Search PubMed⌕ Search

Biomedical subjects

T Thomas

Publications and source records attributed to T Thomas.

At least 253 records · Page 14Linked to original sources
PubMed1992

Antiestrogenic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin: tissue-specific regulation of estrogen receptor in CD1 mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated aromatic hydrocarbon with teratogenic and carcinogenic properties. Previous studies in our and other laboratories have demonstrated that TCDD has antiestrogenic properties. In order to elucidate the mechanism of action of TCDD on estrogen sensitive tissues, we studied its effects on serum estradiol and estrogen receptor (ER) levels in liver and uteri of CD1 mice. Treatment with TCDD did not result in alterations of serum estradiol levels at any of the doses tested (1.0-30 micrograms/kg). In contrast, TCDD treatment induced a dose-dependent decrease in hepatic and uterine ER protein as determined by an enzyme immunoassay and equilibrium binding assays. A decrease in cytosolic and nuclear ER levels in uteri occurred as early as 24 hr after initial treatment with 30 micrograms/kg TCDD and recovery occurred by 14 days. Hepatic cytosolic and nuclear ER also decreased at a dose of 30 micrograms/kg TCDD at 24 hr after treatment, but recovery occurred only by 21 days. Studies in ovariectomized mice indicate that the regulation of hepatic ER by TCDD is independent of ovarian factors, but ovariectomy inhibited the downregulation of uterine ER by TCDD. Furthermore, determination of TCDD-induced cytochrome P-450 levels indicates that the downregulation of uterine ER is uncoupled from induction of hepatic cytochrome P-450. This study indicates that the antiestrogenic effects of low doses of TCDD are mediated through its ability to decrease hepatic and uterine ER and are not due to alterations in serum estradiol levels. Our results on ovariectomized mice indicate that TCDD-induced downregulation of ER is tissue specific and may involve different mechanisms at transcriptional or posttranscriptional levels.

Animals↗
PubMed1992

The potentiation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by tamoxifen in female CD1 mice.

Tamoxifen, an antiestrogen commonly used in breast cancer therapy, potentiated the lethality of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when coadministered to female CD1 mice, despite the virtual lack of toxicity associated with the administration of tamoxifen alone. The 58-day ip LD50 of TCDD was reduced from 330 to 185 micrograms/kg by sc administration of 1 mg/kg/day tamoxifen. A significant dose-response relationship was observed for the potentiating effect of tamoxifen on TCDD lethality. All mice receiving TCDD developed a centrilobular pattern of hepatocellular degeneration and necrosis with perivascular infiltration of inflammatory cells. Clinical chemistry parameters were indicative of liver disease. Abnormalities in mice receiving tamoxifen plus TCDD were similar to, but more severe than, those in mice receiving TCDD only. Seven days after administration of [14C]TCDD, liver retention of radioactivity was increased 80-100% by coadministration of tamoxifen. This elevated retention was associated with a 50 and 37% decrease in excretion of radioactivity by the urinary and fecal routes, respectively. Our results suggest that the potentiation of TCDD toxicity by tamoxifen is associated with decreased excretion of TCDD, leading to elevated liver retention and enhanced severity of liver pathology.

Animals↗
PubMed1992

Reversal of the abnormal development of T cell subpopulations in the thymus of autoimmune MRL-lpr/lpr mice by a polyamine biosynthesis inhibitor.

Polyamines--putrescine, spermidine, and spermine--are a group of positively charged organic molecules that are present in all living cells. They are important regulators of cell growth and differentiation, but the precise mechanism of their action is not known. Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines. Recent studies demonstrated that down-regulation of polyamine biosynthesis by irreversible inhibition of ODC with difluoromethylornithine (DFMO0 is a novel therapeutic approach for the treatment of murine lupus in autoimmune MRL-lpr/lpr mice. Since murine lupus in this strain is associated with a major alteration in thymic T cell subopulations, we questioned whether abnormal polyamine biosynthesis contributes to aberrant T cell maturation in the thymus of MRL-lpr/lpr mice. Thymocytes were analyzed for cell surface markers, CD4 and CD8 by 2-color flow cytometry using their respective monoclonal antibodies. The proportion of thymocyte subsets in disease-free mice (8-10 week of age) was approximately 72% double positive (DP; CD4+CD8+) cells, 5-7% double negative (DN; CD4-CD8-) cells, 11-16% CD4+ cells and 7-8% CD8+ cells. At 14 weeks of age, a stage of clinical disease expression, thymocytes were marked by the presence of approximately 40% DN cells and approximately 25% DP cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

[Sacral perineural cysts. Contribution of magnetic resonance imaging].

In a 41-year old woman complaining of episodic bilateral sciatic pain, MRI showed large sacral cysts developed in the pelvis. The fact that these cysts communicated with the subarachnoidal spaces was not clearly demonstrated by CT. The mechanism underlying the development of this perineural variety of extradural cysts is discussed.

Adult↗
PubMed1992

Cerebral expression of transthyretin: evolution, ontogeny and function.

This paper reviews studies on the synthesis and secretion of the thyroid hormone-binding protein, transthyretin by the choroid plexus. The secretion of transthyretin by the choroid plexus into the cerebrospinal fluid may have an important function in the transport of thyroxine from the blood to the brain. The transthyretin gene is expressed in the choroid plexus of most vertebrates and synthesis of this protein may have evolved in the brain before the liver.

Animals↗
PubMed1992

The reflex ventilatory responses of conscious, newborn rats to alternations of inspiratory oxygen concentration.

We examined the effect of a dynamic, hypoxic stimulus upon the reflex respiratory responses of 15, conscious rat pups on post-natal days 5-7 in order to ascertain the influence of a non-adapting peripheral chemoreceptor discharge upon respiratory control during hypoxia in the newborn. Respiration was measured as integrated airflow into and out of a body plethysmograph. The respiratory response to 6 minutes of a 16-breath cycle (approximately 5 s) in FiO2 between 0.21 and 0.10 (alternating hypoxia) was compared with the response to 6 min of a constant FiO2 of 0.12 (non-alternating hypoxia). Ventilation increased significantly from a control level of 0.12 +/- 0.02 ml/s (mean +/- SEM) to 0.18 +/- 0.02 and 0.17 +/- 0.02 ml/s in non-alternating and alternating hypoxia runs respectively during the first minute (phase 1) of each run, after which ventilation in both run types fell progressively and significantly back towards control levels to reach, by the sixth minute (phase 2), 0.13 +/- 0.01 and 0.12 +/- 0.02 ml/s respectively. No significant difference was found between the levels of ventilation in non-alternating hypoxia and alternating hypoxia during either phase 1 (P greater than 0.10) or phase 2 (P greater than 0.60). No significant alternation was found in any respiratory variable at the frequency of the 16-breath hypoxic cycle during either phase 1 or phase 2 of non-alternating hypoxia. However, a significant alternation, at this frequency, of 37 +/- 6% (P less than 0.05 compared to control) was found in ventilation during phase 1 of alternating hypoxia which was further increased to 62 +/- 8% (P less than 0.05 compared to phase 1) during phase 2. In phase 1 the alternation was due primarily to significant alternation in inspiratory time whilst in phase 2 significant alternation also occurred in tidal volume, expiratory time and mean inspiratory flow. Our results show that the magnitude of hypoxic ventilatory depression (HVD) in the newborn is not affected by an alternating hypoxic stimulus and that, during phase 2, ventilation can still be stimulated by peripheral chemoreceptors. We suggest that peripheral chemoreceptor adaptation is unlikely to be a major cause of HVD in the newborn rat and that the magnitude of HVD is, in part, the result of a competitive interaction between peripheral chemoreceptor stimulation and a centrally-mediated inhibitory action of hypoxia.

Animals↗
PubMed1991

Ionic and ligand-specific effects on the DNA binding of progesterone receptor bound to the synthetic progestin R5020 and the antiprogestin RU486.

Antiprogestin and other antihormones are valuable therapeutic agents in hormone-responsive cancers. A fundamental mechanism in the action of antiprogestin is its binding to PR,3 an intracellular protein that mediates the action of progesterone by direct interaction at the regulatory sites of responsive genes. To elucidate the mechanism of action of PR bound to agonistic and antagonistic ligands, we determined the binding affinity of rabbit uterine PR bound to R5020 and RU486, respectively, with different DNA sequences. We used 2 recombinant plasmid DNAs, pDHf14 and pDHf2, with 60- and 23-base pair inserts of potential Z-DNA-forming (dA-dC)n.(dG-dT)n sequences, respectively, parental plasmid pDPL6 with no insert, calf thymus DNA, and several synthetic polynucleotides in this study. The concentration of DNA required to elute 50% of the receptor bound to DNA-cellulose (EC50) was used as a measure of the relative binding affinity of the receptor for DNA. EC50 values of plasmids pDHf14 and pDHf2 were 1.2 +/- 0.5 (SD) and 2.5 +/- 0.6 micrograms/ml, respectively, for PR bound to R5020. In contrast, EC50 for control plasmid was 350 micrograms/ml. PR.R5020 had lower affinity for calf thymus DNA and polynucleotides compared with pDHf2 and pDHf14. Receptors complexed with the antiprogestin RU486 had lower affinity for the plasmids; EC50 values were 2.4 +/- 0.4 and 10 +/- 1 microgram/ml, respectively, for pDHf14 and pDHf2. This ligand-specific difference in DNA binding was amplified by the presence of 5 mM Mg2+ or Ca2+. The relative binding affinity of PR.R5020 to pDHf14 was 6- and 7-fold higher than that of PR.RU486, in the presence of 5 mM Mg2+ and Ca2+, respectively. These results show that PR.RU486 has lower binding affinity for specific DNA sequences than PR.R5020, but the binding affinity of both receptors is in a range that cannot preclude competitive interactions at the DNA recognition site. The effects of Mg2+ and Ca2+ on PR binding to DNA further suggest that these cations could affect PR recognition of DNA in a ligand-specific manner.

Animals↗
PubMed1991

Polyamine-induced B-DNA to Z-DNA conformational transition of a plasmid DNA with (dG-dC)n insert.

We investigated the ability of natural polyamines putrescine, spermidine, and spermine to provoke a left-handed Z-DNA conformation in a recombinant plasmid (pDHg16) with a 23-base pair insert of (dG-dC)n.(dG-dC)n sequences. Using a monoclonal anti-Z-DNA antibody (Z22) and an enzyme-linked immunosorbent assay protocol, we found that spermidine and spermine were capable of converting pDHg16 to the Z-DNA form. The concentrations of spermidine and spermine at the midpoint of the B-DNA to Z-DNA transition were 280 and 5 microM, respectively, in buffer containing 50 mM NaCl, 1 mM sodium cacodylate, and 0.15 mM EDTA, pH 7.4. A plot of ln[Na+] versus ln [spermine4+], where [Na+] is the bulk NaCl concentration and [spermine4+] is the spermine concentration at the midpoint of the B-DNA to Z-DNA transition, gave a straight line with a slope of 1.2. Structural specificity was clearly evident in the efficacy of three spermidine homologs to induce the Z-DNA conformation in pDHg16. Putrescine and acetylspermidines had no effect on the conformation of the plasmid DNA up to a 3 mM concentration. Control experiments with the parental plasmid (pDPL6) showed no binding of the plasmid DNA with Z22. These results indicate that spermidine and spermine are capable of provoking the left-handed Z-DNA conformation in small blocks of (dG-dC)n sequences embedded in a right-handed B-DNA matrix. Since blocks of (dG-dC)n sequences are found in certain native DNAs, conformational alterations of these regions to the Z-DNA form in the presence of polyamines may have important gene regulatory effects.

Animals↗
PubMed1991

Restoration of the DNA binding activity of estrogen receptor in MRL-lpr/lpr mice by a polyamine biosynthesis inhibitor.

Diverse data link estrogen influences to both the frequency and severity of systemic lupus erythematosus in humans and to murine lupus. A fundamental mechanism of action of estrogen involves the interaction of the hormone with its receptor protein, which is then transformed into the DNA binding form. We measured the concentration of uterine estrogen receptor and its DNA binding in normal BALB/c mice, lupus-prone MRL-lpr/lpr mice, and MRL-lpr/lpr mice that had been treated with 1% difluoromethylornithine (DFMO). Uterine estrogen receptor levels in 20-week-old mice from the 3 groups were not significantly different. In contrast, DNA binding activity was significantly higher in BALB/c mice (mean +/- SD 775 +/- 100 fmoles/mg of DNA) than in untreated MRL-lpr/lpr mice (80 +/- 16 fmoles/mg of DNA) (P less than 0.001). Treatment with 1% DFMO was associated with an increase in uterine estrogen receptor DNA binding (1,100 +/- 218 fmoles/mg of DNA) in MRL-lpr/lpr mice (P less than 0.001). Polyamine levels were 2-6-fold higher in the uterine tissues of untreated MRL-lpr/lpr mice compared with the BALB/c mice and were significantly reduced by DFMO treatment. Our results link uterine polyamine production to a dysfunction of the estrogen receptors in MRL-lpr/lpr mice. Reduction of the polyamine level by the irreversible inhibition of ornithine decarboxylase with DFMO restores estrogen receptor function.

Animals↗
PubMed1991

Variations in amplification and expression of the ornithine decarboxylase gene in human breast cancer cells.

The polyamine biosynthetic pathway plays a critical role in the growth of human breast cancer cells. Ornithine decarboxylase (ODC) is a key enzyme in polyamine biosynthesis. To understand the regulation of ODC activity and polyamine accumulation in breast cancer cells, we studied amplification and expression of the ODC gene in four breast cancer cell lines. ODC gene dosage was analyzed by Southern blot hybridization and was 4- to 12-fold higher in T-47D, MDA-MB-231, and BT-20 cell lines than in the MCF-7 cell line. ODC mRNA level was 2- to 3-fold higher in BT-20 and MDA-MB-231 cell lines than in the other two lines. We also measured ODC activity and polyamine concentration in these cell lines, and determined their sensitivity to an ODC inhibitor, difluoromethylornithine (DFMO). BT-20 cells showed significantly higher ODC activity and polyamine concentrations than the other three cell lines. BT-20 cells were resistant to the growth inhibitory effect of DFMO even at 4 mM concentration, whereas the proliferation of MCF-7, T47D, and MDA-MB-231 cells was inhibited by this drug. These results suggest that different transcriptional and post-transcriptional mechanisms control the regulation of ODC gene expression in breast cancer cell lines.

Adenocarcinoma↗
PubMed1991

Acute plastic deformation of the ulna in a skeletally mature individual.

Acute plastic deformation of a bone refers to traumatic bending or bowing without a detectable cortical defect. We present a case that is unusual in that bowing of the ulna occurred in a skeletally mature individual and was associated with injury to the distal radioulnar joint. In this patient, the symptoms were severe enough to warrant an ulnar osteotomy. The patient regained satisfactory function. Acute plastic deformity should be suspected whenever abnormal curvature of a long bone is noted, even in adults. If the distal radioulnar joint is dislocated, the deformation should be corrected as soon as possible to avoid permanent loss of forearm rotation.

Adolescent↗
PubMed1991

Effects of spherical and astigmatic defocus on acuity and contrast sensitivity: a comparison of three clinical charts.

Two contrast sensitivity charts (Vistech and Pelli-Robson) have become available to the eye care practitioner. Their value as clinical tools for the assessment of visual function may be enhanced because of either an insensitivity to the effects of optical focus or a hypersensitivity to defocus. We compared the sensitivity to defocus of these charts to the traditional Snellen chart by examining the effect of up to +/- 5.00 D of spherical and astigmatic defocus on performance with each chart. In order to simulate the two types of clinical examination scenarios, tests were performed both with and without mydriatic/cycloplegic agents. The Pelli-Robson contrast sensitivity chart was very resistant to the effects of all types of optical defocus. As predicted, the high spatial frequencies on the Vistech chart were sensitive to defocus. However, although contrast sensitivities for the low frequencies were affected less, optical defocus produced significant decreases in low frequency Vistech contrast sensitivity. In addition, the Vistech chart was very insensitive to axis 180 blurring lenses. There was no indication that either contrast sensitivity chart was more sensitive to defocus than the standard Snellen chart.

Adult↗
PubMed1991

Plain abdominal radiography in the detection of acute medical and surgical disease in children: a retrospective analysis.

A retrospective review was performed to determine the utility of plain abdominal radiographs in evaluating children presenting to the emergency department. Clinical features, radiographic interpretation, and final diagnoses of 431 patients seen over one year were recorded. One hundred three (24%) patients had major diseases (ventriculoperitoneal shunt malfunction, foreign body ingestion, appendicitis, intussusception, bowel obstruction, necrotizing enterocolitis, toxic megacolon, blunt abdominal trauma, pyloric stenosis, and Hirschsprung's disease), while the remaining 328 (76%) had minor diseases. Radiographs were categorized as diagnostic, suggestive, normal, incidental, or misleading, with respect to the patient's final diagnosis. No single clinical feature was able to detect all diagnostic radiographs in patients with major diseases. Limiting radiographs to patients with prior abdominal surgery, suspected foreign body ingestion, abnormal bowel sounds, abdominal distention, or peritoneal signs identified all patients with radiographs diagnostic of a major disease while eliminating 48% of studies ordered. Our results suggest that restricting abdominal roentgenograms to patients with at least one of these features will detect most diagnostic radiographs in children with acute abdominal diseases.

Abdomen, Acute↗
PubMed1991

Macronutrient intake and utilization by rats: interactions with type I adrenocorticoid receptor stimulation.

Corticosterone-free (adrenalectomized, ADX) and intact rats were offered experimentally compounded diets in which 65% of available calories were supplied by a single macronutrient (single-diet study). ADX impaired the intake, weight gain (especially as body fat), and efficient utilization of high-protein and high-fat diets. In contrast, no behavioral, metabolic, or compositional changes could be found among ADX rats maintained on a diet high in carbohydrates. When ADX rats were given separate sources of macronutrients (self-selection study) they did not self-select a high-carbohydrate diet. Instead, they displayed a strong fat avoidance and a relative increase in protein intake, the macronutrient they utilize least efficiently. Separate groups of ADX animals were continuously infused with 25 or 125 micrograms.kg-1.day-1 aldosterone, a specific type I adrenocorticoid receptor agonist. Type I receptor stimulation eliminated all ADX-related deficiencies found in the single-diet and self-selection studies: caloric intake, feeding efficiency, carcass composition, and macronutrient preferences were restored to or beyond the corresponding values of adrenal-intact rats. The normal rat's ability to ingest and utilize macronutrients optimally is dependent on corticosterone's stimulation of type I receptors.

Adrenal Glands↗
PubMed1991

The effects of polyamines on the immunogenicity of polynucleotides.

Polyamines--putrescine, spermidine, and spermine--are small organic cations that are present in all living cells. Recent studies revealed that polyamines could provoke a left-handed Z-DNA conformation in poly(dA-dC).poly(dG-dT) and related alternating purine-pyrimidine sequences. In order to examine whether polyamine-induced Z-DNA conformation of poly(dA-dC).poly(dG-dT) is capable of eliciting anti-Z-DNA antibodies, we immunized rabbits with poly(dA-dC).poly(dG-dT) in the presence and absence of spermidine and spermine. Rabbits immunized with the polynucleotide alone produced antibodies reacting toward poly(dA-dC).poly(dG-dT) and heat-denatured calf thymus DNA (ssDNA). In contrast, immunization with poly(dA-dC).poly(dG-dT) complexed with spermidine or spermine produced antibodies reacting with Z-DNA in addition to those binding toward poly(dA-dC).poly(dG-dT) and ssDNA. Antibodies elicited by polynucleotide.polyamine complexes had no reactivity toward polyamines. Solution inhibition studies suggested that anti-poly(dA-dC).poly(dG-dT), anti-ssDNA and anti-Z-DNA antibodies are distinct populations that favor each one of these antigens. Our results suggest that natural polyamines are capable of altering the immunogenicity of polynucleotides by mechanisms involving the stabilization of Z-DNA conformation. This result may have implications in the recent findings of high levels of polyamines and anti-Z-DNA antibodies in the sera of lupus patients and autoimmune mice.

Animals↗
PubMed1991

Open versus closed nailing of femoral fractures in the polytrauma patient.

Thirty-four patients with severe multiple injuries underwent either open or closed nailing of 35 femoral fractures. Open nailing was performed in 17 femurs and closed nailing in 18 femurs. The average abbreviated injury score was 27 in both the open group (range: 17-45) and closed group (range: 22-36). Soft tissue injuries were present in eight (47%) cases in the open group compared to three (16%) in the closed group. The treatment protocol was similar in both groups. Intramedullary nailing was delayed an average of 11 days in the closed group. This was significantly different than the open group where the average time to nailing was less than 24 hours (p less than 0.001). Reamed nails were used in all cases except for two in the closed group. The median time to fracture healing was 5.0 months in the open group and 4.1 months in the closed group, with an average follow-up of 18 months in both groups. Two cases required reoperation (one nonunion and one shortening at the fracture site). Both these cases were in the open group. There were no superficial or deep infections in either group. Closed reamed intramedullary nailing is recommended for treatment of diaphyseal femur fractures in patients with severe coexistent injuries. Open nailing should be reserved for cases in which an adequate reduction cannot be achieved by closed methods.

Adult↗