Gene expression profiles differ markedly in mouse strains that are (or are not) susceptible to hyperthyroidism induced using thyrotropin receptor-expressing adenovirus.

BALB/c mice are susceptible and C57BL/6 mice are resistant to Graves' hyperthyroidism induced by immunization with adenovirus encoding the thyrotropin receptor (TSHR) A-subunit. Both strains develop comparable levels of TSHR antibodies, but potent TSH blocking antibody activity in C57BL/6 mice likely blocks development of hyperthyroidism. We used microarrays to compare gene expression in spleens of mice immunized with A-subunit adenovirus (TSHR-Ad) or control adenovirus (Con-Ad).

Early multipotential pituitary focal hyperplasia in the alpha-subunit of glycoprotein hormone-driven pituitary tumor-transforming gene transgenic mice.

Pituitary tumor-transforming gene (PTTG), a securin protein isolated from pituitary tumor cell lines, is highly expressed in invasive tumors and exhibits characteristics of a transforming gene. To determine the role of PTTG in pituitary tumorigenesis, transgenic human PTTG1 was targeted to the mouse pituitary using the alpha-subunit of glycoprotein hormone. Males showed plurihormonal focal pituitary transgene expression with LH-, TSH-, and, unexpectedly, also GH-cell focal hyperplasia and adenoma, associated with increased serum LH, GH, testosterone, and/or IGF-I levels.

Cell-specific pituitary gene expression profiles after treatment with leukemia inhibitory factor reveal novel modulators for proopiomelanocortin expression.

Leukemia inhibitory factor (LIF) mediates the hypothalamo-pituitary-adrenal stress response. Transgenic mice overexpressing LIF in the developing pituitary have altered pituitary differentiation with expansion of corticotropes, maintenance of Rathke's cleft cysts, and suppression of all other pituitary cell types. Affymetrix GeneChips were used to identify modulators of LIF effects in corticotrope (AtT-20) and somatolactotrope (GH(3)) cells.

Targeted overexpression of luteinizing hormone causes ovary-dependent functional adenomas restricted to cells of the Pit-1 lineage.

The majority of pituitary adenomas in humans are nonmetastasizing, monoclonal neoplasms that occur in approximately 20% of the general population. Their development has been linked to a combination of extrinsic factors and intrinsic defects. We now demonstrate with transgenic mice that targeted and chronic overexpression of LH causes ovarian hyperstimulation and subsequent hyperproliferation of Pit-1-positive cells that culminates in the appearance of functional pituitary adenomas ranging from focal to multifocal expansion of lactotropes, somatotropes, and thyrotropes.

Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background.

When the pituitary or hypothalamus becomes resistant to steroid negative feedback, a vicious cycle ensues, resulting in chronic hypersecretion of luteinizing hormone (LH) from the pituitary and steroids from the ovaries. In women, LH hypersecretion is implicated in infertility, miscarriages, and development of granulosa cell tumors. Progress in defining the underlying mechanisms of LH toxicity, however, has been limited by the lack of well-defined animal models.

Two uncompetitive, activated, and transport sites of the Na+/H+ exchanger for pH regulation in perfused rat kidney.

The purpose of this study is to assess the effect of an apparent alteration in intracellular pH and the effect of amiloride on the activity of the Na+/H+ antiporter in perfused rat kidney. Rat kidney-Na+ retention was determined using tracer 22Na in perfusate composed of HCl-glycine buffer (pH 3.80 to pH 5.

Chronic hypersecretion of luteinizing hormone in transgenic mice selectively alters responsiveness of the alpha-subunit gene to gonadotropin-releasing hormone and estrogens.

Steroid hormones can act either at the level of the hypothalamus or the pituitary to regulate gonadotropin subunit gene expression. However, their exact site of action remains controversial. Using the bovine gonadotropin alpha-subunit promoter linked to an expression cassette encoding the beta-subunit of LH, we have developed a transgenic mouse model where hypersecretion of LH occurs despite the presence of elevated ovarian steroids.

Chronically elevated luteinizing hormone depletes primordial follicles in the mouse ovary.

A few years before reproductive senescence, primordial follicles are depleted from the ovary at a dramatically accelerated rate. It has been proposed that this depletion is due to transient increases in gonadotropin levels. To test this hypothesis, we used mice that produce chronically elevated levels of serum LH via expression of an LHbeta subunit transgene.

Characterization of the equine glycoprotein hormone alpha-subunit gene reveals divergence in the mechanism of pituitary and placental expression.

The equine glycoprotein hormone alpha-subunit gene is expressed in both pituitary and placenta, unlike that of all other nonprimate mammals studied, in which expression is limited to pituitary. Previous studies of the 5'-flanking region of the equine alpha-subunit promoter have revealed unique characteristics as well as similarities with the human alpha-subunit promoter, which demonstrates a similar pattern of tissue-specific expression. We have cloned and sequenced the equine alpha-subunit gene and have used tissue culture systems and transgenic mice to characterize its expression.

Enhanced production of human immunodeficiency virus type 1 by in vitro-infected alveolar macrophages from otherwise healthy cigarette smokers.

Since cellular activation is required for replication of human immunodeficiency virus type 1 (HIV-1), the capacity of alveolar macrophages (AM) from smokers, which are relatively activated, and nonsmokers to support the production of HIV-1JR-FL was examined. Peak HIV-1 p24 antigen level in culture supernatants of infected AM from 13 smokers was significantly higher than that of 13 nonsmokers: 31,394 +/- 8295 versus 7037 +/- 2550 pg/mL (mean +/- SE; P < .002).

Do GnRH neurons express the gene for the NMDA receptor?

Previous studies have revealed that in several animal models, N-methyl-D,L-Aspartate (NMA) stimulates LH secretion by acting at a suprapituitary site. In addition, NMDA receptor antagonists appear to block GnRH neuronal activation on the afternoon of proestrous as evidenced by the lack of c-Fos expression in the neurons and by the absence of an ovulatory LH surge. However, administration of NMA does not induce c-Fos or c-Jun expression in GnRH neurons.

The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus.

The nuclear receptor steroidogenic factor 1 (SF-1) regulates the biosynthesis of the two essential mediators of male sexual differentiation, androgens and Müllerian-inhibiting substance, and is required for adrenal and gonadal development and gonadotropin expression. SF-1 is also expressed in the embryonic ventral diencephalon, subsequently localizing to the ventromedial hypothalamic nucleus, a region important for reproductive behavior. Mice lacking SF-1 secondary to targeted disruption of the Ftz-F1 gene had normal numbers and location of GnRH neurons but exhibited grossly impaired ventromedial hypothalamic nucleus structure.

The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis.

Steroidogenic factor 1 (SF-1), an orphan nuclear receptor, regulates the enzymes that produce sex steroids, and disruption of the Ftz-F1 gene encoding SF-1 precludes adrenal and gonadal development. We now study the role of SF-1 at other levels of the hypothalamic/pituitary/gonadal axis. In Ftz-F1-disrupted mice, immunohistochemical analyses with antibodies against pituitary trophic hormones showed a selective loss of gonadotrope-specific markers, supporting the role of SF-1 in gonadotrope function.

Lactation-induced deficits in NMDA receptor-mediated cortical and hippocampal activation: changes in NMDA receptor gene expression and brainstem activation.

During lactation, there is an inhibition of cortical and hippocampal activation in response to N-methyl-D,L-aspartate (NMA), but not kainate, as assessed by induction of c-Fos expression. To study whether changes in NMDA receptor function may account for this inhibition, NMDA receptor subunit (NMDAR1) mRNA levels were measured by both Northern analysis and in situ hybridization. Analysis of NMDAR1 gene expression by Northern blot analysis did not reveal significant differences between cycling and lactating rats.

Use of Fos-related antigens (FRAs) as markers of neuronal activity: FRA changes in dopamine neurons during proestrus, pregnancy and lactation.

This manuscript describes the use of staining of Fos-related antigens (FRAs) as markers for changes in neuronal activity. The model system consisted of the tuberoinfundibular dopamine (TIDA) neurons located in the arcuate nucleus of the hypothalamus. Under normal conditions, these neurons are devoid of c-Fos staining even though the neurons are tonically active and can express FRAs.

Effects of N-methyl-D-aspartate receptor activation on cFos expression in luteinizing hormone-releasing hormone neurons in female rats.

N-Methyl-D,L-aspartic acid (NMA), an agonist of N-methyl-D-aspartate (NMDA) excitatory amino acid receptors, stimulates the secretion of LH by increasing the release of LHRH. During proestrus, LHRH neurons express cFos in association with the LH surge. To determine the involvement of NMDA receptors in the activation of LHRH neurons on proestrus, we treated animals with an NMDA receptor blocker, MK-801.

Altered luteinizing hormone and prolactin responses to excitatory amino acids during lactation.

We have used excitatory amino acids as tools to elucidate changes in hypothalamic function associated with lactation, focusing on the regulation of luteinizing hormone (LH) and prolactin secretion. In these studies, we have compared the responsiveness to NMA (N-methyl-D,L-aspartate), an agonist for the N-methyl-D-aspartate (NMDA) receptor, with that of kainate, an agonist for another type of glutamate receptor, the kainate receptor. To address the issue of the permeability of the blood-brain barrier to either NMA or kainate, systemic and central administration of the drugs were compared.

Cortical refractoriness to N-methyl-D,L-aspartic acid (NMA) stimulation in the lactating rat: recovery after pup removal and blockade of progesterone receptors.

We have previously reported that lactating rats, unlike cycling rats, are refractory to N-methyl-D,L-aspartic acid (NMA), but not kainate, in terms of behavioral responses and activation of cFos expression in the neocortex and hippocampus. To study the factors involved in the suppression of cortical activation in lactating rats in response to NMA, we examined the effects of removing either the suckling stimulus and/or progesterone. The degree of cFos expression was used as a marker for cortical activation.

Lactation inhibits hippocampal and cortical activation of cFos expression by nivida but not kainate receptor agonists.

Lactation in the rat activates afferent neuronal pathways that cause marked changes in hormone secretion and maternal behavior. Previously, we used excitatory amino acids (EAAs) to challenge the neuroendocrine axis of the lactating rat and showed altered hypothalamic responsiveness to EAAs. In conducting those studies, we noted that the typical hyperactive behavior associated with NMA (N-methyl-d,l-aspartate) treatment was completely absent in lactating animals.

LHRH neurons express cJun protein during the proestrous surge of luteinizing hormone.

LHRH neurons express cFos on the afternoon of proestrus in association with the ovulatory LH surge. This study determined whether LHRH neurons express another proto-oncogene product, Jun, during the estrous cycle. By using immunocytochemical double staining techniques, localization of Jun proteins and LHRH was compared with expression of cFos in LHRH neurons.

Differences in the luteinizing hormone and prolactin responses to multiple injections of kainate, as compared to N-methyl-D,L-aspartate, in cycling rats.

We have previously reported that repetitive iv injections of NMA [N-methyl-D,L-aspartate, the mixed analog acting on the N-methyl-D-aspartate (NMDA) receptor] can induce a consistent increase in LH and PRL secretion in cycling rats, but not in lactating rats. To further explore the use of excitatory amino acids (EAAs) as tools for understanding the regulation of the neuroendocrine reproductive axis, we have examined the effects of multiple injections of kainate, an agonist to another subclass of EAA receptor, on LH and PRL secretion in cycling rats. Recent studies suggest that kainate receptors may be more abundant than NMDA receptors in the hypothalamus.

[Open University and its applicability in Nursing].

The article covers aspects of a educational system, called Open University, which began in England in 1963. Its structure, organization and evaluation are presented, as well as some attempts to implement the methodology in Brazil. The authors suggest that the idea behind the Open University - dissemination of knowledge - should be incorporated by nurses, in order to encourage them towards continuing education, and indicate some organizations through which such programs could be known and extended throughout the country.