Multiprobabilistic prediction in early medical diagnoses

This paper describes the methodology of providing multiprobability predictions for proteomic mass spectrometry data. The methodology is based on a newly developed machine learning framework called Venn machines. Is allows to output a valid probability interval. The methodology is designed for mass spectrometry data. For demonstrative purposes, we applied this methodology to MALDI-TOF data sets in order to predict the diagnosis of heart disease and early diagnoses of ovarian cancer and breast cancer. The experiments showed that probability intervals are narrow, that is, the output of the multiprobability predictor is similar to a single probability distribution. In addition, probability intervals produced for heart disease and ovarian cancer data were more accurate than the output of corresponding probability predictor. When Venn machines were forced to make point predictions, the accuracy of such predictions is for the most data better than the accuracy of the underlying algorithm that outputs single probability distribution of a label. Application of this methodology to MALDI-TOF data sets empirically demonstrates the validity. The accuracy of the proposed method on ovarian cancer data rises from 66.7 % 11 months in advance of the moment of diagnosis to up to 90.2 % at the moment of diagnosis. The same approach has been applied to heart disease data without time dependency, although the achieved accuracy was not as high (up to 69.9 %). The methodology allowed us to confirm mass spectrometry peaks previously identified as carrying statistically significant information for discrimination between controls and cases.

Obesity induced by high-fat diet promotes insulin resistance in the ovary

Besides the effects on peripheral energy homeostasis, insulin also has an important role in ovarian function. Obesity has a negative effect on fertility, and may play a role in the development of the polycystic ovary syndrome in susceptible women. Since insulin resistance in the ovary could contribute to the impairment of reproductive function in obese women, we evaluated insulin signaling in the ovary of high-fat diet-induced obese rats. Female Wistar rats were submitted to a high-fat diet for 120 or 180 days, and the insulin signaling pathway in the ovary was evaluated by immunoprecipitation and immunoblotting. At the end of the diet period, we observed insulin resistance, hyperinsulinemia, an increase in progesterone serum levels, an extended estrus cycle, and altered ovarian morphology in obese female rats. Moreover, in female obese rats treated for 120 days with the high-fat diet, the increase in progesterone levels occurred together with enhancement of LH levels. The ovary from high-fat-fed female rats showed a reduction in the insulin receptor substrate/phosphatidylinositol 3-kinase/AKT intracellular pathway, associated with an increase in FOXO3a, IL1B, and TNF alpha protein expression. These changes in the insulin signaling pathway may have a role in the infertile state associated with obesity. Journal of Endocrinology (2010) 206, 65-74

Patterns of oocyte development in natural habitat and captive Salminus hilarii Valenciennes, 1850 (Teleostei: Characidae)

Fecundity and oocyte development in Salminus hilarii female brood stock were analyzed with the aim of investigating the impact of migration impediment on oogenesis. Histological analyses of the ovaries were performed in adult females caught in two different environments-the TietA(a) River (natural) and captivity-and the gonadossomatic index, oocyte diameter and fecundity determined. Five germ cell development stages (oogonium, perinucleolar, cortical alveoli, vitellogenic, ripe) and two other structures (postovulatory follicles and atretic oocytes) were observed in females caught in the river. Captive animals lacked the ripe oocytes and postovulatory follicles and had a relatively higher number of atretic oocytes. Females in captivity are known to produce larger oocytes, and they release fewer eggs in each spawn (absolute fecundity) when compared with animals that are able to migrate. Our results suggest that the TietA(a) River is undergoing alterations which are being reflected in the reproductive performance of S. hilarii, mainly due to the presence of atretic oocytes in females caught in the river. The lack of postovulatory follicles and ripe oocytes in captive animals reveals that migratory impediment negatively impacts final oocyte maturation. However, the stage of maturation reached is adequate for ovulation induction with hormone manipulation.

Metastatic melanoma positively influences pregnancy outcome in a mouse model: could a deadly tumor support embryo life?

The incidence of melanoma is increasing worldwide. It is one of the leading cancers in pregnancy and the most common malignancy to metastasize to placenta and fetus. There are no publications about experimental models of melanoma and pregnancy. We propose a new experimental murine model to study the effects of melanoma on pregnancy and its metastatic process. We tested several doses of melanoma cells until we arrived at the optimal dose, which produced tumor growth and allowed animal survival to the end of pregnancy. Two control groups were used: control (C) and stress control (SC) and three different routes of inoculation: intravenous (IV), intraperitoneal (IP) and subcutaneous (SC). All the fetuses and placentas were examined macroscopically and microscopically. The results suggest that melanoma is a risk factor for intrauterine growth restriction but does not affect placental weight. When inoculated by the SC route, the tumor grew only in the site of implantation. The IP route produced peritoneal tumoral growth and also ovarian and uterine metastases in 60% of the cases. The IV route produced pulmonary tumors. No placental or fetal metastases were obtained, regardless of the inoculation route. The injection of melanoma cells by any route did not increase the rate of fetal resorptions. Surprisingly, animals in the IV groups had no resorptions and a significantly higher number of fetuses. This finding may indicate that tumoral factors released in the host organism to favor tumor survival may also have a pro-gestational action and consequently improve the reproductive performance of these animals.

The Estrous Cycle Modulates Small Leucine-Rich Proteoglycans Expression in Mouse Uterine Tissues

In the pregnant mouse uterus, small leucine-rich proteoglycans (SLRPs) are drastically remodeled within a few hours after fertilization, suggesting that ovarian hormone levels modulate their synthesis and degradation. In this study, we followed by immunoperoxidase approach, the presence of four members of the SLRP family (decorin, lumican, biglycan, and fibromodulin) in the uterine tissues along the estrous cycle of the mouse. All molecules except fibromodulin, which predominates in the myometrium, showed a striking modulation in their distribution in the endometrial stroma, following the rise in the level of estrogen. Moreover, notable differences in the distribution of SLRPs were observed between superficial and deep stroma, as well as between the internal and external layers of the myometrium. Only biglycan and fibromodulin were expressed in the luminal and glandular epithelia. All four SLRPs were found in cytoplasmic granules of mononucleated cells. The pattern of distribution of the immunoreaction for these molecules in the uterine tissues was found to be estrous cycle-stage dependent, suggesting that these molecules undergo ovarian hormonal control and probably participate in the preparation of the uterus for decidualization and embryo implantation. In addition, this and previous results from our laboratory suggest the existence of two subpopulations of endometrial fibroblasts that may be related to the centrifugal development of the decidua. Anat Rec, 292:138-153, 2009. (c) 2008 Wiley-Liss, Inc.

Development of an adenoviral vector with robust expression driven by p53

Here we introduce a new adenoviral vector where transgene expression is driven by p53. We first developed a synthetic promoter, referred to as PGTx beta containing a p53-responsive element, a minimal promoter and the first intron of the rabbit P-globin gene. Initial assays using plasmid-based vectors indicated that expression was tightly controlled by p53 and was 5-fold stronger than the constitutive CMV immediate early promoter/enhancer. The adenoviral vector, AdPG, was also shown to offer p53-responsive expression in prostate carcinoma cells LNCaP (wt p53), DU-145 (temperature sensitive mutant of p53) and PC3 (p53-null, but engineered to express temperature-sensitive p53 mutants). AdPG served as a sensor of p53 activity in LNCaP cells treated with chemotherapeutic agents. Since p53 can be induced by radiotherapy and chemotherapy, this new vector could be further developed for use in combination with conventional therapies to bring about cooperation between the genetic and pharmacologic treatment modalities. (c) 2007 Elsevier Inc. All rights reserved.

Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation

Glypican-3 (GPC3) is a proteoglycan involved in migration, proliferation and cell survival modulation in several tissues. There are many reports demonstrating a downregulation of GPC3 expression in some human tumors, including mesothelioma, ovarian and breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their in vivo invasive and metastatic capacities together with a higher susceptibility to in vitro apoptosis. Currently, the signaling mechanism of GPC3 is not clear. First, it was speculated that GPC3 regulates the insulin-like growth factor (IGF) signaling system. This hypothesis, however, has been strongly challenged. Recently, several reports indicated that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling. Here we provide new data demonstrating that GPC3 regulates Wnt pathway in the metastatic adenocarcinoma mammary LM3 cell line. We found that GPC3 is able to inhibit canonical Wnt signals involved in cell proliferation and survival, as well as it is able to activate non canonical pathway, which directs cell morphology and migration. This is the first report indicating that breast tumor cell malignant properties can be reverted, at least in part, by GPC3 modulation of Wnt signaling. Our results are consistent with the potential role of GPC3 as a metastasis suppressor.

Egg-laying-hormone immunoreactivity in the neural ganglia and ovary of Haliotis asinina Linnaeus

Immunoreactivity against the abalone egg-laying hormone (aELH) was detected in the fine granules of type 1 and 2 neurosecretory (NS) cells, neurites in the neuropil, and blood sinuses in the connective tissue sheath of the cerebral, pleuropedal, and visceral ganglia of the tropical abalone, Haliotis asinina Linnaeus. The number of positive NS cells, and the intensity of staining in the ganglia, varied and might be related to the stage of ovarian cycle. At any stage, positive cells were most numerous in the pleuropedal, and least numerous in the visceral ganglion. In addition, several cells of the statocyst and associated nerves also exhibited the immunoreactivity. In the ovary, the most intense reactivity was detected in the follicular and granular cells adjacent to mature oocytes, in the trabeculae and the ovarian capsule. The cytoplasm of mature oocytes was also moderately stained. The results indicate that the cerebral, pleuropedal, and visceral ganglia are the main sites of aELH-producing cells. The ovary may also produce aELH locally.

Double stranded DNA-binding studies of potential Rhodium(ll) antitumor complexes

In 1952, Dwyer and coworkers began testing a series of metal complexes for potential inhibition of cancer cell proliferation in animals.[l] The complexes tested were unsuitable for such studies due to their high toxicity. Therefore, no further work was done on the project. However, in 1965, Rosenberg and coworkers revisited the possibility of potential metal-based drugs. Serendipitously, they discovered that cis-diamminedichloroplatinum(lI) (cisplatin) inhibits cell division in E. coli.[2] Further studies of this and other platinum compounds revealed inhibition of tumor cell lines sarcoma 180 and leukemia LI2l0 in mice.[l] Cisplatin was approved by the Food and Drug Administration in 1970 as a chemical chemotherapeutic agent in the treatment of cancer. The drug has primarily been used in the treatment of testicular and ovarian cancers, although the powerful chemotherapeutic properties of the compound indicate use against a variety of other cancers.[3] The toxicity of this compound, however, warrants the development of other metal-based potential antitumor agents. The success of cisplatin, a transition-metal-based chemotherapeutic, opened the doors to a host of research on the antitumor effects of other transition-metal complexes. Beginning in the 1970s, researchers looked to rhodium for potential use in antitumor complexes. Dirhodium complexes with bridging equatorial ligands (Figure I) were the primary focus for this research. The overwhelming majority of these complexes were dirhodium(II) carboxylate complexes, containing two rhodium(II) centers, four equatorial ligands in a lantero formation around the metal center, and an axial ligand on either end. The family of complexes in Figure 1 will be referred to as dirhodium(II) carboxylate complexes. The dirhodium centers are each d? with a metal-metal bond between them. Although d? atoms are paramagnetic, the two unpaired electrons pair to make the complex diamagnetic. The basic formula of the dirhodium(lI) carboxylate complexes is Rh?(RCOO)?(L)? with R being methyl, ethyl, propyl, or butyl groups and L being water or the solvent in which the complex was crystalized. Of these dirbodium(II) carboxylate complexes, our research focuses on Rb la and two other similar complexes Rh2 and Rh3 (Figure 2). Rh2 is an activated form of Rhla, with four acetonitrile groups in place of two of the bidentate acetate ligands. Rh3 is similar to Rhla, with trifluoromethyl groups in place of the methyl groups on the acetate ligands.

Topotecan is a substrate for multidrug resistance associated protein 4

Topotecan (TPT) is a semisynthetic water-soluble derivative of camptothecin (CPT) used as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other malignancies. However, both doselimiting toxicity and tumor resistance hinder the clinical use of TPT. The mechanisms for resistance to TPT are not fully defined, but increased efflux of the drug by multiple drug transporters including P-glycoprotein (PgP), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) from tumor cells has been highly implicated. This study aimed to investigate whether overexpression of human MRP4 rendered resistance to TPT by examining the cytotoxicity profiles using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay and cellular accumulation of TPT in HepG2 cells stably overexpressing MRP4. Two kinds of cell lines, HepG2 with insertion of an empty vector plasmid (V/HepG2), HepG2 cells stably expressing MRP4 (MRP4/HepG2), were exposed to TPT for 4 or 48 hr in the absence or presence of various MRP4 inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO), diclofenac, celecoxib, or MK-571. The intracellular accumulation of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2 cells was determined by incubation of TPT with the cells and the amounts of the drug in cells were determined by validated HPLC methods. The study demonstrated that MRP4 conferred a 12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib, or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity and partially reversed MRP4-mediated resistance to TPT. In addition, the accumulation of TPT was significantly reduced in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding site model was found the best fit for the MRP4-mediated efflux of TPT, with an estimated Km of 1.66 mM and Vmax of 0.341 ng/min/106 cells. Preincubation of MRP4/HepG2 cells with BSO (200 μM) for 24 hr, celecoxib (50 mM), or MK-571 (100 mM) for 2 hr significantly increased the accumulation of TPT over 10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P < 0.05), respectively. By contrast, there was no significant difference in intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered resistance to adefovir dipivoxil (bis-POMPMEA) and methotrexate, two reported MRP4 substrates. MRP4 did not exhibit any significant resistance to other model drugs including vinblastine, vincristine, etoposide, carboplatin, cyclosporine and paclitaxel in both long (48 hr) and short (4 hr) drug-exposure MTT assays. These findings indicate that MRP4 confers resistance to TPT and TPT is the substrate for MRP4. Further studies are needed to explore the role of MRP4 in resistance to, toxicity and pharmacokinetics of TPT in cancer patients.

Changing bodies, changing discourses : women's experiences of early menopause

Early menopause has been constructed by discourses of biological determinism as an untimely, but natural, failure of the female body. Medical discourses in particular have interpreted early menopause as a congenital irregularity and a rare anomaly of menopause at midlife. In this thesis I challenge the notion that early menopause is an innate imperfection related only to women’s age. I propose that early menopause is dependent upon the cultural interpretations of individual women and is constituted through the mercurial and multiple discourses of women who have this embodied experience. Moreover, I reveal that early menopause is a contemporary condition and that its location in history is inextricably bound to discourses of risk, naturalism and the self. Further I make the assumption that having an early menopause both affects and is an effect of women’s fertility, sexuality and subjectivity. I have drawn upon a broad range of sources to provide a sociological analysis of early menopause. Literature on early menopause is dominated by positivist discourses, yet many alternate discourses negotiate these influential constructions. I suggest here that the perception of early menopause as a natural fault is merely a construction by medical discourses and does not incorporate the dynamic discourses of early-menopausal women. Moreover, the restriction of early menopause to a genetic female failure excludes the majority of women who have an early menopause through iatrogenisis. This omission occurs through the failure of positivist discourses to accommodate diversity in discourses. Recent sociological and feminist studies have vindicated menopausal women. They have reconstructed menopause through notions of embodiment and have removed the veil of negativity used by the medical sciences to contain menopausal women (Komesaroff, Rothfield and Daly 1997). The visibility of menopausal women, however, remains connected to age. Menopause has been created as a predictable consequence of aging and as such has come to be synonymous with middle age. Nowadays, even men are said to experience menopause at midlife (Carruthers 1996). But early menopause is constituted within the discourses of women who have this experience. Medico-scientific discourses, based upon theories of genetic inevitability, disregard this perspective. Consequently early menopause is subsumed by naturalistic discourses that relate menopause to midlife. Such restraint reflects the unease created by menopause that does not coincide with prescribed life stages. Women's experiences of their changing bodies are largely unheard. Thus, women who have an early menopause are faced with a chasm of ‘cultural non-recognition’ (Fraser 1997). Conjointly with this discursive repression early-menopausal women face social imbalances that are transacted as both cause and consequence of early menopause. In particular the contemporary creation of early menopause is bound to the social and historical location of women as a group. Women are exploited by the institution of medicine, ‘exposure to environmental toxicity’ (Fraser 1997: 11) and commercialization as causes of early menopause. Yet the corporeal effects of practices of risk avoidance (Beck 1993), social practices (Shilling 1993) and Western consumerism (Lupton 1994) fail to be recognized. I address these problematics through a poststructural and feminist critique that assumes moments of commonality among women, while at the same time recognizes shifting and multiple differences (Nicholson 1999). I suggest here that early menopause falls into cultural misrecognition in Fraser's (1997) terms and argue that it is united concurrently with the gender injustice of androcentrism (Fraser 1997: 21). Fraser (1997: 16) suggests that it is only by relating these dual problematics that we are able to make sense of current dilemmas. Thus I have critiqued early menopause through a connection between individual embodied experiences of early menopause and early menopause as a modern phenomenon that is specific to women. I have attempted to unravel these arguments that simultaneously call to ‘... abolish gender differentiation and to valorize gender specificity’ (Fraser 1997: 21) while at the same time acknowledging their interconnectedness. An approach of merely combining women’s discourses with overarching social issues would be inadequate as not only do these problematics intersect but they also can be opposed. As Fraser (1997: 25) notes with her theory, redressing one aspect of cultural or social analysis can further imbalance another. For instance making visible the diversity and uniqueness of individual experiences of early menopause could detract from acknowledging the contemporary construction of early menopause through social inequality. Crucial to this understanding is a destabilizing of the binary construction of differences between the sexes that makes way for a reconstruction of early menopause through ‘sexual slippage’ (Matus 1995). In this thesis I look for a subtlety between the particular and the collective that views early menopause as concurrently a singular and changeable experience as well as imbedded in social practice. I suggest that these concepts are entwined as interactive effects of early menopause. Thus I have analyzed the bivalent problematics of the embodiment and social location of early menopause as imbricated, dynamic and unending discourses. From this perspective I reviewed the literature that was available on early menopause. In Chapter One I look to descriptions of early menopause and note that it has disappeared into a conglomeration of disparate, mostly medical, discourses that are contradictory. Nevertheless medical discourses offer ‘conclusive’ definitions of early menopause that are based on naturalistic views of the body (Shilling 1994). The determinants used are inconsistent and do not include women's discourses of early menopause. Thus, dominant medical discourses obscure women’s embodied experiences of early menopause and ignore the contemporary causes of early menopause. In Chapter Two I examine the causes of early menopause as a way of explaining the disparity between medical discourses and my anecdotal observations of early menopause as a fairly common contemporary occurrence. The relatively recent escalation in gynaecological surgery, especially hysterectomy, appears to account almost single-handedly for early menopause as a current phenomenon. Moreover, the extraordinary number of women who have their uterus removed at hysterectomy can be interpreted as a modern implementation of ancient anxieties. Women's sexuality has been constructed throughout history as problematic and this unease has been translated through women's bodies as dangerous and in need of control (Greer 1992). Thus social concerns which have evolved historically have emerged through the representation of a woman's uterus as an unseen, dark and mysterious risk (Beck 1993). Medical discourses define this risk and are able to negate the so-called dangers of women's sexuality through the surgical removal of their organs. Widespread negotiation of medical discourses is apparent, as hysterectomy in the modern Western world is the most common of all surgical operations (Hufnagel 1989). It is overwhelmingly the most common cause of early menopause as well. I examine also the historical condemnation of infertile women and how this anxiety has been transposed to the modern world through the commercialization of reproduction. Transactions of this social unease can cause early menopause. For instance the medical technology of in-vitro fertilization (I.V.F.) has been offered as a panacea for the infertility of early menopause but, paradoxically, can cause early menopause as well. Conception through technology has been normalized as a viable option for women who are unable to conceive and understandings of I.V.F. have moved into everyday discourse. Medical discourses have constructed fertility as a saleable item and infertile women expect that they can purchase this merchandise. Human eggs have become lucrative commodities that now are available in the market place. Egg ‘donation’ for I.V.F. programs can hasten the attrition rate of eggs and can cause early menopause in some pre-menopausal women (Rowland 1992: 24). Even the recycling of a woman’s uterus supposedly has become a possibility through the transferring of this ‘used’ organ at hysterectomy to a recipient woman who can use the other woman’s uterus as a ‘gestational garage’ (Rogers 1998). In this way women have been disembodied as mechanical systems with inter-changeable body parts and the potentially detrimental consequences of these commercial transactions are ignored. In addition I show how early menopause can be caused by the connection between the self and the social structure. Women's subjectivity is constituted through the cultural discourses available to them and these discourses affect social behaviour (Lupton 1995). For instance smoking and dieting have been identified as causes of early menopause. These activities have been related to the creation of women’s bodies as hetero-sexually desirable and are endemic to young women (Evans-Young 1995). This suggests that cultural causes of early menopause are transactions of sexual politics. Yet there is a paucity of literature that acknowledges the relationship between women’s subjectivity and early menopause. Thus the second chapter exposes a link between sexual politics and causes of early menopause through women's relationships with risk, naturalism and the self. In Chapter Three I deconstruct early menopause through theoretical considerations. I rely on an overarching poststructuralism that embraces the concept of fragmented plural discourses and the subjectivity of menopausal women as a continuous process (Komesaroff 1997: 61). I have woven these variables through broad feminist critiques (Leonard 1997). Through this eclectic approach I hoped to find some loose alignment between the corporeal, ontological and embodied dimensions of early menopause. The recurring themes of sexuality, fertility and subjectivity emerge through deconstructing discourses of sexual difference as immutable and non-negotiable; exposing ‘premature ovarian failure’ as a discursive construction that censures early-menopausal women; and acknowledging the discourses of individual women as unique, diverse and dynamic. I looked to a method of exposing some of these individual discourses and in Chapter Four I describe a critical research process aimed at understanding early menopause as a lived experience. In the remaining chapters I align these ontological arguments with an analysis of the discourses of women who had experienced or were experiencing an early menopause. This section partly relieves the ‘cultural non-recognition’ of the discourses of early-menopausal women. I recorded the narratives of fifty early-menopausal women through in-depth interviews and used this empirical data to direct the study. This data provides the opportunity to understand early menopause as an assortment of embodied experiences. For instance women’s experiences of age at commencement of menopause spanned over three and half decades. They did not reflect the age specifications prescribed by medical discourses. Rather women interpreted their experiences within their own discourses and determined their menopause as early based upon the expectations of their cultural context. Many of the women experienced changes attributed to menopause at midlife. It was not these changes that were significant to early-menopausal women it was how each woman translated these changes that provided meanings of early menopause. In Chapter Five I introduce the women through a table that connects the varying experiences of each woman. This profile shows that, in the main, the women’s experiences of early menopause were unexpected. I suggest that this is due to the disparity between early-menopausal women’s experiences and the current age and social norms of menopause. By bracketing the women into cohorts patterns emerged displaying differences between women who had menopause in their teens, twenties, thirties and forties. Adolescent women had intense feelings of abnormality and despair. Women who were in their twenties were less devastated by menopause than the younger women but described their sexuality and self-identity as changing. And although some women in their thirties were shocked or dismayed to have an early menopause others were ambivalent or happy. These women also described their sexuality and self-identity through changing discourses. A number of the women who were in their forties said that they were ‘too young for the menopause’ but were far less despondent than the younger women. It seemed that the greater the distance between age norms and social norms the more negatively women responded. Age norms that determine the social norms of women's lives through a ‘biological clock’ are constructed to reflect social values. But age is a social construction that changes over time. Thus it would appear that women’s changing bodies and changing discourses of early menopause are in the process of recreating age and social norms around menopause. In Chapter Six I draw upon women’s narratives that describe a connection between early menopause and sexuality. Yet the respondents were not unified in their constructions of sexuality. For instance a number of the women rejected the containment of their sexuality as absolute and defined in terms of bi-lateral hetero-sexual opposition. The discourses of these women constructed their sexuality as continuously flexible. Some early-menopausal women described this sexual mobility as an equivocal relationship between their sexuality, reproductive capacity and female organs. Other women articulated their sexuality as vacillating, ambiguous and unrepresentative of the so-called ‘true woman’. Several felt that they were not meant to have female reproductive organs at all. Nearly one third of the women had had their uterus removed at hysterectomy and the reproductive organs of two women were rudimentary. Women’s narratives showed that the social value of fertility influences constructions of early menopause. In Chapter Seven I record the contrast between the poignant responses of women who wished to have a baby of their own and other women who resisted discourses that entwine reproductivity with being a woman. For instance some women negotiated fertility through economic discourses of consumerism with the expectation that they could purchase conception as a commodity. Other women welcomed their early menopause as freedom from contraceptive concerns and others had no interest in reproduction at all. Thus discord arose through discourses that problematize early-menopausal women as non-reproductive and discourses that value variability. In addition many of the women’s accounts constructed their subjectivity as mobile, challenging the notion that discourses of the self are immutable. Chapter Eight presents narratives which suggest that the subjectivity of many women was altered continuously by early menopause. Yet some of the women rejected the construction of their subjectivity as unfluctuating. These contradictions reflect the uncertainties of the contemporary world. Nevertheless most respondents found that the tethering of menopause to constructions of midlife was incongruous with their own experiences. Many women refused to accept the label of social redundancy attached to middle-aged women. They moved their subjectivity beyond the reproductive body to a shifting and tractable identity of the self. This thesis demonstrates that the medical construction of early menopause as a rare and natural female flaw varies from women's experiences which suggest that early menopause is common and discursively constructed. This disparity has occurred through the privilege placed upon the construction of bodies as immutable and sexually static. This privileging has obscured the multi-dimensional causes of early menopause and given preference to a mono-causal theory. By exposing the variety of causes of early menopause the medical construction of women through a universal and unalterable body of reproduction is challenged. Moreover, women's discourses of early menopause demonstrate that the medical reduction of early menopause to a spontaneous bio-chemical malfunction has ignored the volatility of women’s embodied experiences. Women experience early menopause variously and through mercurial discourses. I suggest here that women's discourses of their experiences of early menopause reflect recurring and restructuring philosophical quandaries of fertility, sexuality and subjectivity. While there can be no representative claims made from this thesis it contributes to an understanding of the embodied experiences of early menopause. It provides an understanding of the creation of early menopause through social practices and goes part way to redressing the problematics of what Fraser terms ‘cultural non-recognition’. But, more importantly, it acknowledges early menopause as a variety of experiences where women interpret their changing bodies through changing discourses.

Microscopic modifications of the female reproductive tissues of Mustelus antarcticus

The ovarian follicles and oviducal glands have structural organisations similar to other chondrichthyans. Sperm are stored in the oviducal gland of all maturing and mature animals throughout the year and throughout pregnancy. Microscopic features of the uterine epithelium suggest nutrients are supplied to developing embryos without placenta formation.

Molecular characterization and analysis of a truncated serotonin receptor gene expressed in neural and reproductive tissues of abalone

In molluscs, the neurotransmitter serotonin (5-HT) has been linked to a variety of biological roles including gamete maturation and spawning. The possible involvement of 5-HT in abalone gamete release was demonstrated by a dose-dependent increase in Haliotis rubra gonad contractile bioactivity following 5-HT stimulation. Physiological functions associated with 5-HT, are mediated through binding to 5-HT receptors. A cDNA encoding a putative 5-HT receptor consisting of 359 amino acids was isolated from the tropical abalone H. asinina, termed 5-HT_{1 ha}. The 5-HT_{1 ha} shares G-protein-coupled receptor motifs with metazoan 5-HT receptors, including predicted transmembrane domains, active sites for protein kinase action, and N-linked glycosylation sites. However, the third intracellular loop of 5-HT_{1 ha} is relatively short, and only six transmembrane domains are predicted, implying a truncated receptor. Phylogenetic analysis with known 5-HT receptor genes suggests that 5-HT_{1 ha} belongs to the type 1 5-HT receptor family. Expression analysis by RT-PCR showed that 5-HT_{1 ha}  mRNA was present in all tissues examined, including the neural ganglia and gonad tissues. Immunocytochemistry revealed the presence of 5-HT_{1 ha} specifically within the soma of neuronal cells located in the outer cortex of both cerebral and pleuropedal ganglia. In ovarian and testicular tissues, 5-HT_{1 ha} immunoreactivity was observed in epithelial cells of the outer capsule and connective tissue of the trabeculae to which the gamete follicles adhere. Whether this receptor transcript is translated to a functional protein needs to be verified, but if so, it could play a role in reproduction.

Molting and reproduction in portunus pelagicus

This investigation describes ovarian maturation stages in the female reproductive system, evidence for histones in sperm nuclei and novel morphological changes that occur during spermiogenesis in the male blue swimming crab, portunus pelagicus. It also identifies dual functionality of the molt inhibiting hromone on molting and vitellogenesis through RNA inteference.

Intracranial hemorrhage (ICH) in cancer patients treated with bevacizumab : the Memorial Sloan-Kettering experience

Background: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor approved for recurrent glioblastoma (GBM), metastatic breast, colorectal and non-small-cell lung cancers (NSCLC). There has been a potentially increased risk of intracranial hemorrhage (ICH) in patients receiving bevacizumab.

Methods: We retrospectively identified patients with ICH who received bevacizumab between 1 January 2001 and 10 January 2009.

Results: We identified 1024 patients with ICH, 4191 patients who received bevacizumab and 12 (0.3%) who met both our criteria. There were eight women and four men with a median age of 66 years. Primary cancers were ovarian (n = 3), NSCLC (n = 3), colon (n = 1), angiosarcoma (n = 1) and GBM (n = 4). Intracranial tumors were present in 9 of the 12 patients; the remaining three (25%) had no evidence of intracranial pathology. Two hundred and fifty-seven patients with these same primary pathologies and brain tumors were treated with bevacizumab; ICH was seen in nine (3.7%), which was comparable to the 3.6% frequency seen in comparable patients not receiving bevacizumab.

Conclusions: ICH with bevacizumab treatment in this population is rare and does not appear to increase its frequency over the baseline rate of ICH in a comparable population. Most bevacizumab-related ICH occurs into central nervous system tumors but spontaneous hemorrhages were seen.