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M T McDermott

Publications and source records attributed to M T McDermott.

At least 19 recordsLinked to original sources
PubMed2001

The effects of region-specific resistance and aerobic exercises on bone mineral density in premenopausal women.

Epidemiological, cross-sectional, and prospective studies strongly suggest that exercise has beneficial effects on bone mass in premenopausal women. We prospectively compared the effects of resistance or aerobic exercises on regional bone mass in premenopausal active duty military women ranging in age from 19 to 40 years. Subjects were assigned, by preference, to a resistance exercise group or an aerobic exercise group and instructed to exercise at least 30 minutes per day, three times per week, for a period of 1 year. Bone mineral density (BMD) was measured by dual photon absorptiometry at the lumbar spine and femoral neck and by single photon absorptiometry at the mid radius at baseline, 6 months, and 12 months. BMD increments during the study were statistically significant at all sites in both exercise groups. Comparisons between the groups showed that after 12 months, BMD increased similarly in the lumbar spine (2.2% resistance vs. 1.8% aerobics, p = not significant) but more in the resistance group in the femoral neck (5.0% vs. 2.7%, p < 0.001) and the mid radius (7.8% vs. 6.7%, p < 0.05). Both resistance and aerobic exercises increase regional bone mass, particularly cortical bone mass, in premenopausal women. Resistance work appears to have a slightly greater effect on cortical bone than aerobics alone. A combination of aerobics and resistance exercises, therefore, may be a useful strategy for increasing peak bone mass in premenopausal women.

Absorptiometry, Photon↗
PubMed2000

Mapping interfacial chemistry induced variations in protein adsorption with scanning force microscopy.

In this work, we demonstrate the sensitivity of scanning force microscopy (SFM), operated in friction force mode, to adsorbed protein conformation or orientation. We employ patterned films of methyl- and carboxylate-terminated alkanethiolate monolayers on gold as substrates for protein adsorption to observe the effect of each functional group in the same image. Infrared spectroscopic and SFM studies of bovine fibrinogen (BFG) adsorption to single-component monolayers indicate that complete films of BFG that are stable to imaging are formed at each functional group. After adsorption of BFG to a patterned monolayer, we observe a contrast in friction images due to differences in adsorbed BFG conformation or orientation induced by each functional group. We also observe frictional contrast in films of other proteins adsorbed on patterned monolayers. These observations lead to the conclusion that SFM-measured friction is sensitive to adsorbed protein state.

Adsorption↗
PubMed2000

Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.

Clinical familial hypercholesterolemia has been shown to result from mutations in 2 genes, the low density lipoprotein (LDL) receptor on chromosome 19 and apolipoprotein B on chromosome 2. However, we have recently described a Utah pedigree in which linkage to both genes was clearly excluded. A multipoint linkage analysis of 583 markers genotyped on 31 (18 affected) members of this pedigree was undertaken to localize a genetic region that may harbor a third gene that could result in clinical familial hypercholesterolemia. A multipoint log of the odds score of 6.8 was obtained for markers on 1p32. Haplotype carriers and affected status are completely concordant (18/18 persons). The phenotype is also expressed in young children (ages 4 and 9). Specific recombinant individuals in the pedigree restrict the region of linkage to an approximately 17 cM interval between polymorphic markers D1S2130 and D1S1596. This region appears to overlap the region found linked to severe hypercholesterolemia in French and Spanish families. The identification of the gene in this region may provide important pathophysiological insights into new mechanisms that may lead to highly elevated LDL cholesterol and other associated dyslipidemic phenotypes.

Adolescent↗
PubMed1999

Reverse transcription polymerase chain reaction analysis of pituitary hormone, Pit-1 and steroidogenic factor-1 messenger RNA expression in pituitary tumors.

Pit-1 is a transcription factor that appears early in embryonic pituitary gland formation and is necessary for the development of somatotropes, lactotropes and thyrotropes. Steroidogenic factor-1 (SF-1) is another early appearing transcription factor that is involved in the development of gonadotropes. In this study we have compared RT-PCR analysis of hormone mRNA with traditional IHC for classification of 27 pituitary tumors and have evaluated the correlation of Pit-1 and SF-1 mRNA with hormone mRNA. RT-PCR detected concordant hormone mRNA in 100% of GH IHC positive, 100% of PRL IHC positive, 33% of TSH IHC positive, and 93% of gonadotropin IHC positive tumors. IHC, however, was concordant in only 71% of GH mRNA positive, 78% of PRL mRNA positive, 17% of TSH beta mRNA positive, and 76% of FSH beta mRNA positive tumors. Pit-1 mRNA was positive in 87% of tumors in which mRNA for GH, PRL or TSH beta was detected and in only 17% of GH, PRL and TSH beta mRNA negative tumors. SF-1 mRNA was positive in 94% of tumors in which mRNA for FSH beta was present and in no FSH beta mRNA negative tumors. We conclude that RT-PCR analysis of hormone mRNA may be more sensitive than traditional hormone IHC for classification of pituitary tumors. Furthermore, tumor Pit-1 mRNA positively correlates with GH, PRL and TSH beta mRNA while tumor SF-1 mRNA correlates well with FSH beta mRNA. Combined analysis of hormone and transcription factor mRNA in pituitary tumor tissue may therefore be a more meaningful approach to pituitary tumor characterization.

DNA Primers↗
PubMed1998

Functional interactions of an upstream enhancer of the mouse glycoprotein hormone alpha-subunit gene with proximal promoter sequences.

Transcription of the glycoprotein hormone alpha-subunit gene in the pituitary is governed by different promoter elements in thyrotropes and gonadotropes. We recently identified an upstream enhancer that directs a high level of cell type specific expression in transgenic mice and stimulates proximal promoter activity in cultured alphaTSH and alphaT3 cells. To assess the contribution of promoter sequences that functionally interact with the enhancer, we mutated two proximal elements shown to be important in both thyrotrope and gonadotrope cells. Disruption of the pituitary glycoprotein hormone basal element (PGBE), which binds a LIM homeodomain protein, resulted in a decrease in basal promoter activity in both alphaTSH and alphaT3 cells. Enhancer function was completely abolished by the PGBE site mutation in alphaT3 gonadotropes, whereas some stimulatory activity remained in alphaTSH thyrotropes. Mutation of the gonadotrope specific element (GSE), which binds SF1 and is important for basal activity in gonadotropes and TRH response in thyrotropes, resulted in declines in basal and enhanced promoter activity only in alphaT3 cells and not in alphaTSH cells. Despite this decrease in enhanced activity, the GSE mutated promoter still retained some enhancer stimulated activity, suggesting that the PGBE site still functionally interacts in the absence of an intact GSE. This mutation had no effect in alphaTSH cells. These data suggest that although the enhancer works in both cell types it exhibits cell type specific functional characteristics.

Animals↗
PubMed1998

Hydroxylated naphthoquinones as substrates for Escherichia coli anaerobic reductases.

We have used two hydroxylated naphthoquinol menaquinol analogues, reduced plumbagin (PBH2, 5-hydroxy-2-methyl-1,4-naphthoquinol) and reduced lapachol [LPCH2, 2-hydroxy-3-(3-methyl-2-butenyl)-1, 4-naphthoquinol], as substrates for Escherichia coli anaerobic reductases. These compounds have optical, solubility and redox properties that make them suitable for use in studies of the enzymology of menaquinol oxidation. Oxidized plumbagin and oxidized lapachol have well resolved absorbances at 419 nm (epsilon=3.95 mM-1. cm-1) and 481 nm (epsilon=2.66 mM-1.cm-1) respectively (in Mops/KOH buffer, pH 7.0). PBH2 is a good substrate for nitrate reductase A (Km=282+/-28 microM, kcat=120+/-6 s-1) and fumarate reductase (Km=155+/-24 microM, kcat=30+/-2 s-1), but not for DMSO reductase. LPCH2 is a good substrate for nitrate reductase A (Km=57+/-35 microM, kcat=68+/-13 s-1), fumarate reductase (Km=85+/-27 microM, kcat=74+/-6 s-1) and DMSO reductase (Km=238+/-30 microM, kcat=191+/-21 s-1). The sensitivity of enzymic LPCH2 and PBH2 oxidation to 2-n-heptyl-4-hydroxyquinoline N-oxide inhibition is consistent with their oxidation occurring at sites of physiological quinol binding.

Anaerobiosis↗
PubMed1998

Central hyperthyroidism.

Central hyperthyroidism is a rare condition in which thyrotoxicosis results from primary overproduction of TSH by the pituitary gland with subsequent thyroid enlargement and hyperfunction. The two known causes of central hyperthyroidism are TSH-producing pituitary tumors (TSHomas) and the syndrome of PRTH. Both of these entities are characterized by clinical thyrotoxicosis, diffuse goiters, elevated circulating levels of free T4 and T3, and a nonsuppressed serum TSH. It is critical to distinguish central hyperthyroidism from the much more common types of primary hyperthyroidism, all of which have undetectable TSH values. TSHomas and PRTH can usually be differentiated from one another by measuring the serum alpha-subunit and the TSH response to intravenous TRH or exogenous thyroid hormone, and by pituitary imaging studies. TSHomas are usually benign adenomas arising from the monoclonal expansion of neoplastic thyrotropes. Causative oncogenes have not yet been convincingly identified. PRTH is a nonneoplastic disorder caused by inherited mutations in the gene for the thyroid hormone receptor beta; it is a poorly understood variant of GRTH. For unclear reasons, in PRTH, the pituitary gland is resistant to the feedback inhibitory effects of circulating thyroid hormones while peripheral tissues respond normally, causing patients to experience the toxic peripheral effects of thyroid hormone excess. TSHomas are best treated by transphenoidal surgical removal. Radiotherapy is indicated for inoperable or incompletely resected tumors. Octreotide administration is a useful adjunct for preoperatively reducing tumor size and for the medical management of surgical treatment failures. PRTH is ideally treated by chronically suppressing TSH secretion with medications such as D-thyroxine, TRIAC, octreotide, or bromocriptine. If such therapy is ineffective or unavailable, thyroid ablation with radioiodine or surgery may be employed with subsequent close monitoring of both thyroid hormone status and pituitary gland size.

Adenoma↗
PubMed1997

Pit-1 and GATA-2 interact and functionally cooperate to activate the thyrotropin beta-subunit promoter.

The molecular determinants governing cell-specific expression of the thyrotropin (TSH) beta-subunit gene in pituitary thyrotropes are not well understood. The P1 region of the mouse TSHbeta promoter (-133 to -88) region interacts with Pit-1 and an additional 50-kDa factor at an adjacent site that resembles a consensus GATA binding site. Northern and Western blot assays demonstrated the presence of GATA-2 transcripts and protein in TtT-97 thyrotropic tumors. In electrophoretic mobility shift assays, a comigrating complex was observed with both TtT-97 nuclear extracts and GATA-2 expressed in COS cells. The complex demonstrated binding specificity to the P1 region DNA probe and could be disrupted by a GATA-2 antibody. When both Pit-1 and GATA-2 were combined, a slower migrating complex, indicative of a ternary protein-DNA interaction was observed. Cotransfection of both Pit-1 and GATA-2 into CV-1 cells synergistically stimulated mouse TSHbeta promoter activity 8.5-fold, while each factor alone had a minimal effect. Mutations that abrogated this functional stimulatory effect mapped to the P1 region. Finally, we show that GATA-2 directly interacts with Pit-1 in solution. In summary, these data demonstrate functional synergy and physical interaction between homeobox and zinc finger factors and provide insights into the transcriptional mechanisms of thyrotrope-specific gene expression.

Animals↗
PubMed1997

Bridging the gap between monkey neurophysiology and human perception: an ambiguity resolution theory of visual selective attention.

When the visual system must process multiple objects simultaneously, as in the visual search paradigm, the neural coding of individual objects can become ambiguous due to the visual system's extensive use of coarse coding and distributed representations. Here we propose that the primary role of visual selective attention within the ventral object recognition pathway is to resolve these ambiguities. We begin by reviewing previous studies of the effects of attention on neural responses in monkeys, which provide the basis for this hypothesis, and then describe a new set of experiments showing that similar attentional mechanisms operate in the human brain. In these new experiments, event-related potentials (ERPs) were recorded from normal human observers while they performed tasks analogous to those used previously in monkeys. The central finding was that an attention-related ERP wave called the "N2pc component" was present under the same conditions that led to attentional modulations of neural responses in monkey visual cortex. These human electrophysiological results provide a bridge between cognitive-level theories of visual attention and the behavior of individual neurons in visual cortex.

Adolescent↗
PubMed1996

Thyroid hormone receptor beta2 promoter activity in pituitary cells is regulated by Pit-1.

There are three known thyroid hormone receptor (TR) isoforms that arise from two distinct alpha and beta gene loci. TRalpha1 and TRbeta1 mRNAs are found in many tissues, whereas mRNA for the N-terminal TRbeta2 variant derived from the beta locus is readily detectable only in the pituitary gland and derived cell sources such as GH3 somatotropes and TtT-97 thyrotropes. We previously isolated the genomic region governing expression of the TRbeta2 isoform in thyrotropes and showed that transcription arose from multiple origins within a 400-base pair (bp) region. We now report that the region extending 500 bp upstream of the putative AUG codon (A is +1) contains six areas of interaction with the pituitary-specific transcription factor Pit-1. In addition there are separate areas that bind other factors present in thyrotrope cells. Promoter deletions revealed that removal of regions containing the Pit-1 sites at -456 to -432, -149 to -127, and -124 to -102 progressively decreased TRbeta2 promoter activity in thyrotropes. A more proximal footprinted area from -65 to -19, which accounted for the remaining promoter activity, contained sites that interacted with recombinant Pit-1; however, extracts of TtT-97 thyrotropes, which express Pit-1, footprinted this proximal region with a pattern of protection that differed from that produced by Pit-1. A comparative deletional analysis demonstrated that a shorter region extending only 204 bp from the AUG was sufficient to support TRbeta2 promoter activity in GH3 somatotropes. The more proximal Pit-1 sites, including the area from -53 to -19, whose pattern differed from Pit-1 in thyrotrope extracts, showed protection patterns with GH3 extracts that were indistinguishable from recombinant Pit-1. Site-directed mutagenesis that abrogated binding of both recombinant Pit-1 and Pit-1-containing nuclear extracts revealed that the two Pit-1 sites between -149 and -102 were important for TRbeta2 promoter activity with the more proximal being most critical. Finally, we showed that TRbeta2 promoter activity in alpha-TSH cells, which do not transcribe the endogenous TRbeta2 locus or produce Pit-1 protein, could be reconstituted to a level approaching that seen in expressing TtT-97 thyrotropes by cotransfecting a Pit-1 expression vector. Activation by Pit-1 was dependent on the same Pit-1 sites shown to be important for basal TRbeta2 promoter activity in thyrotropes as constructs lacking them by deletion or mutation were not stimulated by Pit-1.

Animals↗
PubMed1996

Determinants of thyrotrope-specific thyrotropin beta promoter activation. Cooperation of Pit-1 with another factor.

Thyrotropin (TSH) beta is a subunit of TSH, the expression of which is limited to the thyrotrope cells of the anterior pituitary gland. We have utilized the thyrotrope-derived TtT-97 thyrotropic tumors to investigate tissue-specific expression of the TSH beta promoter. TSH beta promoter activity in thyrotropes is conferred by sequences between -270 and -80 of the 5'-flanking region. We have recently reported that the proximal region from -133 to -100 (P1) is required for promoter expression in thyrotropes. This region interacts with the pituitary-specific transcription factor Pit-1. While Pit-1 appears necessary for TSH beta promoter activity in thyrotropes, this transcription factor is not alone sufficient for promoter activity in pituitary-derived cells. In this report, we have generated a series of promoter mutations in the P1 region to identify additional protein-DNA interactions and determine their functional significance. We have found that Pit-1 interacts with the distal portion of the P1 region, and a second protein interacts with the proximal segment of this region. Each protein is able to independently interact with the TSH beta promoter, but neither alone can maintain promoter activity. Both proteins appear to be necessary for full promoter activity in thyrotropes. Southwestern analysis with the proximal segment of the P1 region (-117 to -88) reveals interaction with a 50-kDa protein. Interestingly, this protein is not found in the pituitary-derived GH3 cells and may represent a thyrotrope-specific transcription factor. Further characterization of this newly identified DNA-binding protein will further our understanding of the tissue-specific expression of the TSH beta gene.

Animals↗
PubMed1996

The effect of methotrexate on mouse bone cells in culture.

OBJECTIVE: We have recently shown that administration of long-term, low-dose methotrexate (MTX) causes severe osteopenia in female rats. This osteopenia is characterized both by decreased osteoblast function without a decrease in osteoblast numbers, and by increased bone resorption that is believed to represent a physiologic remodeling response by osteoclasts. The present study investigates the effects of varying doses of MTX on mouse bone cells in culture. METHODS: Cells were obtained by sequential digestion of neonatal mouse calvariae, and cultured with fetal calf serum (10% for osteoblast-like cells and 2% for osteoclast-like cells). After 1 week, MTX was added to each culture in concentrations of 0.6 microM, 0.4 microM, 0.2 microM, 0.1 microM, 1 nM, and 0.5 nM. All experiments were done on 24 wells for each MTX concentration and for the controls. The effect on osteoblastic cells was assessed, at 7 days, by cell counts and by measurement of lysate alkaline phosphatase and supernatant osteocalcin levels, and, at 21 days, by analysis of the calcified matrix production, which was cultured with ascorbic acid and beta-glycerophosphate. For osteoclastic cells, cell count and lysate acid phosphatase levels were determined. RESULTS: Levels of osteoblastic cells and lysate alkaline phosphatase were not changed by any of the concentrations of MTX. Matrix calcification and supernatant osteocalcin levels were diminished by MTX in a dose-responsive manner. Osteoclast-like cell numbers and acid phosphatase levels were not significantly affected by MTX. CONCLUSION: These results suggest that diminished mouse osteoblastic cell function occurs with very low mean concentrations of MTX, in a dose-responsive manner. The mechanism seems to be inability of the cell to synthesize and calcify matrix, possibly through defective osteocalcin production. Thus, low-dose MTX may have an important impact on bone density by slowing osteoblastic matrix production.

Acid Phosphatase↗
PubMed1996

Correlation of liver density by magnetic resonance imaging and hepatic iron levels. A noninvasive means to exclude homozygous hemochromatosis.

The diagnosis of hemochromatosis requires liver biopsy and the quantification of hepatic iron. Magnetic resonance imaging (MRI) of the liver shows a characteristic decrease in tissue signal intensity in iron overload states, but its role in the diagnosis of hemochromatosis has not been fully delineated. Forty-three patients (31 men and 12 women) were referred for the evaluation of hemochromatosis based upon a fasting transferrin saturation > 55% and/or a serum ferritin > 400 ng/ml in males or > 300 ng/ml in females. Each patient prospectively underwent MRI of the liver prior to percutaneous liver biopsy and quantitative hepatic iron determination. Homozygous hemochromatosis was diagnosed in 10 patients based upon an hepatic iron/age index > or = 2. MRI was performed with a 1.5 Tesla system using standard spin-echo sequences (T1; TR = 300-500 ms, TE = 13-17 ms, PD; TR = 2,000-2,600 ms, TE = 30 ms). Signal intensity values were blindly determined for regions of interest in liver and skeletal muscle at T1 and proton density. Ratios of liver to muscle (LM) for T1 and proton density (PD) calculated from these values showed a significant correlation with quantitative iron by multiple regression analysis. The LMPD ratio provided the best correlation with hepatic iron (r = -0.6946; p < 0.001). Linear regression analysis also provides an equation that can be used to predict hepatic iron based upon the LMPD ratio; micrograms/g of hepatic iron = (-5,174 x LMPD) + 9,932. All patients with LMPD ratios of > 0.5 had hepatic iron/age indices of < 2.0, thereby excluding homozygous hemochromatosis. These results suggest that LMPD ratios derived from MRI of the liver can accurately predict hepatic iron content. These ratios can be clinically useful in the evaluation of hemochromatosis among patients who either refuse or have contraindications to liver biopsy.

Adult↗
PubMed1996

Adrenal crisis in active duty service members.

Primary adrenal insufficiency is a chronic, debilitating condition that usually produces a variety of characteristic but non-specific clinical features. Up to 25% of patients present instead with acute life-threatening adrenal crisis, marked by severe hypotension and shock. Recognition of the disease in the chronic indolent phase is critical because adrenal steroid replacement effectively relieves symptoms and prevents the development of most acute crises. To illustrate these points, we describe four case histories in which the manifestations of chronic adrenal insufficiency went unrecognized in active duty service members until they presented with near-fatal adrenal crises. The salient clinical features, diagnosis, and treatment of the disease are also reviewed.

Acute Disease↗
PubMed1995

A longitudinal assessment of bone loss in women with levothyroxine-suppressed benign thyroid disease and thyroid cancer.

To determine if differing degrees of levothyroxine (LT4) suppression therapy for benign and malignant thyroid disease are associated with proportionately increased rates of bone loss, this longitudinal assessment of bone densitometry changes (single-photon and dual-photon absorptiometry) was conducted in three groups of subjects: 24 thyroid cancer patients who were treated with near-total thyroidectomy, radioiodine ablation, and aggressive LT4-suppression; 44 patients who were treated with more conservative LT4-suppression for benign thyroid disorders; and 24 normal controls. Bone densitometry values were adjusted for age, weight, height, and menopausal status. The rates of bone loss in benign LT4-suppressed patients were greater than those in controls at the midradius, distal radius, lumbar spine, and femoral neck. The rates of loss in the thyroid cancer patients were also greater than those in the controls at all four sites and greater than in the benign LT4-suppressed patients at the midradius, distal radius, and femoral neck but not in the lumbar spine. Rates of bone loss were not significantly correlated with LT4 dose or with the serum level of T4 or TSH. LT4-suppression therapy for benign thyroid disease is associated with accelerated bone loss. More aggressive LT4-suppression for thyroid cancer is associated with even greater bone loss, particularly in cortical bone regions. These risks must be weighed against the benefits of LT4 therapy in individual patients.

Bone Density↗
PubMed1995

Thyroid adaptation to chronic tetraglycine hydroperiodide water purification tablet use.

Tetraglycine hydroperiodide tablets purify water by liberating 8 mg free iodine/tablet. The effects of ingesting four tablets daily for 3 months on thyroid size, function, and radioactive iodine uptake were studied prospectively in eight healthy volunteers. Serum inorganic iodide increased from 2.7 to approximately 100 micrograms/dL. Urinary iodide excretion rose 150-fold from a pretreatment mean of 0.276 to 40 mg/day. Radioactive iodine uptake was less than 2% after 7 days and remained below 2% in all subjects at 90 days. Mean serum T4 and T3 declined after 7 days. T4 remained below baseline, whereas T3 had recovered by the end of the treatment period. Serum TSH and the TSH response to TRH rose significantly after 7 days and remained elevated at 3 months. The average thyroid volume, determined by ultrasound, increased by 37%. Neither hyperthyroidism nor hypothyroidism was observed. The mean thyroid volume in seven subjects available for repeat determinations an average of 7.1 months after the study was not different from the baseline value. In normal subjects, a reversible TSH-dependent thyroid enlargement occurs in response to the iodine load from daily use of tetraglycine hydroperiodide water purification tablets.

Adaptation, Physiological↗
PubMed1994

The effect of low-dose methotrexate on bone metabolism and histomorphometry in rats.

OBJECTIVE: To ascertain the effects of low-dose methotrexate (MTX) on bone metabolism and histomorphometry in rats. METHODS: Female Sprague-Dawley rats (6 months old, n = 42) were divided into the following 4 groups: intraperitoneal (IP) injections of MTX, with and without ovariectomy, and IP saline (controls), with and without ovariectomy. Injections were given for 16 weeks. The MTX dose was equivalent to a standard dose for rheumatoid arthritis in humans that would yield similar serum MTX levels (0.6 +/- 0.1 mumoles). RESULTS: Bone formation (assessed by serum alkaline phosphatase and osteocalcin levels and histomorphometry) was significantly lower in the MTX groups, and bone resorption (assessed by urinary hydroxyproline levels and histomorphometry) was increased in the MTX groups. Bone mass was significantly diminished in the MTX groups. CONCLUSION: Prolonged administration of low-dose MTX in rats causes significant osteopenia via suppression of osteoblast activity and stimulation of osteoclast recruitment, which results in increased bone resorption.

Animals↗