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Biomedical subjects

D A Thomas

Publications and source records attributed to D A Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2000

DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis.

Granzyme B (GzmB) is a component of cytotoxic lymphocyte granules that can rapidly initiate apoptosis in target cells. While several procaspases are cleaved and activated by GzmB, the absolute requirement of caspase activation for GzmB-induced apoptosis is controversial. In this report, we demonstrate that GzmB can initiate apoptosis in the absence of caspase-3 activity by directly cleaving DFF45/ICAD to liberate activated DFF40/CAD. DFF45/ICAD cleavage occurs less efficiently in cells that lack caspase-3 activity, suggesting that the caspases normally amplify the GzmB death signal. DFF45/ICAD-deficient mouse embryo fibroblasts are partially resistant to GzmB-induced death, demonstrating the biological importance of DFF45/ICAD for GzmB-mediated apoptosis.

Animals↗
PubMed2000

Duration of action of atracurium when given by infusion to critically ill children.

The aim of the study was to investigate the offset time of atracurium when given by continuous infusion on a paediatric intensive care unit and to look for evidence of tolerance. Over a period of 8 months, 20 mechanically ventilated children had a steady-state infusion of atracurium discontinued to enable the assessment of their level of sedation. The offset time of atracurium was assessed by train-of-four (TOF) stimulation of the ulnar nerve. The initial TOF reading was documented as was the time taken to reach a TOF ratio of 0.9. Thirty-five assessments were carried out. The mean offset time of atracurium was 28.7 min (SEM 1.76 min, range 8-56 min). There was no correlation between the dose of atracurium at discontinuation and the offset time of the infusion. The duration of infusion was negatively correlated with the offset time of atracurium, and this effect was most prominent in children who had received infusions for longer than 48 h. When given by continuous infusion, the offset time of atracurium is very variable between individual patients. Infusions administered for longer than 48 h are associated with a significant reduction in the offset time as a result of increasing tolerance.

Adolescent↗
PubMed2000

The effect of induced hypothermia on the duration of action of atracurium when given by infusion to critically ill children.

The aim of the study was to investigate the effect of induced hypothermia on the offset time of atracurium when given by continuous infusion to critically ill children. Over a period of 8 months, six mechanically ventilated children had a steady-state infusion of atracurium discontinued. The offset time of atracurium was assessed by train-of-four (TOF) stimulation of the ulnar nerve; recording the time taken to reach a TOF ratio of 0.9. Nine assessments were carried out. The mean offset time of atracurium was 82 min. This was significantly longer than in patients with temperatures within the normal physiological range. When considering all assessments, performed both in hypothermic and normothermic patients, there is a strong correlation between rectal temperature and the offset time of atracurium. Prolonged moderate hypothermia has a very significant effect on the offset time of atracurium when given by infusion to critically ill children.

Adolescent↗
PubMed2000

Quality of sedation during mechanical ventilation.

The aim of the study was to determine the quality of sedation in ventilated patients on a general paediatric intensive care unit (PICU), including those treated with infusions of neuromuscular blocking agents. Twenty-eight ventilated children on a PICU had their level of sedation determined using an arousability scale dependent upon the response to tracheal suction. Observed levels of sedation were then compared to a predetermined desired level of sedation. A total of 81 assessments were performed and 90% were considered satisfactory. Thirty-two of these assessments were performed in 15 children following the temporary discontinuation of infusions of neuromuscular blocking agents; 97% of these assessments were considered satisfactory. A regime of continuous intravenous midazolam and morphine with additional oral sedation using chloral hydrate and antihistamines when required provides a satisfactory level of sedation for the majority of children ventilated on a PICU, including those treated with infusions of neuromuscular blocking agents.

Administration, Oral↗
PubMed2000

Current role of thalidomide in cancer treatment.

Thalidomide (Thalidomid, Celgene, Warren, NJ) is a putative anti-angiogenesis and immunomodulatory agent that has demonstrated activity in various dermatologic and rheumatologic conditions in addition to Crohn's disease. The biologic effects of thalidomide and the clinical trials conducted in solid tumors, hematologic malignancies, chronic graft-versus-host disease (GVHD), and cancer-related cachexia are reviewed. A summary of the preliminary results of ongoing clinical trials is presented, and the future directions of thalidomide research in the oncology are discussed.

Angiogenesis Inhibitors↗
PubMed2000

Response properties and organization of nociceptive neurons in area 1 of monkey primary somatosensory cortex.

The organization and response properties of nociceptive neurons in area 1 of the primary somatosensory cortex (SI) of anesthetized monkeys were examined. The receptive fields of nociceptive neurons were classified as either wide-dynamic-range (WDR) neurons that were preferentially responsive to noxious mechanical stimulation, or nociceptive specific (NS) that were responsive to only noxious stimuli. The cortical locations and the responses of the two classes of neurons were compared. An examination of the neuronal stimulus-response functions obtained during noxious thermal stimulation of the glabrous skin of the foot or the hand indicated that WDR neurons exhibited significantly greater sensitivity to noxious thermal stimuli than did NS neurons. The receptive fields of WDR neurons were significantly larger than the receptive fields of NS neurons. Nociceptive SI neurons were somatotopically organized. Nociceptive neurons with receptive fields on the foot were located more medial in area 1 of SI than those with receptive fields on the hand. In the foot representation, the recording sites of nociceptive neurons were near the boundary between areas 3b and 1, whereas in the hand area, there was a tendency for them to be located more caudal in area 1. The majority of nociceptive neurons were located in the middle layers (III and IV) of area 1. The fact that nociceptive neurons were not evenly distributed across the layers of area 1 suggested that columns of nociceptive neurons probably do not exist in the somatosensory cortex. In electrode tracks where nociceptive neurons were found, approximately half of all subsequently isolated neurons were also classified as nociceptive. Low-threshold mechanoreceptive (LTM) neurons were intermingled with nociceptive neurons. Both WDR and NS neurons were found in close proximity to one another. In instances where the receptive field shifted, subsequently isolated cells were also classified as nociceptive. These data suggest that nociceptive neurons in area 1 of SI are organized in vertically orientated aggregations or clusters in layers III and IV.

Action Potentials↗
PubMed2000

Microgravity culture reduces apoptosis and increases the differentiation of a human colorectal carcinoma cell line.

Our hypothesis is that rotation increases apoptosis in standard tissue culture medium at shear stresses of greater than approximately 0.3 dyn/cm2. Human MIP-101 poorly differentiated colorectal carcinoma cells were cultured for 6 d in complete medium in monolayers, on Teflon-coated nonadherent surfaces (static three-dimensional [3D]) or in rotating 3D cultures either in microgravity in low-earth orbit (3D microg) or in unit gravity on the ground (3D 1g). Apoptosis (determined morphologically), proliferation (by MIB1 staining), and the expression of epidermal growth-factor receptor (EGF-R), TGF-alpha, or TGF-beta were assessed by immunohistochemistry, while the expression of the differentiation marker carcinoembryonic antigen (CEA) was assessed on Western blots. Over the course of 6 d, static 3D cultures displayed the highest rates of proliferation and lowest apoptosis. This was associated with high EGF-R, TGF-alpha, and TGF-beta expression which was greater than that of a monolayer culture. Both rotated 3D lg and 3D microg cultures displayed lower expression of EGF-R, TGF-alpha, or TGF-beta and proliferation than that of monolayer or static 3D cultures. However, rotated 3D microg displayed significantly less apoptosis and greater CEA expression than rotated 3D 1g cultures. When rotated cultures of MIP-101 cells were grown uncler static conditions for another 3 d, proliferation increased and apoptosis decreased. Thus, rotation appears to increase apoptosis and decrease proliferation, whereas static 3D cultures in either unit or microgravity have less apoptosis, and reduced rotation in microgravity increases CEA expression.

Apoptosis↗
PubMed2000

Progressive multifocal leukoencephalopathy with concurrent Richter's syndrome.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infectious disease caused by the JC virus. It was originally described in patients with chronic lymphocytic leukemia (CLL). Richter's syndrome, or transformation to large cell Lymphoma, occurs in approximately 3% of patients with CLL, and carries a poor prognosis. We report a patient with documented PML and concurrent Richter's transformation outside the central nervous system. Before establishing a definitive diagnosis of PML, radiation therapy to the presumed lymphomatous brain lesion had been considered, raising the issue of whether stereotactic brain biopsy should be considered in every patient in a similar situation. Although this is likely a rare occurrence, patients with Richter's transformation documented at an extra-neural site and a brain lesion may benefit from the establishment of an infectious diagnosis which would influence therapy.

Cell Transformation, Neoplastic↗
PubMed2000

Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia.

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) represents the most common cytogenetic abnormality in adult ALL. It is found in 15% to 30% of patients, and its incidence increases with age. As in children, prognosis in Ph-positive adult ALL is poor. No therapeutic approach has had substantial impact on its unfavorable course. We analyzed the characteristics and outcome of newly diagnosed adults with Ph-positive ALL treated at the M. D. Anderson Cancer Center between 1980 and 1997. The diagnosis of patients was based on typical morphological and immunophenotypic criteria of marrow aspirate and biopsy specimens. Cytogenetic and molecular studies were also performed. A total of 67 patients were included in this study. From 1980 until 1991, 38 patients with Ph-positive ALL were treated with vincristine, Adriamycin, and dexamethasone (VAD), or with acute myeloid leukemia (AML)-like induction protocols. Since 1992 a total of 29 patients received induction therapy with an intensified treatment protocol, called "hyper-CVAD". The outcome of patients treated with standard and intensified treatment regimens was compared and results of our institution contrasted with data obtained from other centers. Ph-positive ALL was present in 67 of 498 patients with newly diagnosed ALL (13%). Patients with Ph-positive ALL had a higher median age (44 versus 34, P=0.007), higher median white blood cell (WBC) counts at presentation (25 versus 8, P=0.0002), and higher peripheral median percentage of blast counts (63 versus 40, P=0.023). FAB subtype L2 (70% versus 49%, P=0.001) and CALLA-positive pre-B immunophenotype (75% versus 37%, P<0.001) predominated among Ph-positive ALL. Myeloid marker coexpression was more frequent in Ph-positive ALL when compared with Ph-negative ALL (52% vs. 27% for CD13, P<0.001, and 44% vs. 27% for CD33, P=0.005). Among patients treated with hyper-CVAD, the complete remission (CR) rate was 90% versus 55% (P=0.002) with pre-hyper-CVAD regimens (VAD and AML-like induction protocols), the median CR duration was 43 weeks versus 32 weeks (P>0.5), median disease-free survival (DFS) was 42 weeks versus 29 weeks (P=0.008), and median survival was 66 weeks versus 45 weeks (P>0.5). Patients with hyperdiploid Ph-positive ALL on hyper-CVAD therapy achieved significantly longer CR duration and DFS than hypo- and pseudodiploid cases (59 weeks versus 42 and 31 weeks, P=0.02 and 0.04, respectively). In contrast, patients treated with regimens prior to hyper-CVAD had significantly shorter CR duration (21 weeks versus 33 and 29 weeks, P=0.03) and DFS with hyperdiploid karyotypes when compared to pseudodiploid and hypodiploid cases (16 weeks versus 30 and 13 weeks, P=0.008). In conclusion, our results demonstrate improved response rate and DFS with current intensive regimens (hyper-CVAD) in patients with Ph-positive ALL, but no advantage in overall survival.

Adult↗
PubMed1999

Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy.

BACKGROUND: Relapses continue to be problematic for adults with acute lymphoblastic leukemia (ALL). New therapies generally are first tested in the salvage setting prior to incorporation into frontline regimens. Defining the prognosis at relapse (or at failure of induction) and subsequently predicting outcome would be useful to select the population in whom to test new strategies, rather than attempting traditional reinduction therapy. METHODS: Between March 1980 and March 1997, 314 eligible adults with primary refractory (24%) or primary relapsed (76%) ALL were treated with various chemotherapy or stem cell transplantation (SCT) regimens. The Cox proportional hazards model was used to assess biologic factors and disease history in relation to survival. RESULTS: A complete remission (CR) was achieved in 97 patients (31%), 21% died prior to a response, and 49% were refractory to salvage therapy. Of the 76 patients refractory to induction therapy for their de novo ALL, 26 patients (34%) achieved a CR with salvage therapy. The median overall CR duration was 6 months. The median overall survival was 5 months; 24% of the patients were alive at 1 year, and the projected survival at 5 years was 3%. Nineteen patients were alive at the time of last follow-up, 10 with 6 weeks to 10 years of continuous CR from the time of their first salvage therapy. SCT consolidation in second CR was performed in 25% of patients; 28% of those who received allogeneic SCT remain in continuous CR at 4 months, 2(1/2) years, 3(1/2) years, and 10 years, whereas all 8 who received autologous SCT have relapsed. Favorable factors for longer survival by multivariate analysis were age <40 years, absence of circulating blasts, and first CR duration longer than 1 year. Patients were stratified into 4 risk groups: Group 1, with no unfavorable features or only short initial CR duration; Group 2, with only increased age or peripheral blasts; Group 3, with any 2 unfavorable features; and Group 4, with all 3 unfavorable features. The median survival times for each group were 11, 6, 4, and 2 months, respectively; 1-year survival rates were 44%, 25%, 12%, and 9%, respectively (P < 0.01). The resulting model was also predictive for CR rates; the corresponding CR rates were 47%, 35%, 14%, and 9%, respectively (P < 0.01). CONCLUSIONS: Salvage therapy for adult ALL patients continues to yield poor results, but it is an area of research where it may be possible to discover new agents or strategies to be incorporated into frontline therapy. The prognostic model derived will be utilized prospectively to select patients for new therapeutic strategies involving such novel agents as liposomal compounds, purine nucleoside phosphorylase inhibitors, and monoclonal antibodies.

Adolescent↗
PubMed1999

Multidrug resistance protein expression in chronic myeloid leukemia: associations and significance.

BACKGROUND: Overexpression of the multidrug resistance gene (MDR1) product, the MDR1 protein (MDR1), has been associated with poor prognosis in several hematologic malignancies. The significance of MDR1 levels in patients with chronic myeloid leukemia (CML) has not been established. METHODS: The authors investigated MDR1 levels and their association with patient and tumor characteristics, responsiveness to therapy, and long term prognosis in 198 CML patients. These included 127 patients in early chronic phase (ECP) CML, 31 patients in late chronic phase (LCP) CML, and 40 patients in accelerated or blastic phase CML. MDR1 expression was analyzed by Western blot analysis and quantitative solid-phase plate radioimmunoassay. MDR1 levels were measured on cell lysates obtained from the bone marrow mononuclear cell fraction. Expression was compared in relation to the median derived from 36 normal control samples. RESULTS: Among patients with CML, high levels of MDR1 were found in 73 of 127 ECP (57%), 20 of 31 LCP (65%), 8 of 27 in accelerated phase (30%), and 8 of 13 in blastic phase (62%) (P value not significant). Furthermore, among the 127 ECP CML patients, high MDR1 levels were associated with age >/=50 years (69% vs. 51%; P < 0. 05), thrombocytosis >700 x 10(9)/L (84% vs. 53%; P < 0.01), and leukocyte counts </=50 x 10(9)/L (70% vs. 46%; P < 0.01). Response to interferon alpha (IFN-alpha) was independent of MDR1 expression; major cytogenetic responses were recorded in 28 of 73 patients with high MDR1 levels and in 16 of 54 patients with low MDR1 levels (38% vs. 30%; P value not significant). No difference in survival based on MDR1 level was observed. A small subset of 17 patients with low MDR1 levels (<1 times normal) had a trend toward worse survival (median, 30 months vs. 73 months; 5-year survival rates of 34% vs. 65%; P = 0.03). CONCLUSIONS: The results of the current study demonstrate that MDR1 overexpression was not associated with disease progression, responsiveness to IFN-alpha therapy, or survival in patients with ECP CML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Granzyme A initiates an alternative pathway for granule-mediated apoptosis.

Granzyme (gzm) B-deficient cytotoxic lymphocytes (CTL) have a severe defect in the rapid induction of target cell apoptosis that is almost completely corrected by prolonged incubation of the CTL effectors and their targets. We show in this report that perforin-dependent, gzmB-independent cytotoxicity is caused by gzmA (or tightly linked genes). CTL deficient for gzmA and gzmB retain normal perforin function, but these CTL have a cytotoxic defect in vivo that is as severe as perforin-deficient CTL. Collectively, these results suggest that perforin provides target cell access and/or trafficking signals for the gzms, and that the gzms themselves deliver the lethal hits. The gzmA pathway appears to function independently from gzmB and may therefore provide a critical "back-up" system when gzmB is inhibited in the target cell.

Animals↗
PubMed1999

Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia.

PURPOSE: To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were > or = 60 years. Patients received Hyper-CVAD alternated with courses of high-dose methotrexate and cytarabine. Granulocyte colony-stimulating factor and prophylactic antibiotics were administered for all eight planned courses. CNS prophylaxis alternated intrathecal methotrexate and cytarabine on days 2 and 7 of each course. RESULTS: Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (+/- 11%); the 3-year continuous CR rate was 61% (+/- 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age > or = 60 years, poor performance status, anemia, thrombocytopenia, peripheral blasts, and increased lactate dehydrogenase level. The 3-year survival rate was 77% for 14 patients younger than 60 years and 17% for 12 patients > or = 60 years (P <.01). Regression analysis identified older age, anemia, and presence of peripheral blasts as independent factors associated with shorter survival. Patients could be stratified according to (1) no or one adverse feature, (2) two adverse features, and (3) all adverse features. The 3-year survival rates were 89%, 47%, and 0%, respectively (P <.01). CONCLUSION: Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.

Adolescent↗
PubMed1998

Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat.

Microinjection of baclofen, a gamma-aminobutyric acidB (GABA[B]) receptor agonist, in the nucleus raphe magnus (NRM) or nucleus reticularis gigantocellularis pars alpha (NGCpalpha) of the rat produces antinociception at doses of 0.1-1.0 ng and hyperalgesia at doses of 30-150 ng in the tail-flick test. The antinociception is proposed to result from disinhibition of spinally-projecting neurons in this region that contain serotonin. The hyperalgesia is proposed to result either from inhibition of these neurons or from disinhibition of a serotonergic pain facilitatory pathway that also originates in this area of the ventromedial medulla. To determine the involvement of bulbospinal serotonergic pathways in the biphasic effects of baclofen, rats were pretreated intrathecally with either 30 microg of methysergide or saline. Ten minutes later, either saline, 0.5 ng or 150 ng of baclofen was microinjected in the NRM and NGCpalpha, and alterations in nociceptive threshold were assessed by the tail-flick and hot-plate tests. Intrathecal pretreatment with methysergide prevented the increase in tail-flick latency produced by 0.5 ng of baclofen, but did not prevent the decrease in tail-flick latency produced by 150 ng of baclofen. Neither dose of baclofen altered hot-plate latency and this lack of effect was unchanged by methysergide. These data support the idea that the antinociceptive effect of low doses of baclofen in the tail-flick test is mediated by disinhibition of a bulbospinal serotonergic projection and release of serotonin in the spinal cord. These data also suggest that the hyperalgesia produced by high doses of baclofen does not result from disinhibition of a serotonergic pain facilitatory pathway, but rather from direct inhibition of tonically-active pain inhibitory neurons in the NRM and NGCpalpha.

Analgesics↗
PubMed1998

Production of fully active recombinant murine granzyme B in yeast.

Granzyme B (GzmB) is a neutral serine protease found in cytotoxic lymphocytes; this enzyme is critically involved in delivering the rapid apoptotic signal to susceptible target cells. GzmB has been difficult to study and has not yet been produced in non-mammalian systems because of the complex processing events that are thought to be required for its activation. In this report, we have successfully produced fully active, soluble recombinant GzmB (rGzmB) in a yeast-based system by fusing GzmB cDNA in frame with yeast alpha-factor cDNA, using the yeast KEX2 signal peptidase to release the processed enzyme into the supernatant of yeast cultures. We expressed the proenzyme form of GzmB as well and determined that pro-GzmB is efficiently converted to its active form by the cysteine proteinase dipeptidyl peptidase I. The fully processed enzyme was able to hydrolyze the synthetic substrate N-t-butyloxycarbonyl-L-alanyl-L-alanyl-L-aspartyl (Boc-Ala-Ala-Asp) thiobenzyl ester with a kcat of 17 s-1 and catalytic efficiency kcat/Km of 181,237 M-1 S-1; the recombinant enzyme is therefore at least twice as active as purified native GzmB. In addition, the recombinant enzyme hydrolyzes Boc-Ala-Ala-Met thiobenzyl ester with a kcat of 3.2 S-1 and a catalytic efficiency kcat/Km of 65,306 M-1 S-1. Purified rGzmB can also cleave the putative substrate caspase-3 into its signature p20/p10 forms. Unlike caspases, rGzmB is not sensitive to inhibition by several peptide-based inhibitors, including Ac-DEVD-CHO, Ac-YVAD-CMK, and ZIETD-FMK, as well as Zn2+ (a known inhibitor of caspase-3). Structural studies of rGzmB may allow us to better understand the substrate specificity of this enzyme and to design better inhibitors.

Animals↗