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SETTING: Glasgow, Scotland, UK. BACKGROUND: Paradoxical reactions in tuberculosis (TB) are a notable example of our incomplete understanding of host-pathogen interactions during anti-tuberculosis treatment. OBJECTIVES: To determine risk factors for a TB paradoxical reaction, and specifically to assess for an independent association with vitamin D use. DESIGN: Consecutive human immunodeficiency virus (HIV) negative adult patients treated for extra-pulmonary TB were identified from an Extended Surveillance of Mycobacterial Infections database. In our setting, vitamin D was variably prescribed for newly diagnosed TB patients. A previously published definition of paradoxical TB reaction was retrospectively applied to, and data on all previously described risk factors were extracted from, centralised electronic patient records. The association with vitamin D use was assessed using multivariate logistic regression. RESULTS: Of the 249 patients included, most had TB adenopathy; 222/249 had microbiologically and/or histologically confirmed TB. Vitamin D was prescribed for 57/249 (23%) patients; 37/249 (15%) were classified as having paradoxical reactions. Younger age, acid-fast bacilli-positive invasive samples, multiple disease sites, lower lymphocyte count and vitamin D use were found to be independent risk factors. CONCLUSION: We speculate that vitamin D-mediated signalling of pro-inflammatory innate immune cells, along with high antigenic load, may mediate paradoxical reactions in anti-tuberculosis treatment.

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BACKGROUND: Pulmonary hypertension is a common complication of chronic obstructive airways disease (COPD) and its presence implies a poor prognosis. However, it is difficult to measure and its specific contribution to symptoms is difficult to quantify. A micromanometer tipped pulmonary artery catheter was used to measure pulmonary artery pressure (PAP) during sleep and on exercise. METHODS: Ten patients (five with COPD receiving long term oxygen therapy and five normal individuals) were studied. Pulmonary artery pressure was recorded continuously during two periods of sleep (breathing oxygen followed by air for the COPD group) and during exercise. RESULTS: In the COPD group PAP during sleep on oxygen was significantly lower than PAP during sleep breathing air (mean (SD) difference 9.6 (5.3) mm Hg, 95% CI 4.9 to 14.3, p= 0.016). PAP during exercise was not significantly different from PAP during sleep breathing air (mean (SD) difference 0.8 (8.9) mm Hg, 95% CI -7.0 to 8.6, p= 0.851). In normal individuals the group mean (SD) PAP was 15 (5.9) mm Hg for the first nocturnal period and 15 (5.7) mm Hg for the second nocturnal period. PAP during exercise was not significantly different from PAP during sleep breathing air (mean (SD) difference 3.3 (2.2) mm Hg, 95% CI 1.1 to 5.5, p= 0.061). CONCLUSION: In patients with COPD, PAP rose significantly during sleep to levels similar to those measured during exercise, but this could be reversed with oxygen.

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It is recognized that exercise produces abnormally large increases in pulmonary artery pressure in patients with pulmonary vascular disease as a consequence of a variety of disorders, but the relationship between pressure and cardiopulmonary exercise performance is poorly understood. This lack of understanding is due (in part) to difficulty making measurements of pulmonary haemodynamics using conventional fluid filled catheters. This article seeks to improve understanding by comparing variables measured during formal exercise testing with simultaneous measurements of pulmonary artery pressure using a micro-manometer tipped catheter. Ten patients with suspected pulmonary hypertension were studied using a micromanometer tipped pulmonary artery catheter, during cardiopulmonary exercise testing. Ventilatory equivalents for oxygen and carbon dioxide correlated with the pulmonary artery pressure measured on exercise, but oxygen pulse and oxygen uptake did not. Ventilatory equivalents, noninvasively measured during exercise, may merit further study as potential surrogates of pulmonary artery pressure and hence be useful in identifying individuals at risk of developing pulmonary hypertension.

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BACKGROUND: The specific contribution of secondary pulmonary hypertension to the morbidity and mortality of patients with underlying lung disease can be difficult to assess from single measurements of pulmonary artery pressure. We have studied patients with secondary pulmonary hypertension using an ambulatory system for measuring continuous pulmonary artery pressure (PAP). We chose to study patients with connective tissue disease because they represent a group at high risk of pulmonary vascular disease, but with little disturbance of lung function. METHODS: Six patients (five with progressive systemic sclerosis and one with systemic lupus erythematosis) were studied. They underwent preliminary cardiopulmonary investigations followed by Doppler echocardiography, right heart catheterisation, and ambulatory pulmonary artery pressure monitoring to measure changes in pressure over a 24 hour period including during a formal exercise test. RESULTS: All patients had pulmonary hypertension as measured by Doppler echocardiography with estimated pulmonary artery systolic pressures of 40-100 mm Hg. Pulmonary function testing revealed virtually normal spirometric values (mean FEV1 86.9% predicted) but marked reduction in CO gas transfer factor (KCO 57.8% predicted). Exercise responses were impaired with mean VO2max 50.6% predicted. Ambulatory PAP monitoring indicated significant changes in pressures with variation in posture and activity throughout 24 hours. Resting PAP did not predict the change in PAP seen on exercise. CONCLUSION: Conventional methods of assessment of the pulmonary circulation based on single measurements in the supine position may underestimate the stresses faced by the right side of the circulation. This ambulatory system allows monitoring of pulmonary haemodynamics continuously over 24 hours during normal activities of daily living. These measurements may increase our understanding of the contribution made by secondary pulmonary hypertension to the morbidity and mortality of the underlying lung disease.

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Dose distributions that result from treating a patient with orthovoltage beams are best determined with a treatment planning system that uses the Monte Carlo method, and such systems are not readily available. In the present work, the Monte Carlo method was used to develop a computer code for determining absorbed dose distributions in orthovoltage radiation therapy. The code was used in planning treatment of a patient with a neuroendocrine carcinoma of the maxillary sinus. Two lateral high-energy photon beams supplemented by an anterior orthovoltage photon beam were utilized in the treatment plan. For the clinical case and radiation beams considered, a reasonably uniform dose distribution (+/- 10%) is achieved within the target volume, while the dose to the lens of each eye is 4-8% of the prescribed dose. Therefore, an orthovoltage photon beam, when properly filtered and optimally combined with megavoltage beams, can be effective in the treatment of cancers below the skin, providing that accurate treatment planning is carried out to establish with accuracy and precision the doses to critical structures.

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The design of a Monte Carlo electron transport code is described, with particular attention being given to the modeling of multiple-scattering, ionization, and bremsstrahlung production. Comparisons of code predictions with experimental data are presented, together with simple radiation therapy applications.

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Electron-beam treatment planning for retinoblastoma was investigated and an optimal treatment plan was devised for a particular case using a new three-dimensional Monte Carlo-based treatment planning system known to be capable of correctly predicting dose perturbations caused by body surface obliquities and tissue heterogeneities. Computed tomography (CT) data files were used to construct a three-dimensional eye phantom representing the anatomy of a child's orbit. Dose distributions in sagittal, transverse, and coronal planes were predicted with 1-mm resolution. Study of these distributions led to an optimal treatment plan consisting of an anterior-lateral pair, with the anterior field being a 10-MeV, 30-mm-diam circular field, centrally blocked by a 10-mm-diam lucite lens shield and the lateral field being a 16-MeV, 30 x 25-mm D-shaped field. The anterior field delivers a therapeutic dose to the ora serrata, but it underdoses the posterior retinal surface behind the lens shield; the lateral field provides the necessary boost dose to the posterior retinal surface. An equally weighted combination of the two fields produces a dose distribution in which the entire retinal surface receives a therapeutic dose, with less than 10% of that dose being delivered to the lens, brain, and the contralateral orbit.

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The Monte Carlo method was used to study perturbations of single I-125 seed dose distributions created by the presence of one or three neighboring seeds for the case of seeds immersed in a water phantom. Perturbation factors were determined within the geometric shadow of neighboring seeds for two-seed designs, four-seed spacings, and several choices of dose point. The results were compared to dose estimates obtained by the simple superposition of single-seed data for one- and two-plane implants. Some significant differences were found.

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An improved electron multiple-scattering distribution is presented in the form of a composite function which combines three expressions valid over different scattering angle regions: a modified relativistic Mott single-scattering term for large angle scattering, a modified Moliere Gaussian term for small angle scattering, and an exponential term for the intermediate angle scattering region. The exponential term has two adjustable parameters which make possible the smooth transition from the large to the small scattering angle regions. The proposed distribution exhibits better agreement with experiment than other multiple-scattering distributions commonly used in Monte Carlo electron transport codes, is amenable to direct sampling over a continuous range of electron energies and step sizes, can be used for elements of any atomic number, and is particularly suitable for use on small memory computers.

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The Monte Carlo method was used to investigate the dose distribution around a 3M Company model 6711 125I seed immersed in a water phantom. Dose rate per unit activity data are presented as a matrix of 63 points surrounding the seed. Relative dose data are presented graphically for two mutually perpendicular directions and compared with the corresponding data for the only other 125I seed currently available, the 3M Company model 6702 125I seed. The 6711 relative dose distribution decreases more rapidly with distance from the seed than does the 6702 relative dose distribution. Uncertainties in the 6711 seed dose distribution produced by end-weld thickness variations were investigated and found to be substantial at certain points.

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The Monte Carlo method was used to investigate dose distributions around the 3M Company model 6701 and model 6702 125I brachytherapy seeds. The transverse axis dose distributions of the two seed models were found to be nearly identical, but the longitudinal axis dose distributions differed significantly. Seed design influences upon dose distributions also were investigated.

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Adenine and hypoxanthine can be utilised by cardiac muscle cells as substrates for the synthesis of ATP. A possible therapeutic advantage of these compounds as high-energy precursors is their lack of vasoactive properties. Myocytes isolated from mature rat heart have been used to establish in kinetic detail the capacity of the heart to incorporate adenine, hypoxanthine and ribose into cellular nucleotides. Maximum rates of catalysis by enzymes on the salvage pathways have been established. Whilst the rate of incorporation of adenine into the ATP pool appears to depend upon intracellular concentrations of adenine and phosphoribosylpyrophosphate, for hypoxanthine the pattern is more complex. Hypoxanthine is salvaged at a slow rate compared with adenine, and is incorporated into GTP and IMP as well as into adenine nucleotides. The rate of incorporation of hypoxanthine into both IMP and ATP is accelerated in myocytes incubated with ribose. However, the rate-limiting reaction appears to be that catalysed by adenylosuccinate synthetase, for the rate of ATP synthesis is not accelerated when hypoxanthine concentration is increased from 10 to 50 microM, while the rate of IMP synthesis is more than doubled. Adenine and hypoxanthine phosphoribosyl transferases are present in equal catalytic amounts, but rat cardiac myocytes have very little adenylosuccinate synthetase activity. Exogenous ribose is incorporated into adenine nucleotides in amounts equimolar with adenine or hypoxanthine.

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In transmission computed tomography, relative X-ray attenuation measurements are made at various angles around a patient's body. These input projection data are reconstructed to yield a cross-sectional view of internal structure. If the body section contains material that severely attenuates the X-ray beam (e.g., surgical clips, lead fragments), high-density streaks that obliterate internal structure will be produced in the process of image reconstruction. This loss of diagnostic information renders the scan useless. A technique has been developed that removes this imaging artifact. The approach views the affected projection data as misinformation. These data are assigned new values, and image reconstruction is performed without changing existing computer hardware or software. Projection data for a head section containing a lead fragment were obtained by Monte Carlo simulation. Three methods of obtaining replacement data were examined. A nearest-neighbor pattern recognition technique yielded excellent results.

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An interactive computer program for calculating treatment times for 60Co single beam, opposing beam, or rotational beam radiation therapy is described. The program allows the user to enter parameters specific to his machine. Analytic expressions are used to represent the depth dose, backscatter factor, tissue-air ratio, collimator factor, and beam attenuation of a block-carrying tray.

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The question of the number of radii which are necessary to accurately determine the average tissue-air ratio (TAR) to be used in 60Co rotational radiation therapy treatment planning was studied using actual patient contours. It was found that 12 radii adequately determine the average TAR for clinical purposes.

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A new method is presented for the removal of streaking artifact in computed tomography. The method uses a nearest-neighbor pattern recognition technique to redetermine ray sums that intersect the foreign object responsible for the streaking. When the method is applied to the removal of streaking artifact caused by lead in a skull phantom, excellent results are obtained.

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