PubMed Health⌕ Search

Biomedical subjects

C A Spencer

Publications and source records attributed to C A Spencer.

At least 19 recordsLinked to original sources
PubMed1992

Genetic and age related models of neurodegeneration in mice: dystrophic axons.

Dystrophic axons (DA) are non-specific lesions that occur in a wide variety of human and animal diseases. In this paper we describe the distribution of these lesions in three newly discovered mouse neurological mutants. The distribution of DA in these mutants is defined by their names, lumbosacral neuroaxonal dystrophy (lnd), located on Chromosome 7, generalized neuroaxonal dystrophy (gnd) and vestibulomotor degeneration (vmd). The last mutant, which has degeneration as well as DA in lateral vestibular nucleus and vestibulo-spinal tracts, dies in the first weeks of life; the first two live for approximately one year. A previously described mutation, dystonia musculorum (dt), was found to produce generalized DA like gnd, but dt/dt mutants die at an early age. DA were also found to occur in the nuclei gracilis and cuneatus, in the area of Clark's column and in lumbo-sacral spinal cord in aging normal mice either fed ad libitum or at a level of 40% dietary restriction. The dietary regimen had little effect on the numbers of DA observed in susceptible areas of the neuroaxis. The mutant models of neuroaxonal dystrophy may prove useful in studies of the pathophysiology of DA in general and of specific inherited diseases of man, such as infantile neuroaxonal dystrophy and Hallervordin-Spatz disease.

Aging↗
PubMed1992

Integration of thyroid hormones with hypothalamic factors on pituitary TSH secretion.

A study employing a newly developed fourth generation immunometric serum TSH assay (assay limit 0.001 mu/l was performed to determine the temporal pattern of inhibition of serum TSH in response to a maximal suppressive dose of thyroid hormone (T3, T4 and TRIAC) as compared to the pattern produced by dopamine (DA) and dexamethasone (DEX). Mean onset of inhibition was 24, 48 and 68 minutes for thyroid hormone, DA and DEX, respectively. The inhibitory pattern was uniform and reproducible for the same or different individuals if data were normalized respective to basal TSH values. Inhibitory pattern with thyroid hormone formed two distinct log linear functions: A rapid phase (phase 1) spanning 48 minutes to 24 hours and a slower phase (phase 2) bridging 24 to 1,000 hours. A diurnal variation in phase 1, but not in phase 2 suppression, was observed. A phase 1 response was also produced by DA and DEX but not phase 2. Low dose TRH infusion studies indicated that thyroid hormone and DEX inhibited thyrotroph response at or beyond the TRH receptor, while DEX appeared to inhibit endogenous TRH secretion. No additive effects of DA or DEX on T3 inhibition were seen in phase 1. These studies provide new insight into the mechanism by which these endocrine factors complementarily regulate TSH secretion in man.

Dexamethasone↗
PubMed1991

Characteristics of 3,5,3'-triiodothyronine sulfate metabolism in euthyroid man.

The sulfated conjugate of T3 (T3S) has long been recognized as a normal product of peripheral thyroid hormone metabolism. In order to better understand the role that T3S may play in this process, the metabolic handling of T3S was studied in euthyroid man. After the iv administration of [125I]T3S in man, T3S was found to be rapidly metabolized with estimated mean MCR of 135 +/- 15 liters/day (L/D) after a bolus injection and 127 +/- 8 L/D employing a constant infusion. The primary route of T3S disposal was by deiodination with an efficiency of 92%. The administration of propylthiouracil (PTU, 300 mg every 6 h x 5 days) and iopanoic acid (IA, 500 mg every day x 5 days), both inhibitors of deiodination, decreased clearance compared to control (87 +/- 9 L/D, P less than 0.01 and 46 +/- 10 L/D, P less than 0.002, respectively). A 3-day fast also reduced the clearance of T3S (56 +/- 10 L/D, P less than 0.002). All three maneuvers decreased the total urinary deiodination fraction of tracer T3S (control 91 +/- 2%, PTU 70 +/- 9%, P less than 0.04, IA 26 +/- 3%, P less than 0.0001, and fasting 58 +/- 6%, P less than 0.01). A strong correlation between T3S clearance and deiodination was noted for fasting and IA only (r = 0.78, P less than 0.003). However, no relationship between clearance and deiodination was noted with PTU administration presumably as a result of a compensatory increase in biliary losses of T3S. The urinary thyronine excretion pattern demonstrated the presence of small amounts of labeled T3,3,3'-T2, and 3,3'-T2S with the major metabolite being T3S itself. TSH levels were not influenced by the infusion of stable T3S designed to achieve a serum value greater than 50 ng/dL. No absorption of intact T3S was detected after its oral ingestion. In conclusion, T3S is rapidly cleared from the serum, primarily by deiodination, may undergo nondeiodinative disposal when hepatic deiodination is inhibited by PTU but not with IA or fasting, and has no intrinsic biological activity. Thus, T3S may serve as a metabolite of T3 for its rapid deiodinative disposal. Although the precise role T3S plays in human thyroid hormone metabolism has not been defined, the metabolic characteristics of T3S appear similar to that of an unidentified alternate T4 metabolite formed in low T3 states of fasting and nonthyroidal illness.

Administration, Oral↗
PubMed1990

Intermediary metabolism in the Swarm rat chondrosarcoma chondrocyte.

The rat chondrosarcoma chondrocyte has the dual capacity to metabolize glucose (mainly via glycolysis) and glutamine (via an oxidative pathway). Glutamine metabolism, unlike that of glucose, is unable to sustain intracellular ATP concentrations. Glutamine consumption by the chondrosarcoma chondrocyte, however, is significantly in excess of its utilization as an amide-group donor in hexosamine synthesis, implying a novel and major role in cell metabolism.

Adenine Nucleotides↗
PubMed1990

The block to transcription elongation is promoter dependent in normal and Burkitt's lymphoma c-myc alleles.

Aberrant c-myc expression patterns occur in human Burkitt's lymphoma cells, which consistently exhibit c-myc chromosomal translocations, mutations within and flanking the translocated allele, a loss of the block to transcription elongation in exon 1, and a promoter shift to use of the upstream P1 promoter. To define the mechanism responsible for the loss of transcription elongation blockage and resulting c-myc deregulation in Burkitt's lymphoma, we analyzed transcription patterns after transfer of normal and Burkitt's lymphoma c-myc alleles into murine cells and Xenopus oocyte germinal vesicles. We have determined that although the mutations within and surrounding several Burkitt's lymphoma c-myc alleles are not sufficient, in themselves, to abrogate the transcription elongation block, transcription initiation from the P2 promoter may be necessary to obtain the block to transcription elongation. To test directly the role of c-myc promoters in programming transcription elongation blockage, we analyzed transcription patterns from in vitro mutagenized c-myc genes containing deletions of either the P1 or P2 promoter. These data confirm that P1-initiated c-myc transcripts do not terminate at discrete sites near the 3' end of exon 1, whereas P2-initiated transcripts either terminate or read through the transcription block signals. Therefore, overexpression and/or constitutive expression from the c-myc P1 promoter may contribute to increased readthrough transcription in Burkitt's lymphoma cells and, hence, to aberrant expression patterns or levels of c-myc steady-state transcripts. In addition, the ability of normal cells to modulate c-myc P2-initiated transcription to either read through or to block elongation provides a fine control mechanism over c-myc steady-state RNA levels.

Alleles↗
PubMed1990

Applications of a new chemiluminometric thyrotropin assay to subnormal measurement.

A new immunochemiluminometric TSH assay (ICMA) was shown to offer improved analytical (+2 SD of zero) and functional (20% interassay coefficient of variation) sensitivity [0.003 vs 0.045 +/- 0.005 (+/- SE; range, 0.01-0.07); 0.018 vs. 0.23 +/- 0.02 (range, 0.10-0.35, mU/L); analytical vs. functional sensitivity limit for the ICMA vs. 10 other TSH immunometric assays, respectively]. The ICMA was used to study the physiological relationship between serum TSH and free T4 [as reflected by free T4 index (FT4I)] values at both steady state and 14 days after acute pharmacological T4 administration (3 mg oral T4 load plus 0.3 mg daily). At steady state, an inverse log/linear relationship was found between serum TSH and FT4I values (log TSH = 2.56 - 0.022 FT4I; r = 0.84; P less than 0.001). Ten to 14 days after acute T4 suppression in 5 euthyroid subjects, serum TSH/FT4I levels had plateaued after decreasing in parallel to the slope of the steady state relationship, suggesting that the degree of T4 suppression of TSH can be predicted from an individual's pituitary TSH/free T4 set-point and the magnitude of the serum T4 elevation achieved. Ambulatory and hospitalized patient sera, previously identified as having low (less than 0.1 mU/L) TSH levels by a less sensitive assay, were restudied by the TSH ICMA. Normal TSH values ranged from 0.39-4.6 mU/L, whereas the majority of hyperthyroid patients [52 of 54 (96% ambulatory) and 22 of 23 (96%, hospitalized)] had undetectable (less than 0.005 mU/L), basal TSH levels and absent TRH stimulated TSH responses. In contrast, most (32 of 37; 86%) of hospitalized nonhyperthyroid patients with low (less than 0.1 mU/L) TSH values due to nonthyroidal illness or glucocorticoid treatment had detectable (greater than 0.01 mU/L) basal and TRH stimulated TSH levels. The positive relationship between basal and TRH-stimulated TSH levels was shown to extend down to the detectability limit of the assay (0.005 mU/L), which further supported the authenticity of the subnormal TSH ICMA measurements. The new TSH ICMA is considered to represent the first of a third generation of clinical TSH assays, since it has a functional (interassay) sensitivity that is 2 orders of magnitude greater than that of typical first generation TSH RIAs and 1 order of magnitude greater than current second generation TSH immunometric methods. Such third generation TSH assays will facilitate both the optimization of T4 therapy as well as the diagnosis of hyperthyroidism in hospitalized patients with nonthyroidal illness.

Adult↗
PubMed1990

Exercise body surface potential mapping in single and multiple coronary artery disease.

Body surface ST integral maps were recorded in 36 coronary artery disease (CAD) patients at: rest; peak, angina-limited exercise; and, 1 and 5 min of recovery. They were compared to maps of 15 CAD patients who exercised to fatigue, without angina, and eight normal subjects. Peak exercise heart rates were similar (NS) in all groups. With exercise angina, patients with two and three vessel CAD had significantly (p less than 0.05) greater decrease in the body surface sum of ST integral values than patients with single vessel CAD. CAD patients with exercise fatigue, in the absence of angina, had decreased ST integrals similar (NS) to patients with single vessel CAD who manifested angina and the normal control subjects. There was, however, considerable overlap among individuals; some patients with single vessel CAD had as much exercise ST integral decrease as patients with three vessel CAD. All CAD patients had persistent ST integral decreases at 5 min of recovery and there was a direct correlation of the recovery and peak exercise ST changes. Exercise ST changes correlated, as well, with quantitative CAD angiographic scores, but not with thallium perfusion scores. These data suggest exercise ST integral body surface mapping allows quantitation of myocardium at ischemic risk in patients with CAD, irrespective of the presence or absence of ischemic symptoms during exercise. A major potential application of this technique is selection of CAD therapy guided by quantitative assessment of ischemic myocardial risk.

Adult↗
PubMed1990

Transcription elongation and eukaryotic gene regulation.

Each step in the synthesis of functional transcript by RNA polymerase II provides a level at which gene expression can be regulated. Control over the elongation phase of transcription is a recognized regulatory mechanism in prokaryotes; however, only recently have examples of conditional transcription elongation blockage been reported in eukaryotic cellular genes. In several cases, control over transcription elongation clearly contributes to the regulated expression of these genes. Indeed, reports that transcription by RNA polymerase II is initiated and paused on many Drosophila promoters, prior to induction of gene expression, suggests that release of an arrested polymerase, as opposed to polymerase recruitment to a disengaged promoter, may be the key regulatory step for many genes thought to be controlled by transcription initiation (Rougvie & Lis, 1988). RNA polymerase II undergoes modifications, such as association with ancillary elongation factors and phosphorylation of its large subunit carboxy terminal domain (CTD), at stages subsequent to recruitment to a promoter and establishment of a pre-initiation complex (Reinberg & Roeder, 1987; Rappaport et al., 1987; Payne et al., 1989; Laybourn & Dahmus, 1989). It is possible that modifications such as these, or others occurring prior to, during or following transcription initiation, may alter the holoenzyme's transcription elongation properties, to allow recognition or read-through of elongation block signals within a transcription unit. In this review, we will present features of transcription elongation blockage in several eukaryotic cellular genes in the context of our understanding of attenuation and premature transcription termination in prokaryotic and viral genes. We will also present evidence supporting the model that modifications to the RNA polymerase II transcription complex are pivotal to the control of transcriptional at the level of elongation.

Animals↗
PubMed1989

Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS)

STUDY OBJECTIVE: To determine alterations in serum thyroid hormone indices in patients with human immunodeficiency virus (HIV) infection. DESIGN: Prospective, single-blind study. SETTING: Large metropolitan hospital where 20% of all patients with the acquired immunodeficiency syndrome (AIDS) in Los Angeles are treated. PATIENTS: Twenty-six inpatients with bronchoscopy-proven Pneumocystis carinii pneumonia and AIDS. Outpatients included 10 persons seropositive for HIV, 10 with AIDS-related complex, and 10 with AIDS. MAIN RESULTS: There were 19 survivors and 7 nonsurvivors of P. carinii infection. Serum triiodothyronine (T3) values generally remained normal until hospitalization, with nonsurvivors having lower values than survivors (0.56 +/- 0.1 nmol/L compared with 1.3 +/- 0.1 nmol/L, P less than 0.002, respectively). Reverse triiodothyronine (rT3) levels were low in persons with AIDS-related complex (0.21 +/- 0.02 nmol/L, P less than 0.001) and in AIDS outpatients (0.17 +/- 0.02 nmol/L, P less than 0.001). Normalization of rT3 occurred after patients were hospitalized (0.28 +/- 0.01 nmol/L). Serum thyroxine-binding globulin values rose with progression of HIV infection (seropositive, 369.7 +/- 18.1 nmol/L, P less than 0.005; AIDS-related complex, 419.1 +/- 37.0 nmol/L, P less than 0.005; AIDS, 423.3 +/- 31.9 nmol/L, P less than 0.005; survivors, 476.3 +/- 24.6 nmol/L, P less than 0.001), whereas nonsurvivors had normal values. All values are compared with normal values (T3, 2.3 +/- 0.04 nmol/L; rT3, 0.28 +/- 0.01 nmol/L; thyroxine-binding globulin, 288.2 +/- 6.9 nmol/L). CONCLUSIONS: Infection with HIV produces unique alterations in thyroid function. A progressive decline in rT3 and elevation in thyroxine-binding globulin accompany advancing HIV infection. The persistence of a normal T3 despite progression of HIV infection may contribute to weight loss. A low serum T3 on admission correlates with mortality.

AIDS-Related Complex↗
PubMed1989

Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.

To elucidate the mechanisms involved in altering serum 3,3',5'-triiodothyronine (rT3) levels with absolute or relative low 3,5,3'-triiodothyronine (T3) states in man, agents capable of lowering circulating T3 levels were sequentially administered to six euthyroid subjects. These agents included propylthiouracil (PTU) (300 mg/6 h X 5 d), dexamethasone (DEX) (2 mg/6 h X 5 d), and thyroxine (T4) (3.0 mg load and 0.3 mg/d X 5 d). [125I] rT3 clearance rates and rT3 production rates were then determined. Increased serum rT3 levels and rT3/T4 values occurred with both PTU and DEX as compared with control, while T4 increased serum rT3 but did so without changing rT3/T4 values. The rT3 clearance rate was significantly decreased by PTU without altering production rate, while DEX increased the rT3 production rate without altering the rT3 clearance rate. T4 administration did not change rT3 clearance but proportionately increased rT3 production. These responses indicate that circulating rT3 predominantly originates from a non-PTU inhibitable deiodinase enzyme system located in extrahepatic tissues. This enzyme system appears to have a high capacity and low affinity for T4 and can be stimulated by DEX administration.

Adult↗
PubMed1988

Body surface potential maps with low-level exercise in isolated left anterior descending coronary artery disease.

One hundred and twenty-lead body surface potential maps (BSPMs) were recorded at rest, at immediate cessation of exercise and after 1 (early) and 5 minutes (late) of recovery in 14 patients with isolated, critical, left anterior descending (LAD) coronary artery stenosis. Exercise endpoints, at an average peak rate of 98 +/- 13, were usual pain worsening in 13 LAD patients, and diagnostic ST depression in lead V5 in 1 patient. Twelve patients also had positive thallium scans. BSPMs were also recorded in 8 normal subjects who exercised to peak heart rates similar to those of the LAD subjects. Spatially, there were similar exercise changes in QRS and ST-segment integral patterns over the precordium and inferior torso in both groups. These were transient in the control group but persisted to late recovery in the LAD group, particularly for ST integral. Quantitatively, multivariate analysis revealed significant temporal differences between the 2 groups. However, the only independent BSPM variable was the sum of ST integral decrease, averaging --2,323 +/- 1,809 microV.s for normal patients between rest and immediate cessation of exercise, compared with -3,828 +/- 2,329 microV.s for the LAD patients (p less than 0.05). Late recovery minus rest difference averaged -1,264 +/- 1,080 microV.s for normal subjects and -2,575 +/- 1,844 microV.s for LAD patients (p less than 0.01). To control for the physiologic changes of exercise, the ST integral temporal differential maps of the normal subjects were subtracted from those of the LAD patients and the sum of negative intergroup differences was assumed to reflect only ischemia. Correlation of ST integral ischemia values at immediate cessation of exercise and late recovery was high (r = 0.88); however, intertechnique correlations of the BSPM variables with quantitative angiographic scores and thallium perfusion scan scores revealed generally low r values (range 0 to 0.52). These data demonstrate that ischemic repolarization changes are detectable and quantifiable by BSPM at low levels of cardiac stress in patients with 1-vessel disease when the usual electrocardiographic criteria of myocardial ischemia are frequently absent. The data further suggest that ST integral changes reflective of myocardial ischemia persist well after the exercise recovery period and that they are complementary to, rather than substitutionary for, other indirect measures of myocardial ischemia.

Adult↗
PubMed1988

Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients.

In either an ambulatory or a hospitalized patient setting, a normal serum sensitive thyrotropin (TSH) value is strongly suggestive of euthyroidism if the patient has intact hypothalamic-pituitary function and is not receiving drugs known to suppress pituitary TSH secretion. In stable ambulatory patients, an abnormal sensitive TSH value is strongly suggestive of clinical or subclinical thyroid hormone excess or deficiency, which can be confirmed by a free thyroxine (T4) index (FT4I) and evaluation for antimicrosomal antibody (AMA) as a marker of autoimmune thyroid disease. In a hospitalized patient, an abnormality in sensitive TSH or FT4I does not necessarily indicate a thyroid problem but may merely reflect a nonthyroidal illness or glucocorticoid or dopamine treatment. A thyrotropin releasing hormone (TRH) test may be needed to diagnose hyperthyroidism in a hospitalized patient with a basal sensitive TSH level of less than 0.1 microU/ml because a detectable TRH response contraindicates hyperthyroidism whereas hyperthyroid patients with nonthyroidal illness have the expected absent response. In a hospitalized patient, hypothyroidism must be diagnosed on the basis of both a high TSH level and a low FT4I because an isolated high TSH value may merely reflect the recovery phase of a nonthyroidal illness. No clinical urgency exists for establishing a diagnosis of subclinical hypothyroidism in a hospitalized patient; definitive determination of thyroid status can be deferred until recovery and discharge.

Autoantibodies↗