TGF-ß-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.

The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-ß-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-ß-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.

IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer.

Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies. SIGNIFICANCE: This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy. See related commentary by Osorio and Zamarin, p. 766.

IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.

Microphysiological heart-liver body-on-a-chip system with a skin mimic for evaluating topical drug delivery.

Body-on-a-chip in vitro systems are a promising technology that aims to increase the predictive power of drug efficacy and toxicity in humans when compared to traditional animal models. Here, we developed a new heart-liver body-on-a-chip system with a skin surrogate to assess the toxicity of drugs that are topically administered. In order to test the utility of the system, diclofenac, ketoconazole, hydrocortisone and acetaminophen were applied topically through a synthetic skin surrogate (Strat-M membrane) and the toxicity results were compared to those of acute drug exposure from systemically applying the compounds. The heart-liver system was successful in predicting the effects for both cardiac and liver functions changes due to the compounds. The difference in the concentrations of drugs applied topically compared to systemically indicates that the barrier properties of the skin surrogate were efficient. One important advantage of this heart-liver system was the capability of showing differential effects of acute and chronic drug exposure which is necessary as part of the International Conference in Harmonisation (ICH) tri-partate guidelines. In conclusion, this work indicates a promising heart-liver body-on-a-chip system that can be used for the assessment of potential drug toxicity from dermal absorption as well as evaluate transport dynamics through the skin in the same system.

Physical, mechanical properties and antimicrobial analysis of a novel CaO·Al2O3 compound reinforced with Al or Ag particles.

Ceramic-metal (CaO·Al2O3-Al and CaO·Al2O3-Ag) compounds were prepared by mechanical milling and consolidated through an in-situ sintering process. The aim of this work is to study the effects of the Al and Ag particles to ceramic-base compound, primarily in the microstructure, and its mechanical and antimicrobial properties. Chemical systems with a 1:1 M ratio between CaCO3 and Al2O3 powder were formed, with the addition of 10 wt% Al or 10 wt% Ag, respectively. The compound material that consolidated were microstructurally characterized through X-ray diffraction, scanning electron microscopy, optic microscopy, and X-ray computed tomography. In addition, the hardness, the fracture toughness, the transversal elastic modulus, and the antimicrobial property were evaluated. The results of X-ray diffraction identified the formation of the calcium aluminate phases, such as CaO·6Al2O3 (hibonite:CA6), CaO·2Al2O3 (grossite:CA2), and CaO·Al2O3 (krotite:CA); as well as Al and Ag were identified in its respective system. In addition, the mechanical properties show changes compared to the reference material that was synthesized under the same conditions and, finally, these materials also have an antimicrobial effect, against the Staphylococcus bacterium that is common in the oral cavity, when studied in synthetic saliva.

Long-Term Electrical and Mechanical Function Monitoring of a Human-on-a-Chip System.

The goal of human-on-a-chip systems is to capture multi-organ complexity and predict the human response to compounds within physiologically relevant platforms. The generation and characterization of such systems is currently a focal point of research given the long-standing inadequacies of conventional techniques for predicting human outcome. Functional systems can measure and quantify key cellular mechanisms that correlate with the physiological status of a tissue, and can be used to evaluate therapeutic challenges utilizing many of the same endpoints used in animal experiments or clinical trials. Culturing multiple organ compartments in a platform creates a more physiologic environment (organ-organ communication). Here is reported a human 4-organ system composed of heart, liver, skeletal muscle and nervous system modules that maintains cellular viability and function over 28 days in serum-free conditions using a pumpless system. The integration of non-invasive electrical evaluation of neurons and cardiac cells and mechanical determination of cardiac and skeletal muscle contraction allows the monitoring of cellular function especially for chronic toxicity studies in vitro. The 28 day period is the minimum timeframe for animal studies to evaluate repeat dose toxicity. This technology could be a relevant alternative to animal testing by monitoring multi-organ function upon long term chemical exposure.

El amor, resonancia esencial del cuidado para la vida, desde la experiencia del familiar donante renal vivo. Lima (Perú) / Love, the essential resonance of care for life, from the experience of the familiar living kidney donor. Lima (Peru)

Resumen Objetivos: El proceso de donación de órganos es el punto de partida de este estudio, cuyo objetivo fue describir y analizar las resonancias de cuidado que el familiar donante renal vivo establece con el familiar receptor en el proceso de donación. Material y métodos: Se desarrolló como una investigación cualitativa descriptiva exploratoria. La muestra estuvo conformada por seis familiares donantes renales vivos residentes en Lima (Perú), determinada por criterio de saturación teórica. La recolección de datos se hizo mediante la entrevista a profundidad realizada en los hogares de los participantes en 2017. Los datos fueron organizados, clasificados, categorizados según criterio de Minayo y las bases teóricas de Boff. Se utilizó el análisis de discurso oral de Orlandi para la construcción de las categorías empíricas que emergieron de los textos. Resultados: Del análisis de discurso emerge el constructo Cuidado-Vida y la resonancia del amor en complementariedad y simultaneidad de las resonancias de Compasión, Ternura, Caricia, Esperanza, categorías que tienen como respaldo teórico, epistémico y filosófico las resonancias del cuidado humano. Conclusiones: Entre las conclusiones del estudio destaca que la resonancia del amor es la categoría principal que emerge desde el familiar donante renal vivo en el constructo Cuidado; vida, se concretiza en el cuidado para la supervivencia, conservación y bien-vivir del familiar receptor de órganos, en el que la resonancia del amor se revela como la gran fuerza que transforma la vida, une y solidariza en conjunción con la compasión, caricia, ternura, esperanza, resonancias que humanizan el cuidado de la familia, sensibilizan el acto de donación de órganos.

Abstract Objectives: The process of organ donation is the starting point of this study, whose objective was to describe and analyze the resonances of care that the living renal donor family establishes with the recipient family member in the donation process. Material and methods: It was developed as an exploratory descriptive qualitative research; the sample consisted of six living renal donor relatives residing in Lima-Peru, determined by criterion of theoretical saturation. The data collection was done through in-depth interviews conducted in the homes of the participants in 2017. The data was organized, classified, categorized according to Minayo criteria and the theoretical basis of Boff. Orlandi's oral discourse analysis was used to construct the empirical categories that emerged from the texts. Results: From the analysis of discourse, the Care-Life construct emerges and the resonance of love simultaneously complements the resonances of Compassion, Tenderness, Caress, Hope, categories that have as theoretical, epistemic and philosophical support the resonances of care human. Conclusions: Among the conclusions of the study, the resonance of love is the main category that emerges from the kidney donor relative in the Care-life construct, it is cemented in the care for the survival, conservation and well-being of the recipient family of organs, where the resonance of love is revealed as the great force that transforms life, unites and solidifies in conjunction with compassion, caress, tenderness, hope, resonances that humanize the care of the family, sensitize the act of organ donation.

Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.

Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function. The presence of the hepatocytes in the system induced cardiotoxic effects from cyclophosphamide and reduced them for terfenadine due to drug metabolism, as expected from each compound's pharmacology. A computational fluid dynamics simulation enabled the prediction of terfenadine-fexofenadine pharmacokinetics, which was validated by HPLC-MS. This in vitro platform recapitulates primary aspects of the in vivo crosstalk between heart and liver and enables pharmacological studies, involving both organs in a single in vitro platform. The system enables non-invasive readouts of cardiotoxicity of drugs and their metabolites. Hepatotoxicity can also be evaluated by biomarker analysis and change in metabolic function. Integration of metabolic function in toxicology models can improve adverse effects prediction in preclinical studies and this system could also be used for chronic studies as well.

Temperature-responsive nanogel multilayers of poly(N-vinylcaprolactam) for topical drug delivery.

We report nanothin temperature-responsive hydrogel films of poly(N-vinylcaprolactam) nanoparticles (νPVCL) with remarkably high loading capacity for topical drug delivery. Highly swollen (νPVCL)n multilayer hydrogels, where n denotes the number of nanoparticle layers, are produced by layer-by-layer hydrogen-bonded assembly of core-shell PVCL-co-acrylic acid nanoparticles with linear PVPON followed by cross-linking of the acrylic acid shell with either ethylene diamine (EDA) or adipic acid dihydrazide (AAD). We demonstrate that a (νPVCL)5 film undergoes dramatic and reversible swelling up to 9 times its dry thickness at pH = 7.5, indicating 89v/v % of water inside the network. These hydrogels exhibit highly reversible ∼3-fold thickness changes with temperature variations from 25 to 50°C at pH = 5, the average pH of human skin. We also show that a (νPVCL)30 hydrogel loaded with ∼120µgcm-2 sodium diclofenac, a non-steroidal anti-inflammatory drug used for osteoarthritis pain management, provides sustained permeation of this drug through an artificial skin membrane for up to 24h at 32°C (the average human skin surface temperature). The cumulative amount of diclofenac transported at 32°C from the (νPVCL)30 hydrogel after 24h is 12 times higher than that from the (νPVCL)30 hydrogel at 22°C. Finally, we demonstrate that the (νPVCL) hydrogels can be used for multiple drug delivery by inclusion of Nile red, fluorescein and DAPI dyes within the νPVCL nanoparticles prior to hydrogel assembly. Using confocal microscopy we observed the presence of separate dye-loaded νPVCL compartments within the hydrogel matrix with all three dyes confined to the nanogel particles without intermixing between the dyes. Our study provides opportunity for development of temperature-responsive multilayer hydrogel coatings made via the assembly of core-shell nanogel particles which can be used for skin-sensitive materials for topical drug delivery.

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women.

BACKGROUND: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. OBJECTIVE AND RATIONALE: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. SEARCH METHODS: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. OUTCOMES: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-off values are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. WIDER IMPLICATIONS: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.

Experiencias de los adultos mayores en la pr ctica del Tai Chi Qi Gong. Tumbes, Perú / Experiences of older adults in the practice of Tai Ji Qi Gong, Tumbes, Peru

El tai-chi qi gong es una combinación de ejercicio físico y técnicas de relajación, utilizado para mejorar la salud física y mental de sus practicantes. Objetivos: develar y analizar comprehensivamente las experiencias de los adultos mayores en la práctica del tai chi qi gong en una posta médica de EsSalud, Tumbes–Perú. Material y métodos: investigación cualitativa, desarrollada bajo el enfoque acción participación. Los sujetos de investigación fueron los adultos mayores que asisten al Programa del Adulto Mayor. La información fue recogida mediante entrevistas a profundidad considerando en todo momento los principios éticos del Informe de Belmont; el tamaño de la muestra se determinó por el método de saturación; obteniéndose siete discursos representativos, el tratamiento de los datos fue mediante el método de análisis de contenido. Resultados: Tai chi qi gong: una experiencia positiva. II. Experimentado los beneficios del tai chi con las siguientes sub categorías disminuyendo dolencias corporales, aumentado la agilidad corporal, mejorando el estado de ánimo, liberando tensiones mentales. III. Practicando los ejercicios del tai chi en casa. Conclusiones: la práctica del tai chi qi gong tiene consecuencias muy favorables para la salud de los adultos mayores porque permite desarrollar en gran manera el sentido de equilibrio, con un importante mejoramiento de su condición física, funcional y emocional y un claro aumento del nivel de calidad de vida.

Tai ji qi gong is a combination of exercise and relaxation techniques used to improve physical and mental health of its practitioners. Objectives: unmasking and comprehensively analyze the experiences of older adults in the practice of tai chi qi gong at a health post EsSalud, Tumbes - Peru. Material and Methods: qualitative research, developed under the action approach participation. Research subjects were older adults who attend the Elderly Program. The information was collected through in-depth interviews at all times considering the ethical principles of the Belmont Report; the sample size was determined by the method of saturation; yielding seven representative speeches, treatment of data was by the method of content analysis. Results: Tai chi qi gong: A positive experience. II. Experienced the benefits of tai chi with the following sub categories decreasing bodily ailments, increased body agility, improving mood, releasing mental stress. III. Practicing tai chi exercises at home. Conclusions: the practice of tai chi qi gong has very favorable to the health of older adults consequences because it allows develop greatly the sense of balance, with a significant improvement in their physical, functional and emotional condition and a clear increase in the level of quality of life.

Association of obesity and overweight with the prevalence of insulin resistance, pre-diabetes and clinical-biochemical characteristics among infertile Mexican women with polycystic ovary syndrome: a cross-sectional study.

OBJECTIVE: To study the association of obesity and overweight with the prevalence of insulin resistance (IR), pre-diabetes and clinical-biochemical characteristics among infertile Mexican women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective cross-sectional study. SETTING: Level-three medical institution, an infertility clinic in Mexico City. PARTICIPANTS: We included infertile Mexican women with diagnosis of PCOS according to the Rotterdam criteria: group 1 (n=83), normal weight (body mass index (BMI) 18.5-24.9 kg/m(2)); group 2 (n=217), overweight (BMI 25-29.9 kg/m(2)); and group 3 (n=238), obese (BMI≥30 kg/m(2)). PRIMARY AND SECONDARY OUTCOME MEASURES: IR was determined by homeostatic model assessment (HOMA) >2.5 and pre-diabetes by fasting glucose between 5.6 and 6.9 mmol/L and/or glucose value between 7.8 and 11 mmol/L at 2 hours during an oral glucose tolerance test. We compared clinical-biochemical characteristics among groups. RESULTS: Prevalence of IR for groups 1, 2 and 3 was 19.3%, 56.2% and 78.2%; overweight and obesity increase the IR OR (CI 95%) to 5.3 (2.9 to 9.8) and 14.9 (8.0 to 28), respectively. Prevalence of pre-diabetes for groups 1, 2 and 3 was 7.2%, 17.5% and 31.5%; overweight and obesity increase the pre-diabetes OR (CI 95%) to 2.7 (1.1 to 6.7) and 5.9 (2.4 to 14), respectively. Acanthosis nigricans was more frequent in group 3 than group 1. Free Androgen Index (FAI) and thyroid-stimulating hormone (TSH) levels were lower in group 1 than in groups 2 and 3. Progesterone and sex hormone-binding globulin (SHBG) levels were higher in group 1 than in groups 2 and 3. Dehydroepiandrosterone sulfate (DHEA-S) was higher in group 1 than group 3. CONCLUSIONS: Obese and overweight infertile Mexican women with PCOS, attending to an infertility clinic, have a higher prevalence of IR and pre-diabetes compared with normal-weight women with PCOS. Therapeutic interventions should include those that improved metabolic functioning prior to attempting pregnancy in these groups of women.

Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels.

Enhancing skin permeation is important for development of new transdermal drug delivery formulations. This is particularly relevant for non-steroidal anti-inflammatory drugs (NSAIDs). To address this, semisolid gel and solid hydrogel film formulations containing gellan gum as a gelling agent were developed and the effects of penetration enhancers (dimethyl sulfoxide, isopropyl alcohol and propylene glycol) on transport of the NSAID diclofenac sodium was quantified. A transwell diffusion system was used to accelerate formulation development. After 4h, diclofenac flux from a superior formulation of the semisolid gel or the solid hydrogel film was 130±11µg/cm(2)h and 108±7µg/cm(2)h, respectively, and significantly greater than that measured for a currently available diclofenac sodium topical gel (30±4µg/cm(2)h, p<0.05) or solution formulation (44±6µg/cm(2)h, p<0.05) under identical conditions. Over 24h diclofenac transport from the solid hydrogel film was greater than that measured for any new or commercial diclofenac formulation. Entrapment of temperature-responsive nanogels within the solid hydrogel film provides temperature-activated prolonged release of diclofenac. Diclofenac transport was minimal at 22°C, when diclofenac is entrapped within temperature-responsive nanogels incorporated into the solid hydrogel film, but increased 6-fold when the temperature was increased to skin surface temperature of 32°C. These results demonstrate the feasibility of the semisolid gel and solid hydrogel film formulations that can include thermo-responsive nanogels for development of transdermal drug formulations with adjustable drug transport kinetics.

Adrenal androgen excess and body mass index in polycystic ovary syndrome.

CONTEXT: Adrenal hyperandrogenism affects approximately 25% of polycystic ovary syndrome (PCOS) patients but its relation to obesity is not totally understood. OBJECTIVE: This study aimed to assess dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels in relation to body mass index (BMI) in PCOS. DESIGN AND SETTING: This was a prospective observational study at an institutional practice at an obstetrics/gynecology hospital. PARTICIPANTS: The study included 136 PCOS patients, 20-35 years old, and 42 age-matched control women. The participants were classified with the BMI cutoff value of 27 kg/m(2) as follows: 1) high-BMI PCOS patients; 2) low-BMI PCOS patients; 3) high-BMI control women; and 4) low-BMI control women. The data were reanalyzed with the BMI cutoff value of 30 kg/m(2) to corroborate the findings in obese and nonobese patients. MAIN OUTCOME MEASURE(S): Blood samples were taken and LH, FSH, insulin, T, androstenedione (A4), DHEA, DHEAS, and glucose levels were determined. Homeostatic model assessment was calculated. Pelvic and abdominal ultrasound for ovarian morphology and adipose tissue, respectively, were performed. RESULTS: Obese PCOS patients presented significantly more insulin resistance than nonobese PCOS patients. The LH levels and LH/FSH ratio were significantly higher in low-BMI than in high-BMI PCOS patients. The A4 and DHEAS levels were significantly higher in nonobese than in obese PCOS patients. A significant correlation between LH and A4 in nonobese PCOS patients was observed. The frequency of hyperandrogenism by increased A4, and DHEA along with DHEAS was significantly higher in low-BMI PCOS patients compared with high-BMI PCOS patients. Some findings observed with the BMI cutoff value of 27 kg/m(2) changed with the cutoff value of 30 kg/m(2). CONCLUSIONS: Low BMI more so than high BMI is associated with increased LH, high A4, DHEA, and DHEAS levels in PCOS patients. The BMI cutoff value of 27 kg/m(2) classified better than 30 kg/m(2) for hormonal and metabolic characteristics.

[Convenience clinic redefine polycystic ovary syndrome (Stein-Leventhal)]. / Conveniencia clínica de redefinir al síndrome de poliquistosis ovárica (Stein-Leventhal).

In 1935 during a medical meeting behalf in New Orleans was presents a study that included seven cases of women that suffered menstrual dysfunctions, hirsutism and sterility, for laparotomy the description of the ovaries had a pearly white color and it was hypertrophic, the cuneiform resection in both ovaries resulted in correction of the menstrual dysfunction and two of them got pregnancy later on, receiving the name of polycystic ovary syndrome (PCOS). The technological advance facilitates the hormonal analyses demonstrating the hyperandrogenism existence and the mechanism of the anovulation, the PCOS showed to be heterogeneous, reason why it was hindered to define it, this advanced the current trend to question the existence of the PCOS and to accept the convenience, either to change the name or to redefine it, leaving it as a simple syndrome with several phenotypes. The endocrine component includes abnormal secretion of insulin and consequently outlying resistance to this hormone, likewise is hyperandrogenism, dislipoproteinemia and obesity. The hormonal exams are unnecessary for the diagnostic and treatment; it is convenient to demonstrate for sonography the ovarian growth. Other dysfunctions like the congenital suprarenal hyperplasia, hyperprolactinemia and hypotiroidism should be discarded. The treatment should be individualized with relationship to the reason of the consultation and the patients age. It has not been demonstrated that the sensibilitizers use to the insulin avoids long term cardiovascular illness and diabetes. Therefore, the phenotype is heterogeneous with a fickle metabolic component and for it has arisen the restlessness of a better definition of the SPO.

Obesity differentially affects phenotypes of polycystic ovary syndrome.

Obesity or overweight affect most of patients with polycystic ovary syndrome (PCOS). Phenotypes are the clinical characteristics produced by the interaction of heredity and environment in a disease or syndrome. Phenotypes of PCOS have been described on the presence of clinical hyperandrogenism, oligoovulation and polycystic ovaries. The insulin resistance is present in the majority of patients with obesity and/or PCOS and it is more frequent and of greater magnitude in obese than in non obese PCOS patients. Levels of sexual hormone binding globulin are decreased, and levels of free androgens are increased in obese PCOS patients. Weight loss treatment is important for overweight or obese PCOS patients, but not necessary for normal weight PCOS patients, who only need to avoid increasing their body weight. Obesity decreases or delays several infertility treatments. The differences in the hormonal and metabolic profile, as well as the different focus and response to treatment between obese and non obese PCOS patients suggest that obesity has to be considered as a characteristic for classification of PCOS phenotypes.

Hedgehog regulates angiogenesis of intersegmental vessels through the VEGF signaling pathway.

BACKGROUND: The cellular mechanisms regulating branching and growth of the intersegmental vessels (ISVs) are not well understood. We have carried out studies demonstrating that Hedgehog (Hh) signaling is a major regulator of intersomitic vessel growth. RESULTS: Inhibition of Hh activity by cyclopamine completely blocks formation of intersomitic vessels in the avian embryo. Examination of gene expression patterns in Hh-deficient embryos shows that components of the VEGF and Notch signaling pathways are down-regulated. However, we find no evidence that Notch signaling plays a significant role in regulation of intersomitic vessel growth. Indeed, it appears that Hh modulation of Vascular Endothelial Growth Factor, VEGF, is the primary regulator of growth of intersomitic vessels in the avian embryo. CONCLUSIONS: Inhibition of the VEGF pathway results in absence of ISVs, whereas stimulation of VEGF expression leads to precocious branching of ISVs. These results demonstrate that Hh is an essential modulator of VEGF expression during developmental angiogenesis.

Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.

RATIONALE: Positive signals, such as vascular endothelial growth factor, direct endothelial cells (ECs) to specific locations during blood vessel formation. Less is known about repulsive signal contribution to shaping vessels. Recently, "neuronal guidance cues" have been shown to influence EC behavior, particularly in directing sprouting angiogenesis by repelling ECs. However, their role during de novo blood vessel formation remains unexplored. OBJECTIVE: To identify signals that guide and pattern the first mammalian blood vessels. METHODS AND RESULTS: Using genetic mouse models, we show that blood vessels are sculpted through the generation of stereotyped avascular zones by EC-repulsive cues. We demonstrate that Semaphorin3E (Sema3E) is a key factor that shapes the paired dorsal aortae in mouse, as sema3E(-/-) embryos develop an abnormally branched aortic plexus with a markedly narrowed avascular midline. In vitro cultures and avian grafting experiments show strong repulsion of ECs by Sema3E-expressing cells. We further identify the mouse notochord as a rich source of multiple redundant neuronal guidance cues. Mouse embryos that lack notochords fail to form cohesive aortic vessels because of loss of the avascular midline, yet maintain lateral avascular zones. We demonstrate that lateral avascular zones are directly generated by the lateral plate mesoderm, a critical source of Sema3E. CONCLUSIONS: These findings demonstrate that Sema3E-generated avascular zones are critical regulators of mammalian cardiovascular patterning and are the first to identify a repulsive role for the lateral plate mesoderm. Integration of multiple, and in some cases redundant, repulsive cues from various tissues is critical to patterning the first embryonic blood vessels.