AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman\u27s reproductive lifespan, resulting in menopause. Mullerian inhibiting substance (MIS) (or anti-Mullerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy

Damage Analysis of Reinforced Concrete Structures with Substandard Detailing

The goal of this study is to investigate seismic behaviour of existing R/C buildings designed and constructed in accordance with standards that do not meet current seismic code requirements. In these structures, not only flexure, but also shear and bond-slip deformation mechanisms need to be considered, both separately and in combination. To serve this goal, a finite element model is developed for inelastic seismic analysis of complete planar R/C frames. The proposed finite element is able to capture gradual spread of inelastic flexural and shear deformations as well as their interaction in the end regions of R/C members. Additionally, it is capable of predicting shear failures caused by degradation of shear strength in the plastic hinges of R/C elements, as well as pullout failures caused by inadequate anchorage of the reinforcement in the joint regions. The finite element is fully implemented in the general inelastic finite element code IDARC2D and it is verified against experimental results involving individual column and plane frame specimens with nonductile detailing. It is shown that, in all cases, satisfactory correlation is established between the model predictions and the experimental evidence. Finally, parametric studies are conducted to illustrate the significance of each deformation mechanism on the seismic response of the specimens under investigation. It is concluded, that all deformation mechanisms, as well as their interaction, should be taken into consideration in order to predict reliably seismic damage of R/C structures with substandard detailing

Wellness through a comprehensive Yogic breathing program – A controlled pilot trial

<p>Abstract</p> <p>Background</p> <p>Increasing rates of psychosocial disturbances give rise to increased risks and vulnerability for a wide variety of stress-related chronic pain and other illnesses. Relaxation exercises aim at reducing stress and thereby help prevent these unwanted outcomes. One of the widely used relaxation practices is yoga and yogic breathing exercises. One specific form of these exercises is Sudarshan Kriya and related practices (SK&P) which are understood to have favourable effects on the mind-body system. The goal of this pilot study was to design a protocol that can investigate whether SK&P can lead to increased feeling of wellness in healthy volunteers.</p> <p>Methods</p> <p>Participants were recruited in a small university city in Sweden and were instructed in a 6-day intensive program of SK&P which they practiced daily for six weeks. The control group was instructed to relax in an armchair each day during the same period. Subjects included a total of 103 adults, 55 in the intervention (SK&P) group and 48 in the control group. Various instruments were administered before and after the intervention. Hospital Anxiety Depression Scale measured the degree of anxiety and depression, Life Orientation Test measured dispositional optimism, Stress and Energy Test measured individual's energy and stress experiences. Experienced Deviation from Normal State measured the experience of altered state of consciousness.</p> <p>Results</p> <p>There were no safety issues. Compliance was high (only 1 dropout in the SK&P group, and 5 in the control group). Outcome measures appeared to be appropriate for assessing the differences between the groups. Subjective reports generally correlated with the findings from the instruments. The data suggest that participants in the SK&P group, but not the control group, lowered their degree of anxiety, depression and stress, and also increased their degree of optimism (ANOVA; p < 0.001). The participants in the yoga group experienced the practices as a positive event that induced beneficial effects.</p> <p>Conclusion</p> <p>These data indicate that the experimental protocol that is developed here is safe, compliance level is good, and a full scale trial is feasible. The data obtained suggest that adult participants may improve their wellness by learning and applying a program based on yoga and yogic breathing exercises; this can be conclusively assessed in a large-scale trial.</p> <p>Trial Registration</p> <p>Australian Clinical Trial Registry ACTRN012607000175471.</p

3, 3′5 Triiodo L Thyronine Induces Apoptosis in Human Breast Cancer MCF-7cells, Repressing SMP30 Expression through Negative Thyroid Response Elements

Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver.In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRβ, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions.This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer

Poverty in Consumer Culture:Towards a Transformative Social Representation

International audienceIn this article, we consider the representations of poverty within consumer culture. We focus on four main themes – social exclusion, vulnerability, pleasure and contentment – that capture some of the associations that contemporary understandings have made with poverty. For each theme, we consider the portrayals of poverty from the perspective of key agents (such as marketers, media, politicians) and then relate this to more emic representations of poverty by drawing on a range of contemporary poverty alleviating projects from around the world. We conclude with a set of guidelines for relevant stakeholders to bear in mind when elaborating their representations of poverty. These guidelines may act as a platform to transform marginalising representations of poverty into more empowering representations