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Biomedical subjects

S McDonald

Publications and source records attributed to S McDonald.

At least 19 recordsLinked to original sources
PubMed1996

Differential dose-response to oral xemilofiban after antecedent intravenous abciximab. Administration for complex coronary intervention.

BACKGROUND: Placebo-controlled randomized trials of parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated reduced ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers are being developed to allow more sustained receptor antagonism with potential for long-term secondary prevention. Sequential therapy with abciximab followed by an oral IIb/IIIa antagonist has not previously been reported. The clinical safety and pharmacodynamics of a sequential therapeutic strategy are unknown. METHODS AND RESULTS: Of 74 consecutive patients enrolled in a placebo-controlled, dose-ranging pharmacokinetic/pharmacodynamic study of xemilofiban, a new oral nonpeptide GP IIb/IIIa antagonist, after elective intracoronary stent placement, 17 patients received abciximab during stent deployment as a weight-adjusted intravenous bolus and 12-hour infusion at the discretion of the investigator. Ex vivo platelet aggregation in response to 20 mumol/L ADP and 4 micrograms/mL collagen was measured over time after the first dose of either xemilofiban (5, 10, 15, or 20 mg) or placebo (ticlopidine) administered 8 to 18 hours after termination of abciximab and again after 1 week of twice-daily oral administration of study drug. At baseline, patients who had received abciximab had lower platelet aggregation in response to both agonists (P < .001). A significant dose-response relationship to xemilofiban was observed. Patients who had received abciximab had lower ADP-induced (P < or = .010) and collagen-induced (P < or = .029) platelet aggregation after xemilofiban. This pharmacodynamic interaction was no longer evident at 1 week. No significant clinical bleeding events or blood product transfusions were observed in this trial. CONCLUSIONS: Both the magnitude and the duration of pharmacodynamic response to xemilofiban were enhanced by prior abciximab treatment. The potentiated pharmacodynamic response was not evident after 1 week. This observation has implications for the safety and efficacy of sequential parenteral-oral GP IIb/IIIa blockade therapy and may be useful in deriving dose regimens for orally administered compounds.

Abciximab↗
PubMed1996

Clinical insights into pragmatic theory: frontal lobe deficits and sarcasm.

The validity of psycholinguistic theories of sarcasm was explored by examining subjects with mainly frontal lobe (FL) damage and concomitant concreteness of thought. The majority of FL subjects could interpret consistent verbal exchanges but not literally contradictory (sarcastic) verbal exchanges which implied that the literal meaning of a sarcastic comment needs to be rejected in order for the inference to be detected. Subsidiary analyses confirmed that failure on sarcasm tasks was associated with poor conceptual skills. Ability to process attitude was not associated with success at recognizing sarcasm. This suggested that attitude is not pivotal to the detection of sarcastic inference.

Adolescent↗
PubMed1996

Frequency and correlates of fatigue in lung cancer patients receiving radiation therapy: implications for management.

The medical records of 50 consecutive patients receiving radiation therapy for histologically diagnosed lung cancer were retrospectively reviewed to determine the frequency of fatigue and its relationship to pain, depression, and other potentially treatable correlates. Fatigue developed in 39 of the 50 patients (78%), and was not strongly related to demographic or disease variables. Pain was experienced by 40 patients (80%), but depression was noted in the records of only six patients (12%). Onset of fatigue closely followed development of pain in only 11 patients. Lower frequency of fatigue in patients with previous surgery or chemotherapy and the likelihood of a response shift suggest these were not significant causes of fatigue. Previous studies highlight a higher frequency of depression in cancer patients and a correlation with treatment-related fatigue. Prospective studies on the relationship between depression and fatigue and the ability of antidepressants to ameliorate treatment-related fatigue are needed.

Adult↗
PubMed1996

Assessment of pragmatic communication skills in adolescents after traumatic brain injury.

Deficits in pragmatic communication ability have a significant impact on functional outcome from traumatic brain injury (TBI), particularly during adolescence, when sophisticated social communication skills are developing. There are few published tests designed to assess pragmatic skills in this age group. In the present study, four tasks designed to tap various aspects of pragmatic communication ability were administered to three brain-injured adolescents and 36 of their uninjured peers aged 15-18 years. The tasks evaluated the ability to negotiate, hint, describe a simple procedure, and understand sarcasm. The four tasks were found to tap distinct aspects of pragmatic ability in control subjects. Further, within the control group, task performance was related more to non-verbal reasoning ability than vocabulary skills. Scores for two of the three TBI subjects were poorer than those of their peers, while a third mildly injured subject performed within normal limits. Pragmatic task scores were consistent with the results of neuropsychological testing in the three TBI subjects. Implications for clinical management and recommendations for future research are discussed.

Adolescent↗
PubMed1996

Haemostatic changes in the pulmonary blood during cardiopulmonary bypass.

Pulmonary injury may result from the use of cardiopulmonary bypass (CPB). We investigated changes in the haemostatic system in the pulmonary vein during CPB compared with blood that circulated through the bypass circuit. Paired samples were taken from the pulmonary vein and central venous pressure (CVP) line during the peri-operative period from ten patients. Plasma levels of factor VII (P < 0.001), prekallikrein (P < 0.05), antithrombin III (P < 0.001) and heparin cofactor II (P < 0.005) were decreased in the pulmonary vein after 20 min of bypass compared with pre-operative levels. In the pulmonary vein there was a significant increase in neutrophil expressed CD11b (P < 0.001), neutrophil elastase: alpha 1-antitrypsin complexes (P < 0.001), endothelin-1(P < 0.001) and thrombin-antithrombin complexes (P < 0.001) by the end of bypass compared with pre-operative levels. There was no significant change in monocyte expressed CD11b, factor XII or C1-esterase inhibitor in the pulmonary vein for the study period. None of these variables were significantly different in the pulmonary vein compared with CVP line. In the pulmonary vein plasma levels of activated factor VII decreased following heparin administration (P < 0.001) in the majority of patients which was coincidental to an increase (P < 0.001) in tissue factor pathway inhibitor (TFPI). This increase in TFPI was significantly higher in the pulmonary vein compared with CVP line (P < 0.05) There was a decrease in neutrophil count by 20 min on CPB in both the pulmonary vein and CVP line (P < 0.001) and this did not return to pre-operative levels in the pulmonary vein. Soluble thrombomodulin levels decreased by 20 min on CPB in the CVP line (P < 0.05) but tended to increase in the pulmonary vein, although this was not statistically significant. In conclusion we found evidence of thrombin generation and possible endothelial damage together with increased neutrophil activation and adhesion molecule expression in the pulmonary vein during CPB which may play an important role in the development of post-CPB pulmonary injury.

Adult↗
PubMed1996

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06.

PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer (NSCLC) have a poor clinical outcome. We conducted a prospective study to evaluate the merit of chemotherapy administered concurrently with hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Treatment consisted of two cycles of oral etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5 days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS: Seventy-six assessable patients with a Karnofsky performance status > or = 60 and adequate organ function who had received no prior therapy were evaluated for clinical outcome and toxic effects. After a minimum follow-up duration of 21 months, the 1- and 2-year survival rates and the median survival duration were 67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for patients with weight loss of < or = 5%. Toxicity was significant; 57% developed grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4 lung toxicity. However, only 6.6% of patients had grade 4 or lethal nonhematologic toxicity, which included three treatment-related deaths (two of pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation therapy with oral etoposide and cisplatin plus hyperfractionated radiation therapy is feasible. The survival outcome from this regimen compares favorably with that of other chemoradiation trials and even of multimodality trials that have included surgery.

Administration, Oral↗
PubMed1996

Dose-area product measurements in paediatric radiography.

The dose-area product (DAP) could provide a useful quantity for monitoring doses for paediatric radiography, because it is a sensitive parameter, which is simple to record. A study of DAP measurements has been carried out for single radiographic projections for paediatric patients and comparisons made with measurements of entrance dose. The technique has been used to investigate doses for examinations performed with and without a grid. There is a linear relationship between DAP and entrance dose, with a variation of +/- 20% for pelvis, abdomen, spine and skull radiographs, but data for chests are more scattered. Logarithm of the DAP is linearly related to an equivalent patient diameter and reference levels could be set in terms of DAP either by patient age range or size. Effective doses determined from DAPs were 0.1-0.3 mSv for abdomen, pelvis and spine anteroposterior radiographs for 5-15 year olds, and less than 0.03 mSv for 0 and 1 year olds. Doses for examinations performed without a grid were only 20% of those for which a grid was used in the X-ray room studied. Significant reductions in doses for paediatric radiology can be achieved, where the use of grids can be avoided.

Adolescent↗
PubMed1995

A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis.

PURPOSE: Radiation-induced pulmonary reactions have classically been viewed as distinct phases--acute pneumonitis and, later, fibrosis--occurring at different times after irradiation and attributed to different target cell populations. We prefer to view these events as a continuum, with no clear distinction between the temporal sequence of the different pulmonary reactions; the progression is the result of an early activation of an inflammatory reaction, leading to the expression and maintenance of a cytokine cascade. In the current study, we have examined the temporal and spatial expression of cytokine and extracellular matrix messenger ribonucleic acid (mRNA) abundance in fibrosis-sensitive mice after thoracic irradiation. METHODS AND MATERIALS: Radiation fibrosis-prone (C57BL/6) mice received thoracic irradiation of 5 and 12.5 Gy. At Day 1, and 1, 2, 8, 16, and 24 weeks after treatment, animals were killed and lung tissue processed for light microscopy and isolation of RNA. Expression of cytokine and extracellular matrix mRNA abundance was evaluated by slot-blot analysis and cellular localization by in situ hybridization and immunochemistry. RESULTS: One of the cytokines responsible for the inflammatory phase (IL-1 alpha) is elevated at 2 weeks, returns to normal baseline values, then increases at 8 weeks, remaining elevated until 26 weeks when lung fibrosis appears. Transforming growth factor-beta (TGF beta), a proliferative cytokine, is elevated at 2 weeks, persists until 8 weeks, and then returns to baseline values. In parallel with the cytokine cascade, the fibrogenic markers for CI/CIII/IV (collagen genes) correlate by showing a similar early and then later elevation of activity. For instance, the collagen gene expression of CI/CIII is a biphasic response with an initial increase at 1-2 weeks that remits at 8 weeks, remains inactive from 8 to 16 weeks, and then becomes elevated at 6 months when collagen deposition is recognized histopathologically. CONCLUSION: These studies clearly demonstrate the early and persistent elevation of cytokine production following pulmonary irradiation. The temporal relationship between the elevation of specific cytokines and the histological and biochemical evidence of fibrosis serves to illustrate the continuum of response, which, we believe, underlies pulmonary radiation reactions and supports the concept of a perpetual cascade of cytokines produced immediately after irradiation, prompting collagen genes to turn on, and persisting until the expression of late effects becomes apparent pathologically and clinically.

Animals↗
PubMed1995

Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems.

Toxicity of the respiratory system is a common side effect and complication of anticancer therapy that can result in significant morbidity. The range of respiratory compromise can extend from acute lethal events to degrees of chronic pulmonary decompensation, manifesting years after the initial cancer therapy. This review examines the anatomic-histologic background of the lung and the normal functional anatomic unit. The pathophysiology of radiation and chemotherapy induced lung injury is discussed as well as the associated clinical syndromes. Radiation tolerance doses and volumes are assessed in addition to chemotherapy tolerance and risk factors and radiation-chemotherapy interactions. There are a variety of measurable endpoints for detection and screening. Because of the wide range of available quantitative tests, it would seem that the measurement of impaired lung function is possible. The development of staging systems for acute and late toxicity is discussed and a new staging system for Late Effects in Normal Tissues (LENT) is proposed.

Clinical Protocols↗
PubMed1995

An investigation into techniques for reducing doses from neo-natal radiographic examinations.

A survey of radiation doses received by infants having radiography in a neo-natal unit was undertaken at Aberdeen Maternity Hospital. Options for dose reduction recommended by the CEC Lake Starnberg Group were investigated. Techniques were implemented for clinical evaluation after assessments of image quality with test objects and phantoms. Clinical image quality of radiographs was evaluated by paediatric radiologists using CEC criteria. Results revealed a clear relationship between entrance dose and patient weight, indicating that reference doses for infants could be linked to weight. At the start of the study the mean entrance dose for chest anteroposterior (AP) radiographs was 65 microGy and the dose-area product 12.3 mGy cm2 for a system with 2.5 mm aluminum filtration using 50 kVp X-rays with a 200 speed class film/screen system. A 400 speed class film/screen combination was investigated but not evaluated clinically, because the image quality was not considered acceptable. Addition of 0.1 mm copper to the filtration of the X-ray tube reduced entrance doses by 50%, but the technique was not adopted, because of a poorer image quality with only 72% of features in clinical images being reproduced to an acceptable standard, compared with 87% with the original system. Use of faster processing chemicals, an increase in filtration to 3.5 mm aluminium and a tube potential of 60 kVp resulted in a 40% reduction in mean entrance dose to 37 microGy with satisfactory clinical image quality.

Body Weight↗
PubMed1995

The 'dice' game: a new test of pragmatic language skills after closed-head injury.

There are few clinical tools available to assess communication skills following closed-head injury. This paper describes one such task in which the subject is required to explain a board game to a naive listener. The explanation is taped, transcribed and the content is quantified. Reliability studies demonstrated that the test can be consistently scored. A group of 43 normal subjects was investigated, and some variation in performance according to age and educational background was revealed. A group of 20 brain-injured male adults with executive-type deficits were then compared to a matched subgroup of the controls. The clinical group produced less essential information and relatively more unnecessary information than their non-brain-damaged counterparts. Qualitative features of discourse disorganization were also revealed.

Adolescent↗
PubMed1995

Phenotypic analysis of the glomerular and periglomerular mononuclear cell infiltrates in the Thy 1.1 model of glomerulonephritis.

BACKGROUND: The phenotype of macrophages invading the mesangium and periglomerular region has not been described in experimental mesangial proliferative glomerulonephritis, although it has implications for the mechanism of entry of these cells into these locations and their function once there. We have, therefore, determined the phenotype of the periglomerular leukocytic infiltrate in the Thy 1.1 model of mesangial proliferative glomerulonephritis and compared it with that of cells invading the mesangium. EXPERIMENTAL DESIGN: The Thy 1.1 model was induced in Lewis rats, and sections were taken at 1 hour and at 1, 4, 9, 30, and 90 days postinduction. Immunohistochemistry was performed using monoclonal antibodies against macrophage markers (ED-1, CD4, RT1-B, and ED-2), chains of the beta 2 integrins (CD18, CD11a, and CD11b), T and B cell markers (CD8, T cell receptor, interleukin-2 receptor, and MRC OX33), and markers of mesangial cell proliferation (proliferating cell nuclear antigen, alpha-smooth muscle actin). Sections were compared with those obtained from control animals. RESULTS: In untreated rats, a striking resident periglomerular macrophage population (phenotype ED-1-ve ED-2-ve CD4+ve RT1-B+ve CD18+ve CD11a+ve CD11b+ve) was found, confirming a previous report. From 24 hours postinduction, this resident macrophage population was supplemented by a population whose predominant phenotype (ED-1+ve ED-2-ve CD4+ve RT1-B+ve CD18+ve CD11a+ve CD11b+ve) was identical to that of macrophages infiltrating the mesangium. Both infiltrates peaked at 4 days and returned to base-line levels by 1 to 3 months. There was no significant lymphocyte infiltrate within the glomerulus and only a minimal periglomerular T cell infiltrate. CONCLUSIONS: These data show, first, that disease limited to the mesangium can lead directly to periglomerular macrophage infiltration. Second, the presence of CR3 (i.e., CD11b and CD18) and LFA-1 (i.e., CD11a and CD18) on the macrophage infiltrate indicates that both ligands are important for cells to enter the mesangium and periglomerular areas. Third, the marked phenotypic and temporal similarities between the mesangial and periglomerular macrophage infiltrates suggests that a common factor(s) is involved in their pathogenesis. Finally, expression of RT1-B (Ia) but not ED-2 is reported to be typical of interstitial dendritic cells rather than tissue macrophages, suggesting a unique function for the glomerular and periglomerular macrophage infiltrate in this model.

Animals↗
PubMed1994

Flow cytometric quantification of the proliferation-associated nuclear antigen p105 and DNA content in advanced head & neck cancers: results of RTOG 91-08.

PURPOSE: p105 is a proliferation-associated nuclear antigen which identifies proliferating but not resting cells. The objectives of this Radiation Therapy Oncology Group (RTOG) protocol (91-08) were: (1) to correlate tumor proliferative potential estimated using the p105 assay and deoxyribonucleic acid (DNA) analysis with treatment outcome in patients irradiated for advanced squamous cell carcinoma of the head and neck; and (2) to evaluate the potential of p105 labeling indices as a predictive assay. METHODS AND MATERIALS: Paraffin blocks of pretreatment biopsies of the primary tumor or metastatic neck nodes of patients with Stage III or IV squamous cell carcinoma of the head and neck treated with radiotherapy alone in three previous RTOG protocols (79-13, 79-15, and 83-13) were retrospectively obtained. From these paraffin blocks, areas of tumor were selected based on histological examinations and sectioned. Nuclei suspensions were then prepared and processed for p105 antibody and DNA staining and subsequent flow cytometric quantification of p105 labeling indices and DNA content and correlation with local-regional control and survival. RESULTS: Paraffin blocks of tumor biopsies from 148 out of a total of 598 eligible patients were available. Of these, 143 were analyzable. The median and (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (LI-S), and p105 antigen density (AD) were: 66.6 (3.85-99.5), 9 (1.55-36), and 93.2 (7.4-628.5), respectively. Deoxyribonucleic acid was diploid in 67 (47%), aneuploid in 22 (15%) and mixed aneuploid/diploid in 54 (38%) patients. There was a strong correlation between AD and DNA ploidy. Antigen density was above median in 91.5% of the aneuploid or mixed aneuploid/diploid tumors, but only in 8.5% of the diploid tumors. Patients with aneuploid or mixed aneuploid/diploid tumors had significantly greater local-regional failures than patients with diploid tumors (p = .0180). Those with p105 LI-C below the median or p105 AD above the median also had significantly greater local-regional failures (p = .0500 and p = .0167, respectively). Patients with p105 AD below the median had significantly better survival than those above the median (p = .0444), although there was no significant difference in survival with respect to DNA ploidy or p105 LI-C. Multivariate analyses showed that T-stage (p = .0001) and p105 AD (p = .0044) were significant prognostic factors for local-regional control, and T-stage (p = .0080), N-stage (p = .0021), primary site (p = .0110), and p105 AD (p = .0326) were significant prognostic factors for survival. CONCLUSION: These results suggest that flow cytometric quantitation of the proliferation-associated nuclear antigen p105 and DNA content of pretreatment tumor biopsies may be a potentially useful predictive assay in patients irradiated for advanced squamous cell carcinomas of the head and neck.

Analysis of Variance↗
PubMed1994

Preliminary results of a pilot study using WR-2721 before fractionated irradiation of the head and neck to reduce salivary gland dysfunction.

PURPOSE: Based on in vivo evidence of radioprotection of the salivary glands using WR-2721, a pilot study was undertaken to determine the feasibility, toxicity, and salivary function of patients receiving WR-2721, while undergoing radiation therapy to the head and neck. METHODS AND MATERIALS: Patients undergoing radiation therapy for cancer of the head and neck were eligible if the major salivary glands received more than 45 Gy. WR-2721 was administered over 6 min IV, 10-15 min prior to each dose of radiation five times per week. Saliva was collected and measured prior to radiation therapy, weekly during radiation therapy, 1 month postradiation therapy, and every 3 months thereafter. Flow rates of unstimulated whole saliva, stimulated whole saliva, and stimulated parotid saliva were measured using standard techniques. 99mTc salivary scintiscans were performed prior to radiation therapy, 1 month postradiation therapy and every 3 months thereafter. Nine patients are presently enrolled on the first dose level (100 mg/m2) of this study. Eight completed per protocol, two with minor decreases of total WR-2721 doses. Two patients progressed with distant metastases soon after completion of therapy. All available data are included in the analysis. Median follow-up for all patients is 18 months. RESULTS: Flow rates of unstimulated whole saliva decreased significantly during radiation therapy reaching 5.6% of baseline at 9 months postradiation therapy, subsequently recovering to 20% of baseline, then remaining stable over time. Stimulated whole salivary flow rate similarly decreased during radiation therapy and reached its nadir (11% of baseline) at 3 months postradiation therapy, improving to 27% of baseline by 2 years. The stimulated parotid flow rate decreased during radiation therapy to 1.4% of pretreatment levels. Significant recovery took place 6 months postradiation therapy and by 18 months values had recovered to 54% of baseline. 99mTc salivary scintiscans confirmed this rebound of parotid function postradiation therapy. Toxicity was minimal with the exception of one patient who received only 27% of the planned total drug dose due to grade 3 hypotension after the eighth treatment. No recovery of salivary function has been seen in this patient; flow rates remain zero in all three areas tested 21 months after radiation. CONCLUSIONS: Administration of WR-2721 prior to each dose of radiation was feasible and without significant toxicity at 100 mg/m2. Salivary gland function improved over time after completion of radiation, particularly the parotid. Future directions include escalation of WR-2721 dose to 200 mg/m2 and then 300 mg/m2, and a Phase III randomized trial will be undertaken once the optimal dose is established.

Amifostine↗
PubMed1994

Error types in ideomotor apraxia: a qualitative analysis.

Seventeen brain-damaged subjects with dominant hemisphere pathology and 24 matched control subjects were asked to perform simple familiar gestures under four conditions: (1) verbal command (pantomime), (2) imitation, (3) with the actual object, and (4) verbal command a second time. The subjects subsequently watched a video of an actor performing simple movements and decided whether or not these were performed accurately. The gestural production task was videoed and analyzed for error type. Error type remained consistent over the four task conditions, although subgroups of patients made different types of errors. One group of patients with Ideomotor Apraxia (IMA) made more errors but of the same type as the controls, i.e., movement-related errors and the use of "body part as object" (BPO). The second group made mainly substituted (i.e. unrelated) movements and perseverative errors. The second group of subjects was also poorer at discriminating incorrectly performed movements in the recognition task. BPO errors were commonly made by the control group and they were also chosen as correct in the recognition task. This indicated that use of BPO may reflect a convention in symbolising gestures rather than pathology. The performance of the IMA subjects was discussed in relation to current theories of the mechanisms underlying apraxia.

Adult↗