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Biomedical subjects

S McDonald

Publications and source records attributed to S McDonald.

At least 19 recordsLinked to original sources
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↗
PubMed1994

An ethical dilemma: risk versus responsibility.

1. In the psychiatric community, two highly profitable diagnoses currently are filling psychiatric hospitals: dissociative disorder and multiple personality disorder. Certainly these patients need help, and psychiatric nurses are well-qualified to plan their scope of care. However, when the hospital reported on in this article exploited these diagnoses by encouraging practices that extended lengths of stay and restricted patient's rights, the nurses were forced to speak out as advocates for the patients. 2. The dissociative disorder unit housed 10 patients billed at an intensive care unit rate of $1,200 per day. One patient's average fee per day was $1,560; multiply this by 10 patients, and the hospital received $15,600 per day from this unit alone. 3. Financial calculation is not what nurses are used to thinking about; indeed, it somehow seems unbefitting to link nursing care with any mention of monetary gain. Yet, this is exactly the sort of information that nurses must have in order to understand how hospital politics may influence their situation.

Abreaction↗
PubMed1993

Combined Betaseron R (recombinant human interferon beta) and radiation for inoperable non-small cell lung cancer.

PURPOSE: Based on in vitro evidence of radiosensitization by Betaseron (beta-IFN), a Phase I/II study was undertaken to determine toxicity and response using combined radiation (RT) and B-IFN in patients with unresectable Stage III and nonsmall cell lung cancer. METHODS AND MATERIALS: Varying doses of beta-IFN(10 to 90 x 10(6) IU) were administered IV immediately preceding RT on the first three days of weeks 1, 3, and 5. The RT dose was 1.8 Gy/day, 5 days/week for a total of 54 or 59.4 Gy. RESULTS: Thirty-nine patients were entered, 32 of whom were evaluable. The median follow-up time at time of analysis was 60 months. Responses were based on CT scan. The response rate for the total group was 81% with 44% achieving complete response. Seventy-eight percent of patients with complete response survived a minimum of 21 months. Twenty-six patients had Stage III A/B disease with a median tumor size of 6.5 cm. and median survival was 19.7 months. The 5-year actuarial survival for this group was 31%, with a plateau persisting after 3 years. There were no treatment related deaths nor any event of life threatening toxicity. Of eight patients surviving 3-5 years, no long-term toxicity has been observed. Karnofsky indices were 90-100 and respiratory symptoms were minimal. CONCLUSION: beta-IFN is well-tolerated. Response and survival rates are sufficiently encouraging to warrant further investigation in a randomized trial which has been accepted as an RTOG study awaiting drug availability.

Adult↗
PubMed1993

Pulmonary changes induced by combined mouse beta-interferon (rMuIFN-beta) and irradiation in normal mice--toxic versus protective effects.

This study in normal mice was undertaken to investigate possible enhancement of pulmonary toxicity by interferon-beta (IFN-beta) combined with single doses of irradiation. A pharmacokinetic study preceded the toxicity study to determine the optimal route and timing of IFN administration. Graded single doses of radiation were combined with graded doses of IFN. Pulmonary toxicity was determined using endpoints of alveolar surfactant and procollagen in lung lavage fluid at 7 days, breathing frequency, lethality and histology. Increased lethality was seen when IFN was combined with irradiation at 12.5 Gy vs. irradiation alone. This occurred between 20 and 30 weeks post treatment with no increased breathing frequency or surfactant release, suggesting independent mechanisms of injury. Increased breathing frequency after 40 weeks, usually associated with fibrosis, was less pronounced for IFN treated vs. irradiation only controls. Ultrastructural studies at 72 weeks suggest reduced fibrosis in lungs of IFN treated vs. irradiation only controls. Supporting this was the finding that Procollagen III, a biosynthetic precursor of collagen, was increased in the lavage fluid at 7 days for all radiation doses but decreased with the addition of IFN at 12.5 and 15 Gy. Interferons can act either as sensitizers or radioprotectors, depending on the biological system and type of interferon. Our study suggests that while IFN-beta may increase the acute effects of radiation in the mouse lung, some protection from radiation-induced fibrosis, possibly related to alteration of immune mechanisms, may exist.

Animals↗
PubMed1993

Human studies on abecarnil a new beta-carboline anxiolytic: safety, tolerability and preliminary pharmacological profile.

1. Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a beta-carboline with high affinity for benzodiazepine receptors, was tested in healthy male subjects; single doses of abecarnil were given in five dosage levels (1 mg, 5 mg, 10 mg, 20 mg, 40 mg) and in a multiple dose study in four dosage levels (15 mg, 30 mg, 60 mg, 90 mg day-1) for 7 days. On two days following multiple dose treatment, placebo was given in single-blind conditions (follow-up). In each dosage level, in both studies drug was given to 10 subjects (7: verum, 3: placebo). 2. Safety and tolerability were evaluated by changes in vital signs, incidence and severity of adverse reactions and biochemical and haematological screening. Drug effects were estimated utilizing a bipolar visual analogue scale (poles: 'sleepy'-'alert') and a psychomotor task, the digit symbol substitution task. The pharmacokinetics of single and multiple doses were also determined in the multiple dose study. 3. Abecarnil was generally well tolerated. In the single dose study the most frequently reported side effects associated with abecarnil at high doses (20 and 40 mg) were dizziness, unsteady gait, and lack of concentration. A decrement in performance on the digit symbol substitution task was also observed in the two high dosage groups 20 mg and 40 mg. Evaluation of visual analogue scale ratings did not reveal a sedative effect even at higher doses. 4. In the multiple dose study the most frequently reported side effects during the treatment period were dizziness, unsteady gait, and lack of concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Radiation oncology residents' computer workstation.

We are investigating the feasibility of using the Macintosh computer as a workstation platform for radiation oncology residents because of its ease of use, graphics capability, and low cost. Hypercard was chosen as the programming environment because it easily mixes graphics, text, and control functions in an integrated screen display. Furthermore, it results in a system that can be relatively easily extended and customized by individual users with varying degrees of computer skills. We have developed several software modules in order to test the ability of this environment to support the demands of such a workstation. Modules created thus far include various clinical physics aids and tutorials, treatment planning guides, oncology databases, and others. The software runs on all Macintosh configurations, but calculation speeds are improved when a 68020 or greater processor is used. In general, we have been pleased with the implementation thus far. Graphics display capability is good, but design and entry of graphics have proved labor-intensive. Searching is fast and text is easily entered and manipulated. Finished modules can be customized with minimal computer training, but implementing complex new functions requires familiarity with Hypercard's programming language. New modules, once developed, are easily integrated into the workstation universe, suggesting that cooperative development of the workstation by multiple contributors is realistically achievable.

Computer Graphics↗