Mechanistic and therapeutic implications of angiogenesis in endometriosis

Like tumor metastases, endometriotic implants require neovascularization to proliferate and invade into ectopic sites within the host. Endometrial tissue, with its robust stem cell populations and remarkable regenerative capabilities, is a rich source of proangiogenic factors. Among the most potent and extensively studied of these proteins, vascular endothelial growth factor has emerged as a critical vasculogenic regulator in endometriosis. Accordingly, angiogenesis of the nascent endometriotic lesion has become an attractive target for novel medical therapeutics and strategies to inhibit vascular endothelial growth factor action. Vascular endothelial growth factor gene regulation in endometrial and endometriosis cells by nuclear receptors, other transcription factors, and also by infiltrating immune cells is emphasized. New data showing that oxidative and endoplasmic reticulum stress increase vascular endothelial growth factor expression are provided. Finally, we review the clinical implications of angiogenesis in this condition and propose potential antiangiogenic therapies that may become useful in the control or eradication of endometriotic lesions.

Effect of IGF-I therapy on VLDL apolipoprotein B100 metabolism in type 1 diabetes mellitus

Abnormal lipid metabolism may be related to the increased cardiovascular risk in type 1 diabetes. Secretion and clearance rates of very low density lipoprotein (VLDL) apolipoprotein B100 (apoB) determine plasma lipid concentrations. Type 1 diabetes is characterized by increased growth hormone (GH) secretion and decreased insulin-like growth factor (IGF) I concentrations. High-dose IGF-I therapy improves the lipid profile in type 1 diabetes. This study examined the effect of low-dose (40 microg.kg(-1).day(-1)) IGF-I therapy on VLDL apoB metabolism, VLDL composition, and the GH-IGF-I axis during euglycemia in type 1 diabetes. Using a stable isotope technique, VLDL apoB kinetics were estimated before and after 1 wk of IGF-I therapy in 12 patients with type 1 diabetes in a double-blind, placebo-controlled trial. Fasting plasma triglyceride (P < 0.03), VLDL-triglyceride concentrations (P < 0.05), and the VLDL-triglyceride-to-VLDL apoB ratio (P < 0.002) significantly decreased after IGF-I therapy, whereas VLDL apoB kinetics were not significantly affected by IGF-I therapy. IGF-I therapy resulted in a significant increase in IGF-I and a significant reduction in GH concentrations. The mean overnight insulin concentrations during euglycemia decreased by 25% after IGF-I therapy. These results indicate that low-dose IGF-I therapy restores the GH-IGF-I axis in type 1 diabetes. IGF-I therapy changes fasting triglyceride concentrations and VLDL composition probably because of an increase in insulin sensitivity.

Normal VLDL metabolism despite altered lipoprotein composition in type 1 diabetes mellitus

Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

Effect of regular physical training on age-associated alteration of body composition in men

Body composition changes with increasing age in men, in that lean body mass decreases whereas fat mass increases. Whether this altered body composition is related to decreasing physical activity or to the known age-associated decrease in growth hormone secretion is uncertain. To address this question, three groups of healthy men (n = 14 in each group), matched for weight, height and body mass index, were investigated using dual-energy X-ray absorptiometry, indirect calorimetry and estimate of daily growth hormone secretion [i.e. plasma insulin-like growth factor I (IGF-I-) levels]. Group 1 comprised young untrained subjects aged 31.0 +/- 2.1 years (mean +/- SEM) taking no regular physical exercise; group 2 consisted of old untrained men aged 68.6 +/- 1.2 years; and group 3 consisted of healthy old men aged 67.4 +/- 1.2 years undergoing regular physical training for more than 10 years with a training distance of at least 30 km per week. Subjects in group 3 had for the past three years taken part in the 'Grand Prix of Berne', a 16.5-km race run at a speed of 4.7 +/- 0.6 min km-1 (most recent race). Fat mass was more than 4 kg higher in old untrained men (P < 0.01, ANOVA) than in the other groups (young untrained men, 12.0 +/- 0.9 kg; old untrained men, 16.1 +/- 1.0 kg; old trained men, 11.0 +/- 0.8 kg), whereas body fat distribution (i.e. the ratio of upper to lower body fat mass) was similar between the three groups. The lean mass of old untrained men was more than 3.5 kg lower (P < 0.02, ANOVA) than in the other two groups (young untrained men, 56.4 +/- 1.0 kg; old untrained men, 52.4 +/- 1.0 kg; old trained men, 56.0 +/- 1.0 kg), mostly because of a loss of skeletal muscle mass in the arms and legs (young untrained men, 24.0 +/- 0.5 kg; old untrained men 20.8 +/- 0.5 kg; old trained men, 23.6 +/- 0.7 kg; P < 0.01, ANOVA). Resting metabolic rate per kilogram lean mass decreased with increasing age independently of physical activity (r = -0.42, P < 0.005). Fuel metabolism was determined by indirect calorimetry at rest. Protein oxidation was similar in the three groups. Old untrained men had higher (P < 0.001) carbohydrate oxidation (young untrained men, 13.2 +/- 1.0 kcal kg-1 lean mass; old untrained men, 15.2 +/- 1.3 kcal Kg-1; old trained men, 7.8 +/- 0.8 kcal kg-1), but lower (P < 0.05, ANOVA) fat oxidation (young untrained men, 10.1 +/- 1.2 kcal kg-1 lean mass; old untrained men, 6.5 +/- 1.0 kcal kg-1; old trained men, 13.7 +/- 1.0 kcal kg-1) than the other two groups. Mean plasma IGF-I level in old trained men was higher than in old untrained men (P < 0.05), but was still lower than that observed in young untrained men (P < 0.005) (young untrained men, 236 +/- 24 ng mL-1; old untrained men, 119 +/- 13 ng mL-1; old trained men, 166 +/- 14 ng mL-1). In summary, regular physical training in older men seems to prevent the changes in body composition and fuel metabolism normally associated with ageing. Whether regular physical training in formerly untrained old subjects would result in similar changes awaits further study.

Suprasellar germinomas in childhood and adolescence: diagnostic pitfalls

The clinical and neuro-endocrine data of seven young male patients with suprasellar germinomas seen between 1984 and 1992 are reported. The most common initial symptom was 'idiopathic' central diabetes insipidus (DI), which occurred in all seven patients. The time interval between the appearance of this first clinical sign and the definitive diagnosis of a suprasellar germinoma ranged from 3 to 66 months. Raised prolactin levels and growth hormone deficiency were indicators of a process located in the hypothalamic-pituitary region. An increased beta-HCG level in the serum or the CSF confirmed the diagnostic suspicion of a germinoma and was helpful as a tumor marker in follow-up. Neuro-radiologic studies (CT or MRI) were also disappointing in the early stage when patients presented only with DI. Later on, as patients developed additional symptoms or signs related to the tumor, imaging studies were positive. Given the variable rate of tumor progression, the nonspecific early signs of hypothalamic-pituitary dysfunction (DI) as well as the often negative early imaging studies, the diagnosis of suprasellar germinoma is difficult but should always be considered in the presence of so-called 'idiopathic' central DI. Repeated brain MRIs are mandatory in young patients with idiopathic DI in order not to miss an underlying suprasellar germinoma.

Impact of environmental estrogens on Yfish considering the diversity of estrogen signaling.

Research on endocrine disruption in fish has been dominated by studies on estrogen-active compounds which act as mimics of the natural estrogen, 17β-estradiol (E2), and generally exert their biological actions by binding to and activation of estrogen receptors (ERs). Estrogens play central roles in reproductive physiology and regulate (female) sexual differentiation. In line with this, most adverse effects reported for fish exposed to environmental estrogens relate to sexual differentiation and reproduction. E2, however, utilizes a variety of signaling mechanisms, has multifaceted functions and targets, and therefore the toxicological and ecological effects of environmental estrogens in fish will extend beyond those associated with the reproduction. This review first describes the diversity of estrogen receptor signaling in fish, including both genomic and non-genomic mechanisms, and receptor crosstalk. It then considers the range of non-reproductive physiological processes in fish that are known to be responsive to estrogens, including sensory systems, the brain, the immune system, growth, specifically through the growth hormone/insulin-like growth factor system, and osmoregulation. The diversity in estrogen responses between fish species is then addressed, framed within evolutionary and ecological contexts, and we make assessments on their relevance for toxicological sensitivity as well as ecological vulnerability. The diversity of estrogen actions raises questions whether current risk assessment strategies, which focus on reproductive endpoints, and a few model fish species only, are protective of the wider potential health effects of estrogens. Available - although limited - evidence nevertheless suggests that quantitative environmental threshold concentrations for environmental protection derived from reproductive tests with model fish species are protective for non-reproductive effects as well. The diversity of actions of estrogens across divergent physiological systems, however, may lead to and underestimation of impacts on fish populations as their effects are generally considered on one functional process only and this may underrepresent the impact on the different physiological processes collectively.

Metabolic and hormonal response to intermittent high-intensity and continuous moderate intensity exercise in individuals with type 1 diabetes: a randomised crossover study.

AIMS/HYPOTHESIS To investigate exercise-related fuel metabolism in intermittent high-intensity (IHE) and continuous moderate intensity (CONT) exercise in individuals with type 1 diabetes mellitus. METHODS In a prospective randomised open-label cross-over trial twelve male individuals with well-controlled type 1 diabetes underwent a 90 min iso-energetic cycling session at 50% maximal oxygen consumption ([Formula: see text]), with (IHE) or without (CONT) interspersed 10 s sprints every 10 min without insulin adaptation. Euglycaemia was maintained using oral (13)C-labelled glucose. (13)C Magnetic resonance spectroscopy (MRS) served to quantify hepatocellular and intramyocellular glycogen. Measurements of glucose kinetics (stable isotopes), hormones and metabolites complemented the investigation. RESULTS Glucose and insulin levels were comparable between interventions. Exogenous glucose requirements during the last 30 min of exercise were significantly lower in IHE (p = 0.02). Hepatic glucose output did not differ significantly between interventions, but glucose disposal was significantly lower in IHE (p < 0.05). There was no significant difference in glycogen consumption. Growth hormone, catecholamine and lactate levels were significantly higher in IHE (p < 0.05). CONCLUSIONS/INTERPRETATION IHE in individuals with type 1 diabetes without insulin adaptation reduced exogenous glucose requirements compared with CONT. The difference was not related to increased hepatic glucose output, nor to enhanced muscle glycogen utilisation, but to decreased glucose uptake. The lower glucose disposal in IHE implies a shift towards consumption of alternative substrates. These findings indicate a high flexibility of exercise-related fuel metabolism in type 1 diabetes, and point towards a novel and potentially beneficial role of IHE in these individuals. TRIAL REGISTRATION ClinicalTrials.gov NCT02068638 FUNDING: Swiss National Science Foundation (grant number 320030_149321/) and R&A Scherbarth Foundation (Switzerland).

Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C).

As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland may account for a form of combined pituitary hormone deficiency (CPHD). A mutation in a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (PROP1), has been identified as causing the Ames dwarf (df) mouse phenotype, and thereafter, different PROP1 gene alterations have been found in humans with CPHD. We report on the follow-up of two consanguineous families (n = 12), with five subjects affected with CPHD (three males and two females) caused by the same nucleotide C to T transition, resulting in the substitution of Arg-->Cys in PROP1 at codon 120. Importantly, there is a variability of phenotype, even among patients with the same mutation. The age at diagnosis was dependent on the severity of symptoms, ranging from 9 months to 8 yr. Although in one patient TSH deficiency was the first symptom of the disorder, all patients became symptomatic by exhibiting severe growth retardation and failure to thrive, which was mainly caused by GH deficiency (n = 4). The secretion of the pituitary-derived hormones (GH, PRL, TSH, LH, and FSH) declined gradually with age, following a different pattern in each individual; therefore, the deficiencies developed over a variable period of time. All of the subjects entered puberty spontaneously, and the two females also experienced menarche and periods before a replacement therapy was necessary.

Domains of expansin gene expression define growth regions in the shoot apex of tomato

Expansins are members of a multigene family of extracellular proteins, which increase cell wall extensibility in vitro and thus are thought to be involved in cell expansion. The major significance of the presence of this large gene family may be that distinctly expressed genes can independently regulate cell expansion in place and time. Here we report on LeExp9, a new expansin gene from tomato, and compare its expression in the shoot tip with that of LeExp2 and LeExp18. LeExp18 gene is expressed in very young tissues of the tomato shoot apex and the transcript levels are upregulated in the incipient primordium. LeExp2 mRNA accumulated in more mature tissues and transcript levels correlated with cell elongation in the elongation zone. In situ hybridization experiments showed a uniform distribution of LeExp9 mRNA in submeristematic tissues. When gibberellin-deficient mutant tomatoes that lacked elongation of the internodes were treated with gibberellin, the phenotypic rescue was correlated with an increase in LeExp9 and LeExp2, but not LeExp18 levels. We propose that the three expansins define three distinct growing zones in the shoot tip. In the meristem proper, gibberellin-independent LeExp18 mediates the cell expansion that accompanies cell division. In the submeristematic zone, LeExp9 mediates cell expansion at a time that cell division comes to a halt. LeExp9 expression requires gibberellin but the hormone is not normally limiting. Finally, LeExp2 mediates cell elongation in young stem tissue. LeExp2 expression is limited by the available gibberellin. These data suggest that regulation of cell wall extensibility is controlled, at least in part, by differential regulation of expansin genes.

N-myc downstream regulated gene-1 expression correlates with reduced pancreatic cancer growth and increased apoptosis in vitro and in vivo

The role of N-myc downstream regulated gene-1 (NDRG1) in cancer has recently gained interest, as potential regulator of cell death and tumor suppressor. Although its normal function in the pancreas is largely unknown, loss of NDRG1 expression is associated with a more aggressive tumor phenotype and poor outcome in pancreatic cancer patients.

Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia

Patients with critical limb ischaemia have a high rate of amputation and mortality. We tested the hypothesis that non-viral 1 fibroblast growth factor (NV1FGF) would improve amputation-free survival.

Increased endometrial placenta growth factor (PLGF) gene expression in women with successful implantation

To analyze the vascularization of the endometrium via hysteroscopy and to assess its correlation with angiogenic factor gene expression and embryo implantation rate.

Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology

To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH).