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T L Smith

Publications and source records attributed to T L Smith.

At least 163 records · Page 9Linked to original sources
PubMed1996

Ethanol enhances the in situ phosphorylation of MARCKS and protein kinase C activity in primary cultures of astrocytes.

Protein kinase C (PKC) plays an important regulatory role in astrocyte function. Chronic exposure to ethanol for 4 days resulted in an increase in Ca2+-dependent PKC activity in the supernatant fraction of astrocyte homogenates. Only Ca2+-independent PKC activity could be observed in the membrane fraction and this activity was unaffected by ethanol exposure. Chronic ethanol exposure also increased the in situ phosphorylation of MARCKS in permeabilized astrocytes both in the absence or presence of the PKC activator, phorbol 12 -myristate 13 -acetate (PMA). These results suggest an increase in the expression of one or more astrocytic PKC isoforms after chronic ethanol exposure.

Animals↗
PubMed1996

Cholestane-3 beta, 5 alpha, 6 beta-triol stimulates phospholipid synthesis and CTP-phosphocholine cytidyltransferase in cultured LLC-PK cells.

The present study was conducted to examine the effect, if any, of triol on the rate of total or individual phospholipid synthesis by LLC-PK cells in culture. LLC-PK cells were incubated in medium with or without 10 micrograms/ml of 5 alpha-cholestane-3 beta, 5 alpha,6 beta-triol (triol) for 24 h. Triol-treated and control cells were then incubated with medium containing either [14C]glycerol or [32P]phosphate for 1, 6 or 12 hr. In triol-treated cells, the amount of labeled glycerol and [32P]phosphate incorporated into glycerophospholipids and phospholipids (PL), respectively, were higher in triol-treated cells than in control cells, indicating a higher rate of PL synthesis in triol-treated cells. The results also showed that the increase in PL synthesis was higher in magnitude for some PL than others, thus disturbing the ratios among the PL fractions in the cell membrane. CTP-phosphocholine cytidyltransferase activity was greatly enhanced in the cytosolic as well as the particulate fractions of the triol-treated cells, which explains the increase of PC synthesis under triol effect. The rate of [3H]acetate incorporation into the total and free fatty acid fractions was significantly increased in triol-treated cells. The activation of the cytidyl transferase enzyme was related to the enhanced de novo synthesis and cellular uptake of fatty acids in triol-treated cells, which make fatty acids more available in these cells and can upregulate the enzyme. The increased synthesis of phospholipids in the triol cells and the increased level of phospholipid in these cells (as micrograms lipid phosphorus/mg cell protein) observed in our previous study indicate changes in the phospholipid head group composition of the triol cells. These changes can affect several membrane properties and membrane bound enzymes.

Acetates↗
PubMed1996

Interactions of nonpeptide angiotensin II receptor antagonists at imidazoline/guanidinium receptor sites in rat forebrain.

Imidazoline/guanidinium receptive sites (IGRS) are shown to be present in the subfornical organ and hypothalamic arcuate nucleus by a derivative of cirazoline, 2-(3-amino-4-[125I]iodophenoxy)methylimidazoline ([125I]AMIPI). Because many of the nonpeptide angiotensin II (Ang II) receptor antagonists contain imidazole ring structures, they may interact with IGRS. Therefore, we studied competitive activity of Ang II and several nonpeptide Ang II receptor antagonists [DuP 753 (losartan), EXP 3174, CV11974, and PD123319] at IGRS in rat forebrain. The results showed specific binding of 944 +/- 169 fmol/mg protein in the subfornical organ (n = 11) and of 367 +/- 27 fmol/mg protein in the arcuate nucleus (n = 6) at 0.4 nM [125I]AMIPI, as defined by competition with 10 microM cirazoline. Specific [125I]AMIPI binding was competed for completely by 10 microM idazoxan or clonidine as further characterization of IGRS. Ang II and the nonpeptide AT1 and AT2 antagonists did not significantly compete for specific [125I]AMIPI binding in either brain region at concentrations of 10 microM (< 20% competition with each compound), which is 10- to 100-fold higher than the concentration necessary to compete completely for their respective Ang II receptor subtypes. Only at the highest concentration (100 microM) did losartan compete significantly for binding (56 +/- 8%). Therefore, Ang II receptor antagonists interact with IGRS in rat forebrain cardiovascular areas only at high concentrations.

Angiotensin II↗
PubMed1996

Control of arteriovenous anastomoses in rabbit ear model of digital perfusion.

The arteriovenous anastomoses (AVA) of the cutaneous microcirculation of the hands and feet are fundamental determinants of thermoregulatory blood flow and may be involved in cold intolerance. These direct microvascular studies are an initial characterization of adrenergic receptor subtypes participating in control of AVA in the ears of anesthetized male New Zealand White rabbits. Adrenergic alpha 1-stimulation with phenylephrine produced AVA constriction, whereas terazosin (an alpha 1-antagonist) produced dilation and attenuated the responses to phenylephrine. Adrenergic alpha 2-stimulation with UK-14304 produced constriction of the AVA, whereas atipamezole (an alpha 2-antagonist) produced dilation and attenuated the responses to UK-14304. When equimolar concentrations of antagonists were studied, the AVA dilation produced by alpha 2-blockade was greater than that produced by alpha 1-blockade. Norepinephrine (a mixed alpha 1- and alpha 2-agonist) also produced vasoconstriction, which was attenuated by both prazosin (an alpha 1-antagonist) and atipamezole. In summary, 1) AVA contain a heterogeneous mixture of both alpha 1- and alpha 2-receptors, and 2) alpha 2-receptors may have a greater influence than alpha 1-receptors on overall tone in AVA.

Animals↗
PubMed1996

Significance of cytogenetic clonal evolution in chronic myelogenous leukemia.

PURPOSE: To describe the incidence and significance of clonal evolution patterns. PATIENTS AND METHODS: We analyzed 264 patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed clonal evolution between 1967 and 1993. RESULTS: The median survival time following clonal evolution was 19 months. Factors associated with worse survival (P < .01) were as follows: chromosome 17 abnormality or chromosomal translocations other than Ph, high percentage of abnormal metaphases, longer time to clonal evolution, and presence of other accelerated-phase features. A recursive partitioning technique (CART) identified different risk groups. The best group (37 patients; no chromosome 17 abnormality, abnormal metaphases < 16%, and interval to clonal evolution < or = 24 months) had an estimated median survival time of 54 months. The worst two groups included 27 patients with chromosome 17 abnormalities and > or = 36% abnormal metaphases (estimated median survival time, 6 months), and 22 patients with other accelerated features and > or = 16% abnormal metaphases (estimated median survival time, 7 months). The intermediate group had an estimated median survival time that ranged from 13 to 24 months. Prior interferon therapy evaluated within risk groups showed a significant survival advantage only in the intermediate-risk group. A multivariate analysis showed similar results, and identified the following independent poor prognostic variables: chromosome 17 abnormality, percentage of abnormal metaphases (cutoff, 24%), longer time to clonal evolution (cutoff, 24 months), other accelerated-phase features, and no prior interferon therapy. Patients with none, one, two, three, or more of the first four features had median survivals times of 51, 24, 14, and 7 months, respectively. CONCLUSION: The prognostic significance of clonal evolution in CML is not uniform and is related to the specific abnormality, time to its development, its predominance in metaphases, and the presence of other accelerated features, and it may be modified by specific therapies.

Bone Marrow Transplantation↗
PubMed1996

Design and results of phase I cancer clinical trials: three-year experience at M.D. Anderson Cancer Center.

PURPOSE: Alternatives to the standard design for conducting phase I trials are proposed with increasing frequency. This study was undertaken to determine how phase I trials are currently conducted and to provide a basis for evaluation of evolving methodology. SUBJECTS AND METHODS: All published phase I trials from a single institution over a 3-year period were reviewed to determine the method of selection of the recommended dose for a phase II trial of a new agent, type and extent of toxicity, number of patients treated at the recommended dose, and clinical response. RESULTS: All 23 published trials used the standard method of entering cohorts of patients at increasing dose levels and observing toxic effects to determine the dose recommended for phase II study. Among 610 patients, 26% were treated at or within 10% of the recommended dose and 35% were treated with less than 50% of the recommended dose or on a trial that yielded no recommended dose. Among 18 trials using agents previously tested in humans, fewer patients were treated at much less than the recommended dose. For trials in which myelosuppression was dose-limiting, the estimated probability of serious myelosuppression associated with the recommended dose ranged from 23% to 66%. Nineteen patients (3%) responded to therapy. CONCLUSION: This summary of phase I trials recently conducted at M.D. Anderson Cancer Center confirms the need for alternative methods, provides baseline information against which alternatively conducted trials can be compared, and demonstrates some practical clinical trial issues not generally considered when alternative methods are proposed.

Antineoplastic Agents↗
PubMed1996

Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience.

PURPOSE: Adjuvant chemotherapy for breast cancer has been the routine practice in the past decade. A number of studies have observed an increased incidence of treatment-related leukemias following chemotherapy with alkylating agents and/or topoisomerase II inhibitors. We evaluated the incidence of treatment-related leukemias in breast cancer patients treated in four adjuvant and two neoadjuvant chemotherapy trials at The University of Texas M.D. Anderson Cancer Center. PATIENTS AND METHODS: Between 1974 and 1989, 1,474 patients with stage II or III breast cancer were treated in six prospective trials of adjuvant (n = 4) or neoadjuvant (n = 2) chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (CTX) (FAC) with or without other drugs. The median observation time was 97 months. In 1,107 patients, FAC chemotherapy was given postoperatively; 367 patients received induction chemotherapy, as well as postoperative chemotherapy. Eight hundred ten patients had surgery followed by radiotherapy and chemotherapy; 664 patients had surgery and chemotherapy only. Patients in two adjuvant and one neoadjuvant study received higher cumulative doses of CTX compared with those in the other studies. RESULTS: Fourteen cases of leukemia were observed. Twelve of these patients had received radiotherapy and chemotherapy, and two had received chemotherapy only. Six of the reported patients with leukemia were treated with a cumulative CTX dose of greater than 6 g/ m2. Five of these patients had received both radiotherapy and chemotherapy. The median latency period in the 14 patients was 66 months (range, 22 to 113). Six of 10 patients with adequate cytogenetic analyses had abnormalities that involved chromosomes 5 and/or 7. The rest of the patients had nonspecific cytogenetic abnormalities or lacked cytogenetic information. The 10-year estimated leukemia rate was 1.5% (95% confidence interval [CI], 0.7% to 2.9%) for all patients treated, 2.5% (95% CI, 1.0% to 5.1%) for the radiotherapy-plus-chemotherapy group, and 0.5% (95% CI, 0.1% to 2.4%) for the chemotherapy-only group; this difference was statistically significant (P = .01). The 10-year estimated leukemia risk for the higher-dose (> 6 g/m2) CTX group was 2% (95% CI, 0.5% to 5.0%) compared with 1.3% (95% CI, 0.4% to 3.0%) for the lower-dose group, a difference that was not statistically significant (P = .53). CONCLUSION: These data illustrate that patients treated with adjuvant FAC chemotherapy plus radiotherapy have a slightly increased risk of leukemia. This information needs to be considered in the treatment plans for patients with breast cancer. However, for most patients, the benefits of adjuvant therapy exceed the risk of treatment-related leukemia.

Adult↗
PubMed1996

Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients?

PURPOSE: Because of the high heterogeneity of EWS gene fusions with FLI1 and ERG genes due to variable chromosomal breakpoint locations in Ewing tumors (ET) (14 different chimeric transcripts identified so far), we evaluated the clinical impact of the expression of diverse fusion transcripts in ET patients. PATIENTS AND METHODS: In a European multicenter study, 147 ET were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) and the molecular data statistically compared with all clinical data available. RESULTS: Most tumors expressed chimeric transcripts with fusion of EWS exon 7 to FLI1 exon 6 (75 of 147) (type I) or five (39 of 147) and EWS exon 10 to FLI1 exon 5 (eight of 147) or 6 (five of 147). In five cases, chimerism between EWS exon 9 and FLI1 exons 4 and EWS exon 7 and FLI1 exon 7 or 8 was observed. Fifteen cases of EWS-ERG rearrangement were identified. In 85 of these patients treated in the European Cooperative Ewing Sarcoma Studies, molecular results were analyzed in comparison to age, sex, tumor localization, tumor volume, and disease extension. No significant correlation between the various fusion types and these features were observed. Relapse-free survival (RFS) for the 31 patients with localized disease and fusion type I tended to be longer compared with the 24 patients with localized tumors bearing other chimeric transcripts (P = .04). CONCLUSION: Results suggest a possible advantage in PFS for patients with localized disease and fusion type I transcripts, although this will require prospective validation with a larger number of patients and longer follow-up periods.

Adolescent↗
PubMed1996

Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer.

PURPOSE: To determine the long-term clinical course of patients with metastatic breast cancer (MBC) who achieved a complete remission with doxorubicin-alkylating agent-containing combination chemotherapy programs. PATIENTS AND METHODS: To assess the long-term prognosis of MBC, we reviewed our experience with 1,581 patients treated on consecutive doxorubicin and alkylating agent-containing front-line treatment protocols between 1973 and 1982. Treatment was administered for a maximum duration of 2 years. Characteristics of long-term survivors were evaluated, and hazard rates for progression were calculated. RESULTS: From this group, 263 (16.6%) achieved complete responses (CR) and 49 (3.1%) remained in CR for more than 5 years. After a median duration of 191 months, 26 patients remain in first CR, four patients died in CR at times ranging from 118 to 234 months, 18 patients died of breast cancer, and one is alive with metastatic disease. Compared with the overall CR and total patient populations, the long-term CR group had more premenopausal patients, a younger median age, a lower tumor burden, and better performance status. The hazard function shows a substantial drop in risk of progression after approximately 3 years from initiation of therapy. Ten long-term CR patients developed second primary cancers: breast (3), ovary (2), pancreas (1), endometrium (1), colon (1), head and neck (1), and lung (1). CONCLUSION: Most patients with MBC treated with systemic therapies have only temporary responses to treatment, but some patients continue in CR following initial treatment. These data show that a small percentage of patients achieve long-term remissions with standard chemotherapy regimens. Remission consolidation strategies are needed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Factors predicting complete remission and subsequent disease-free survival after a second course of induction therapy in patients with acute myelogenous leukemia resistant to the first.

Patients with newly diagnosed acute myelogenous leukemia (AML) with persistent leukemia after their first course (CO1) of induction chemotherapy are generally given a second similar course, although their outcome is known to be worse than CO1 responders even when a complete remission (CR) is achieved. To identify specific patients who should or should not receive a second induction course identical to the first we analyzed outcome in 370 patients with persistent AML after CO1 who received a second identical course. One hundred and forty-two (38%) achieved CR on this course; median subsequent disease-free survival (DFS) in these 142 was 29 weeks and 10% were alive in CR at 5 years. The 5-year DFS of CO2 responders was significantly lower than that of CO1 responders (10 vs 24%, P < 0.001). Logistic regression identified pretreatment cytogenetic abnormalities (except inv 16, t(8;21), or t(15;17)), presence of an antecedent hematologic disorder or secondary AML as each having unfavorable prognostic import similar to the case in untreated patients. Treatment with "high-dose' rather than standard-dose cytarabine increased the probability of 2nd course CR. The occurrence of pneumonia, sepsis, or major hemorrhage were prognostically unfavorable, primarily in the high-dose cytarabine group, and, once in CR, DFS was shorter in this group. Equations predicting probability of 2nd course CR were derived. If validated prospectively these could be used to assign patients to either receive a second course of initial induction therapy or to change to salvage or investigational therapy after the first course. Alternatively, they could be used to stratify patients entering a prospective randomized trial comparing these two strategies.

Adult↗
PubMed1996

Effect of magnesium on secretion of platelet-derived growth factor by cultured human arterial smooth muscle cells.

Two conditioned media were prepared by culturing human umbilical artery smooth muscle cells (SMC) in 75 cm2 flasks with minimum essential medium (MEM) under magnesium (Mg) sufficient (900 microM) or deficient (100 microM) conditions for 72 h ([900]- and [100]-MEM), respectively. A third conditioned medium was obtained by adjusting the Mg concentration of half of the [100]-MEM to 900 microM ([100-900]-MEM). SMC in 12-well plates were incubated in one of the three conditioned media and the growth rates of SMC were determined by [3H]-thymidine incorporation and cell counting. The growth rate in [100-900]-MEM was significantly higher than in [900]- and [100]-MEM. When platelet derived growth factor (PDGF) was neutralized by the addition of a mixture of anti-PDGF-AA and -BB antibodies, [3H]-thymidine incorporation in [100-900]-MEM decreased by 23.3 per cent, but only by 7.0 per cent in [900]-MEM. The quantity of PDGF in the Mg-deficient media was greater than in the magnesium-sufficient media at all indicated times, as shown by radioimmunoassay for PDGF-BB or -AB. These results indicate that Mg deficiency increases the secretion of PDGF by SMC.

Antibodies↗
PubMed1996

An evaluation of the history of a marijuana withdrawal syndrome in a large population.

Case reports and laboratory research indicate the existence of a cannabis withdrawal syndrome. However, the data tell us little about the prevalence and clinical characteristics of a marijuana withdrawal syndrome in people who have used the drug but who did not enter treatment for cannabis dependence. Face-to-face semi-structured interviews applying standard diagnostic criteria were used in the present study to gather data from 5611 men and women, recruited between 1991 and 1995 through the Collaborative Study of the Genetics of Alcoholism (COGA). Almost 41% of the sample had no history of marijuana use (Group 1), 28% had consumed this drug less than 21 times in any single year (Group 2), and 31% used it at least that frequently (Groups 3 and 4). Almost 16% of the more frequent marijuana users related a history of a marijuana withdrawal syndrome, and these Group 4 subjects had used the drug almost daily for an average of almost 70 months. The typical withdrawal symptoms included "nervous, tense, restlessness", "sleep disturbance" and "appetite change". While Group 4 subjects were more likely to have developed dependence on most types of drugs, even when alcohol and drug use patterns were statistically taken into account, marijuana use was still significantly related to a self-report of a history of marijuana withdrawal.

Adult↗
PubMed1996

The pharmacologic approach to the painful hand.

The management of reflex sympathetic dystrophy with oral, topical, and parenteral medications is complex. This article outlines the pharmacologic options available to treat dystrophic pain, provides an overview of mechanisms-of-action, and defines relative indications for administration.

Hand↗
PubMed1996

The painful hand.

RSD can be approached using objective criteria in a logical and systematic fashion. Frustration during treatment is common because (1) the pathophysiology of RSD is incompletely understood, (2) there is significant variation in presentation because of disparate premorbid anatomy and physiology, and (3) the natural history may be affected by incomplete treatment. Therapeutic efforts that theoretically should be effective may fail, and a trial-and-error approach is often mandatory. In spite of vigorous intervention using all known strategies, patients may continue to have pain and disability that progresses to stiffness and arthrofibrosis. Early recognition and prompt intervention, however, provide the best opportunity for clinical improvement.

Hand↗
PubMed1995

Platelet monoamine oxidase activity levels in subgroups of alcoholics: diagnostic, temporal, and clinical correlates.

Platelet monoamine oxidase (MAO) activity levels were measured in 47 male inpatient alcoholics to determine whether this biological marker might be useful in differentiating subtypes of alcoholics. Of the subgrouping methods tested, only type 2 alcoholics defined by the criteria of Gilligan et al had significantly lower platelet MAO activity than type 1 alcoholics at intake, but this finding was not stable over time in a subset of subjects. Neither separating male veteran alcoholics into either of two other variations of the type 1/type 2 subtypes, nor classifying the sample into primary alcoholics versus primary ASPD with secondary alcoholism categories, yielded significant differences between subgroups. Generally, enzyme activity levels (Vmax) were higher about 10 days after stopping drinking compared to platelet MAO values determined in thrombocytes obtained after approximately 4 weeks abstinence; these levels remained relatively stable 3 months later in a cohort of subjects. Tobacco smoking was significantly negatively correlated to platelet MAO activity levels.

Adolescent↗
PubMed1995

P22 Arc repressor: role of cooperativity in repression and binding to operators with altered half-site spacing.

Dimers of P22 Arc repressor bind to half-sites of the 21 bp arc operator and interact cooperatively to stabilize a DNA-bound tetramer. Mutation of Ser35 (a residue in the dimer-dimer interface) to Arg or Leu disrupts cooperative binding. The mutant proteins have near wild-type stabilities, give operator footprints like wild-type, and prevent binding of RNA polymerase to the Pant promoter in vitro. These mutants are, however, largely inactive in vivo. Thus, although cooperativity is not structurally required for repression, it appears that the additional DNA-binding energy from dimer-dimer cooperativity is required for normal biological function. Altering the spacing between the DNA half-sites by even one base-pair eliminates dimer-dimer cooperativity, indicating that Arc dimers need to be oriented correctly by half-site binding to allow the interactions that stabilize the tetrameric complex.

Bacteriophage P22↗