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Biomedical subjects

James Thomas

Publications and source records attributed to James Thomas.

At least 19 recordsLinked to original sources
PubMed2007

Quantitative real-time 3-dimensional stress echocardiography: a preliminary investigation of feasibility and effectiveness.

BACKGROUND: Use of rapidly emerging real-time 3-dimensional (3D) echocardiography promises to improve the diagnostic accuracy of stress echocardiography (SE). However, widespread acceptance of 3D-SE, based on real-time 3D echocardiography, is hampered in part by lack of efficient, accurate, and objective analysis tools. METHODS: We propose novel algorithms for interactive visualization, registration (alignment), and quantitative analysis of prestress and poststress real-time 3D echocardiography to facilitate an objective diagnosis. In a preliminary evaluation, two experts independently performed wall-motion analysis in 15 patients with known/suspected coronary artery disease, using the novel quantitative 3D-SE methods. RESULTS: Compared with previously reported values for conventional 2-dimensional SE, improved interexpert agreement (kappa = 0.85) was observed for segment-wise classification of normal/abnormal wall motion using the novel 3D-SE methods. Overall, 6 of 6 patients with abnormal myocardial segments were correctly identified by both experts with 3D-SE, compared with 4 of 6 with conventional 2-dimensional SE. CONCLUSION: Initial results are promising and indicate the feasibility and potential of our proposed quantitative 3D-SE methodologies for improving diagnosis of wall-motion abnormalities.

Adult↗
PubMed2006

Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.

PURPOSE: Regular physical activity reduces the risk of developing colon cancer, however, its influence on patients with established disease is unknown. PATIENTS AND METHODS: We conducted a prospective observational study of 832 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on various recreational physical activities approximately 6 months after completion of therapy and were observed for recurrence or death. To minimize bias by occult recurrence, we excluded patients who experienced recurrence or died within 90 days of their physical activity assessment. RESULTS: Compared with patients engaged in less than three metabolic equivalent task (MET) -hours per week of physical activity, the adjusted hazard ratio for disease-free survival was 0.51 (95% CI, 0.26 to 0.97) for 18 to 26.9 MET-hours per week and 0.55 (95% CI, 0.33 to 0.91) for 27 or more MET-hours per week. The adjusted P for trend was .01. Postdiagnosis activity was associated with similar improvements in recurrence-free survival (P for trend = .03) and overall survival (P for trend = .01). The benefit associated with physical activity was not significantly modified by sex, body mass index, number of positive lymph nodes, age, baseline performance status, or chemotherapy received. Moreover, the benefit remained unchanged even after excluding participants who developed cancer recurrence or died within 6 months of activity assessment. CONCLUSION: Beyond surgical resection and postoperative adjuvant chemotherapy for stage III colon cancer, for patients who survive and are recurrence free approximately 6 months after adjuvant chemotherapy, physical activity appears to reduce the risk of cancer recurrence and mortality.

Aged↗
PubMed2006

Phase II study of erlotinib in patients with advanced biliary cancer.

PURPOSE: Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months. METHODS: Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally. RESULTS: Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash. CONCLUSION: Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.

Adult↗
PubMed2006

Assessment of contractility of purified smooth muscle cells derived from embryonic stem cells.

The aims of this study were to develop a method for deriving purified populations of contractile smooth muscle cells (SMCs) from embryonic stem cells (ESCs) and to characterize their function. Transgenic ESC lines were generated that stably expressed a puromycin-resistance gene under the control of either a smooth muscle alpha-actin (SMalphaAlpha) or smooth muscle-myosin heavy chain (SM-MHC) promoter. Negative selection, either overnight or for 3 days, was then used to purify SMCs from embryoid bodies. Purified SMCs expressed multiple SMC markers by immunofluorescence, immunoblotting, quantitative reverse transcription-polymerase chain reaction, and flow cytometry and were designated APSCs (SMalphaAlpha-puromycin-selected cells) or MPSCs (SM-MHC-puromycin-selected cells), respectively. Both SMC lines displayed agonist-induced Ca(2+) transients, expressed functional Ca(2+) channels, and generated contractile force when aggregated within collagen gels and stimulated with vasoactive agonists, such as endothelin-1, or in response to depolarization with KCl. Importantly, subcutaneous injection of APSCs or MPSCs subjected to 18 hours of puromycin selection led to the formation of teratomas, presumably due to residual contamination by pluripotent stem cells. In contrast, APSCs or MPSCs subjected to prolonged puromycin selection for 3 days did not form teratomas in vivo. These studies describe for the first time a method for generating relatively pure populations of SMCs from ESCs which display appropriate excitation and contractile responses to vasoactive agonists. However, studies also indicate the potential for teratoma development in ESC-derived cell lines, even after prolonged differentiation, highlighting the critical requirement for efficient methods of separating differentiated cells from residual pluripotent precursors in future studies that use ESC derivatives, whether SMC or other cell types, in tissue engineering applications.

Actins↗
PubMed2006

Innate stimuli accentuate end-organ damage by nephrotoxic antibodies via Fc receptor and TLR stimulation and IL-1/TNF-alpha production.

Innate stimuli are well recognized as adjuvants of the systemic immune response. However, their role in driving end-organ disease is less well understood. Whereas the passive transfer of glomerular-targeting Abs alone elicited minimal renal disease, the concomitant delivery of innate stimuli triggered severe nephritis, characterized by proliferative glomerulonephritis with crescent formation, and tubulointerstitial disease. Specifically, stimulating TLR2, TLR3, TLR4, and TLR5 by using peptidoglycan, poly(I:C), LPS, and flagellin, respectively, all could facilitate anti-glomerular Ab-elicited nephritis. In this model, innate and immune triggers synergistically activated several cytokines and chemokines, including IL-1, IL-6, TNF-alpha, and MCP-1, some of which were demonstrated to be absolutely essential for the development of renal disease. Genetic studies revealed that, whereas the innate trigger is dependent on TLR/IL-1R-associated kinase-mediated signaling, the immune component was contingent on FcR-mediated signals. Importantly, infiltrating leukocytes as well as intrinsic glomerular cells may both serve to integrate these diverse signals. Extrapolating to spontaneous immune-mediated nephritis, although the adaptive immune system may be important in generating end-organ targeting Abs, the extent of damage inflicted by these Abs may be heavily dependent on cues from the innate immune system.

Adjuvants, Immunologic↗
PubMed2006

Sigmoid notch osteotomy for posttraumatic dorsal dislocation of the distal radioulnar joint: A case report.

Instability of the distal radioulnar joint (DRUJ) is associated most commonly with injury to the soft-tissue restraints of that joint, particularly the triangular fibrocartilage complex. The dorsal rim of the sigmoid notch, however, also plays an important role as a bony restraint to dorsal subluxation. We report a case of posttraumatic dorsal dislocation of the DRUJ associated with a depressed fracture of the dorsal rim of the sigmoid notch. This was treated with soft-tissue release and corrective osteotomy of the dorsal rim of the sigmoid notch to restore DRUJ stability and congruency.

Adult↗
PubMed2006

Ratings of perceived exertion of ACSM exercise guidelines in individuals varying in aerobic fitness.

The physiological responses of high (HF) and low fit (LF) individuals at given perceived exercise intensities were compared to ranges provided by the American College of Sports Medicine (ACSM). Participants were 7 LFand 8 HF men between the ages of 22 and 26 years. All participants performed a maximum oxygen uptake and lactate threshold test and two 15-min experimental runs in which they exercised at a constant perceived exercise intensity (RPE 13 and 17). The LF group exhibited significantly greater maximum oxygen uptake reserve ( % VO2R, p < .05) and velocity of lactate threshold (p < .01) values than HF at RPE 13 and 17. Both groups had significantly greater % VO2R and maximum heart rate values at RPE 13 in comparison with the ACSM ranges, using the highest value for the given range (p < or = .001).

Adult↗
PubMed2006

Use of remote sensing and geographic information systems to predict locations of Anopheles darlingi-positive breeding sites within the Sibun River in Belize, Central America.

Previous studies have identified several anopheline species integral to the transmission of malaria in Belize. The highly efficient vector, Anopheles darlingi Root, is currently considered the most important. The preferred larval habitat of An. darlingi has been described as floating detritus patches, which are commonly associated with overhanging spiny bamboo, Guadua longifolia (E. Fourn.), along river margins. The objectives of this study were to use remote sensing and geographic information system (GIS) tools to 1) define the landscape features (i.e., river curvature, land cover, and house locations) associated with An. darlingi-positive breeding habitats and 2) determine the association between cleared land cover and the growth of spiny bamboo. A systematic survey was conducted in which all detritus patches of at least 1 m2 were sampled, mapped using GPS, and characterized by cause of habitat lodging. Bamboo stretches growing along the river margins also were mapped. Spatial analyses of satellite imagery found no associations between river characteristics or land cover with positive An. darlingi habitats. In addition, there was no significant difference in cleared versus forested land cover in relation to the presence or absence of bamboo. Results indicate that the average distance from homes to negative habitats was significantly greater than from positive detritus mats. Based on the land cover and river characteristics used, our results do not support the use of remote sensing as a predictive tool to locate specific areas within rivers positive for An. darlingi habitats.

Animals↗
PubMed2005

Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer.

PURPOSE: Epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) and ligand expression is frequently seen in hepatocellular cancers (HCCs). Erlotinib (Tarceva, OSI-774; OSI Pharmaceuticals, Melville, NY) is a receptor tyrosine kinase inhibitor with specificity for the EGFR/HER1. METHODS: The primary objective of this study was to determine the proportion of patients with advanced HCC who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was given continuously at a dose of 150 mg per day orally. RESULTS: Thirty-eight patients with HCC were enrolled. Median age of the patients was 69 years (range, 27 to 83 years). A majority of patients (63%) had an Eastern Cooperative Oncology Group performance status of 1. Forty-seven percent of patients had received prior chemotherapy for advanced HCC. EGFR/HER1 expression was detected in 88% of the patients. Median number of cycles per patient was two (range, 1 to 26). Twelve (32%; CI 95%, 18 to 49) of the 38 patients with HCC were progression-free at 6 months. Three patients had partial radiologic responses of duration of 2, 10, and 11 months, respectively. Disease control was seen in 59% of the patients. Median overall survival time was 13 months. Ten patients (26%) had toxicity-related dose reductions of erlotinib. Grade 3/4 skin toxicity or diarrhea was encountered in five and three patients, respectively. CONCLUSION: Results of this trial suggest a benefit for EGFR/HER1 blockade with erlotinib in patients with HCC manifested by disease control. Additional studies with erlotinib as a single agent or in combination with other agents are warranted.

Administration, Oral↗
PubMed2005

Exploring the evidence-practice gap: a workshop report on mixed and participatory training for HIV prevention in Southern Africa.

BACKGROUND: The gap between what is known and what is done about public health (the evidence-practice gap) needs addressing. One solution may be through mixed and participatory training in accessing and appraising research. APPROACH: Residential workshops trained policy-makers, practitioners and researchers from seven southern-African countries in evidence-based decision-making for HIV prevention. They included training in accessing, critiquing and summarizing research, whilst remaining responsive to the priorities of the participants. REFLECTIONS: Drawing on the participants' feedback and our observations, we reflected on how these workshops may have addressed the evidence-practice gap. We identified three areas: access to research, understanding of research and the relevance of research. The workshops enabled a small group of people to access relevant research in a timely manner. However, more needs to be done to disseminate research findings appropriately as any long-term impact will be affected by the political and economic context in which participants work. We are confident that the participants went away with increased understanding of the purposes and processes of research, but for research to make a difference, the research community needs to emphasise more the publication of research findings written for potential users. The workshops were most successful in influencing researchers to consider bridging the evidence-practice gap by producing more relevant research, applicable to policy-makers and practitioners. CONCLUSION: This intensive intervention has the potential to reduce the evidence-practice gap for HIV prevention in southern Africa by training non-researchers to engage with research, whilst providing an opportunity for researchers to engage with policy-makers and practitioners.

Africa, Southern↗
PubMed2005

Phase I study of piritrexim and gemcitabine in patients with advanced solid tumors.

OBJECTIVES: In this phase I study, the combination of piritrexim and gemcitabine was given to establish the maximum tolerated dose and the recommended phase II dose, and to determine a toxicity and efficacy profile. METHODS: Fifty-two patients with normal and impaired renal function were enrolled on this phase I study. The starting dose was piritrexim 10 mg 3 times daily (5 days of the week for 3 weeks and 1 week off each 28-day cycle) and gemcitabine 1000 mg/m2 on days 1, 8, and 15. The piritrexim was escalated in a stepwise fashion with this dose of gemcitabine and then with gemcitabine 1000 mg/m2 for days 1 and 15. RESULTS: The recommended phase II dose of this combination was felt to be piritrexim 50 mg/day (10 mg every morning, 20 mg every noon, and 20 mg every evening) with gemcitabine 1000 mg/m2 on days 1, 8, and 15, and piritrexim 75 mg/day (25 mg thrice daily) with gemcitabine 1000 mg/m2 on days 1 and 15. Neutropenia and thrombocytopenia were the most often reported toxicity. Dose-limiting toxicity was thrombocytopenia in both groups. The number of renal-impaired patients enrolled was too small to establish a maximum tolerated dose for this group (piritrexim became unavailable), but the combination was tolerated in the patients with impaired renal dysfunction. There was 1 complete response, 1 partial response, and 1 minimal response. CONCLUSION: The combination of piritrexim and gemcitabine was determined to be tolerable in heavily pretreated patients for use in solid tumors.

Administration, Oral↗
PubMed2005

Standardized mean differences in individually-randomized and cluster-randomized trials, with applications to meta-analysis.

The magnitude of the effect of an intervention on a quantitative outcome may be expressed as a standardized mean difference by dividing the difference in means by the standard deviation of the outcome. This is useful to compare outcomes measured using different scales, especially in meta-analysis. However, uncertainty about the standard deviation leads to complicated formulae to avoid bias and to compute the correct standard error. We review approximate and exact formulae and argue for the use of the exact formulae. We then extend the formulae to cluster-randomized trials, and show how the calculations may be implemented using published results. We also describe methods for estimating the standard deviation. Various pitfalls are identified which can lead to major errors especially in the cluster-randomized setting.

Bias↗
PubMed2005

Determining structure and function of steroid dehydrogenase enzymes by sequence analysis, homology modeling, and rational mutational analysis.

The short-chain oxidoreductase (SCOR) family of enzymes includes over 6,000 members identified in sequenced genomes. Of these enzymes, approximately 300 have been characterized functionally, and the three-dimensional crystal structures of approximately 40 have been reported. Since some SCOR enzymes are steroid dehydrogenases involved in hypertension, diabetes, breast cancer, and polycystic kidney disease, it is important to characterize the other members of the family for which the biological functions are currently unknown and to determine their three-dimensional structure and mechanism of action. Although the SCOR family appears to have only a single fully conserved residue, it was possible, using bioinformatics methods, to determine characteristic fingerprints composed of 30-40 residues that are conserved at the 70% or greater level in SCOR subgroups. These fingerprints permit reliable prediction of several important structure-function features including cofactor preference, catalytic residues, and substrate specificity. Human type 1 3beta-hydroxysteroid dehydrogenase isomerase (3beta-HSDI) has 30% sequence identity with a human UDP galactose 4-epimerase (UDPGE), a SCOR family enzyme for which an X-ray structure has been reported. Both UDPGE and 3-HSDI appear to trace their origins back to bacterial 3alpha,20beta-HSD. Combining three-dimensional structural information and sequence data on the 3alpha,20beta-HSD, UDPGE, and 3beta-HSDI subfamilies with mutational analysis, we were able to identify the residues critical to the dehydrogenase function of 3-HSDI. We also identified the residues most probably responsible for the isomerase activity of 3beta-HSDI. We test our predictions by specific mutations based on sequence analysis and our structure-based model.

3-Hydroxysteroid Dehydrogenases↗
PubMed2004

Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2.

Tissue inhibitor of metalloproteinase 1 (TIMP1) is a contributory factor to fibrosis of a variety of organs including the liver. UTE-1 is a regulatory DNA motif essential for TIMP1 promoter activity in a variety of cell types including hepatic stellate cells (HSC), the key profibrogenic cells of the liver. In this study we identify RUNX1 and RUNX2 as UTE-1-binding proteins that are induced at the post-transcriptional level during activation of HSC. RUNX1 is expressed in at least two major isoforms, RUNX1B and RUNX1A. Overexpression of full-length RUNX1B isoform in HSC repressed TIMP1 promoter activity, whereas the truncated RUNX1A isoform and RUNX2 functioned as stimulators. To gain further understanding of the way in which RUNX1 isoforms differentially regulate TIMP1 transcription, we investigated the relationship between the UTE-1 site and its adjacent upstream serum-response element (SRE) in the promoter. The UTE-1 and SRE sites cooperate in a synergistic fashion to stimulate transcription of a heterologous minimal active promoter providing that they are in close proximity. The key regulatory sequence within the SRE is an AP-1 site that in HSC directs high level transcription via its interaction with JunD. RUNX1A was shown to interact directly with JunD, and by contrast RUNX1B failed to interact with JunD. Co-expression studies showed that RUNX1B can repress JunD-stimulated TIMP1 promoter activity. From these observations we propose that JunD and RUNX factors assemble at the adjacent SRE and UTE-1 sites in the TIMP1 promoter and form functional interactions that stimulate transcription. However, RUNX1B is unable to interact with JunD, and as such its occupancy at the UTE-1 site disrupts the optimal assembly of transcriptional activators required for directing high level TIMP1 promoter function.

Amino Acid Motifs↗
PubMed2004

The conservative management of interstitial pregnancy.

OBJECTIVES: To evaluate the effectiveness of systemic methotrexate in the treatment of interstitial pregnancy. DESIGN: Prospective observational study. SETTING: An Early Pregnancy Assessment Unit in a London teaching hospital. SAMPLE: Twenty consecutive women diagnosed with an interstitial pregnancy. METHODS: Women were diagnosed with an interstitial pregnancy based on transvaginal ultrasound findings. Single dose, intramuscular methotrexate was administered on day 0. A second dose of methotrexate was given if the beta-hCG levels had not fallen by 15% between days four and seven. Weekly follow up continued until the serum beta-hCG < 5 IU. MAIN OUTCOME MEASURE: The resolution of serum beta-hCG levels without the need for surgical intervention. RESULTS: Two hundred and ninety-three ectopic gestations were diagnosed over a 42-month period. Twenty of these were interstitial in nature, with a median initial serum beta-hCG of 6452 IU. Of the 20 interstitial pregnancies, 17 cases received systemic methotrexate. Sixteen were treated successfully (94%), including all of the four cases with fetal heart activity present. A second methotrexate dose was given to six patients. Two cases were managed expectantly. Two cases underwent laparotomy and cornual resection: one elected for surgical management at the outset and one as a result of suspected ectopic rupture after two doses of methotrexate. There were no other complications. CONCLUSIONS: Systemic methotrexate is a safe and highly effective treatment for interstitial pregnancy. Surgery can be avoided in the majority of women with this condition. Early recognition of the cornual pregnancy with transvaginal ultrasound is essential.

Abortifacient Agents, Nonsteroidal↗
PubMed2003

Cardiac effects of burn injury complicated by aspiration pneumonia-induced sepsis.

Early fluid resuscitation, antimicrobials, early excision, and grafting have improved survival in the early postburn period; however, a significant incidence of pneumonia-related sepsis occurs after burn injury, often progressing to multiple organ failure. Recent studies have suggested that this initial injury (burn injury) primes the subject, producing an exaggerated response to a second insult, such as pneumonia-related sepsis. We developed an experimental animal model that included a third-degree burn over 40% of the total body surface area, followed by sepsis (intratracheal administration of Streptococcus pneumoniae, 4 x 106 colony-forming unit), which was produced either 48 or 72 h after burn injury in adult male rats. Hearts harvested after either burn alone, sepsis alone, or burn plus sepsis were used to assess either contractile function (Langendorff) or cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-10 (ELISA). Experimental groups included the following: 1). sham (sham burn and no sepsis); 2). burn injury alone studied either 24, 48, or 72 h postburn; 3). pneumonia-related sepsis in the absence of burn injury; and 4). pneumonia-induced sepsis studied either 48 or 72 h after an initial burn injury. Burn injury alone (24 h) or sepsis alone produced myocardial contractile defects and increases in pro- and anti-inflammatory cytokine secretion by cardiomyocytes. Sepsis that occurred 48 h postburn exacerbated the cardiac contractile defects seen with either burn alone or sepsis alone. Sepsis that occurred 72 h postburn produced contractile defects resembling those seen in either burn alone or sepsis alone. In conclusion, our data suggest that burn injury primes the subject such that a second insult early in the postburn period produces significantly greater cardiac abnormalities than those seen with either burn alone or sepsis alone.

Animals↗