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T McShane

Publications and source records attributed to T McShane.

12 recordsLinked to original sources
PubMed1999

Alterations in insulin-like growth factor-1 gene and protein expression and type 1 insulin-like growth factor receptors in the brains of ageing rats.

Ageing in mammals is characterized by a decline in plasma levels of insulin-like growth factor-1 that appears to contribute to both structural and functional changes in a number of tissues. Although insulin-like growth factor-1 has been shown to provide trophic support for neurons and administration of insulin-like growth factor-1 to ageing animals reverses some aspects of brain ageing, age-related changes in insulin-like growth factor-1 or type 1 insulin-like growth factor receptors in brain have not been well documented. In this series of studies, insulin-like growth factor-1 messenger RNA and protein concentrations, and type 1 insulin-like growth factor receptor levels were analysed in young (three to four- and 10-12-month-old), middle-aged (19-20-month-old) and old (29-32-month-old) Fisher 344 x Brown Norway rats. Localization of insulin-like growth factor-1 messenger RNA throughout the lifespan revealed that expression was greatest in arteries, arterioles, and arteriolar anastomoses with greater than 80% of these vessels producing insulin-like growth factor-1 messenger RNA. High levels of expression were also noted in the meninges. No age-related changes were detected by either in situ hybridization or quantitative dot blot analysis of cortical tissue. However, analysis of insulin-like growth factor-1 protein levels in cortex analysed after saline perfusion indicated a 36.5% decrease between 11 and 32 months-of-age (P<0.05). Similarly, analysis of type 1 insulin-like growth factor receptor messenger RNA revealed no changes with age but levels of type 1 insulin-like growth factor receptors indicated a substantial decrease with age (31% in hippocampus and 20.8 and 27.3% in cortical layers II/III and V/VI, respectively). Our results indicate that (i) vasculature and meninges are an important source of insulin-like growth factor-1 for the brain and that expression continues throughout life, (ii) there are no changes in insulin-like growth factor-1 gene expression with age but insulin-like growth factor-1 protein levels decrease suggesting that translational deficiencies or deficits in the transport of insulin-like growth factor-1 through the blood-brain barrier contribute to the decline in brain insulin-like growth factor-1 with age, and (iii) type 1 insulin-like growth factor receptor messenger RNA is unchanged with age but type 1 insulin-like growth factor receptors decrease in several brain regions. We conclude that significant perturbations occur in the insulin-like growth factor-1 axis with age. Since other studies suggest that i.c.v. administration of insulin-like growth factor-1 reverses functional and cognitive deficiencies with age, alterations within the insulin-like growth factor-1 axis may be an important contributing factor in brain ageing.

Aging↗
PubMed1998

Distribution and levels of insulin-like growth factor I mRNA across the life span in the Brown Norway x Fischer 344 rat brain.

Previous studies have reported changes in insulin-like growth factor I (IGF-I) mRNA expression during early postnatal development of the rat brain. Although changes in IGF-I gene expression have been documented in a wide range of central nervous system structures during early development and investigated in the hippocampus during aging, no study has compared changes in IGF-I gene expression in different brain regions across the life span. The present study assessed the distribution of IGF-I gene expression using in situ hybridization in rats aged 2-30 months. Dot blots were used as a quantitative assessment of cortical IGF-I mRNA. Results indicate that both the distribution and levels of brain IGF-I mRNA do not change significantly between 2 and 30 months of age in the rat. However, in spite of relatively constant levels of mRNA, other studies from our laboratory have demonstrated that cortical IGF-I protein levels decrease 36.6% between 11 and 32 months of age, suggesting that IGF-I function is decreased with increasing age.

Aging↗
PubMed1997

Aging of the female reproductive system: a window into brain aging.

The menopause marks the permanent end of fertility in women. It was once thought that the exhaustion of ovarian follicles was the single, most important explanation for the transition to the menopause. Over the past decade, this perception has gradually changed with the realization that there are multiple pacemakers of reproductive senescence. We will present evidence that lends credence to the hypothesis that the central nervous system is a critical pacemaker of reproductive aging and that changes at this level contribute to the timing of the menopause. Studies demonstrate that an increasing de-synchronization of the temporal order of neuroendocrine signals may contribute to the accelerated rate of follicular loss that occurs during middle age. We suggest that the dampening and destabilization of the precisely orchestrated ultradian, circadian, and infradian neural signals lead to miscommunication between the brain and the pituitary-ovarian axis. This constellation of hypothalamic-pituitary-ovarian events leads to the inexorable decline of regular cyclicity and heralds menopausal transition.

Aged↗
PubMed1996

Dynamic changes in gonadotropin releasing hormone receptor mRNA content in the mediobasal hypothalamus during the rat estrous cycle.

The purpose of the present study was to determine if GnRH receptor mRNA levels in the rat brain undergo changes during the estrous cycle. We focused on the arcuate and ventromedial nuclei of the hypothalamus and on the hippocampus which are sites in the rat central nervous system that have been shown to contain measurable amounts of GnRH receptor mRNA. Groups of regularly cycling female rats were decapitated at 08.00 and 17.00 h of each day of the estrous cycle, trunk blood was collected for radioimmunoassay analysis of circulating LH levels, and the brains were processed for 'in situ' hybridization. A cDNA probe encoding the rat pituitary GnRH receptor was transcribed 'in vitro' in the presence of (33)P-alpha UTP and used under saturating conditions to label GnRH receptor mRNA. The results show that in the arcuate and ventromedial nuclei GnRH receptor mRNA levels are relatively high during diestrus 1, they decline slightly during diestrus 2 before they rise to the highest levels at 08.00 h of proestrus. By 17.00 h of proestrus, GnRH receptor mRNA levels had declined to the lowest levels of the estrous cycle where they remain through the morning of estrus. The GnRH receptor mRNA levels rise again sharply during the afternoon of estrus. The changes in the hippocampus follow a similar pattern in that a decline in GnRH receptor mRNA levels to its lowest levels occurs between 08.00 and 17.00 h of proestrus. However, the changes in the hippocampus did not reach statistical significance. It is concluded that GnRH receptor mRNA levels in the arcuate and ventromedial nuclei are upregulated in the morning of proestrus, probably by rising estradiol levels, in preparation for the GnRH-LH preovulatory surge while this effect of estradiol is not apparent in the hippocampus.

Animals↗
PubMed1992

Effect of interferon-gamma on complement gene expression in different cell types.

We have studied the expression of the complement components C2, C3, factor B, C1 inhibitor (C1-inh), C4-binding protein (C4-bp) and factor H in human peripheral blood monocytes, skin fibroblasts, umbilical vein endothelial cells (HUVEC) and the human hepatoma cell line G2 (Hep G2) in the absence and the presence of interferon-gamma (IFN-gamma). E.l.i.s.a. performed on culture fluids, run-on transcription assays, Northern blot and double-dilution dot-blot techniques confirmed that monocytes expressed all six components, whereas fibroblasts, HUVEC and HepG2 each expressed five of the six components. Fibroblasts and HUVEC did not synthesize C4-bp, and Hep G2 did not produce factor H. In addition to these differences, the synthesis rates of C3, C1-inh and factor H were not the same in all cell types. However, the synthesis rates of C2 and factor B were similar in all four cell types. The half-lives of the mRNAs were shorter in monocytes than in other cell types. Monocyte factor H mRNA had a half-life of 12 min in monocytes, compared with over 3 h in fibroblasts and HUVEC. The instability of factor H mRNA in monocytes may contribute to their low factor H secretion rate. IFN-gamma produced dose-dependent stimulation of C2, factor B, C1-inh, C4-bp and factor H synthesis by all cell types expressing these proteins, but decreased C3 synthesis in all four cell types. Cell-specific differences in the response to IFN-gamma were observed. The increased rates of transcription of the C1-inh and factor H genes in HUVEC were greater than in other cell types, while the increased rate of transcription of the C2, factor B and C1-inh genes in Hep G2 cells was less than in other cell types. IFN-gamma did not affect the stability of C3, factor H or C4 bp mRNAs, but increased the stability of factor B and C1-inh mRNAs and decreased the stability of C2 mRNA. Although these changes occurred in all four cell types studied, the half-life of C1-inh mRNA in monocytes was increased almost 4-fold, whereas the increases in the other cell types were less than 30%. These data show that the constitutive synthesis rates of complement components may vary in the different cell types. They also show that the degree of change in synthesis rates in response to IFN-gamma in each of the cell types often varies due to differences in transcriptional response, sometimes in association with changes in mRNA stability.

Carrier Proteins↗
PubMed1978

Recombinant plasmids containing Xenopus laevis globin structural genes derived from complementary DNA.

Details are presented of the in vitro synthesis of double-stranded DNA complementary to purified Xenopus globin messenger RNA, using a combination of reverse transcriptase, fragment 'A' of E. coli DNA polymerase 1 and S1 endonuclease. After selection of duplex DNA molecules approaching the length of Xenopus globin messenger RNA by sedimentation of the DNA through neutral sucrose gradients, the 3'-OH termini of the synthetic globin gene sequences were extended with short tracts of oligo dGMP using terminal transferase. This material was integrated into oligo dCMP-extended linear pCR1 plasmid DNA and amplified by transfection of E. coli. Plasmids carrying globin sequences were identified by hybridization of 32P-labelled globin mRNA to total cellular DNA in situ, by hybridization of purified plasmids to globin cDNA in solution, by analysis of recombinant DNA on polyacrylamide and agarose gels, and by heteroduplex mapping. The results show that extensive DNA copies of Xenopus globin mRNA have been integrated into recombinant plasmids.

Animals↗
PubMedDate not supplied

Neuroendocrine concomitants of reproductive aging.

Depletion of ovarian follicles is often thought to be the determining factor in female reproductive aging. However, increasing evidence suggests that neural and neuroendocrine changes play important causative roles in the decline of regular reproductive cycles leading to the menopause. A blunting or suppression in the daily pattern of secretion of several neuroendocrine hormones has been documented in aging laboratory animals and humans. Investigators have designed experiments to test whether these changes reflect multiple unrelated changes in the regulation of each of these hormones, or whether these alterations result from a fundamental change in the time-keeping mechanism that underlie these patterns of hormone secretion. Oscillations that occur approximately every 24 h are a hallmark of most living organisms. These cycles provide the organism with the capability of coordinating events that occur at higher (hourly) and lower (weekly or monthly) frequencies within an individual organism, and with the capability of synchronizing these events with the external environment. In mammals, the hypothalamic suprachiasmatic nucleus is thought to be a master oscillator that regulates most circadian rhythms in mammals. Perturbations in temporal organization occur during aging and influence multiple physiological systems, including reproductive cyclicity in females. Thus, the question for neuroendocrinologists is: Do changes in the cyclic pattern of hormone secretion reflect a change in the master oscillator, and do these changes play a role in female reproductive aging? Data from our laboratory demonstrate that the timing of the preovulatory and steroid-induced luteinizing hormone (LH) surge changes during middle-age in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Reproductive endocrinology and toxicological pathology over the life span of the female rodent.

Understanding the pathology of the female reproductive system with respect to toxicology requires a basic understanding of morphology and function of the system over time because the nature of the female reproductive system is cyclical. Thus, the morphology and the endocrinology is dependent on age and time, as form follows function and function follows form. The life span of the rodent is used as an outline to present an overview of key morphological and endocrinological events important for toxicologic pathologists to consider in study evaluations. Environmental and pharmaceutical compounds differentially impact the organs individually and/or the system in its entirety in a time- and dose-dependent way. Examples are used to illustrate the consequences of exposures at different times and with different outcomes.

Animals↗