The role of anandamide during pregnancy : A short tale about the endocannabinoid system

The success of any species depends on its reproductive efficiency. Sexual procreation is initiated by interactions between a sperm and an egg leading to fertilization. The fertilized egg (embryo) undergoes several mitotic cell divisions, ultimately producing the blastocyst. The nurturing of an offspring within the body and production of a live birth is an enduring task, requiring safeguard regulatory systems at various critical steps. At the moment, there is still a significant knowledge gap in understanding the mechanisms by which a successful pregnancy is achieved. It is difficult to define the hierarchical landscape of the molecular pathways during human pregnancy, because of experimental difficulties and ethical restrictions on research with human embryos. It is hoped that experiments on mice and other animal models that bear certain reproductive similarities with humans combined with those feasible experiments in humans would generate meaningful information to address this critical issue. A deeper insight into these processes will help to generate new ideas and concepts for improving fertility and pregnancy-associated health issues in humans. During the last years, several studies have provided evidence that lipid mediators are important signaling molecules in coordinating a series of events during pregnancy. Increasing evidence points toward the pathophysiological significance of endocannabinoids, a group of bioactive lipid-signaling molecules, in both female and male fertility.Sociedad Argentina de Fisiologí

The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes

Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the ‘missing heritability problem’. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and adenosine triphosphate synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility

Anandamide Induces Sperm Release from Oviductal Epithelia through Nitric Oxide Pathway in Bovines

Mammalian spermatozoa are not able to fertilize an egg immediately upon ejaculation. They acquire this ability during their transit through the female genital tract in a process known as capacitation. The mammalian oviduct acts as a functional sperm reservoir providing a suitable environment that allows the maintenance of sperm fertilization competence until ovulation occurs. After ovulation, spermatozoa are gradually released from the oviductal reservoir in the caudal isthmus and ascend to the site of fertilization. Capacitating-related changes in sperm plasma membrane seem to be responsible for sperm release from oviductal epithelium. Anandamide is a lipid mediator that participates in the regulation of several female and male reproductive functions. Previously we have demonstrated that anandamide was capable to release spermatozoa from oviductal epithelia by induction of sperm capacitation in bovines. In the present work we studied whether anandamide might exert its effect by activating the nitric oxide (NO) pathway since this molecule has been described as a capacitating agent in spermatozoa from different species. First, we demonstrated that 1 µM NOC-18, a NO donor, and 10 mM L-Arginine, NO synthase substrate, induced the release of spermatozoa from the oviductal epithelia. Then, we observed that the anandamide effect on sperm oviduct interaction was reversed by the addition of 1 µM L-NAME, a NO synthase inhibitor, or 30 µg/ml Hemoglobin, a NO scavenger. We also demonstrated that the induction of bull sperm capacitation by nanomolar concentrations of R(+)-methanandamide or anandamide was inhibited by adding L-NAME or Hemoglobin. To study whether anandamide is able to produce NO, we measured this compound in both sperm and oviductal cells. We observed that anandamide increased the levels of NO in spermatozoa, but not in oviductal cells. These findings suggest that anandamide regulates the sperm release from oviductal epithelia probably by activating the NO pathway during sperm capacitation

The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2)

Objective Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995â\u80\u932009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results During 2005â\u80\u932009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

The effect of weeding time on raspberry (Rubus idaeus L.) crops yield and weed community in Rio Negro Province, Argentina

Raspberry (Rubus idaeus L.) is the most important crop in the (Andean Shire), an area situated at the south of Rio Negro Province in the south of Argentina. Organic berries production in this area increased significantly in the last ten years. Weed management in raspberry organic crops is performed by tillage. Excessive tillage can reduce weed species diversity and increase both soil erosion and production costs. Field experiments were carried out with summer and fall fruiting raspberry varieties within the periods 2005–06 and 2006–07 with the aim of studying the effect of different weeding times on (i) raspberry yield, (ii) fruit quality and (iii) weed community richness and abundance. The fruit harvest was carried out two or three times a week during all harvest period for each variety. In addition, fruit quality was assessed at different harvest times. From spring to the end of harvest weed cover and weed species richness were measured for each treatment. The results showed that the most frequent weed removal did not exceed the yield obtained with three weeding operations carried out during spring and summer. This meant an important reduction in cost production, with the advantage of maintaining weed diversity. The presence of weeds did not affect fruit quality. Summer fruiting variety was more competitive than fall fruiting variety.EEA BarilocheFil: Scursoni, Julio Alejandro. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Vegetal; ArgentinaFil: Cortada, A. Vivero Humus SA; ArgentinaFil: Rezzano, Carlos. Universidad Nacional de Rio Negro. Tecnicatura en Producción Vegetal Orgánica (UNRN/UBA); ArgentinaFil: Martinez, E. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Agencia de Extensión Rural El Bolsón; ArgentinaFil: Vercelli, Federico . Universidad Nacional de Rio Negro. Tecnicatura en Producción Vegetal Orgánica (UNRN/UBA); ArgentinaFil: Ancalao, Marcos. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Campo Forestal San Martín; ArgentinaFil: Cobelo, Claudia Monica. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Agencia de Extensión Rural El Bolsón; Argentin

Progesterone is essential for protecting against LPS-induced pregnancy loss. LIF as a potential mediator of the anti-inflammatory effect of progesterone.

Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders

LPS-induced PGE₂ and PGF_2α production is mediated by endocannabinoids.

<p>A) PGE₂ production for uterine explants incubated with LPS (1 ug/ml) and AM251 (10 nM) or SR144528 (10 nM) for 24 h. ANOVA test. a, p<0.001 vs control or AM251 or SR144528; b, p<0.001 vs control or AM251; c, p<0.001 vs LPS. n = 6. B) PGF_2α production for uterine explants incubated with LPS (1 ug/ml) and AM251 (10 nM) or SR144528 (100 nM) for 24 h. ANOVA test. a, p<0.001 vs control or AM251 or SR144528; b, p<0.01 vs control or AM251; c, p<0.001 vs control or SR144528; d, p<0.001 vs LPS; e, p<0.01 vs LPS. n = 5.</p

AEA augments PGE₂ metabolite levels.

<p>Uterine explants were incubated without/with m-AEA (100 nM) for 24 h. A) PGE₂ production assessed by RIA; B) PGEM quantification assessed by PGE metabolite EIA kit. Student t Test. a, p<0.001 vs control; b, p<0.01 vs control. n = 5. Both metabolites were assessed in the same sample. PGEM, Prostaglandin E₂ metabolite.</p

AEA mediates LPS-induced PG production.

<p>A) PGE₂ production for uterine explants incubated with LPS (1 ug/ml), m-AEA (100 nM), URB597 (1 uM), LPS plus m-AEA (100 nM) or LPS plus URB597 (1 uM) for 24 h. ANOVA test. a, p<0.001 vs control; b, p<0.01 vs LPS; c, p<0.001 vs LPS. n = 7. B) PGF_2α production for uterine explants incubated with LPS (1 ug/ml), m-AEA (100 nM), URB597 (1 uM), LPS plus m-AEA (100 nM) or LPS plus URB597 (1 uM) for 24 h. ANOVA test. a, p<0.001 vs control; b, p<0.01 vs LPS; c, p<0.05 vs control; d, p<0.01 vs control. n = 7.</p