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T Thomas

Publications and source records attributed to T Thomas.

At least 163 records · Page 9Linked to original sources
PubMed1997

The roles of adenosine in regulating the respiratory and cardiovascular systems in chronically hypoxic, adult rats.

1. We have investigated the roles of adenosine in regulating the respiratory and cardiovascular systems of rats that were made chronically hypoxic for 3-4 weeks from 6 weeks of age (CH rats) in an hypoxic chamber at 12% O2. They were studied under anaesthesia while breathing 12% O2 and during acute hypoxia (breathing 8% O2 for 5 min) before and after addition of the adenosine receptor antagonist 8-phenyltheophylline (8-PT, 10 mg kg-1). The results were compared with those obtained from normoxic (N) rats in a previous study. 2. CH rats breathing 12% O2 had greater minute ventilation (VP) than N rats breathing air, but their levels of arterial blood pressure (ABP), heart rate (HR), femoral vascular conductance (FVC) and cerebral vascular conductance (CVC) were fully comparable. 8-PT increased tidal volume (VT) in CH rats indicating a greater tonic central inhibitory influence of adenosine on VT than in N rats. However, 8-PT had no effect on cardiovascular variables, indicating no tonic cardioinhibitory or vasodilator influence of adenosine in CH rats. 3. Acute hypoxia in CH rats increased VE such that at the 5th minute of 8% O2 absolute VE was comparable to that of N rats breathing 8% O2. Moreover, in CH rats 8-PT increased VT at the 5th minute of 8% O2 indicating that the central inhibitory influence of adenosine limits the ability to maintain VT in acute hypoxia as it does in N rats. 4. Eight per cent O2 also produced a full in ABP in CH rats that was comparable to that induced in N rats by the larger change from air to 8% O2. However, the changes in HR were similar in CH and N rats while the increases in FVC and CVC were smaller in CH rats. This suggests that the ability of the secondary effects of hyperventilation and of the baroreceptor reflex to maintain cardiac output and thereby ABP is reduced in CH rats. 5. Whereas 8-PT substantially reduced the hypoxia-induced increases in FVC and CVC in N rats, it had a small effect in CH rats (P = 0.054 and 0.06, respectively). Further, acute hypoxia in CH rats had no effect on the K+ concentration in the venous efflux of hindlimb K+ (KV+) before or after 8-PT treatment. We suggest that in CH rats, the dilator influence of adenosine in acute hypoxia occurs via actions on the blood vessel walls: there was no evidence that adenosine can release dilator concentrations of K+ from skeletal muscle fibres in CH rats as proposed for N rats.

Adenosine↗
PubMed1997

Megakaryocytic progenitors can be generated ex vivo and safely administered to autologous peripheral blood progenitor cell transplant recipients.

We evaluated different culture conditions to obtain a lineage-selected proliferation of clonogenic megakaryocytic progenitors (MP). In low-density (LD) or CD34+ cell cultures, the best results were obtained in serum-free medium in the presence of megakaryocyte growth and development factor, stem cell factor, interleukin-3 (IL-3), IL-6, IL-11, FLT-ligand, and macrophage inflammatory protein-1alpha. In paired studies, expansion of LD cells was less effective than expansion of CD34+ cells, and pre-enrichment of CD34+ cells using negative depletion of lineage-positive cells produced significantly larger quantities of MP than pre-enrichment using positive selection. MP proliferation peaked on day 7 in culture, and an 8- +/- 5-fold expansion of CD34+/CD61+ cells, a 17- +/- 5-fold expansion of colony-forming units-megakaryocytes, and a 58- +/- 14-fold expansion of the total number of CD61+ cells was obtained. In a feasibility clinical study, 10 cancer patients (8 with breast cancer and 2 with non-Hodgkin's lymphoma) undergoing autologous peripheral blood progenitor cell (PBPC) transplant received MP generated ex vivo (range, 1 to 21 x 10(5)/kg CD61 cells) together with unmanipulated PBPC. Eight patients received a single allogeneic platelet transfusion, whereas platelet transfusion support was not needed in 2 of the 4 patients receiving the highest doses of cultured MP. This result compares favorably with a retrospective control group of 14 patients, all requiring platelet transfusion support. Adverse reactions or bacterial contamination of cell cultures have not been observed. In conclusion, MP can be expanded ex vivo and safely administered to autologous transplant recipients. Further clinical trials will indicate the reinfusion schedule able to consistently abrogate the need for allogeneic platelet transfusion support in autologous transplantation.

Cells, Cultured↗
PubMed1997

Cerebrovascular endothelial dysfunction mediated by beta-amyloid.

beta-Amyloid (A beta) toxicity has a critical role in the pathology of Alzheimer's disease (AD) but its function in the neurodegenerative process is not clearly established. Recently, we demonstrated a novel action of beta-amyloid on peripheral blood vessels: endothelial dysfunction through reactive oxygen species. Here we report the direct effect of A beta on cerebrovascular endothelium. Following treatment with A beta 1-40, bovine cerebral arteries showed characteristic features of endothelial dysfunction such as increased contraction to vasoconstrictor and diminished relaxation to endothelium-dependent vasodilators. Electron microscopy revealed significant damage to the endothelium by A beta. Pretreatment with the antioxidant superoxide dismutase (SOD) and PBN (n-tert-butyl-alpha-phenylnitrone) antagonized the effects of A beta. Endothelial damage induced by A beta could produce ischemic and inflammatory changes contributing to the pathology of AD.

Amyloid beta-Peptides↗
PubMed1997

Effects of chain length modification and bis(ethyl) substitution of spermine analogs on purine-purine-pyrimidine triplex DNA stabilization, aggregation, and conformational transitions.

The natural polyamines--putrescine, spermidine, and spermine--are known to stabilize pyrimidine-purine-pyrimidine and purine-purine-pyrimidine triplex DNA formation. We studied the ability of two tetramine and two pentamine analogs of spermine and their bis(ethyl) derivatives to stabilize triplex DNA formation between 5'-TG3TG4TG4TG3T-3' and its target duplex probe, consisting of the oligonucleotides 5'-TCGAAG3AG4AG4AG3A-3' and 5'-TCGATC3TC4TC4TC3T-3'. We used electrophoretic mobility shift assay (EMSA), melting temperature (Tm) measurements, and circular dichroism (CD) spectroscopy to evaluate the effects of these novel polyamine analogs on triplex DNA stability, dissociation constants, aggregation, and conformation. In general, pentamines were more efficacious than tetramines in stabilizing triplex DNA, although most of the polyamines with pendant free amino groups caused DNA aggregation below 50% conversion to triplex DNA. Ethyl substitution of these pendant amino groups lowered their efficacy approximately 2-fold in stabilizing triplex DNA; however, this effect was more than compensated for by the lack of DNA aggregation in the presence of bis(ethyl)polyamines. A concentration-dependent increase in the Tm of triplex DNA was observed in the presence of polyamines. CD spectral measurements showed distinct differences in the conformation of triplex DNA stabilized in the presence of polyamines compared to the CD spectra of the oligonucleotides alone. Temperature-dependent CD spectra of triplex DNA showed monophasic melting in the absence and presence of polyamines, suggesting duplex/triplex --> single-stranded DNA transition. These results indicate that structural modifications of polyamines is an effective strategy to develop triplex DNA-stabilizing ligands, with potential applications in antigene therapeutics.

Circular Dichroism↗
PubMed1997

beta-amyloid-induced endothelial necrosis and inhibition of nitric oxide production.

Deposits of amyloid beta-peptide (A beta) in senile plaques and cerebral blood vessels is the prominent feature of Alzheimer's disease (AD), regardless of genetic predisposition. The cellular origin of cerebral deposits of A beta or its precise role in the neurodegenerative process has not been established. Recently we demonstrated a novel action of beta-amyloid on blood vessels--vasoactivity and endothelial damage through superoxide radicals. Since endothelial dysfunction is associated with vascular degenerative diseases, we examined the direct action of A beta on endothelial cells in culture. Cells treated with A beta displayed characteristics of necrotic cell death which was prevented by the free radical scavenging enzyme superoxide dismutase. Stimulation of endothelial nitric oxide (NO) production by the calcium ionophore, A23187, or bradykinin was inhibited by beta-amyloid. We conclude that an imbalance of NO and oxygen radicals may mediate the A beta-induced endothelial damage on endothelial cells in culture and may also contribute to a variety of pathophysiological conditions associated with aging: hypertension, cerebral ischemia, vasospasm, or stroke.

Amyloid beta-Peptides↗
PubMed1997

Germ line chimeras from female ES cells.

Murine embryonic stem cells (ES cells) are pluripotent cells that can contribute to all tissues of developing mice including the germ line when aggregated with 8-cell-stage embryos or injected into the blastocoel cavity of murine blastocysts. As well as for in vitro studies, they are used to introduce mutations into the murine genome, thereby producing new mutant mouse lines. All ES cell lines so far described that contribute to the germ line have been male. However, for many studies female ES cell lines may be essential. Female ES cells may be particularly useful for mutating genes located on the X chromosome which would otherwise be hemizygously lethal in males. We show here that female ES cells are able to form germ line chimeras and to sex convert a male host embryo.

Animals↗
PubMed1997

Novel embryonic regulation of Ca(2+)-activated K+ channel expression in Drosophila.

The slowpoke gene of Drosophila melanogaster encodes a Ca(2+)-activated K+ channel that is expressed in neurons, muscles, tracheal cells and the middle midgut. The entire transcriptional control region of slowpoke is contained in 11 kb of genomic DNA. Previous work has identified four different tissue-specific promoters (Promoters C1, C1b, C1c and C2) and sequences that regulate their activity. Here we describe and contrast the regulation of neuronal and muscle expression during embryogenesis with its regulation during larval and adult stages. Embryonic regulation is fundamentally different. The embryo uses Promoter C1 and a previously undescribed promoter, called Promoter Ce, to drive neuronal expression. The expression patterns of these promoters are distinct. Muscle expression arises from Promoter C2 as in other developmental stages. A downstream intronic region has been shown to contain control elements that modulate promoter activity differently in embryos, larvae and adults. Embryonic CNS expression is not dependent on the intron, however; its deletion has substantial effects on neuronal expression in larvae and adults. In embryonic muscle, removal of the intron eliminates muscle expression even though this deletion does not reduce larval muscle expression.

Animals↗
PubMed1997

Mechanism of action of a tyrphostin, 3,4-dihydroxy-alpha-cyanothiocinnamamide, in breast cancer cell growth inhibition involves the suppression of cyclin B1 and the functional activity of cyclin B1/p34cdc2 complex.

Tyrphostins are a group of compounds specifically targeted for the inhibition of tyrosine phosphorylation in signal transduction pathways. We studied the effects of a tyrphostin, 3,4-dihydroxy-alpha-cyanothiocinnamamide (tyrphostin-47), on hormone-responsive MCF-7 and hormone-unresponsive MCF-7-5C cell growth by DNA analysis for a period of 10 days. The growth of both cell lines was inhibited by this drug at 50 and 100 microM concentrations. Flow cytometric analysis showed that tyrphostin treatment caused a significant delay in the progression of MCF-7 cells through G1 and S phases of the cell cycle. The level of cyclin B1, a component of the mitosis promoting factor (MPF), was reduced by 90% in the presence of 100 microM tyrphostin. The other component of MPF, p34cdc2 kinase, was not affected; however, its functional activity was dramatically reduced, as determined by histone H1 phosphorylation assay. In contrast, G1 cyclins (D1 and E) and tyrosine kinase activity were not markedly affected by tyrphostin-47, as determined by Western immunoblot detection with specific antibodies. Our results suggest that a possible mechanism of tyrphostin action in breast cancer cells might involve the suppression of cyclin B1 and inhibition of the functional activity of cyclin B1/p34cdc2 complex. Our data indicate that the cell cycle machinery might be a target for developing novel drugs for breast cancer.

Breast Neoplasms↗
PubMed1997

Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND.

dHAND and eHAND are related basic helix-loop-helix (bHLH) transcription factors that are expressed in mesodermal and neural crest-derived structures of the developing heart. In contrast to their homogeneous expression during avian cardiogenesis, during mouse heart development we show that dHAND and eHAND are expressed in a complementary fashion and are restricted to segments of the heart tube fated to form the right and left ventricles, respectively. dHAND and eHAND represent the earliest cardiac chamber-specific transcription factors yet identified. Targeted gene deletion of dHAND in mouse embryos resulted in embryonic lethality at embryonic day 10.5 from heart failure. Our description of the cardiac phenotype of dHAND mutant embryos is the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches and reveals a novel cardiogenic subprogramme for right ventricular development.

Animals↗
PubMed1997

A new 'two step' procedure for 4.5 log depletion of T and B cells in allogeneic transplantation and of neoplastic cells in autologous transplantation.

To evaluate a new 'two step' method for purging T, B and neoplastic cells from hematopoietic progenitor cells (PC), PCs were collected by apheresis and some suspensions were deliberately contaminated with 2-5% breast cancer cells. PCs were first processed through CellPro columns for positive selection of cells that express CD34. After this first step, the mean CD34+ cell recovery was 68 +/- 12%, and CD34+ cell purity was 61 +/- 11%; CD3+ and neoplastic cell depletion were 2.1 +/- 0.4 and 1.9 +/0 0.4 logs, respectively. Cells were further processed through the StemSep device for direct depletion of T and B cells or of breast cancer cells. After the first and the second step, overall CD34+ cell recovery was 50 +/- 7%, T and B cell removal was 4.7 +/- 0.4 log and neoplastic cell purging was 4.4 +/- 0.3 log, ie significantly superior to methods described in the past.

Antigens, CD34↗
PubMed1997

beta-Amyloid induces cerebrovascular endothelial dysfunction in the rat brain.

beta-Amyloid toxicity plays a central role in the pathology of Alzheimer's disease. Contraction and relaxation responses of pressurized rat posterior cerebral artery were studied before and after in vitro exposure to beta-amyloid. The peptide-induced characteristic features of endothelial dysfunction including enhanced vasoconstriction with serotonin and diminished relaxation to endothelium-dependent vasodilators acetylcholine and bradykinin. Response to the endothelium-independent vasodilator nitroprusside was not affected by beta-Amyloid. beta-amyloid inhibition of acetylcholine-induced vasodilation was prevented by the oxygen radical scavenging enzyme superoxide dismutase. Endothelial destruction and the protective effect of superoxide dismutase was verified by electron microscopy. The results suggest that beta-amyloid peptide produces endothelial dysfunction in cerebral microvessels through reactive oxygen species.

Acetylcholine↗
PubMed1997

Promoting wellness in individuals with coronary heart disease.

The care of patients with coronary heart disease is focused toward assisting each individual to maximize his or her level of wellness by understanding and adhering to the prescribed medical regimen as a means for reducing or eliminating modifiable cardiovascular risk factors. Despite the role of risk modification in the management of coronary heart disease, lack of adherence to prescribed regimens is a fundamental problem. Behavioral models have examined factors that explain the likelihood of engaging in risk modification efforts and provide a rich theoretical basis for describing and predicting various aspects of behavioral change; however, difficulty in achieving sustained risk modification for individuals with diagnosed coronary heart disease makes it important to examine new directions for study. This article presents a model for wellness motivation related to the prevention of cardiovascular disease and outlines potential intervention strategies to enhance motivation in behavioral change.

Coronary Disease↗
PubMed1997

Beta-amyloid-induced coronary artery vasoactivity and endothelial damage.

Amyloid beta-peptide (A beta) deposition has been associated with coronary heart disease and neurodegenerative diseases. A link between A beta and free radical generation has been explored in neuronal tissue. We report here on the effect of A beta on pressurized segments of coronary resistance arteries and the role of free radicals. A small oscillatory response to A beta (10[-6] M) that consisted of a relaxation followed by constriction and a return to the basal diameter was observed in all vessels. The thromboxane A2 analog U46619 produced a significantly greater constriction compared with the response before treatment with A beta. The presence of the antioxidant enzyme superoxide dismutase (SOD) reduced both the response to A beta alone and the enhanced response to U46619. Vasodilation responses to acetylcholine (10[-9]-10[-5] M) were virtually eliminated at all concentrations by A beta. We confirmed endothelial cell damage by A beta with electron microscopy. The results suggest that A beta deposition in coronary resistance arteries causes endothelial damage that is mediated through superoxide radicals.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Secondary rhytidectomy.

A postoperative questionnaire was sent to all secondary rhytidectomy patients inquiring about their social and physical recovery time, complications related to either the initial or secondary surgery, and the onset of any new medical problems or the commencement of any new medications between the two surgeries. The overall satisfaction rates for both surgeries, time interval between the two operations, and their perception of the years of youthful appearance gained from either operation were also investigated. The overall satisfaction rate was slightly higher for the secondary facial rhytidectomy (4.49) than for the primary rejuvenation of the face (3.97) (p < 0.06). Patients perceived themselves as looking an average of 9.31 years younger following primary surgery, as compared to an average of 10.19 years younger following the secondary rhytidectomy (p < 0.50). The average time interval between the primary and secondary rhytidectomy surgeries was 8.48 years (range = 1 to 16 years). Twenty-nine ancillary procedures were performed during the initial rhytidectomy and 70 ancillary procedures were selected during the secondary rhytidectomy (p < 0.001). There was no statistically significant difference for the physical and social recovery time between the two procedures. Fourteen of 33 patients (42.4 percent) requiring a secondary rhytidectomy had developed a new medical problem prior to the second surgery (p < 0.001) and 19 patients (57.6 percent) were started on a new medication (p < 0.001). It was concluded from this study that the secondary rhytidectomy patients are more inclined to be satisfied (approaching statistical significance), are more likely to undergo ancillary procedures, and, being 10 years older, are more prone to have medical problems with deleterious effects on surgery and to be on medications with potential ill effects. Also, observations have been made that the previous scars pose some limitations, with the anatomical changes from the previous surgeries often requiring masterful planning and execution. Skin circulation is, in general, superior, enduring more tension.

Adult↗
PubMed1997

A source of adenosine involved in cardiovascular responses to defense area stimulation.

We have investigated the source of central adenosine important in modulating the cardiovascular response to hypothalamic defense area (HDA) stimulation in alpha-chloralose-anesthetized rats. Microinjections of an ecto-5'-nucleotidase inhibitor, alpha,beta-methylene ADP (alpha,beta-meADP), were made into caudal nucleus of the solitary tract (cNTS) and rostral ventrolateral medulla (RVLM), and its effects on HDA-evoked responses were observed. Stimulation of HDA evoked an increase in arterial pressure and a secondary rise in arterial pressure after stimulation ceased. There was also an increase in heart rate and hindlimb blood flow. alpha,beta-meADP had no effect on resting levels of arterial pressure, heart rate, and hindlimb blood flow when injected into the cNTS or RVLM. alpha,beta-meADP also had no effect on the HDA-evoked tachycardia and increase in muscle blood flow. However, alpha,beta-meADP reduced the primary increase in arterial pressure evoked by HDA stimulation when microinjected into the cNTS. In contrast, alpha,beta-meADP reduced the secondary increase in arterial pressure when microinjected into the RVLM. From these results, we suggest that at least part of the adenosine released centrally during HDA stimulation is derived extracellularly from ATP metabolism.

5'-Nucleotidase↗
PubMed1997

Mojave rattlesnake envenomation in southern California: a review of suspected cases.

To clarify whether Mojave rattlesnake (Crotalus scutulatus scutulatus) envenomations occurring in California cause typical crotalid tissue effects, pain, edema, and ecchymosis, we reviewed charts of snakebite victims at a tertiary care teaching hospital and a moderate-size community hospital. Forty-two patients were bitten within the range of Mojave rattlesnakes. Eight snakes were identified as Mojave rattlesnakes (group 1); of these, four were confirmed by experts in snake identification (group 1a). Fifteen patients were reported bitten by other rattlesnake species (group 2), and in 19 envenomations the species was unknown (group 3). Seventy-five percent of patients in group 1 were reported to have local edema at the envenomation site compared with all of the patients in group 2. Ecchymosis was found in 25% of group 1 patients and 73% of group 2 patients. Pain was documented in only 12% of group 1 and 67% of group 2 victims. Neurotropic events, many severe, were found in 75% of group 1 patients compared with 7% of those in group 2. Although this study does not have the power to justify statistical evaluation, C. scutulatus envenomations do appear inclined to less tissue reaction. A disturbing trend toward severe neurotropic manifestations was also suggested in presumed Mojave rattlesnake envenomations.

Adolescent↗
PubMed1997

In vivo vascular damage, leukocyte activation and inflammatory response induced by beta-amyloid.

beta-amyloid toxicity is central to the pathology of Alzheimer's disease. Recent evidence implicates vascular dysfunction as a contributing factor to the dementia of Alzheimer type. Using intravital microscopy we demonstrate that in vivo administration of beta-amyloid produces extensive vascular disruption including endothelial and smooth muscle damage, adhesion and migration of leukocytes across arteries and venules. Amyloid angiopathy with vascular damage and inflammatory changes are hallmarks in the brains of Alzheimer disease victims. The vascular actions of beta-amyloid are distinct from the neurotoxic properties of the peptide and were prevented by the free radical scavenging enzyme superoxide dismutase. Oxygen radical mediated vascular dysfunction may induce ischemic and inflammatory responses leading to neurodegeneration as seen in Alzheimer's disease.

Alzheimer Disease↗