SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

Background: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities.

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol.

Background: A "mismatch" sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in "mismatch" girls with early puberty.

Methods: Randomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.

microRNAs in newborns with low birth weight: relation to birth size and body composition.

Background: Children with low birth weight (LBW) have a higher risk of developing endocrine-metabolic disorders later in life. Deregulation of specific microRNAs (miRNAs) could underscore the programming of adult pathologies. We analyzed the miRNA expression pattern in both umbilical cord serum samples from LBW and appropriate-for-gestational-age (AGA) newborns and maternal serum samples in the 3rd trimester of gestation, and delineated the relationships with fetal growth, body composition, and markers of metabolic risk.

Posterior Cervical Brown Fat and CXCL14 Levels in the First Year of Life: Sex Differences and Association With Adiposity.

Context: Brown adipose tissue (BAT) is particularly abundant in neonates, but its association with measures of adiposity and metabolic health in early infancy is poorly delineated. Besides sustaining nonshivering thermogenesis, BAT secretes brown adipokines that act on systemic metabolism. The chemokine CXCL14 has been identified as a brown adipokine in experimental studies.

Gut microbiota in adolescent girls with polycystic ovary syndrome: Effects of randomized treatments.

Background: Girls with obesity and polycystic ovary syndrome (PCOS) and women with PCOS have altered gut microbiota.

Objective: To study the gut microbiota composition of girls with PCOS without obesity (age, 15.8 years; body mass index [BMI] 25 kg/m ) and the effects of randomized treatments with an oral contraceptive (OC, N = 15) or with spironolactone-pioglitazone-metformin (SPIOMET, N = 15) for 1 year.

Toward a Treatment Normalizing Ovulation Rate in Adolescent Girls With Polycystic Ovary Syndrome.

Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligomenorrhea, and commonly driven by hepato-visceral fat excess ("central obesity") ensuing from a mismatch between prenatal and postnatal nutrition, on a background of genetic susceptibility. There is no approved treatment for adolescent PCOS. We report the pooled results of 2 pilot studies in nonobese girls with PCOS (N = 62, age 15.

Reduced circulating levels of chemokine CXCL14 in adolescent girls with polycystic ovary syndrome: normalization after insulin sensitization.

Objective: CXCL14 (C-X-C motif chemokine ligand-14) is a chemokine released by active brown fat, showing protective effects against insulin resistance in experimental models. Polycystic ovary syndrome (PCOS) in adolescent girls is usually related to hepato-visceral fat excess and insulin resistance, and associates with comorbidities such as type 2 diabetes. Treatment with a low-dose combination of one antiandrogen and antimineralocorticoid drug (spironolactone) and two insulin sensitizers (pioglitazone/metformin) (SPIOMET) is particularly effective in improving these metabolic derangements.

Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes.

Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets.

Towards a simple marker of hepato-visceral adiposity and insulin resistance: The Z-score change from weight-at-birth to BMI-in-childhood.

Background: Insulin resistance and hepato-visceral (central) fat excess are thought to contribute to an earlier timing of adrenarche/pubarche and puberty/menarche; this earlier timing in turn relates often to a mismatch between prenatal and postnatal weight gain, which can be estimated by calculating the Z-score change from birth weight (BW) to body mass index (BMI) in childhood.

Methods: We tested the hypothesis that this calculation may serve as a proxy of insulin resistance and hepato-visceral adiposity in prepuberty by reappraising a cohort of children (mean age, 8.5 years), born appropriate- (AGA, n = 41) or small-for-gestational age (SGA, n = 45), followed since birth (n = 76) or since the age of 3 years (n = 10).

Body Composition and Circulating Polyunsaturated Fatty Acids at Age 6 Years: A Longitudinal Pilot Study.

Maternal polyunsaturated fatty acid (PUFA) status during pregnancy may influence birth outcomes and offspring adiposity during childhood. Cord blood PUFA levels associate positively with maternal PUFA and negatively with the newborn's abdominal adiposity. However, longitudinal, prospective studies consistently evaluating maternal and cord blood and PUFA levels in childhood and their association with the child's body composition are so far lacking.

Towards a circulating marker of hepato-visceral fat excess: S100A4 in adolescent girls with polycystic ovary syndrome - Evidence from randomized clinical trials.

S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato-visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment.

Brown adipose tissue in prepubertal children: associations with sex, birthweight, and metabolic profile.

Background/objectives: Individuals born small-for-gestational age (SGA), especially those who experience postnatal catch-up growth, are at increased risk for developing endocrine-metabolic abnormalities before puberty. In adults, brown adipose tissue (BAT) has been associated with protection against metabolic disorders, such as obesity, type 2 diabetes, and dyslipidaemia. Here, we assessed for the first time whether BAT activation differs between prepubertal children born SGA or appropriate-for-gestational age (AGA).

Reduced Prenatal Weight Gain and/or Augmented Postnatal Weight Gain Precedes Polycystic Ovary Syndrome in Adolescent Girls.

Objective: Hepato-visceral fat excess is a feature of polycystic ovary syndrome (PCOS). Risk factors for such excess include low prenatal weight gain and high postnatal weight gain. This study examined whether adolescent PCOS was preceded by a relatively low birth weight and/or a relatively high BMI at diagnosis.

Integrative analysis reveals novel pathways mediating the interaction between adipose tissue and pancreatic islets in obesity in rats.

Aims/hypothesis: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis.

Methods: Wistar rats were fed a standard or cafeteria diet for 30 days.

Surface-based cryopreservation strategies for human embryonic stem cells: a comparative study.

Human embryonic stem cells (hESC) hold tremendous potential in the emerging fields of gene and cell therapy as well as in basic scientific research. One of the major challenges regarding their application is the development of efficient cryopreservation protocols for hESC since current methods present poor recovery rates and/or technical difficulties which impair the development of effective processes that can handle bulk quantities of pluripotent cells. The main focus of this work was to compare different strategies for the cryopreservation of adherent hESC colonies.

3D cultures of human neural progenitor cells: dopaminergic differentiation and genetic modification. [corrected].

Central nervous system (CNS) disorders remain a formidable challenge for the development of efficient therapies. Cell and gene therapy approaches are promising alternatives that can have a tremendous impact by treating the causes of the disease rather than the symptoms, providing specific targeting and prolonged duration of action. Hampering translation of gene-based therapeutic treatments of neurodegenerative diseases from experimental to clinical gene therapy is the lack of valid and reliable pre-clinical models that can contribute to evaluate feasibility and safety.

Microencapsulation technology: a powerful tool for integrating expansion and cryopreservation of human embryonic stem cells.

The successful implementation of human embryonic stem cells (hESCs)-based technologies requires the production of relevant numbers of well-characterized cells and their efficient long-term storage. In this study, cells were microencapsulated in alginate to develop an integrated bioprocess for expansion and cryopreservation of pluripotent hESCs. Different three-dimensional (3D) culture strategies were evaluated and compared, specifically, microencapsulation of hESCs as: i) single cells, ii) aggregates and iii) immobilized on microcarriers.

Alginate encapsulation as a novel strategy for the cryopreservation of neurospheres.

Primary cultures of brain cell neurospheres are valuable in vitro models for neurotoxicology and brain cell research. Such applications would greatly benefit from the development of efficient cryopreservation protocols that assure the availability of viable and genetically stable stocks of functional neurospheres. In this work we aimed at developing an integrated strategy allowing for long-term culture and cryopreservation of brain cell neurospheres with high viability and reduced recovery time postthawing.

Cryopreservation of adherent cells: strategies to improve cell viability and function after thawing.

The commonly applied cryopreservation protocols routinely used in laboratories worldwide were developed for simple cell suspensions, and their application to complex systems, such as cell monolayers, tissues, or biosynthetic constructs, is not straightforward. In particular for monolayer cultures, cell detachment and membrane damage are often observed after cryopreservation. In this work, combined strategies for the cryopreservation of cells attached to Matrigel-coated well plate's surfaces were investigated based on cell entrapment in clinicalgrade, ultra-high viscosity alginate using two cell lines, neuroblastoma N2a and colon adenocarcinoma Caco-2, with distinct structural and functional characteristics.

Cryopreservation in micro-volumes: impact upon Caco-2 colon adenocarcinoma cell proliferation and differentiation.

Recent advances in cell-based therapies require new approaches for cell cryopreservation, capable of dealing with large number of samples and providing specific conditions for each cell type. Reduction of sample volume from the commonly used 1 mL to 25 microL in 30-well micro-cryosubstrates improves cryopreservation by allowing automation, data handling and access to individual wells without thawing the whole cryosubstrate. This system was evaluated for the storage of Caco-2 colon adenocarcinoma cells, which differentiate spontaneously after long-term culture.

Encapsulation of adenoviral vectors into chitosan-bile salt microparticles for mucosal vaccination.

The objective of this study is the incorporation of adenoviral vectors into a microparticulate system adequate for mucosal delivery. Microencapsulation of the vectors was accomplished by ionotropic coacervation of chitosan, using bile salts as counter-anion. The process was optimized in order to promote high encapsulation efficiency, with a minimal loss of viral infectivity.