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Biomedical subjects

A McMahon

Publications and source records attributed to A McMahon.

At least 19 recordsLinked to original sources
PubMed1996

Cloning and characterization of cDNAs for novel proteins with glutamic acid-proline dipeptide tandem repeats.

cDNAs with identical 3' sequences containing a hexanucleotide repeat -(GAGCCG)9- were isolated from rat pheochromocytoma and brain cDNA libraries. The cDNA with the longest open reading frame codes for a protein of 24.6 kDa containing a 16-fold -(Glu-Pro)- dipeptide repeat within a glutamate and proline rich region at its deduced C-terminus. cDNAs with the identical 3' sequence and a divergent 5' sequence were isolated from a rat skeletal muscle cDNA library. The latter are predicted to code for a protein of 15.5 kDa with a C-terminal repetitive domain identical to that in the pheochromocytoma and brain cDNAs. The cDNAs recognize a 1.8 kb mRNA species present in a variety of tissues, being particularly abundant in cardiac and skeletal muscle.

Amino Acid Sequence↗
PubMed1996

Induction of adrenal tyrosine hydroxylase mRNA by single immobilization stress occurs even after splanchnic transection and in the presence of cholinergic antagonists.

Immobilization (IMO) stress elevates plasma catecholamines and increases tyrosine hydroxylase (TH) gene expression in rat adrenals. This study examined the mechanism(s) of IMO-induced changes in adrenal TH mRNA levels. Innervation of the adrenal medulla is predominantly cholinergic and splanchnicotomy as well as nicotinic receptor antagonists prevent the cold-induced rise in TH mRNA levels. In this study, the IMO-induced rise in plasma catecholamines, but not TH mRNA levels, was reduced by the antagonist chlorisondamine. Muscarinic antagonist atropine also did not prevent the IMO stress-elicited rise in TH mRNA. Furthermore, denervation of the adrenals by unilateral splanchnicotomy did not block the IMO-induced rise in TH mRNA but completely prevented the induction of neuropeptide Y mRNA. These results suggest that (1) the large increase in adrenal TH gene expression elicited by a single IMO stress is not regulated via cholinergic receptors or splanchnic innervation, and (2) there is a dissociation between regulatory mechanisms of catecholamine secretion and elevation of TH gene expression in the adrenal medulla of rats during IMO stress.

Adrenal Medulla↗
PubMed1995

The effects of hexachlorobenzene on circulating levels of adrenal steroids in the ovariectomized rat.

Hexachlorobenzene (HCB), is a global pollutant that resists degradation and possesses a propensity to bioaccumulate. However, the effect of HCB on adrenal function remains largely unknown. Thus, circulating levels of adrenal steroids in HCB-exposed (0.0, 1.0, 10.0, or 100.0 mg/kg/day--for 30 days by gavage) adult ovariectomized Sprague-Dawley rats (N = 32) were investigated. A terminal blood sample was collected for HCB residue analysis, and levels of circulating progesterone (P4), corticosterone (CS), and aldosterone (ALD) were quantified. Mean serum CS levels were significantly (P = 0.02) reduced by HCB exposure, starting with the lowest dose group (1.0 mg/kg/day for 30 days), whereas no differences in mean serum P4 and ALD levels were observed. Since it has been argued that the rodent possesses the ability to produce small amounts of cortisol and that levels of this glucocorticoid are altered in pathological states, serum cortisol (C) levels were also measured. Circulating levels of C were significantly lower (P < 0.05) in the highest dose group compared with controls. The presence of C in serum was confirmed by reverse-phase HPLC. These data suggest that even at the lowest dose studied, HCB exposure induces alterations in steroidogenesis of cells of the adrenal cortex inner zone.

Adrenal Cortex↗
PubMed1995

QT dispersion in essential hypertension.

Increased QT dispersion is associated with sudden cardiac death in congestive heart failure, hypertrophic cardiomyopathy, and following acute myocardial infarction. Patients with hypertension, in particular those with left ventricular hypertrophy, are also at greater risk of sudden cardiac death. We examined whether QT dispersion, which is easily obtained from a routine ECG, correlates with echo LVH. Sixty-nine untreated patients with essential hypertension had QT dispersion measured from a surface 12-lead electrocardiogram, and two-dimensional echocardiography performed to measure interventricular septal thickness, posterior wall thickness, and left ventricular internal diameter. Office blood pressure was recorded, and in 56 patients, 24 h ambulatory blood pressure monitoring was also done. Multivariate analysis demonstrated significant relationships between QT dispersion and office systolic blood pressure, and left ventricular mass index. Similar findings were obtained when QT dispersion was corrected for heart rate (QTc dispersion). After patients with electrocardiographic left ventricular hypertrophy (n = 5) were excluded from the analysis, the above relationships persisted. Increased QT dispersion is thus found in those essential hypertensives at greatest risk of sudden death. Since this relationship persists even in the absence of electrocardiographic left ventricular hypertrophy, measurement of QT dispersion might be a simple, non-invasive screening procedure to identify those hypertensives at greatest risk of sudden death.

Adolescent↗
PubMed1995

Ultrastructural changes in ovarian follicles of monkeys administered hexachlorobenzene.

OBJECTIVE: To test hexachlorobenzene (HCB), an environmental pollutant, for its potential toxicity to the ovary. DESIGN: Nonhuman primates were orally administered the pollutant at doses between 0.01 and 10 mg of HCB/kg of body weight to test viability of ovarian follicles. At the end of dosing period, the monkeys received a compound that contained follicle-stimulating and luteinizing hormones to stimulate development of follicles that would be examined by electron microscopy. ANIMALS: Twenty, 6- to 13-year-old cynomolgus monkeys were randomly assigned to 5 groups. PROCEDURE: The HCB, in concentrations of 0.01, 0.1, 1.0, and 10.0 mg/kg, was orally administered with glucose in gelatin capsules for 13 weeks. Monkeys receiving capsules containing glucose only served as controls. After the 13th week, monkeys were given a compound that contained follicle-stimulating and luteinizing hormones daily during days 2 to 7 from the start of menses. On day 8 of the menstrual cycle, 5,000 IU of human chorionic gonadotropin was administered, and 35 to 38 hours later, 1 ovary from each monkey was obtained during laparotomy. Approximately 1-mm cubes of tissue from each ovary were harvested, fixed by immersion in buffered 2% glutaraldehyde, and processed for transmission electron microscopy. RESULTS: Ultrastructure of ovarian follicles was altered in the monkeys administered HCB. Lesions were observed in the follicles from monkeys given the lowest concentrations of HCB, and comprised condensed mitochondria in the developing ova and follicular cells that contained nuclei with deep indentations and abnormal accumulation of cytoplasmic lipid droplets. Alterations, such as herniation of the ooplasm, degeneration of the follicular cells, and appearance of abnormal spaces between follicular cells were observed in the follicles from monkeys of the 0.1 to 1.0 mg of HCB/kg dosage groups. The most relevant alterations were seen in the mitochondrion, an organelle that appeared to be most sensitive to the compound. Mitochondria were condensed, with abnormal intracristal spaces in the lower-dosage groups, and were markedly degenerated in the 10 mg/kg group. The effect of HCB were dose-related. CONCLUSION: The HCB is a reproductive system toxicant, and its damaging effects may be a result of augmentation of lipid peroxidation, especially in the primary follicle, which abnormally affects cellular membranes and thus, impairs their permeability.

Administration, Oral↗
PubMed1994

Induction of tyrosine hydroxylase gene expression by a nonneuronal nonpituitary-mediated mechanism in immobilization stress.

Stress stimulates the sympathoadrenal system, causing activation of the catecholamine biosynthetic enzymes. Here we examine the changes of gene expression of tyrosine hydroxylase (TH; EC 1.14.16.2), the initial enzyme of catecholamine biosynthesis, with stress. A single immobilization of rats led to a large transient elevation in TH mRNA and a small elevation in TH immunoreactive protein and activity. Repeated daily immobilizations triggered more sustained changes in TH mRNA levels. After two immobilizations, the levels remained elevated even 3 days later. The rise in TH mRNA was followed by increased immunoreactive protein but only a small elevation in activity. With seven repeated immobilizations, the animals did not appear to adapt and still manifested a further rise in TH mRNA. TH activity was markedly elevated and returned to control levels 7 days after the immobilization. The rise in TH mRNA with a single immobilization occurred even in adrenals of hypophysectomized rats that underwent splanchnic nerve section. Immobilization for 30 min was sufficient to increase TH mRNA. The effect was abolished by the transcriptional inhibitor actinomycin D. Mobility gel-shift assays revealed increased binding of c-Fos and c-Jun to the AP-1 transcription factor site after a single immobilization, and the binding was not further elevated with repeated stress. This study shows that a single immobilization can activate TH gene expression by a nonneuronal nonpituitary-mediated pathway associated with increased binding of AP-1 transcription factors.

Adrenal Glands↗
PubMed1994

Experimental control of axial pattern in the chick blastoderm by local expression of Wnt and activin: the role of HNK-1 positive cells.

Small grafts from transfected mammalian cell lines that secrete activin or express Wnt-1 RNA were made to the marginal zone of entire chick blastoderms in culture. Grafts from appropriate control cell lines produced no effects on development. The activin-secreting grafts, implanted before streak formation, could cause the streak to form opposite their marginal position even when this was 180 degrees distant around the blastoderm from the original presumptive streak site. Alternatively, opposed twin streaks were observed, one at the original presumptive site and one in relation to the graft. Wnt-expressing grafts implanted early could also reposition axis formation, but only to graft sites within approximately 100 degrees of angular distance from the host's presumptive streak origin. No Wnt-induced twinning was observed. Grafts of both experimental cell types intermixed were the most effective in reorientating, twinning, or globally disturbing the axial pattern and led to second axes with the least delay, relative to normal development, in reaching headfold stages. The incidence and distribution of cells positive for the epitope HNK-1 was investigated during early stages of normal and of experimentally twinned development. Only two nonhypoblast regions of HNK-1 expression were consistently observed in normal early development; a sector in the germ wall area opaca, behind the site of streak formation, and then a localised region of intensely, newly expressing cells arising in epiblast and in anteriormost parts of the (epiblast-derived) streak at the half-length streak stage. Both "activin only" and "activin/Wnt" mixed grafts, although not control grafts, became surrounded by new sectors of "germ wall" HNK-1 positivity. Such positivity may therefore mark a cell group with a signaling role (but no anatomical participation) in streak initiation. However, there was no change of the local background incidence of epiblastic HNK-1 positivity in the structure of streaks induced by "activin only" grafts. This indicates that most cells of the streak are specified by relatively local induction, rather than deriving from selective aggregation. Only grafts including the Wnt-expressing cells gave rise to obvious new HNK-1 expression within epiblast-derived cells anteriorly, as does the complete normal streak. This suggests that the Wnt class of response pathway can complement the activin one in producing rostrocaudally complete axial pattern, as has been suggested for amphibian development.

Activins↗
PubMed1994

Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors.

Changes in intermediate filament gene expression occur at key steps in the differentiation of cell types in the mammalian CNS. Neuroepithelial stem cells express the intermediate filament protein nestin and down-regulate it sharply at the transition from proliferating stem cell to postmitotic neuron. Nestin is also expressed in muscle precursors but not in mature muscle cells. We show here that in transgenic mice, independent cell type-specific elements in the first and second introns of the nestin gene consistently direct reporter gene expression to developing muscle and neural precursors, respectively. The second intron contains an enhancer that functions in CNS stem cells, suggesting that there may be a single transcriptional mechanism regulating the CNS stem cell state. This enhancer is much less active in the PNS. The identification of these elements facilitates analysis of mechanisms controlling the switch in gene expression that occurs when muscle and brain precursors terminally differentiate.

Animals↗
PubMed1993

Hexachlorobenzene toxicity in the monkey primordial germ cell without induced porphyria.

Hexachlorobenzene is a persistent chlorinated organic chemical that has been detected in many tissues from a variety of species including human ovary and human ovarian follicular fluid. When administered in high dosage to nonhuman primates, hexachlorobenzene causes destruction of ovarian primordial germ cells in association with systemic toxicity. The purpose of these experiments was to assess relative ovarian germ cell sensitivity at much lower dosages of hexachlorobenzene that do not produce systemic effects and additionally to evaluate oocyte function by means of the response to superovulation, fertilization, and embryo cleavage during a cycle of in vitro fertilization in the cynomolgus monkey. Hexachlorobenzene in dosages of 0.1, 1.0, and 10.0 mg/kg/day was administered orally by gelatin capsule for 90 days. There was a dose-dependent accumulation of HCB in serum and other tissues without any change in the serum estradiol response to human menopausal gonadotropin, oocyte recovery, oocyte maturation, oocyte fertilization in vitro, and early embryo cleavage rate. There was a dose-related toxic effect observed in primordial germ cells at the lowest dose despite no evidence of systemic or hepatic effects. As there were no changes in the urinary porphyrin excretion, the mechanism of hexachlorobenzene ovotoxicity may be distinct from hexachlorobenzene-induced cytochrome P-450-dependent inhibition of uroporphobilinogen decarboxylase in the liver, although such intraovarian metabolism cannot be excluded.

Animals↗
PubMed1992

Regulated expression of the tyrosine hydroxylase gene by membrane depolarization. Identification of the responsive element and possible second messengers.

Prolonged depolarization has been used as a model of adaptive changes in the expression of various proteins, such as ion channels and neurotransmitter biosynthetic enzymes, in response to increased trans-synaptic activity in the nervous system. In depolarized PC12 cells, tyrosine hydroxylase (TH) mRNA levels increased severalfold (Kilbourne, E. J., and Sabban, E. L. (1990) Mol. Brain Res. 8, 121-127). In this study, membrane depolarization caused an increase in the expression of the reporter gene chloramphenicol acetyltransferase (CAT), under transcriptional control of the 5' region of the rat TH gene. These results indicate that membrane depolarization leads to increased transcription of the TH gene. Protein kinase C inhibitors had no effect on the induction of TH mRNA by depolarization, as well as the increase in formation of CAT under control of the upstream region of the TH gene. The depolarization responsive element in the TH gene was mapped to the region containing the cAMP responsive element. This region of the TH gene also increased CAT activity in response to the calcium ionophore, ionomycin. Interestingly, combined treatment with cAMP analogs and membrane depolarization had a greater effect than either alone on TH mRNA levels, as well as on CAT activity in PC12 cells transfected with the plasmid containing the cAMP responsive element.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Hexachlorobenzene (HCB) suppresses circulating progesterone concentrations during the luteal phase in the cynomolgus monkey.

Hexachlorobenzene (HCB) is a known reproductive toxin. However, the full spectrum of its reproductive toxicity is unknown. Consequently, the effect of HCB on serum oestradiol (E2) and progesterone (P4) concentrations during the follicular (days 1-9), periovulatory (days 10-14) and luteal (days 15 to beginning of next menses) phases was investigated in the spontaneously cycling cynomolgus monkey. Adult female cynomolgus monkeys (n = 16) were randomly assigned to one of four treatment groups and orally doses with gelatin capsules containing HCB (0.0, 0.1, 1.0 and 10.0 mg kg-1 body wt. day-1) mixed with glucose. A 10-week acclimitization phase was followed by 13 weeks of dosing. HCB induced a dose-dependent suppression of serum P4 concentrations during the luteal phase. However, circulating levels of P4 were unaffected during the follicular and periovulatory phases of the menstrual cycle. Serum E2 concentrations, body weight, menstrual cycle length and duration of menses were not affected by HCB treatment. The range of menstrual cycle length and duration range of menses, however, were broader in the highest dose group. We conclude that HCB interfers with mechanisms regulating ovarian steroidogenesis and suppresses P4 levels during the luteal phase in the cynomolgus monkey.

Animals↗
PubMed1992

Ovarian toxicity of hexachlorobenzene (HCB) in the superovulated female rat.

Hexachlorobenzene (HCB) is a persistent environmental contaminant which has been measured in human serum, fat, semen, and follicular fluid. In animal testing HCB has been shown to be a reproductive toxin. Discrepant results were obtained from prior studies concerning the effect of HCB treatment on ovarian steroidogenesis. The current study was designed to assess the impact of HCB on the ovary and gonadal steroid levels in the superovulated rat. Female Sprague-Dawley rats (n = 24) were dosed with HCB (0.0, 1.0, 10.0, or 100.0 mg/kg BW/day) for 21 days. All rats received 10 IU pregnant mare serum gonadotropin (PMSG) s.c. on day 18 of treatment and 15 IU of human chorionic gonadotropin (hCG) on day 20. A terminal blood sample was collected and circulating levels of estradiol (E2) and progesterone. (P4) were determined. Serum concentrations of P4 were significantly (p less than 0.0034) elevated by HCB treatment at all dose levels. Ovarian weights were significantly increased (p less than 0.05) in the lowest dose group only compared to the control group. Serum concentrations of E2, uterine weight, weight gain, and general animal health were not affected by HCB treatment. We conclude that during HCB treatment the rat ovary remains responsive to gonadotropin stimulation. Moreover, it is suggested that HCB effects on ovarian steroidogenesis are indirect.

Animals↗
PubMed1992

Is indoramin an effective alternative to prostatectomy?

Alpha-1-adrenergic antagonists are recommended for symptomatic treatment of patients awaiting prostatic surgery. Their efficacy has been confirmed in placebo controlled clinical trials, but to date no comparison of their effects with the results of subsequent prostatectomy has been made. Fifty-five patients awaiting prostatectomy were assessed (by symptom scores and peak urinary flow rates) prior to treatment, on indoramin 20 mg bd, and 2 months following prostatectomy. Side effects while taking indoramin were experienced by 36% of patients. Despite an overall improvement in mean symptom scores, 26% of patients with obstructive and 30% of those with irritative symptoms who were assessed while taking indoramin failed to experience any improvement. Of the 31 patients assessed while on indoramin and again following surgery, prostatectomy produced a greater symptomatic relief than indoramin. The increase in peak flow rate following prostatectomy was 11.7 ml/s compared with 3.2 ml/s on indoramin. However, 5 patients preferred to continue taking indoramin rather than proceeding to surgery. Indoramin is no substitute for prostatectomy. Although some patients might benefit from treatment while awaiting surgery, significant side effects may severely restrict its use for this purpose. The response to indoramin cannot be used as an accurate predictor of response to prostatectomy.

Humans↗
PubMed1992

Regulation of expression of dopamine beta-hydroxylase in PC12 cells by glucocorticoids and cyclic AMP analogues.

Regulation of catecholamine biosynthesis is crucial in the adaptation to various physiological conditions, such as stress, and in several disorders, including hypertension and depression. In this study we have found that in PC12 cells, the mRNA levels of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the formation of norepinephrine from dopamine, can be regulated by glucocorticoids and cyclic AMP (cAMP) analogues. Treatment with dexamethasone increased DBH mRNA levels by 6 h. with maximal elevation (four- to fivefold) obtained after 1 day of exposure, and these levels were maintained for up to 4 days. DBH mRNA levels were also elevated on treatment of PC12 cells with 8-bromo cAMP for 8 h to 1 day. The response to 8-bromo cAMP, however, was bimodal, because DBH mRNA levels declined below control values on treatment for > 1 day. In combined treatments with 8-bromo cAMP and dexamethasone, the cAMP effect was dominant. To begin to characterize the regulation of DBH mRNA, genomic clones for rat DBH were isolated, and 1 kb of the 5' flanking region was sequenced. Several putative regulatory elements, which may be involved in cAMP and glucocorticoid regulation, were identified, including two adjacent cAMP response elements, another element that can also bind members of the ATF/CREB family of transcription factors, a NF-kappa B-like sequence, several AP-2 sites, and three core glucocorticoid receptor binding sequences.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Regulation of tyrosine hydroxylase and dopamine beta-hydroxylase mRNA levels in rat adrenals by a single and repeated immobilization stress.

Adrenal catecholamines are known to mediate many of the physiological consequences of the "fight or flight" response to stress. However, the mechanisms by which the long-term responses to repeated stress are mediated are less well understood and possibly involve alterations in gene expression. In this study the effects of a single and repeated immobilization stress on mRNA levels of the adrenal catecholamine biosynthetic enzymes, tyrosine hydroxylase and dopamine beta-hydroxylase, were examined. A repeated 2-hr daily immobilization for 7 consecutive days markedly elevated both tyrosine hydroxylase and dopamine beta-hydroxylase mRNA levels (about six- and fourfold, respectively). In contrast, tyrosine hydroxylase but not dopamine beta-hydroxylase mRNA levels were elevated immediately following a single immobilization. The elevation in tyrosine hydroxylase mRNA with a single immobilization was as high as with seven daily repeated immobilizations. This elevation was not sustained and returned toward control values 24 hr later. Both tyrosine hydroxylase and dopamine beta-hydroxylase mRNA levels were elevated immediately following two daily immobilizations to levels similar to those observed after seven immobilizations and were maintained 24 hr later. The results indicate that both tyrosine hydroxylase and dopamine beta-hydroxylase mRNA levels are elevated by stress; however, the mechanism and/or timing of their regulation are not identical.

Adrenal Glands↗