38 research outputs found
Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
Background Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels. Methods We performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild- type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein. Results Functional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such as HOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS. Conclusion A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management
Paced-Mating Increases the Number of Adult New Born Cells in the Internal Cellular (Granular) Layer of the Accessory Olfactory Bulb
The continuous production and addition of new neurons during life in the olfactory bulb is well accepted and has been extensively studied in rodents. This process could allow the animals to adapt to a changing environment. Olfactory neurogenesis begins in the subventricular zone where stem cells proliferate and give rise to young undifferentiated neuroblasts that migrate along the rostral migratory stream to the olfactory bulb (OB). Olfaction is crucial for the expression of sexual behavior in rodents. In female rats, the ability to control the rate of sexual interactions (pacing) has important physiological and behavioral consequences. In the present experiment we evaluated if pacing behavior modifies the rate of new cells that reach the main and accessory olfactory bulb. The BrdU marker was injected before and after different behavioral tests which included: females placed in a mating cage (control), females allowed to pace the sexual interaction, females that mated but were not able to control the rate of the sexual interaction and females exposed to a sexually active male. Subjects were sacrificed fifteen days after the behavioral test. We observed a significant increase in the density of BrdU positive cells in the internal cellular layer of the accessory olfactory bulb when females paced the sexual interaction in comparison to the other 3 groups. No differences in the cell density in the main olfactory bulb were found. These results suggest that pacing behavior promotes an increase in density of the new cells in the accessory olfactory bulb
Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study
Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders
Transferencia de investigaciones virológicas a sectores educativos y generales de la comunidad
La educación es la única y verdadera herramienta válida, por excelencia, para lograr cambios positivos en la historia, en la política, en la salud o en cualquiera otro aspecto importante de la vida de los hombres. Entonces, deberíamos insistir en mejorar la calidad educativa de los ciudadanos y alumnos de todos los niveles, mejorando necesariamente la actualización de los saberes de los funcionarios, profesionales y docentes para que se inscriba en el discurso cotidiano. El desconocer, no prepararse, nos lleva a crisis sociales que inevitablemente incrementan flagelos como la pobreza, la pérdida de biodiversidad, las guerras, las epidemias, entre otros. Así, desde donde se produce y construye el conocimiento científico, la Universidad Nacional de Córdoba, Facultad de Ciencias Médicas y específicamente el Instituto de Virología "Dr. José María Vanella" también se promueve el objetivo de extensión comunitaria, brindando este proyecto a docentes, alumnos y comunidad en general de la provincia de Córdoba como servicio educativo y actualización. Las temáticas son variadas, los talleres convocan a la Divulgación científica y tecnológica de infecciones virales de importancia sanitaria su conocimiento, prevención y difusión, no solo para el sector educativo sino también para la comunidad en general.
Las actividades son talleres, conferencias, laboratorios, jornadas de un día hasta dos semanas. Las metodologías aplicadas son charlas dialogadas, vídeos, dinámica de grupos, Hay evaluaciones de seguimiento a través de comentarios, relatos, encuestas.
Todas las actividades de extensión del InViV cuentan con la aprobación de la Facultad Ciencias Médicas a través de las Res. Decanales anuales.Fil: Balangero, Marcos. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Gil, Pedro Ignacio: Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Gil, Pedro Ignacio: Universidad Nacional de Córdoba. Secretaría de Ciencia y Tecnología; ArgentinaFil: Frutos: María Cecilia: Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Frutos: María Cecilia: Universidad Nacional de Córdoba. Secretaría de Ciencia y Tecnología; ArgentinaFil: Díaz, Luis Adrián. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de
Virología "Dr. José María Vanella"; Argentina.Fil: Ré, Viviana. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Farias, Adrián Alejandro. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Spinsanti, Lorena. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Venezuela, Raúl Fernando. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Kiguen, Ana Ximena. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Konigheim, Brenda. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Pisano, María Belén. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil:Masachessi, Gisela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Barril, Patricia Angélica. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Varella"; Argentina.Fil: Barril, Patricia Angelica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Castro, Gonzalo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Batallán, Pedro Gonzalo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Batallán, Pedro Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Quaglia, Agustín.Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Tauro, Laura Beatriz. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Tauro, Laura Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Flores, Fernando Sebastián. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Flores, Fernando Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Beranek, Mauricio. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Beranek, Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Maturano, Eduardo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Rodríguez, Pamela Elizabeth. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Cámara, Jorge Augusto. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil, Albrieu Llinás, Guillermo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil, Albrieu Llinás, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Estudios en Comunicación, Expresión y Tecnologías; Argentina.Fil: Adamo, María Pilar. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ghietto, Lucía María. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ghietto, Lucía María. Universidad Nacional de Córdoba. Secretaría de Ciencia y Tecnología; ArgentinaFil: Pedranti, Mauro Sebastián. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Giordano, Miguel Oscar. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Martínez, Laura Cecilia.Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Isa, Maria Beatriz. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Ascheri, Stella Maris. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Paredes, Norma Gladys. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Contigiani, Marta Silvia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Benítez, Marta. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Theiler, Gerardo. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Augello, Marysol. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Fosatti, L. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; ArgentinaFil:Moreno, F. Colegio San Martín; Argentina.Fil:Marín, M. Colegio Nuestra Señora del Sagrado Corazón; Argentina.Fil: Carreras, G. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Navarro, A. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Fuentes, M. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Santiago, T. Provincia de Córdoba. Ipem 323 de Villa Angelelli; Argentina.Fil: Cámara, Alicia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Paglini, María Gabriela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Cuffini, Cecilia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Gallego, Sandra Verónica.Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Aguilar, Javier. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Paván, Jorge. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Fil: Nates, Silvia Viviana. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Virología "Dr. José María Vanella"; Argentina.Enfermedades Infecciosa
Handbook of Active Ageing and Quality of Life: From Concepts to Applications
La edición de este libro estuvo a cargo de Fermina Rojo-Pérez y Gloria Fernández-Mayoralas.El documento adjunto contiene la cubierta, portada e índice del libro.This handbook presents an overview of studies on the relationship of active ageing and quality of life. It addresses the new challenges of ageing from the paradigm of positive ageing (active, healthy and successful) for a better quality of life. It provides theoretical perspectives and empirical studies, including scientific knowledge as well as practical experiences about the good ageing and the quality of later life around the world, in order to respond to the challenges of an aged population. The handbook is structured in 4 sections covering theoretical and conceptual perspectives, social policy issues and research agenda, methods, measurement instrument-scales and evaluations, and lastly application studies including domains and geographical contexts.Peer reviewe
Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study
Summary
Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally.
Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies
have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of
the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income
countries globally, and identified factors associated with mortality.
Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to
hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis,
exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a
minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical
status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary
intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause,
in-hospital mortality for all conditions combined and each condition individually, stratified by country income status.
We did a complete case analysis.
Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital
diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal
malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome
countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male.
Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3).
Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income
countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups).
Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome
countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries;
p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients
combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11],
p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20
[1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention
(ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety
checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed
(ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of
parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65
[0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality.
Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome,
middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will
be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger
than 5 years by 2030
Sexual stimulation increases the survival of new cells in the accessory olfactory bulb of the male rat.
Sexual behavior in rodents is modulated by the olfactory system. The olfactory bulb (OB) is a structure that undergoes continues neurogenesis in adulthood. We have previously shown that 15 days after males rats pace the sexual interaction and ejaculate 1 or 3 times, there is an increase in the density of new cells that reach the accessory olfactory bulb (AOB). The aim of the present study was to evaluate if sexual behavior in male rats increases the density of new neurons that survive 45 days after sexual behavior in the AOB and in the main OB (MOB). Male rats were randomly divided in four groups: 1) Control (Ctr), males without sexual interaction; 2) Exposed (Exp), males only exposed to a sexually receptive female; 3) No pacing (NP), males that mated in conditions in which the female paced the sexual interaction; 4) One ejaculation (1E), males that paced the sexual interaction with a receptive female and ejaculated once; and 5) Three ejaculations (3E), males that paced the sexual interaction and were allowed to ejaculate three times. All males were injected with the DNA synthesis marker 5-bromo-2-deoxyuridine (BrdU), and were tested in one of the above conditions. 45 days later they were sacrificed, and the OBs were processed to identify new cells and evaluate if they had differentiated into neurons. Our data indicate that males that ejaculated 3 times showed an increase in the density of new cells that survive in the posterior part of the granular cell layer of the AOB and have more new neurons that the control group. However, no significant differences were found in the percentage of new cells that differentiate into neurons. No significant increase in the density of new cells was observed in the MOB. Our data show that pacing the sexual interaction until 3 ejaculations increases the density of new cells and neurons in the granular layer of the AOB, confirming that sexual behavior induces long-lasting plastic changes in the OB
Sexual behavior increases cell proliferation in the rostral migratory stream and promotes the differentiation of the new cells into neurons in the accessory olfactory bulb of female rats.
We have previously demonstrated that 15 days after female rats pace the sexual interaction, there is an increase in the number of new cells that reach the granular cell layer (GrL) of the accessory olfactory bulb (AOB). The aim of the present study was to evaluate if the first sexual experience in the female rat increases cell proliferation in the subventricular zone (SVZ) and the rostral migratory stream (RMS). We also tested if this behavior promotes the survival of the new cells that integrate into the main olfactory bulb (MOB) and AOB 45 days after the behavioral test. Sexually naive female rats were injected with the DNA synthesis marker 5´-bromo-2´-deoxyuridine (BrdU) on the day of the behavioral test. They were randomly divided into the following groups: Female rats placed alone in the mating cage (1); Females exposed to amyl acetate odor (banana scent, 2); Females that could see, hear and smell the male but physical contact was not possible (exposed to male, 3); Female rats that could pace the sexual interaction (4); and females that mated without the possibility of pacing the sexual interaction (5). Animals were sacrificed 2 days after the behavioral test (proliferation) or 45 days later (survival). Our results show that 2 days after females were exposed to banana scent or to the male, they had a higher number of cells in the SVZ. Females that mated in pace and no-paced conditions had more new cells in the RMS. At 45 days, no significant differences were found in the number of new cells that survived in the MOB or in the AOB. However, mating increased the percentage of new cells that differentiated into neurons in the GrL of the AOB. These new cells expressed c-Fos after a second sexual encounter just before the females were sacrificed. No significant differences in plasma levels of estradiol and progesterone were observed between groups. Our results indicate that the first sexual experience increases cell proliferation in the RMS and mating 45 days later enhances the number of new cells that differentiate into neurons in the AOB. These new neurons are activate
Neurogenesis in the olfactory bulb induced by paced mating in the female rat is opioid dependent
<div><p>The possibility to control the rate of sexual stimulation that the female rat receives during a mating encounter (pacing) increases the number of newborn neurons that reach the granular layer of the accessory olfactory bulb (AOB). If females mate repeatedly, the increase in the number of neurons is observed in other regions of the AOB and in the main olfactory bulb (MOB). It has also been shown that paced mating induces a reward state mediated by opioids. There is also evidence that opioids modulate neurogenesis. In the present study, we evaluated whether the opioid receptor antagonist naloxone (NX) could reduce the increase in neurogenesis in the AOB induced by paced mating. Ovariectomized female rats were randomly divided in 5 different groups: 1) Control (not mated) treated with saline, 2) control (not mated) treated with naloxone, 3) females that mated without controlling the sexual interaction (no-pacing), 4) females injected with saline before pacing the sexual interaction and 5) females injected with NX before a paced mating session. We found, as previously described, that paced mating induced a higher number of new cells in the granular layer of the AOB. The administration of NX before paced mating, blocked the increase in the number of newborn cells and prevented these cells from differentiating into neurons. These data suggest that opioid peptides play a fundamental role in the neurogenesis induced by paced mating in female rats.</p></div