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Turner syndrome (TS) is due to a complete or partial loss of an X chromosome in female patients and is not currently part of newborn screening (NBS). Diagnosis is often delayed, resulting in missed crucial diagnostic and therapeutic opportunities.

Purpose:Turner syndrome is a developmental disorder caused by partial or complete monosomy for the X chromosome in 1 in 2,500 females. We hypothesized that single-nucleotide polymorphism (SNP) array genotyping could provide superior resolution in comparison to metaphase karyotype analysis to facilitate genotype–phenotype correlations.Methods:We genotyped 187 Turner syndrome patients with 733,000 SNP marker arrays. All cases met diagnostic criteria for Turner syndrome based on karyotypes (60%) or characteristic physical features. The SNP array results confirmed the diagnosis of Turner syndrome in 100% of cases.Results:We identified a single X chromosome (45,X) in 113 cases. In 58 additional cases (31%), other mosaic cell lines were present, including isochromosomes (16%), rings (5%), and Xp deletions (8%). The remaining cases were mosaic for monosomy X and normal male or female cell lines. Array-based models of X chromosome structure were compatible with karyotypes in 104 of 116 comparable cases (90%). We found that the SNP array data did not detect X-autosome translocations (three cases) but did identify two derivative Y chromosomes and 13 large copy-number variants that were not detected by karyotyping.Conclusion:Our study is the first systematic comparison between the two methods and supports the utility of SNP array genotyping to address clinical and research questions in Turner syndrome.Genet Med 16 1, 53–59.

Congenital aortic valve fusion is associated with aortic dilation, aneurysm, and rupture in girls and women with Turner syndrome. Our objective was to characterize aortic valve structure in subjects with Turner syndrome and to determine the prevalence of aortic dilation and valve dysfunction associated with different types of aortic valves.

Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.

AbstractBackground:Fetuses with prenatal diagnoses of 45,X Turner syndrome (TS) and abnormal fetal ultrasounds have poor prognoses for survival, but with modern medical management, those that do survive to birth may have good clinical outcomes. Fetuses with incidental diagnoses of mosaicism for 45,X associated with normal ultrasounds have a high survival rate and may have no or only mild features of TS. Current Guidelines:At present, appropriate treatment for girls with TS may include growth-promoting therapy and pubertal induction with the dual aims of optimizing adult height and facilitating psychosocial adjustment. Current recommendations advocate mimicking normal physiology as much as possible, with use of microdose estradiol to initiate puberty. Healthcare providers should play a role in helping girls psychosocially adapt to ovarian failure. We now recognize there is an unacceptably high rate of premature mortality in adults with TS, mainly because of complications from congenital heart disease. Cardiac magnetic resonance imaging is recommended to screen for individuals at high risk for serious complications.Copyright © 2009 S. Karger AG, Basel

Turner syndrome is a relatively common disorder of female development with cardinal features of short stature and congenital cardiovascular defects (CHD). Turner syndrome is the most common established cause of aortic dissection in young women, but has received little attention outside pediatric literature. This review focuses on emerging knowledge of the characteristics of aortic disease in Turner syndrome in comparison with Marfan-like syndromes and isolated aortic valve disease.

Turner syndrome (TS), or monosomy X, occurs in ?12000 live born females. Intelligence is normal and short stature is the most obvious and consistent feature of the syndrome. Congenital cardiovascular disease affects ?50% of individuals and is the major cause of premature mortality in adults. Unfortunately, this most important aspect of the syndrome has received little attention outside of pediatric medicine, and adult cardiological follow-up is seriously lacking. This review describes the spectrum of cardiovascular defects with particular attention to identifying risk factors for aortic dissectionrupture. X-chromosome genetic pathways implicated in Turner cardiovascular disease, including premature coronary artery disease, are discussed. Recent guidelines for diagnosis and treatment of girls and women with TS are reviewed.

Turner syndrome is the most common sex chromosome disorder in females, and is caused by a total or partial deletion of one X chromosome. The purpose of this study was to describe the auditory phenotype in a large group of individuals with Turner Syndrome, with analysis focusing on hearing loss and age, as well as the phenotypic relationship to karyotype variation.

Menopause is associated with increased visceral adiposity and reduced insulin sensitivity. It remains unclear whether these changes are due primarily to ovarian failure or aging. The aim of this study was to clarify the impact of ovarian failure on body composition and insulin sensitivity in young women.

Turner syndrome (TS) is a sex chromosome condition that occurs in approximately 1/2,500 live female births. Despite the prevalence of this chromosomal condition, the challenges these women face throughout their lives are not fully understood. This qualitative research study aimed to characterize the subjective experiences of individuals with TS throughout their lifespan, to investigate their concerns and obstacles, and to offer insight into the strengths and weaknesses of health care delivery, as they perceived them. Ninety‐seven girls and women with TS and 21 parents consented to participate in this interview study. Interviews were semi‐structured and open‐ended in design. Questions sought to elicit responses relating to existing concerns associated with their condition and positive and negative health care experiences. Participants were divided into four age categories (childhood, adolescence, adulthood, and mature adulthood) to facilitate a comparative analysis across the age spectrum. Regardless of age, infertility was the most frequently cited concern followed closely by short stature. Sexual development and function and general health were also viewed as challenges by a number of participants in each age group. Although the relative weight of these four concerns tended to shift based upon the individual's age and life experiences, all four issues remained significant throughout the lifespan. Enhanced awareness of the evolving physical and psychological challenges faced by girls and women with TS may help health care providers (HCPs) improve the quality of life for these individuals. Published 2005 Wiley‐Liss, Inc.

Microscopy of sectioned neonatal mouse ovaries established the predominance of primordial follicles in Day 3 samples and the predominance of primary follicles by Day 8. To identify genetic determinants of the primordial to primary follicle transition, the transcriptome of Day 1 or Day 3 mouse ovaries was contrasted by differential display with that of Day 8 ovaries. This manuscript examines one of the up-regulated genes, the novel Nalp14gene, whose transcript displayed 18- and 127-fold increments from Day 1 to Days 3 and 8, respectively. First noted by in situ hybridization in oocytes encased by primary follicles, Nalp14transcripts were continuously expressed through the preovulatory stage. The transcripts declined when meiotic maturation resumed, and they were markedly diminished by the 2-cell embryo stage. The corresponding 3281-base pair, full-length cDNA coded for a 993 residue/104.6-kDa germ cell-specific protein. A member of the multifunctional NACHT NTPase family, the NALP14 protein featured 14 iterations of the leucine-rich-repeat domain, a region implicated in protein-protein interaction. Protein BLAST analysis of the NALP14 sequence revealed 2 previously reported germ cell-specific homologs (i.e., MATER [Maternal Antigen That Embryos Require], RNH2 [RiboNuclease/Angiogenin Inhibitor 2], and NALP4c). The structural attributes, expression pattern, and cellular localization of MATER and RNH2 largely conformed to those reported for NALP14.

Failure to detect co-expression of estrogen receptor-alpha (ERα) and proliferation 'markers' such as Ki67 in human mammary epithelium led to the view that estrogen acts indirectly to stimulate mammary epithelial proliferation. The mitotic index was so low in prior studies, however, that transient co-expression of ERα and Ki67 during the cell cycle could have been below detection limits. Immunohistochemistry was used on mammary tissue sections from estrogen treated rhesus monkeys to investigate co-expression of ERα and the proliferation antigen Ki67. Using the same methods, we investigated the cell localization of proteins involved in estrogen-induced proliferation, including cyclin D1, stromal cell-derived factor (SDF)-1, and MYC. ERα was co-expressed with the proliferation marker Ki67 as well as with SDF-1, MYC and cyclin D1 in mammary epithelial cells from estrogen-treated monkeys. ERα is expressed in proliferating mammary epithelial cells together with the estrogen-induced proteins MYC, cyclin D1 and SDF-1, consistent with a direct mitogenic action by estrogen in primate mammary epithelium.

We previously reported the discovery of a novel mammalian H1 linker histone termed H1FOO (formerly H1OO), a replacement H1, the expression of which is restricted to the growing/maturing oocyte and to the zygote. The significance of this pre-embryonic H1 draws on its substantial orthologous conservation, singular structural attributes, selectivity for the germ cell lineage, prolonged nucleosomal residence, and apparent predominance among germ cell H1s. Herein, we report that the intronic, single-copy, five-exon (≥5301 base pair) H1foogene maps to chromosome 6 and that the corresponding primary H1footranscript gives rise to two distinct, alternatively spliced mRNA species (H1fooαand H1fooβ). The expression of the oocytic H1FOOtranscript and protein proved temporally coupled to the recruitment of resting primordial follicles into a developing primary follicular cohort and thus to the critical transition marking the onset of oocytic growth. The corresponding potential protein isoforms (H1FOOαand H1FOOβ), both nuclear localization sequence-endowed but export consensus sequence-free and possessing a significant net positive charge, localized primarily to perinucleolar heterochromatin in the oocytic germinal vesicle. Further investigation will be required to define the functional role of the H1FOO protein in the ordering of the chromatin of early mammalian development as well as its potential role in defining the primordial-to-primary follicle transition.

There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer.

It has been suggested that locally produced insulin-like growth factor binding protein 4 (IGFBP4) inhibits ovarian follicular growth and ovulation by interfering with IGF action. According to this hypothesis, IGFBP4-expressing follicles should demonstrate atresia, whereas healthy dominant follicles should be devoid of IGFBP4. Alternatively, according to this view, there could be constitutive expression of the inhibitory IGFBP4 but selective expression of an IGFBP4 protease in dominant follicles, allowing the follicle to mature and ovulate because of degradation of the binding protein. To examine these views concerning the role of IGFBP4 in primate follicular selection, we analyzed cellular patterns of IGFs 1 and 2, IGFBP4, and the IGFBP4 protease (pregnancy-associated plasma protein A [PAPP-A]) mRNA expression in ovaries from late follicular phase rhesus monkeys using in situ hybridization. The IGF1 mRNA was not detected, but the IGF2 mRNA was abundant in theca interna and externa of all antral follicles and was present in the granulosa of large preovulatory and ovulatory follicles. The IGFBP4 mRNA was selectively expressed by LH receptor (LHR) mRNA-positive theca interna cells of healthy antral follicles (defined by aromatase and gonadotropin receptor expression) and by LHR-expressing granulosa cells found only in large preovulatory and ovulatory follicles (defined by size and aromatase expression). The PAPP-A mRNA was abundant in granulosa cells of most follicles without obvious relation to IGFBP4 expression. Ovarian IGFBP4 mRNA levels were markedly increased after treatment with the LH analog, hCG, whereas IGF2 and PAPP-A mRNAs were not significantly altered. In summary, IGFBP4 expression appears to be associated with follicular selection, not with atresia, in the monkey ovary. The IGFBP4 is consistently expressed in healthy theca interna and in luteinized granulosa cells, likely under LH regulation. The IGFBP4 protease, PAPP-A, is widely expressed without apparent selectivity for IGFBP4-expressing follicles or for dominant follicles. These observations suggest that IGFBP4 or an IGFBP4 proteolytic product may be involved with LH-induced steroidogenesis and/or luteinization rather than with inhibition of follicular growth.

BACKGROUND: Mater is a maternal effect gene required for early embryonic development in mice, and its protein serves as an autoantigen in a mouse model of autoimmune premature ovarian failure. METHODS: Human MATER cDNA was cloned by PCR techniques. The mRNA and protein were determined using hybridization and immunodetection respectively. The cDNA and protein sequences were analysed using bioinformatics software. RESULTS: Human MATER gene spans a ~63 kbp DNA at chromosome 19 and is composed of 15 exons and 14 introns. Expression of its mRNA (~4.2 kb) is restricted to the oocytes. Human MATER cDNA (3885 nt) shows an open reading frame (3600 nt) encoding a polypeptide chain composed of 1200 residues with a predicted molecular mass of 134 236 Da. MATER protein (~134 kDa) was detected in human oocytes. The human and mouse cDNA share 67% homology while their deduced polypeptide chains have 53% identity of amino acids. Also, their protein structures have a number of similar features. CONCLUSIONS: The human MATER and mouse Mater genes and proteins are conserved. Characterization of the human MATER and its protein provides a basis for investigating their clinical implications in autoimmune premature ovarian failure and infertility in women.

Mater is a maternal effect gene required for early embryonic development in mice, and its protein serves as an autoantigen in a mouse model of autoimmune premature ovarian failure.

Insulin-like growth factor-I (IGF-I) expression is highly correlated with ovarian follicular growth and granulosa cell proliferation in both pre-pubertal and mature murine ovaries. Igf1gene deleted mice are infertile, with ovarian follicles arrested at an early stage of development. To elucidate the cause of follicular dysfunction in Igf1null mice, this study compared granulosa cell proliferation at baseline and in response to exogenous oestradiol (E2) in prepubertalIgf1null and wild-type (WT) littermate mice. The basal granulosa cell mitotic index was 3.8±0.48 in WT and 1.3±0.7 in Igf1null mice (P=0.03). After E2 treatment, WT granulosa mitotic index was 12.7±0.0 vs 5.5±0.8 for Igf1null mice (P<0.001). Granulosal BRDU incorporation was also significantly reduced as were cyclin D2 and B1 immunoreactivities in Igf1null compared with WT mice. The incidence of apoptosis was not increased in Igf1null follicles, although BAX immunostaining was increased. These data suggest that IGF1 is essential for normal basal and oestrogen-induced granulosa cell proliferation and follicular growth.

Estrogen has many positive effects on neural tissue in experimental model systems, including stimulation of neurite growth and neurotransmitter synthesis and protection against diverse types of neural injury. In humans, estrogen treatment is reputed to protect against Alzheimer's disease. To investigate potential mediators of estrogen's action and determine whether selective estrogen receptor modulators (SERMs) such as tamoxifen have estrogen‐like effects in the primate brain, we evaluated the expression of glucose transporters and insulin‐like growth factor 1 (IGF1) and its receptor in the frontal cortex of ovariectomized rhesus monkeys. We treated one group for 3 days with vehicle, another with 17β estradiol (E2), and a third with tamoxifen. The expression of facilitative glucose transporters (Gluts) 1, 3, and 4 was investigated using in situhybridization, immunohistochemistry, and immunoblot analysis. Gluts 3 and 4 were concentrated in cortical neurons and Glut1 in capillaries and glial cells. E2 treatment induced two‐ to fourfold increases in Glut3 and Glut4 mRNA levels and lesser but significant increases in Glut3 and 4 protein levels. E2 treatment induced an ~70% increase in parenchymal Glut1 mRNA levels, but did not appreciably affect vascular Glut1 gene expression. IGF1 and IGF1 receptor mRNAs were concentrated in cortical neurons in a distribution similar to Gluts 3 and 4. IGF1 mRNA levels were significantly increased in E2‐treated animals but IGF1 receptor mRNA levels were not altered by hormone treatment. Tamoxifen increased cerebral cortical Glut3 and 4 mRNA levels, but did not affect Glut1, IGF1, or IGF1 receptor expression. This study provides novel data showing that Gluts 3 and 4 and IGF1 are coexpressed by primate cerebral cortical neurons, where their expression is enhanced by estrogen. These findings suggest that up‐regulation of glucose transporter and IGF1 expression may contribute to estrogen's salutary effects on neural tissue. Tamoxifen, an antiestrogen at the breast, is shown to have estrogenlike effects on higher brain centers in the monkey, suggesting that some SERMs may share estrogen's neuroprotective potential for menopausal women.— Cheng, C., Cohen, M., Wang, J., Bondy, C. Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex. FASEB J.15, 907–915 (2001)

This study investigated the effect of sex steroids and tamoxifen on primate mammary epithelial proliferation and steroid receptor gene expression. Ovariectomized rhesus monkeys were treated with placebo, 17β estradiol (E2) alone or in combination with progesterone (E2/P) or testosterone (E2/T), or tamoxifen for 3 days. E2 alone increased mammary epithelial proliferation by ~sixfold (P<0.0001) and increased mammary epithelial estrogen receptor (ERα) mRNA expression by ~50% (P<0.0001; ERβ mRNA was not detected in the primate mammary gland). Progesterone did not alter E2's proliferative effects, but testosterone reduced E2‐induced proliferation by —40% (P< 0.002) and entirely abolished E2‐induced augmentation of ERα expression. Tamoxifen had a significant agonist effect in the ovariectomized monkey, producing a ~threefold increase in mammary epithelial proliferation (P<0.01), but tamoxifen also reduced ERαexpression below placebo level. Androgen receptor (AR) mRNA was detected in mammary epithelium by in situhybridization. AR mRNA levels were not altered by E2 alone but were significantly reduced by E2/T and tamoxifen treatment. Because combined E2/T and tamoxifen had similar effects on mammary epithelium, we investigated the regulation of known sex steroid‐responsive mRNAs in the primate mammary epithelium. E2 alone had no effect on apolipoprotein D (ApoD) or IGF binding protein 5 (IGFBP5) expression, but E2/T and tamoxifen treatment groups both demonstrated identical alterations in these mRNAs (ApoD was decreased and IGFBP5 was increased). These observations showing androgen‐induced down‐regulation of mammary epithelial proliferation and ER expression suggest that combined estrogen/androgen hormone replacement therapy might reduce the risk of breast cancer associated with estrogen replacement. In addition, these novel findings on tamoxifen's androgen‐like effects on primate mammary epithelial sex steroid receptor expression suggest that tamoxifen's protective action on mammary gland may involve androgenic effects.— Zhou, J., Ng, S., Adesanya‐Famuiya, O., Anderson, K., Bondy, C. A. Testosterone inhibits estrogen‐induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J.14, 1725–1730 (2000)

In the study reported here, we investigated the effect of androgens on recruitment of resting, primordial follicles into the actively growing pool. Healthy, random-cycling female rhesus monkeys were treated with testosterone, dihydrotestosterone (DHT), or vehicle for 3–10 days, after which ovaries were collected for histological analysis. The first stage of follicle growth is the formation of the primary follicle, consisting of an oocyte surrounded by a single layer of cuboidal granulosa cells. The number of primary follicles was significantly increased over time in testosterone-treated animals. In situ hybridization showed that androgen treatment resulted in an increase to 3-fold in insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes. DHT effects were comparable to those of testosterone, showing that these are androgen receptor-mediated phenomena. These data show that androgens promote initiation of primordial follicle growth and implicate oocyte-derived IGF-I in this activation process.

Longitudinal bone growth, and hence stature, are functions of growth plate chondrocyte proliferation and hypertrophy. Insulin‐like growth factor 1 (Igf1) is reputed to augment longitudinal bone growth by stimulating growth plate chondrocyte proliferation. In this study, however, we demonstrate that chondrocyte numbers and proliferation are normal in Igf1null mice despite a 35% reduction in the rate of long bone growth. Igf1null hypertrophic chondrocytes differentiate normally in terms of expressing specialized proteins such as collagen X and alkaline phosphatase, but are smaller than wild‐type at all levels of the hypertrophic zone. The terminal hypertrophic chondrocytes, which form the scaffold on which long bone growth extends, are reduced in linear dimension by 30% in Igf1null mice, accounting for most of their decreased longitudinal growth. The expression of the insulin‐sensitive glucose transporter, GLUT4, is significantly decreased and the insulin‐regulated enzyme glycogen synthase kinase 3β (GSK3) is hypo‐phosphorylated in Igf1null chondrocytes. Glycogen levels were significantly decreased and ribosomal RNA levels were reduced by almost 75% in Igf1null chondrocytes. These data suggest that Igf1 promotes longitudinal bone growth by ‘insulin‐like’ anabolic actions which augment chondrocyte hypertrophy.— Wang, J., Zhou, J., Bondy, C. A. Igf1 promotes longitudinal bone growth by insulin‐like actions augmenting chondrocyte hypertrophy. FASEB J. 13, 1985–1990 (1999)

To characterize the cellular sites and hormonal regulation of uterine androgen receptor gene expression in the monkey.

The regulation of insulin-like growth factor-I (IGF-I) and related peptides during motoneuron regeneration was examined in the facial nerve following facial nerve transection. One to 39 days after axotomy, the mRNAs and peptides of IGF-I, type-I insulin-like growth factor receptor (IGFR), insulin-like growth factor binding proteins 1-5 (IGFBP-1-5), and glial fibrillary acidic protein (GFAP) were assayed in brain stem sections by in situhybridization and immunohistochemistry. Relative mRNA levels of IGF-I, IGFR, IGFBP-2, and GFAP in the ipsilateral facial nucleus were highest 4-7 days after transection and declined thereafter. Double immunostaining experiments showed that both IGF-I and IGFBP-2 were localized in GFAP-positive astrocytic processes, many of which were perineuronal. Peak staining intensity was found 4-7 days after transection and immunoreactivity still was present after 21-35 days. IGFR mRNA was found in some regenerating neurons; however, IGFR peptide was not detected in these neurons or in any other cells in the facial nucleus. Our findings suggest that astrocytic production of IGF-I and IGFBP-2 may accompany regeneration of neurons undergoing retrograde changes induced by axotomy.

In situ hybridization was used to map insulin-like growth factor (IGF) system gene expression in ovaries from an anencephalic infant and several young women. Growing oocytes in infant and mature ovaries expressed transcripts for IGF-I and IGF-II, respectively, and all oocytes expressed abundant IGF-I receptor transcripts, raising the possibility of autocrine IGF function in oocyte maturation. IGF-I mRNA was not detected in the mature ovary, but IGF-II mRNA was localized in follicular blood vessels and in granulosa cells (GC) and was especially abundant in the GC of atretic as opposed to young follicles. IGF-I receptor mRNA was abundant in GC of antral and atretic follicles, and was expressed at low levels in the thecal and interstitial compartments. IGF-binding protein (IGFBP) 1 mRNA was not detected, but IGFBPs 2–5 mRNAs each demonstrated a unique ovarian distribution. IGFBP2 mRNA was abundant in GC and thecal cells at all stages of development. IGFBP3 mRNA was detected only in the endothelium of ovarian blood vessels. IGFBP4 mRNA was also localized in endothelium, but in addition was present in stromal connective tissue and in GC of the one Graafian follicle detected in this study, but not consistently in atretic follicles. IGFBP5 mRNA was expressed by luminal or cumulus GC in virtually all follicles and was highly abundant in stromal interstitial cells of the mature ovary.Insofar as our limited sample allows developmental analysis, gene expression for the IGF-I receptor and IGFII in GC and for IGFBP5 in interstitial cells appeared to be developmentally or hormonally regulated, as their mRNAs were significantly more abundant in mature ovaries than in ovaries from an anencephalic infant. GC gene expression for IGFBP2 and IGFBP5, in contrast, appears to be constitutive. In summary, the intensity, compartmentalization, and developmental regulation of IGF system gene expression in the human ovary support the view that IGFs play an important and complex role in ovarian physiology. The striking evidence of IGF ligand and receptor gene expression in human oocytes suggests that IGFs have a role in growth from the earliest moments in development.

To study the cellular patterns of gene expression for insulin-like growth factors I and II (IGF-I and IGF-II), their receptors and specific high-affinity binding proteins (IGFBPs) in the human testis.

In situ hybridization was used to evaluate EGR 1 (NGFI-A) gene expression in the rat brain following focal ischemia caused by middle cerebral artery occlusion (MCAO). At 1 h postlesion (PL), there was a striking increase in EGR1 mRNA in neurons throughout the ipsilateral cortex, with a lesser increase occurring in a patchy distribution in the contralateral cortex. The ipsilateral hemispheric reaction was maximal at 1 h PL, slightly reduced after 3 and 5 h, and resolved after 24 h. Sham surgery limited to meningeal disruption resulted in a similar though less intense induction of EGR1 gene expression in the ipsilateral cortex only. After MCAO but not sham surgery, there was a vivid induction of EGR1 mRNA in the ipsilateral hippocampal formation (CA3 > CA1 > DG). While the hemispheric cortical and hippocampal increases in EGR1 expression had normalized at 24 h PL, intense EGR1 gene expression was seen in neurons of the infarct rim for several days. EGR1 mRNA was also increased in reactive glial cells in the infarct zone from 1 to 9 days after the infarct. In summary, successive waves of transient EGR1 gene expression mark the brain's response to ischemic injury: these include the widespread, unilateral cortical induction associated with the phenomenon of spreading depression, an apparent trans-synaptic activation of contralateral cortex and ipsilateral hippocampal formation—and more sustained responses in injured but surviving neurons and reactive glial cells. The extensive EGR1 expression demonstrated in this experimental paradigm suggests that EGR1 is a fundamental component of neural cell activation. Copyright 1993, 1999 Academic Press

1. Quantitative in situ hybridization histochemistry was used to examine the regulation of aldose reductase messenger RNA in the rat lens after the induction of diabetes mellitus or after feeding a 50% (w/w) galactose diet. 2. Although increased staining for aldose reductase in the lens epithelium has previously been observed by immunohistochemistry after 3 weeks of diabetes or after 7 days of galactose feeding, we have not been able to detect any increase in the amount of aldose reductase messenger RNA in these cells as compared with controls (113 ± 7%, 105 ± 9%, 100 ±7%, respectively) at these time points (P >0.05). 3. After 15 days of galactose feeding, however, there was a significant increase of 140% (± 12%) in the amount of aldose reductase messenger RNA in the lens epithelial cells as compared with controls (P = < 0.001). 4. These results demonstrate that increased availability of galactose, a high-affinity substrate for the enzyme, leads to increased aldose reductase messenger RNA, which suggests a role for aldose reductase in sugar metabolism in the lens.

To assess the distribution of insulin-like growth-factor-related proteins during autoimmune CNS demyelination and remyelination, experimental autoimmune encephalomyelitis was produced by injecting Lewis rats with an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. Tail weakness appeared at 10-12 days and was followed by hind and forelimb weakness. Paraplegia and incontinence were observed in some animals. From 8-40 days postinoculation (dpi), spinal cord sections were used to correlate lesion location and severity with mRNA distributions of insulin-like growth factor I (IGF-I), IGF-binding protein 2 (IGFBP-2), IGF-I-receptor (IGFR-I), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP). These were determined semiquantitatively by in situ hybridization. Fourteen dpi, there were inflammatory infiltrates and demyelination in both white matter (WM) and grey matter (GM). IGF-I and GFAP mRNAs were increased in these lesions and transcripts encoding myelin basic protein (MBP) were greatly reduced. Large lesions with extensive demyelination were evident in both WM and GM when mRNA levels of GFAP and IGF-I peaked 26 dpi. MBP mRNA levels began increasing 21 dpi and peaked 26 dpi, when a few thin regenerating myelin sheaths were found morphologically. Astrocytes, identified by their morphology and GFAP immunoreactivity, expressed very low levels of IGFBP-2 mRNA and peptide in normal controls; their levels were significantly higher 14 dpi, peaked 26 dpi, and then gradually decreased. Some neurons, as well as oligodendroglia in areas undergoing remyelination, expressed IGFR-I. Although levels of IGF-I, IGFBP-2, and GFAP mRNAs were highest in lesion areas, levels were also elevated around lesions and in some normal-appearing areas of WM and GM 14-40 dpi. The gene expression of both IGF-I and IGFBP-2 by hypertrophic GFAP-positive astrocytes was demonstrated 14-40 dpi by combined in situ hybridization and immunocytochemistry as well as by double immunostaining. Coexpression of IGF-I and IGFBP-2 in the same astrocyte was a frequent finding. Relative increases in both IGF-I, GFAP, IGFBP-2, IGFR-I, and MBP mRNAs peaked at about the same time. This suggests that during lesion progression and recovery, astrocytic expression of IGF-I-related peptides may reduce immunemediated myelin injury. We also suggest that astrocytic IGFBP-2 in lesions may help target IGF-I to IGFR-I-expressing oligodendrocytes and promote remyelination of demyelinated axons. Copyright 1994, 1999 Academic Press

The decline of growth hormone (GH) and insulin-like growth factor I (ICF-I) production during aging has been likened to the decrease in gonadal steroids in menopause. The repletion of GH/IGF-I levels in aging individuals is suggested to restore the lean tissue anabolism characteristic of youth1. In addition to anabolic effects on musculoskeletal tissues, GH also stimulates mammary glandular growth in some species2–4, although its effects on primate mammary growth remain unclear5. Some clinical observations implicate GH in human mammary growth, for example, gynecomastia occurs in some children treated with GH (ref. 6), and tall stature and acromegaly are associated with an increased incidence of breast cancer7,8. To investigate the effects of GH/IGF-I augmentation on mammary tissue in a model relevant to aging humans, we treated aged female rhesus monkeys with GH, IGF-I, GH + IGF-I or saline diluent for 7 weeks. IGF-I treatment was associated with a twofold increase, GH with a three- to fourfold increase, and GH + IGF-I with a four- to fivefold increase in mammary glandular size and epithelial proliferation index. These mitogenic effects were directly correlated with circulating GH and IGF-I levels, suggesting that either GH or its downstream effector IGF-I stimulates primate mammary epithelial proliferation.

1.Coexisting with oxytocin or vasopressin in the cell bodies and nerve terminals of the hypothalamic-neurohypophysial system are smaller amounts of other peptides. For a number of these “copeptides” there is strong evidence of corelease with the major magnocellular hormones. Guided by the location of their specific receptors we have studied the effects of three copeptides, dynorphin, cholecystokinin (CCK), and corticotropin releasing hormone (CRH), on the secretion of oxytocin and vasopressin from isolated rat neural lobe or neurointermediate lobe preparationsin vitro.2.Dynorphin is coreleased with vasopression from neural lobe nerve terminals and acts on neural lobe kappa-opiate receptors to inhibit the electrically stimulated secretion of oxytocin. Naloxone augments oxytocin release from the neural lobe in a manner directly proportional to the amount of vasopressin (and presumably dynorphin) released.3.Cholecystokinin, coreleased with oxytocin by neural lobe terminals, has been shown to have high-affinity receptors located in the NL and to stimulate secretion of both oxytocin and vasopressin. CCK's secretagogue effect was independent of electrical stimulation and extracellular Ca2+ and was blocked by an inhibitor of protein kinase C.4.CRH, coreleased with OT from the neural lobe, has receptors in the intermediate lobe of the pituitary, but not in the neural lobe itself. CRH stimulates the secretion of oxytocin and vasopressin from combined neurointermediate lobes but not from isolated neural lobes. Intermediate lobe peptides, alpha and gamma melanocyte stimulating hormone, induced secretion of oxytocin and vasopressin from isolated neural lobes. Their effect was, like that of CCK, independent of electrical stimulation and extracellular Ca2+ and blocked by an inhibitor of protein kinase C.5.Among the CRH-producing parvocellular neurons of the paraventricular nucleus, in the normal rat, approximately half also produce and store vasopressin. After removal of glucocorticoid influence by adrenalectomy, virtually all of the CRH neurons contain vasopressin.6.The two subtypes of CRH neurosecretory cells found in the normal rat possess different topographical distributions in the paraventricular nucleus, suggesting the possibility of differential innervation. Stress selectively activates the vasopression containing subpopulation of CRH neurons, indicating that there are separate channels of regulatory input controlling the two components of the parvocellular CRH neurosecretory system.

Turner syndrome is the most common chromosomal abnormality in female subjects, affecting 1 in 2000 live births. The condition is associated with a generalized vasculopathy as well as congenital cardiac and other defects. We report aneurysmal dilation of medium caliber arteries involving the celiac axis and coronary vessels in two women with Turner syndrome.