Search PubMed⌕ Search

Biomedical subjects

T Thomas

Publications and source records attributed to T Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2001

Estrogen and raloxifene activities on amyloid-beta-induced inflammatory reaction.

The prevalence of Alzheimer's disease (AD) in women is double that of men. Several studies indicate that use of estrogen after menopause by women may reduce the risk of developing AD. The risk of estrogen-dependent tumors associated with estrogen replacement therapy has prompted the use of alternatives, like the SERM raloxifene, which exert estrogen agonist effects on selected target tissues. Whether SERMS provide cognitive and cardiovascular benefits comparable to those of estrogens is an active area of investigation in women's health. A chronic inflammatory process is central to the pathology of Alzheimer's disease. Using an animal model we compared the anti-inflammatory activity of orally administered estrogens (2 mg/kg) and raloxifene (3 mg/kg) in ovariectomized rats. Morphological analysis of Abeta(1-40)-induced inflammatory reaction featured adhesion and transmigration of leukocytes across the vessel wall, endothelial disruption, and platelet activation. Estrogen showed remarkable anti-inflammatory action, whereas raloxifene had no significant beneficial effect. Inhibition of the inflammatory process may contribute to the reported efficacy of estrogen in the treatment of AD.

Administration, Oral↗
PubMed2001

Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications.

Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using polyamine biosynthetic inhibitors indicate that alterations in cellular polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing polyamine biosynthetic enzymes support a role of polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with polyamine biosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of polyamine action in cell proliferation. Consistent with the role of polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during polyamine catabolism. In addition, the ability of polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in polyamine catabolic or efflux pathways. A large body of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, polyamine analogues as well as oligonucleotide/polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer.

Animals↗
PubMed2001

Autosomal dominant familial frontonasal dermoid cysts: a mother and her identical twin daughters.

A dermoid cyst is an ectodermal cyst that contains an epithelial lining as well as adnexal structures, and may occur in numerous areas of the body. The nasal dermoid accounts for 1% of all dermoid cysts and 3-12% of head and neck dermoid cysts. While there have been familial cases reported, a genetic inheritance for nasal dermoids has not been suggested. We present the first reported case of a mother and her identical twin daughters who were all found to have evidence of frontonasal dermoid cysts. Our case and a review of literature seem to implicate an autosomal dominant inheritance in certain instances of nasal dermoids.

Child, Preschool↗
PubMed2001

Evidence for the involvement of purinergic signalling in the control of respiration.

The ventrolateral medulla has a critical role in the generation and patterning of respiration via an extensive network of respiratory neurones. We have investigated the effects of activating purinergic P2 receptors within the ventrolateral medulla of the anaesthetised rat on the overall pattern of respiratory activity. In addition, using immunohistochemical techniques, we have identified the subtypes of P2X receptors in the ventrolateral medulla. Unilateral microinjection of ATP into the ventrolateral medulla reduced in a dose-dependent manner, or abolished, resting phrenic nerve discharge recorded as an indication of central inspiratory drive. ATP also elicited increases in blood pressure and variable changes in heart rate. These effects were mimicked by microinjection of the P2X receptor agonist alpha,beta-methylene ATP into the ventrolateral medulla. Whilst microinjection of suramin, a P2 receptor antagonist, had no effect on resting cardiorespiratory variables it blocked the respiratory and cardiovascular effects of ATP microinjected into the ventrolateral medulla. Immunohistochemical staining using IgG antibodies showed that P2X1, P2X2, P2X5 and P2X6, but not P2X3, P2X4 or receptor subunits were localised in the rostral ventrolateral medulla.Our results indicate that several P2X receptor subtypes are localised within areas of the ventrolateral medulla that are important for cardiorespiratory control (including the pre-Bötzinger and Bötzinger complexes), and that activation of these receptors can have profound effects on both the cardiovascular and the respiratory networks. Our pharmacological data suggest that different P2X subunits in this region may co-assemble to form hetero-oligomeric assemblies as well as homomultimers within this region.

Adenosine Triphosphate↗
PubMed2001

Gentamicin and other antibiotic toxicitiy.

Antibiotics have the potential to cause significant ocular toxicity when they gain access to the inside of the eye. The aminoglycosides, in particular gentamicin, are the most toxic of the antibiotics commonly used in ophthalmology. Extreme caution should be used when administering a periocular injection of aminoglycoside for treatment or prophylaxis of infection. Intraocular injection of aminoglycoside for gram-negative coverage in endophthalmitis management has been replaced in most cases by ceftazidime. Ceftazidime provides excellent coverage against gram-negative bacteria with less potential for retinal toxicity at therapeutic dosages. Experimental and clinical studies have shown that intraocular vancomycin is safe and effective treatment against gram-positive organisms causing endophthalmitis. A combination of ceftazidime and vancomycin provides broad-spectrum coverage for virtually all bacteria causing endophthalmitis and is the current intraocular treatment of choice.

Animals↗
PubMed2001

Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women.

Although fat mass is related to bone mineral density (BMD), the potential mechanism(s) of this effect remain to be defined. Thus, we assessed the role of the candidate hormones, leptin, insulin, and estrogen in mediating fat mass effects on the skeleton. Specifically, we related these hormones and fat mass to BMD at the total hip, mid-lateral spine, and mid-distal radius in a sample of 137 premenopausal women (age range 21-54 years), 165 postmenopausal women (34-93 years), and 343 men (23-90 years) recruited from the general population. Fat mass and BMD were significantly related in pre- and postmenopausal women at multiple sites, whereas this relationship was only weakly present in men at the total hip. Serum leptin levels were also significantly related to BMD in the women, but not in the men. Insulin was associated with hip BMD in the women, and bioavailable estradiol (E2) was correlated with BMD at all sites in men and in postmenopausal women. In the women, adjusting for leptin reduced the strength of the association between fat mass and BMD, with further adjustments for insulin or bioavailable E2 having no additional effects. Adjusting for leptin in the men had no consistent effect on the relationship between fat mass and BMD. Collectively, these data suggest that there is a sexual dimorphism in the relationship of fat mass and leptin to BMD, with both being positively associated with BMD in women but not in men. In women, leptin may also mediate at least part of the protective effect of fat mass on the skeleton.

Adipose Tissue↗
PubMed2001

A vascular connection to Alzheimer's disease.

Alzheimer"s disease (AD) is characterized by a progressive and debilitating dementia in elderly people. The causes of this disease are not known, but major risk factors include old age and a family history of dementia, Down"s syndrome, female gender, low level of education, and head injury. There is no known cure for Alzheimer"s disease. The disease is characterized by abnormal accumulation of amyloid-beta peptide and the protein Tau in the nerve cells and extracellular space of certain regions of the brain. Cerebral amyloid angiopathy is another marker for Alzheimer"s disease. In autopsies, small cerebral arterial blood vessels and capillaries show signs of inflammation, amyloid accumulations, and a focal breach of the blood-brain barrier. This review focuses on the results of recent investigations of vascular responses to infusion of amyloid-beta(1-40), the means of preventing vascular damage, using a live animal (rat) model, and the combination of intravital video recordings of the mesenteric microvascular bed with electron microscopic analyses of the same vascular segments. We propose that the cerebral vascular changes in patients with Alzheimer"s disease probably precede the neuronal damage and dementia.

Alzheimer Disease↗
PubMed2001

Errors: can indicators measure the magnitude?

Errors in medicine, especially medication errors, have long been recognized as a dimension of quality of care and organizational performance. Recently, however, the magnitude of the issue, or its potential impact on cost, quality of care and patient safety have catapulted this issue to the forefront of national debate on the appropriateness of patient care management. There are still fundamental issues associated with the measurement of errors. Should errors that do not cause patient harm receive much attention? Could there be organizational or system issues that predispose to errors? Are there acceptable measurement models that allow comparative analysis and trending of institutional error rate profiles? This paper presents a systematic review of the measurement aspects for errors in medicine, emphasizing the medication errors' dimension. An indicator-based, epidemiological model of measurement is proposed which will allow a systematic inquiry into the issues of both preventable and non-preventable errors and their potential for patient harm.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2001

Effects of ribosomes and intracellular solutes on activities and stabilities of elongation factor 2 proteins from psychrotolerant and thermophilic methanogens.

Low-temperature-adapted archaea are abundant in the environment, yet little is known about the thermal adaptation of their proteins. We have previously compared elongation factor 2 (EF-2) proteins from Antarctic (Methanococcoides burtonii) and thermophilic (Methanosarcina thermophila) methanogens and found that the M. burtonii EF-2 had greater intrinsic activity at low temperatures and lower thermal stability at high temperatures (T. Thomas and R. Cavicchioli, J. Bacteriol. 182:1328-1332, 2000). While the gross thermal properties correlated with growth temperature, the activity and stability profiles of the EF-2 proteins did not precisely match the optimal growth temperature of each organism. This indicated that intracellular components may affect the thermal characteristics of the EF-2 proteins, and in this study we examined the effects of ribosomes and intracellular solutes. At a high growth temperature the thermophile produced high levels of potassium glutamate, which, when assayed in vitro with EF-2, retarded thermal unfolding and increased catalytic efficiency. In contrast, for the Antarctic methanogen adaptation to growth at a low temperature did not involve the accumulation of stabilizing organic solutes but appeared to result from an increased affinity of EF-2 for GTP and high levels of EF-2 in the cell relative to its low growth rate. Furthermore, ribosomes greatly stimulated GTPase activity and moderately stabilized both EF-2 proteins. These findings illustrate the different physiological strategies that have evolved in two phylogenetically related but thermally distinct methanogens to enable EF-2 to function satisfactorily.

Blotting, Western↗
PubMed2001

Leptin reduces ovariectomy-induced bone loss in rats.

Bone mineral density increases with fat body mass, and obesity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and directly related to fat body mass. We report here the effects of leptin administration compared with estrogen therapy on ovariectomy-induced bone loss in rats. Leptin was effective at reducing trabecular bone loss, trabecular architectural changes, and periosteal bone formation. Interestingly, the combination of estrogen and leptin further decreased bone turnover compared with that in estrogen-treated ovariectomized rats. Leptin also significantly increased osteoprotegerin mRNA steady state levels and protein secretion and decreased RANK ligand mRNA levels in human marrow stromal cells in vitro. Our findings suggest that leptin could modulate bone remodeling in favor of a better bone balance in rats. This study is the first evidence that leptin therapy has a significant effect in preventing ovariectomy-induced bone loss, and this effect may at least in part be mediated by the osteoprotegerin/RANK ligand pathway.

Animals↗
PubMed2001

Regulation of cell cycle and cyclins by 16alpha-hydroxyestrone in MCF-7 breast cancer cells.

It has been suggested that alterations in estradiol (E(2)) metabolism, resulting in increased production of 16alpha-hydroxyestrone (16alpha-OHE(1)), is associated with an increased risk of breast cancer. In the present study, we examined the effects of 16alpha-OHE(1)on DNA synthesis, cell cycle progression, and the expression of cell cycle regulatory genes in MCF-7 breast cancer cells. G(1) synchronized cells were treated with 1 to 25 nM 16alpha-OHE(1) for 24 and 48 h. [(3)H]Thymidine incorporation assay showed that 16alpha-OHE(1) caused an 8-fold increase in DNA synthesis compared with that of control cells, whereas E(2) caused a 4-fold increase. Flow cytometric analysis of cell cycle progression also demonstrated the potency of 16alpha-OHE(1) in stimulating cell growth. When G(1) synchronized cells were treated with 10 nM 16alpha-OHE(1) for 24 h, 62+/-3% of cells were in S phase compared with 14+/-3% and 52+/-2% of cells in the control and E(2)-treated groups respectively. In order to explore the role of 16alpha-OHE(1) in cell cycle regulation, we examined its effects on cyclins (D1, E, A, B1), cyclin dependent kinases (Cdk4, Cdk2), and retinoblastoma protein (pRB) using Western and Northern blot analysis. Treatment of cells with 10 nM 16alpha-OHE(1) resulted in 4- and 3-fold increases in cyclin D1 and cyclin A, respectively, at the protein level. There was also a significant increase in pRB phosphorylation and Cdk2 activation. In addition, transient transfection assay using an estrogen response element-driven luciferase reporter vector showed a 15-fold increase in estrogen receptor-mediated transactivation compared with control. These results show that 16alpha-OHE(1) is a potent estrogen capable of accelerating cell cycle kinetics and stimulating the expression of cell cycle regulatory proteins.

Breast Neoplasms↗
PubMed2001

Role of cytoskeletal elements in the recruitment of Cx43-GFP and Cx26-YFP into gap junctions.

Cytoskeletal elements may be important in connexin transport to the cell surface, cell surface gap junction plaque formation and/or gap junction internalization. In this study, fluorescence recovery after photobleaching was used to examine the role of microfilaments and microtubules in the recruitment and coalescence of green fluorescent protein-tagged Cx43 (Cx43-GFP) or yellow fluorescent tagged-Cx26 (Cx26-YFP) into gap junctions in NRK cells. In untreated cells, both Cx26-YFP and Cx43-GFP were recruited into gap junctions within photobleached areas of cell-cell contact within 2 hrs. However, disruption of microfilaments with cytochalasin B inhibited the recruitment and assembly of both Cx26-YFP and Cx43-GFP into gap junctions within photobleached areas. Surprisingly, disruption of microtubules with nocodazole inhibited the recruitment of Cx43-GFP into gap junctions but had limited effect on the transport and clustering of Cx26-YFP into gap junctions within the photobleached regions of cell-cell contact. These results suggest that the recruitment of Cx43-GFP and Cx26-YFP to the cell surface or their lateral clustering into gap junctions plaques is dependent in part on the presence of intact actin microfilaments while Cx43-GFP was more dependent on intact microtubules than Cx26-YFP.

Actin Cytoskeleton↗
PubMed2000

The murine gene, Traube, is essential for the growth of preimplantation embryos.

Little is known about the genetic control of preimplantation development. We have isolated, characterized, and mutated a previously undescribed mouse gene, Traube (Trb), essential for preimplantation development. Similar protein coding sequences are found in rats, humans, and yeast. The TRB protein contained two amino-terminal acidic domains, a leucine zipper, and three putative nuclear localization signals. The Trb gene was expressed at low levels ubiquitously early in development and became restricted to the liver and the central nervous system from E11.5 onward. Myc-tagged TRB protein was localized to the nucleus, and in a large proportion of the cells to the nucleoli. The Trb mutant embryos halted in development at the compacted morula stage at E2.5. At E3.5 they started to decompact and a day later they disintegrated and died. The observed defect was cell autonomous, as mutant cells failed to participate in the formation of chimeric embryos. The Trb mutant embryos showed a 50% reduction of the total cell number. The mutant embryos exhibited a paucity of ribosomes, polyribosomes, and rough endoplasmic reticulum. This paucity of ribosomes together with the localization of TRB to the nucleoli, the site of ribosome synthesis, suggests that TRB is involved in the synthesis of ribosomes.

Alleles↗
PubMed2000

A role for adenosine in modulating cardio-respiratory responses: a mini-review.

Evidence is provided that purine nucleotides play a major role in modulating cardio-respiratory control through actions at specific sites in the central nervous system (CNS). The accumulation of adenosine in the extracellular space of the nucleus tractus solitarius (NTS) on hypothalamic defence area stimulation is described, and is shown to result from the extracellular breakdown of neurally released adenosine triphosphate (ATP). The actions of adenosine in modulating synaptic actions in the NTS are discussed in relation to the potential presynaptic action of adenosine in modulating transmitter release. Actions of adenosine and ATP at other sites in the medulla concerned with cardio-respiratory control are discussed. The inter-relationships between ATP and adenosine are mentioned.

Adenosine↗
PubMed2000

Failure-free survival following brachytherapy alone or external beam irradiation alone for T1-2 prostate tumors in 2222 patients: results from a single practice.

PURPOSE: To evaluate failure-free survival (FFS) for brachytherapy (BT) alone compared to external beam radiotherapy (EBRT) alone for Stage T1-2 Nx-No Mo patients over the same time period by a single community-based practice in the prostate-specific antigen (PSA) era. MATERIALS AND METHODS: The database of Arizona Oncology Services (a multiphysician radiation oncology practice in the Phoenix metropolitan area) was reviewed for patients meeting the following criteria: (1) T1 or T2 Nx-No Mo prostate cancer; (2) no prior or concurrent therapy including hormones; (3) treatment period 12/88-12/95; and (4) treatment with either EBRT alone or BT alone ((125)I or (103)Pd). This yielded 1527 EBRT and 695 BT patients; no patients meeting the above criteria were excluded from analysis. Median follow-up for EBRT patients was 41.3 months and, for BT patients, 51.3 months. Patients were not randomized to either therapy but rather received EBRT or BT based upon patient, treating, and/or referring physician preference. PSA failure was defined according to the ASTRO consensus guidelines. The median patient age was 74 years for both groups. RESULTS: Failure-free survival at 5 years for EBRT and BT are 69% and 71%, respectively (p = 0.91). For T stage, no significant difference in FFS at 5 years is observed between EBRT and BT for either T1 (78% vs. 83%, p = 0.47) or T2 (67% vs. 67%, p = 0.89) tumors. Analysis by Gleason score shows superior outcomes for Gleason 8-10 lesions treated with EBRT vs. BT (5-year FFS 52% vs. 28%, p = 0.04); outcomes for lower grade lesions (Gleason 4-6) when analyzed by Gleason score alone do not significantly differ according to treatment received. Patients with initial PSA values of 10-20 ng/dL have an improved FFS with EBRT vs. BT at 5 years (70% vs. 53%, p = 0.001); outcomes for patients with initial PSA ranges of 0-4 ng/dL, of > 4-10 ng/dL, and > 20 ng/dL did not differ significantly by treatment received. FFS was also determined for presenting Gleason score/PSA combinations; all Gleason combinations in the initial PSA range >10-20 ng/dL had superior outcomes with EBRT compared to BT, and this reached statistical significance for Gleason scores of 2-4 (72% vs. 58%, p = 0.026), Gleason 7 (67% vs. 28%, p = 0.002), and Gleason 8-10 (63% vs. 23%, p = 0.05). CONCLUSION: In our patient population, either EBRT or BT appear equally efficacious for patients with T1/T2 disease with Gleason scores </= 6 or PSA </= 10 ng/dL. Patients with presenting Gleason scores of 8-10 or PSA > 10 ng/dL (but </= 20 ng/dL) appear to fare significantly worse with BT alone compared to EBRT alone. Neither EBRT nor BT alone was particularly effective for patients with a presenting PSA > 20 ng/dL, as would be anticipated from the significant risks of occult distant metastasis in this group. To our knowledge, this is the first report comparing the outcome of EBRT and BT treatment in patients treated concurrently by a single group, and these results, achieved in a community-based practice, compare favorably to data from academic centers regarding external beam, brachytherapy, or surgical outcomes and should be generalizable to the community at large.

Aged↗