thyroïdiennes infracliniques (hypothyroïdie et hyperthyroïdie infracliniques) représentent un facteur de risque modifiable, bien que modéré, de la maladie coronarienne et de la mortalité. L'efficacité du traitement de ces dysfonctions thyroïdiennes infracliniques doit encore être prouvée du point de vue cardiovasculaire et de la mortalité. Il est nécessaire d'effectuer des études contrôlées contre placebo avec le risque cardiovasculaire et la mortalité comme critères d'efficacité, avant de pouvoir proposer des recommandations sur le dépistage des ces dysfonctions thyroïdiennes dans la population adulte.

Decrease in luteinizing hormone pulse frequency during a five-hour peripheral Ghrelin infusion in the ovariectomized rhesus monkey

RESUME : La ghrelin est un peptide sécrété par l'estomac jouant un rôle important dans le maintien de l'homéostasie énergétique. Ses taux plasmatiques sont augmentés durant des périodes prolongées de déficit nutritionnel. Une carence énergétique étant souvent associée à une inhibition de l'axe hypothalamo-hypophyso-ovarien, nous avons postulé que l'augmentation des taux circulant de ghrelin pourrait diminuer l'activité du générateur hypothalamique de pulsations de GnRH. Le protocole expérimental impliquait des singes rhésus adultes ovariectomisés (n=6) qui dans un premier temps recevaient durant 3 heures une perfusion de solution saline physiologique afin de mesurer la sécrétion pulsatile de LH à l'état basai. L'expérience se poursuivait alors durant 5 heures par une perfusion intraveineuse de ghrelin humaine (un bolus de 100-150µg suivi par 100-150µg/h) ou le maintien de la perfusion de solution saline physiologique. Des échantillons de sang étaient prélevés toutes les 15 minutes. La perfusion de ghrelin a augmenté ses taux plasmatiques de 2.9 fois par rapport aux valeurs de base. L'administration de ghrelin a significativement diminué la fréquence des pulsations de LH (de 0.89±0.07/h à l'état basai à 0.57±0.10/h durant la perfusion de ghrelin; p<0.05, moyenne±SEM), alors que la fréquence des pulsations de LH est restée inchangée durant la perfusion de solution physiologique. L'amplitude des pulsations de LH n'a pas été modifiée. La ghrelin a également stimulé de manière significative la sécrétion de cortisol et d'hormone de croissance, mais n'a toutefois pas eu d'effet sur la sécrétion de leptin. En conclusion, la ghrelin peut inhiber l'activité du générateur de pulsations de GnRH et pourrait ainsi contribuer à l'inhibition de l'axe de la reproduction observée durant des périodes de carence nutritionnelle, comme notamment chez les patientes souffrant d'anorexie mentale. La ghrelin peut également activer l'axe hypothalamo-hypophyso-surrénalien. Le lien dans cette situation entre l'activation de l'axe surrénalien et l'inhibition de l'axe de la reproduction reste à démontrer. ABSTRACT: Ghrelin, a nutrition-related peptide secreted by the stomach, is elevated during prolonged food deprivation. Because undernutrition is often associated with a suppressed reproductive axis, we have postulated that increasing peripheral ghrelin levels will decrease the activity of the GnRH pulse generator. Adult ovariectomized rhesus monkeys (n = 6) were subjected to a 5-h iv human ghrelin (100- to 150µg bolus followed by 100-150 µg/h) or saline infusion, preceded by a 3-h saline infusion to establish baseline pulsatile LH release. Blood samples were collected at 15-min intervals throughout the experiment. Ghrelin infusion increased plasma ghrelin levels 2.9-fold of baseline. Ghrelin significantly decreased LH pulse frequency (from 0.89 ± 0.07/h in baseline to 0.57 ± 0.10/h during ghrelin infusion; P<0.05, mean ± SEM), whereas LH pulse frequency remained unchanged during saline treatment. LH pulse amplitude was not affected. Ghrelin also significantly stimulated both Cortisol and GH release, but had no effect on leptin. We conclude that ghrelin can inhibit GnRH pulse activity and may thereby mediate the suppression of the reproductive system observed in conditions of undernutrition, such as in anorexia nervosa. Ghrelin also activates the adrenal axis, but the relevance of this to the inhibition of GnRH pulse frequency remains to be established.

Eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia have similar clinical, endoscopic and histological findings.

BACKGROUND: Some patients with a phenotypic appearance of eosinophilic oesophagitis (EoE) respond histologically to PPI, and are described as having PPI-responsive oesophageal eosinophilia (PPI-REE). It is unclear if PPI-REE is a GERD-related phenomenon, a subtype of EoE, or a completely unique entity. AIM: To compare demographic, clinical and histological features of EoE and PPI-REE. METHODS: Two databases were reviewed from the Walter Reed and Swiss EoE databases. Patients were stratified into two groups, EoE and PPI-REE, based on recent EoE consensus guidelines. Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least a 6-week course of treatment. RESULTS: One hundred and three patients were identified (63 EoE and 40 PPI-REE; mean age 40.2 years, 75% male and 89% Caucasian). The two cohorts had similar dysphagia (97% vs. 100%, P = 0.520), food impaction (43% vs. 35%, P = 0.536), and heartburn (33% vs. 32%, P = 1.000) and a similar duration of symptoms (6.0 years vs. 5.8 years, P = 0.850). Endoscopic features were also similar between EoE and PPI-REE; rings (68% vs. 68%, P = 1.000), furrows (70% vs. 70%, P = 1.000), plaques (19% vs. 10%, P = 0.272), strictures (49% vs. 30%, P = 0.066). EoE and PPI-REE were similar in the number of proximal (39 eos/hpf vs. 38 eos/hpf, P = 0.919) and distal eosinophils (50 vs. 43 eos/hpf, P = 0.285). CONCLUSIONS: EoE and PPI-responsive oesophageal eosinophilia are similar in clinical, histological and endoscopic features and therefore are indistinguishable without a PPI trial. Further studies are needed to determine why a subset of patients with oesophageal eosinophilia respond to PPI.

A fluorescent hormone biosensor reveals the dynamics of jasmonate signalling in plants.

Activated forms of jasmonic acid (JA) are central signals coordinating plant responses to stresses, yet tools to analyse their spatial and temporal distribution are lacking. Here we describe a JA perception biosensor termed Jas9-VENUS that allows the quantification of dynamic changes in JA distribution in response to stress with high spatiotemporal sensitivity. We show that Jas9-VENUS abundance is dependent on bioactive JA isoforms, the COI1 co-receptor, a functional Jas motif and proteasome activity. We demonstrate the utility of Jas9-VENUS to analyse responses to JA in planta at a cellular scale, both quantitatively and dynamically. This included using Jas9-VENUS to determine the cotyledon-to-root JA signal velocities on wounding, revealing two distinct phases of JA activity in the root. Our results demonstrate the value of developing quantitative sensors such as Jas9-VENUS to provide high-resolution spatiotemporal data about hormone distribution in response to plant abiotic and biotic stresses.

Regulation of the vitellogenin gene B1 promoter after transfer into hepatocytes in primary cultures.

The estrogen-dependent and tissue-specific regulation of the Xenopus laevis vitellogenin gene B1 promoter has been studied by lipid-mediated DNA transfer into Xenopus hepatocytes in primary culture. Hepatocytes achieve an efficient hormonal control of this promoter through a functional interaction between the estrogen responsive elements and a promoter proximal region upstream of the TATA box, which is characterized by a high density of binding sites for the transcription factors CTF/NF-1, C/EBP and HNF3. DNA accessibility to restriction enzymes within the chromosomal copy of the vitellogenin gene B1 promoter shows that the estrogen responsive unit and the promoter proximal region are sensitive to digestion in uninduced and estrogen-induced hepatocytes but not in erythrocyte nuclei. Together, these findings support the notion that chromatin configuration as well as the interplay of promoter elements mediate proper hormone-dependent and tissue-specific expression of the B1 vitellogenin gene.

The fetal hypothalamus has the potential to generate cells with a gonadotropin releasing hormone (GnRH) phenotype.

BACKGROUND: Neurospheres (NS) are colonies of neural stem and precursor cells capable of differentiating into the central nervous system (CNS) cell lineages upon appropriate culture conditions: neurons, and glial cells. NS were originally derived from the embryonic and adult mouse striatum subventricular zone. More recently, experimental evidence substantiated the isolation of NS from almost any region of the CNS, including the hypothalamus. METHODOLOGY/FINDINGS: Here we report a protocol that enables to generate large quantities of NS from both fetal and adult rat hypothalami. We found that either FGF-2 or EGF were capable of inducing NS formation from fetal hypothalamic cultures, but that only FGF-2 is effective in the adult cultures. The hypothalamic-derived NS are capable of differentiating into neurons and glial cells and most notably, as demonstrated by immunocytochemical detection with a specific anti-GnRH antibody, the fetal cultures contain cells that exhibit a GnRH phenotype upon differentiation. CONCLUSIONS/SIGNIFICANCE: This in vitro model should be useful to study the molecular mechanisms involved in GnRH neuronal differentiation.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Cross-sectional analysis of testosterone therapies in hypopituitary men on stable pituitary hormone replacement.

OBJECTIVE: The last decade has seen a proliferation in options for testosterone replacement. However, little is known as to the benefits of different treatment modalities. Our objective was to determine the testosterone prescription pattern and to examine the impact on various outcome measures. SUBJECTS AND METHODS: A total of 816 adult-onset hypopituitary males on stable pituitary replacement for at least 1 year were identified from the KIMS database. Patients were classified as either eugonadal (n = 106), or hypogonadal (n = 710) on intramuscular (IM, n = 558), oral (n = 74), transdermal (n = 61), and depot (n = 17) testosterone. RESULTS: After 1 year of stable pituitary replacement therapy, body composition, cardiovascular parameters, GH replacement and quality of life were not significantly different in androgen-replaced hypogonadal patients compared to eugonadal patients. There were no differences in outcome variables within the hypogonadal group according to the testosterone replacement regimen used and no difference in response to GH therapy. CONCLUSIONS: The majority of hypopituitary patients in the last decade have received IM testosterone. Body composition, cardiovascular parameters, GH replacement and quality of life were not different between eugonadal and hypogonadal patients and were not differentially affected by the mode of testosterone replacement. These findings are reassuring that there is no major difference in response to different testosterone replacement regimens.

cis- and trans-acting elements of the estrogen-regulated vitellogenin gene B1 of Xenopus laevis.

Vitellogenin genes are expressed under strict estrogen control in the liver of female oviparous vertebrates. Gene transfer experiments using estrogen-responsive cells have shown that the 13 bp perfect palindromic element GGTCACTGTGACC found upstream of the Xenopus laevis vitellogenin gene A2 promoter mediates hormonal stimulation and thus, was called the estrogen-responsive element (ERE). In the Xenopus vitellogenin genes B1 and B2 there are two closely adjacent EREs with one or more base substitutions when compared to the consensus ERE GGTCANNNTGACC. On their own, these degenerated elements have only a low or no regulatory capacity at all but act together synergistically to form an estrogen-responsive unit (ERU) with the same strength as the perfect palindromic 13 bp element. Analysis of estrogen receptor binding to the gene B1 ERU revealed a cooperative interaction of receptor dimers to the two adjacent imperfect EREs which most likely explains the synergistic stimulation observed in vivo. Furthermore, a promoter activator element located between positions --113 and --42 of the gene B1 and functional in the human MCF-7 and the Xenopus B3.2 cells has been identified and shown to be involved in the high level of induced transcription activity when the ERE is placed at a distance from the promoter. Finally, a hormone-controlled in vitro transcription system derived from Xenopus liver nuclear extracts was exploited to characterize two additional novel cis-acting elements within the vitellogenin gene B1 promoter. One of them, a negative regulatory element (NRE), is responsible for repression of promoter activity in the absence of hormone. The second is related to the NF-I binding site and is required, together with the ERE, to mediate hormonal induction. Moreover, we detected three trans-acting activities in Xenopus liver nuclear extracts that interact with these regions and demonstrated that they participate in the regulation of the expression of the vitellogenin promoter in vitro.

Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram.

Neuropeptides appear to play a role in the pathophysiology of depression and electroconvulsive treatment and lithium affect these compounds in human cerebrospinal fluid (CSF) and rodent brain. Consequently, we investigated whether long-term treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram (Cit) would also affect neuropeptides in CSF of depressed patients. Changes in CSF monoamine metabolites were also explored. CSF concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI), neuropeptide Y (NPY)-LI, and Cit were determined in 21 patients with major depression. Lumbar puncture was performed in the morning at baseline and was repeated after at least 4 wk of Cit treatment (40 mg/d). The severity of depression was assessed by the Hamilton Rating Scale for Depression (HAMD). Cit treatment was associated with a significant increase in NPY-LI and decrease in CRH-LI. An evaluation of the relationship between changes in concentrations of NPY-LI, CRH-LI, and the clinical response showed significant correlations between these parameters. Significant NPY and CRH changes in CSF following treatment as well as correlations to changes in HAMD support the hypothesis that these two peptides play a role in affective disorders and are markers of therapeutic response.

Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family.

AIM: To describe a large family with autosomal dominant parkinsonism. BACKGROUND: Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. MATERIAL AND METHODS: Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2, SCA3, UCHL1, SNCA, LRRK2, PINK1, PRKN, PGRN, FMR1 premutation, and MAPT. The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. RESULTS: Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for alpha-synuclein. CONCLUSION: Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.