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Biomedical subjects

H S Taylor

Publications and source records attributed to H S Taylor.

At least 19 recordsLinked to original sources
PubMed2001

Efficient liposome-mediated gene transfection and expression in the intact human uterus.

Although gene therapy has been used for correction of metabolic defects in diseases such as cystic fibrosis, as adjuvant treatment in cancer, and in the treatment of infectious diseases, there has been no report of gene transfer to the intact female reproductive tract. We assessed the ability to transfect the human uterus ex vivo and thereby evaluate the applicability of gene therapy to gynecology. The uterine lumen was accessed transcervically, using an intrauterine insemination catheter. pcDNA3.1 plasmid containing the Escherichia coli lacZ reporter gene was delivered to each uterus via liposome-mediated transfection. Control uteri were transfected with empty pcDNA3.1. Immunohistochemical analysis revealed beta-galactosidase expression in the lacZ-treated uteri in endometrial epithelial cells, endometrial stromal cells, and myometrium to a depth of 1.75 cm from the endometrial-myometrial junction. Highest expression was seen in endometrial glandular epithelial cells, with significant expression in the stroma and adjacent myometrium. Each of these cell types in the control uteri showed no beta-galactosidase expression. Successful gene transfection and expression in the intact human uterus can be accomplished easily, rapidly, and efficiently. Gene therapy may have wide applicability in the treatment and study of gynecologic disease.

Adult↗
PubMed2001

Maternal Hoxa10 is required for pinopod formation in the development of mouse uterine receptivity to embryo implantation.

Hoxa10 is a homeobox gene that is expressed both during the embryogenesis of the genitourinary tract and in the adult reproductive tract. Maternal Hoxa10 expression is necessary for endometrial receptivity to blastocyst implantation. The mechanism by which Hoxa10 induces endometrial development to a state of receptivity is unknown as HOXA10-deficient endometrium appears histologically normal. We altered the expression of Hoxa10 in the uterus of cycling adult female mice and examined the uterus at the time of implantation by transmission electron microscopy for alterations in epithelial morphology. Pinopods are projections on the surface of the uterine endometrial epithelial cells that develop transiently at the time of endometrial receptivity. Blocking Hoxa10 expression by transfection of Hoxa10 antisense into the cycling mouse uterus before implantation dramatically decreased pinopod number. Constitutively expressing Hoxa10 in the uterus just before the normal time of pinopod formation resulted in increased pinopod number. Therefore, Hoxa10 is necessary for pinopod development. Hox genes have been implicated in both the regulation of cellular proliferation and the determination of developmental fate. Hoxa10 exemplifies this dual role in the uterus by regulating both endometrial stromal cell proliferation and epithelial cell morphogenesis. Taken together, these results demonstrate that maternal Hoxa10 has an essential role in pinopod development and this function of Hoxa10 likely contributes to endometrial receptivity for the purpose of blastocyst implantation.

Animals↗
PubMed2001

Risks of smoking to reproductive health: assessment of women's knowledge.

OBJECTIVE: Our aim was to assess the knowledge of women regarding the gender-specific health risks associated with smoking. STUDY DESIGN: A cross-sectional survey was given to 388 female hospital employees. Knowledge of smoking-related illnesses that are specific to women was assessed. Regression analysis was used to discern potential predictors of this knowledge. RESULTS: Most women are aware that smoking causes respiratory disease (99%), lung cancer (99%), heart disease (96%), and pregnancy complications (91%). Few women are aware of the health risks of smoking that are specific to women, such as infertility (22%), osteoporosis (30%), early menopause (17%), spontaneous abortion (39%), ectopic pregnancy (27%), and cervical cancer (24%). Knowledge of these health risks was not predicted by age, education, or smoking status. Health care professionals were no more likely than other women to have knowledge of these risks. CONCLUSION: Most women are unaware of the health risks specific to women from smoking. Even female health care professionals do not generally have greater knowledge of these conditions. Further public health measures are necessary to increase knowledge of smoking risks that may be particularly relevant to women. This increase in knowledge has the potential to reduce significantly the smoking-related illnesses in women.

Adolescent↗
PubMed2001

Molecular markers of implantation: clinical implications.

The endometrium has been conventionally studied using histologic criteria. Our understanding of endometrial physiology has been advanced tremendously by research into the molecules that mediate its development and function. These molecules demonstrate a dynamic expression pattern through the menstrual cycle and have been implicated in endometrial growth, differentiation, and receptivity. These molecules include secreted proteins (endometrial bleeding-associated factor, glycodelin-A, insulin-like growth factor binding protein-1), cell-surface receptors (integrins), and nuclear transcription factors (HOXA10 and HOXA11). The homeobox genes Hoxa10 and Hoxa11 are necessary for implantation because mice with mutations in these genes exhibit a failure of implantation. HOXA10 and HOXA11 have been shown to be important for implantation in humans as well. Knowledge of endometrial molecular dynamics may now be used to enhance our ability to diagnose implantation defects. It may soon be possible to treat individual molecular defects by protein supplementation or gene therapy.

Animals↗
PubMed2001

HOXA10 expression is repressed by progesterone in the myometrium: differential tissue-specific regulation of HOX gene expression in the reproductive tract.

HOX genes are essential regulators of development in all multicellular organisms, including humans. We have previously shown that HOXA10 is expressed in the developing uterus and later in the adult human endometrium. HOX genes regulate endometrial development in response to sex steroids. Here, we demonstrate that HOXA10 is expressed in the myometrium as well. In situ hybridization reveals abundant HOXA10 expression, and Northern analysis demonstrates differential HOX gene expression in the myometrium throughout the menstrual cycle. HOXA10 expression decreases in the midsecretory phase, coinciding with high serum progesterone levels. Treatment of primary myometrial cell cultures with progesterone decreases HOXA10 expression in vitro-paralleling the expression seen in vivo. Despite the presence of progesterone receptors in the endometrium and myometrium, HOXA10 is differentially regulated in each tissue by progesterone. HOXA10 expression is induced in the stroma and decreased in the myometrium by progesterone. The differential tissue-specific response of this gene in response to progesterone is likely mediated by sex steroid receptor coactivators or corepressors. Decreased myometrial expression of developmental regulatory genes such as HOXA10 in the nonpregnant uterus may dedifferentiate the myometrium and allow growth in preparation for pregnancy.

Blotting, Northern↗
PubMed2000

Alteration of maternal Hoxa10 expression by in vivo gene transfection affects implantation.

Mice with a targeted mutation of the Hoxa10 gene demonstrate uterine factor infertility. It is unclear if the defect in the uterine environment arises due to the absence of Hoxa10 expression during embryonic development or in the adult. We have recently demonstrated that HOXA10 expression in human endometrium rises dramatically at the time of implantation, suggesting maternal expression of Hoxa10/HOXA10 may be essential to the process. To assess the importance of maternal Hoxa 10 expression, the uteri of day 2 pregnant mice were injected with a DNA/liposome complex containing constructs designed to alter maternal Hoxa10 expression before implantation. Transfection with a Hoxa10 antisense oligodeoxyribonucleotide significantly decreased the number of implantation sites. Transfection with a plasmid which constitutively expresses Hoxa10 optimized survival of implanted embryos resulting in increased litter size. These results demonstrate that maternal Hoxa10 expression is essential for implantation and is the first report of the maternal alteration of a gene known to affect implantation specifically. We also demonstrate that DNA/liposome complexes containing the same Hoxa10 constructs that alter fertility in mice, can affect Hoxa10 expression in a human endometrial cell line. Alteration of human endometrial HOXA10 via liposome-mediated gene transfection is a potential contraceptive agent or fertility treatment.

Animals↗
PubMed2000

Implantation in the human: the role of HOX genes.

HOX genes are transcription factors that are essential for the proper development of the müllerian tract in the embryonic period. It has been discovered that HOX genes are expressed in the adult uterus. Two of them, Hoxa10 and Hoxa11, have been demonstrated to be necessary for uterine receptivity and implantation in mice. Recent evidence also suggests such a role for HOX genes in humans. They are likely to be essential regulators of endometrial development in preparation for implantation. This article reviews the role of the HOX genes in the reproductive tract, their patterns of expression and regulation, the outcome of deficient HOX gene expression, and their potential mechanisms of action. The process of implantation is complex, and many molecular markers have been found expressed at high levels in the endometrium in the peri-implantation window. Targeted disruption has revealed that most of these molecules are redundant and not essential for implantation. The importance of Hox genes in this process has been well documented, and they remain one of the few well-characterized molecules necessary for implantation.

Animals↗
PubMed2000

The role of HOX genes in the development and function of the female reproductive tract.

HOX genes are a family of regulatory genes that encode transcription factors and are essential during embryonic development. These genes are highly conserved between species such that all metazoans possess a common genetic system for embryonic patterning. This system is conserved in the reproductive tract, where HOX genes are involved in the development of the müllerian system. The reproductive tract is unusual in that HOX genes continue to be expressed in the adult. HOX genes are essential both for appropriate reproductive tract development and for adult function. This article reviews the role of HOX genes in the development of the reproductive tract and the effect of HOX gene mutations on the development of the reproductive tract in both mice and humans. It then reviews the role and regulation of HOX genes in the adult function of the reproductive tract, specifically evidence that HOX genes are important for human endometrial development and receptivity.

Animals↗
PubMed2000

In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system.

Diethylstilbestrol (DES) was widely used to treat pregnant women through 1971. The reproductive tracts of their female offspring exposed to DES in utero are characterized by anatomic abnormalities. Here we show that DES administered to mice in utero produces changes in the expression pattern of several Hox genes that are involved in patterning of the reproductive tract. DES produces posterior shifts in Hox gene expression and homeotic anterior transformations of the reproductive tract. In human uterine or cervical cell cultures, DES induces HOXA9 or HOXA10 gene expression, respectively, to levels approximately twofold that induced by estradiol. The DES-induced expression is not inhibited by cyclohexamide. Estrogens are novel morphogens that directly regulate the expression pattern of posterior Hox genes in a manner analogous to retinoic acid regulation of anterior Hox genes. Alterations in HOX gene expression are a molecular mechanism by which DES affects reproductive tract development. Changes in Hox gene expression are a potential marker for the effects of in utero drug use that may become apparent only at late stages of development.

Animals↗
PubMed1999

Mutation analysis of the EMX2 gene in Kallmann's syndrome.

OBJECTIVE: To investigate the possibility that a mutation in the human EMX2 gene may be involved in Kallmann's syndrome. DESIGN: In vitro experiment. SETTING: Academic Medical Center. PATIENTS: One hundred and twenty patients with Kallman's syndrome or idiopathic hypogonadotrophic hypogonadism (IHH). INTERVENTION: Peripheral blood leukocytes were used to obtain DNA. MAIN OUTCOMES MEASURES: Single-stranded conformational polymorphism (SSCP) analysis was used to identify possible mutations of the EMX2 gene. RESULTS: One hundred and twenty patients with Kallmann's syndrome or IHH, had no mutations noted in this gene. CONCLUSION: It is unlikely that EMX2 mutations are a clinically significant cause of IHH or Kallman's syndrome.

Adolescent↗
PubMed1999

HOX gene expression is altered in the endometrium of women with endometriosis.

HOXA10 and HOXA11 are homeobox genes that function as transcription factors essential to embryonic development. We have recently described a role for each of these two genes in regulating endometrial development in the adult during the course of a menstrual cycle. Both Hoxa10 and Hoxa11 are essential for implantation in the mouse and appear to play a similar role in women. To investigate the role of HOX genes in the endometrium of women with endometriosis, quantitative Northern blot analysis was performed on the endometrium of 40 normal cycling controls and 40 patients with documented endometriosis. Patients with endometriosis failed to show the expected mid-luteal rise in HOX gene expression as demonstrated in the controls. Aberrant HOX gene expression suggests that altered development of the endometrium at the molecular level may contribute to the aetiology of infertility in patients with endometriosis.

Adult↗
PubMed1999

Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium.

Under the influence of sex steroids, human endometrium undergoes sequential development in preparation for implantation. Hoxa11 is essential for implantation in the mouse. Here we describe a potential role for HOXA11 in human endometrial development and implantation. Northern analysis demonstrates that HOXA11 is expressed in a menstrual cycle phase-dependent fashion in adult human endometrium. HOXA11 messenger RNA levels dramatically increase at the time of implantation and remain increased in pregnancy. In vitro, HOXA11 expression is increased in response to estrogen or progesterone. There is a dose-responsive increase over the physiologic range of progesterone concentration. Pretreatment with Cyclohexamide does not decrease the response to estrogen. Steroids are novel regulators HOX gene expression. The spatial and temporal pattern of HOXA11 expression in the human endometrium suggests a role in endometrial development, implantation, and maintenance of pregnancy.

Embryo Implantation↗
PubMed1998

HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.

Hox genes are well-known transcriptional regulators that play an essential role in directing embryonic development. Mice that are homozygous for a targeted disruption of the Hoxa10 gene exhibit uterine factor infertility. We have recently demonstrated that HOXA10 is expressed in the adult human uterus. To examine expression of HOXA10 during the menstrual cycle, Northern blot analysis and in situ hybridization were performed. Expression of HOXA10 dramatically increased during the midsecretory phase of the menstrual cycle, corresponding to the time of implantation and increase in circulating progesterone. Expression of HOXA10 in cultured endometrial cells was stimulated by estrogen or progesterone. Stimulation of HOXA10 by progesterone was concentration-dependent within the physiologic range, and the effect of estrogen was inhibited by cycloheximide. These results identify sex steroids as novel regulators of HOX gene expression. HOXA10 may have an important function in regulating endometrial development during the menstrual cycle and in establishing conditions necessary for implantation in the human.

Cells, Cultured↗
PubMed1998

A regulatory element of the empty spiracles homeobox gene is composed of three distinct conserved regions that bind regulatory proteins.

Homeobox genes encode a class of highly evolutionarily conserved transcription factors that control embryonic development. The Drosophila melanogaster empty spiracles gene is the homolog of the two human homeobox genes EMX1 and EMX2. These genes are necessary for central nervous system development. We used a regulatory element of the empty spiracles gene to study the control of homeobox gene expression. The 1.2-kilobase (kb) cis-regulatory element located 3 kb 5' of the transcription start site of the empty spiracles gene was analyzed by evolutionary sequence comparisons, gel mobility shift assays, DNase footprinting, and the generation of transgenic flies. The corresponding element from a related species, Drosophila hydei, was cloned. Three discrete, approximately 100 base pair (bp) regions of sequence homology were identified. Each had two blocks of 10 to 40 bp of near perfect sequence identity. Fusion proteins were produced containing the Abdominal-B homeodomain or the empty spiracles homeodomain, known regulators of empty spiracles gene expression. Gel mobility shift assays showed that each of the three regions is bound by both proteins. DNase footprinting revealed closely linked empty spiracles and Abdominal-B binding sites. We then generated transgenic flies containing a reporter linked to individual conserved regions of the enhancer. Reporter expression was evident only outside of the usual empty spiracles expression domain. These elements are not sufficient alone; a combinatorial model is proposed. Conserved discrete areas within a homeobox gene regulatory element, which function as homeodomain protein transcription factor binding sites, are used in a combinatorial fashion to regulate these developmentally important genes.

Animals↗
PubMed1998

Interleukin-8 in the human endometrium.

We have previously shown that interleukin-8 (IL-8), a cytokine with neutrophil chemotactic/activating and T cell chemotactic activity, is produced by human endometrial stromal and glandular cells in culture. The present study investigated the temporal and spatial expression of IL-8 messenger ribonucleic acid (mRNA) and protein in the human endometrium. Endometrial tissue (n = 52) was obtained from human uteri after hysterectomy conducted for reasons other than endometrial disease or from endometrial biopsies. The day of the menstrual cycle was established from women's menstrual history and was confirmed by histology. Half of the tissues (n = 26) were snap-frozen in liquid nitrogen, cellular RNA was extracted, and Northern blots were hybridized with a riboprobe complementary to a specific sequence of IL-8 mRNA. The remaining tissues (n = 26) were processed for frozen sections, and immunohistochemistry was performed using mouse antihuman IL-8 antibody. Comparison of IL-8 mRNA levels throughout the menstrual cycle revealed that late secretory and early to midproliferative phase IL-8 expression was significantly greater than midcycle expression (P < 0.02). Analysis of the IL-8 immunohistochemistry revealed that IL-8 protein is found in the surface epithelium and glands throughout the menstrual cycle. There was no detectable immunoreactive IL-8 in the stromal cells. We conclude that IL-8 is produced in the human endometrium in vivo, and the variations of IL-8 mRNA throughout the menstrual cycle suggest that sex hormones may regulate its gene expression. We speculate that IL-8 may modulate the timely recruitment of neutrophils and lymphocytes into the endometrium.

Animals↗
PubMed1997

A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes.

The mammalian female reproductive system arises from the uniform paramesonephric duct. The molecular mechanisms that establish differential development along this axis are unknown. We determined the pattern and timing of genes of the Hoxa axis in the development of the Müllerian tract. Hoxa-9, Hoxa-10, Hoxa-11, and Hoxa-13 are all expressed along the length of the paramesonephric duct in the embryonic mouse. After birth, a spatial Hox axis is established, corresponding to the postnatal differentiation of this organ system in the mouse. Hoxa-9 is expressed in the fallopian tubes, Hoxa-10 in the uterus, Hoxa-11 in the uterus and uterine cervix, and Hoxa-13 in the upper vagina. This expression pattern follows the paradigm of spatial colinearity but is a novel exception to temporal colinearity that has been considered typical of Hox genes. These genes remain expressed in the adult mouse and are expressed in the same pattern in the human. The female reproductive system undergoes dramatic structural and functional changes during the estrous cycle and in pregnancy, retaining a high degree of developmental plasticity. The late establishment of a Hox axis and persistent expression of Hox genes in the adult may play an important role in preserving this plasticity.

Adult↗
PubMed1993

The role of cholinergic systems in visuospatial processing and memory.

Few studies have specifically addressed the cholinergic role in visuospatial memory. In the present study, we employed a randomized double-blind repeated measures design to investigate the effects of scopolamine on Judgement of Line Orientation (JLO) and two distinct visuospatial memory tasks. Complex Figures (CF) is a test of drawn reproduction similar to the Rey complex figure. The Spatial Array Memory Test (SAMT) is a two-dimensional free-recall visuospatial test which minimizes constructive skills and allows sensitive measurement of placement errors. Scopolamine impaired performance on JLO and CF. However, no effects of scopolamine on SAMT were apparent even though the SAMT is sensitive to aging and right temporal-lobe lesions. Selective effects of scopolamine on focused versus distributed attention may account for these differential results.

Adult↗