Methotrexate polyglutamates as a marker of patient compliance and clinical response in psoriasis: a single-centre prospective study.

BACKGROUND: Methotrexate is activated by the sequential addition of glutamic acid residues to form methotrexate polyglutamates (MTXPG(1-5)). MTXPG(1-5) inhibit enzymes of the folate-purine-pyrimidine pathways, and longer-chain MTXPG(3-5) species are more active. OBJECTIVES: To determine the pattern of erythrocyte MTXPG(1-5) in patients initiated on oral methotrexate for psoriasis, and to investigate the potential utility of MTXPGs as markers of compliance and/or clinical response. METHODS: This was a single-centre, prospective study of 55 adult patients with chronic plaque psoriasis initiated on weekly oral methotrexate. Erythrocyte MTXPG(1-5) concentrations were measured (at weeks 4, 8, 12, 24 and 52) using high-performance liquid chromatography. Methotrexate responders achieved ≥ 50% improvement in Psoriasis Area and Severity Index or physician's global score of 'clear'/'nearly clear' at 24 weeks. RESULTS: MTXPG levels were measured in 14-33 patients at each time point. All MTXPG(1-5) species were detected at week 4 of therapy. Steady state for long-chain MTXPG(3-5) and total MTXPG(1-5) was achieved by week 24. MTXPG(3) emerged as the predominant MTXPG species (from week 12 onwards) and reflected overall polyglutamate status (correlating strongly with MTXPG(2-5) , MTXPG(3-5) and MTXPG(4-5) ; R = 0·76-0·95, P < 1·55 × 10(-5)). Age, renal function and sex were not significant determinants of MTXPG(3) concentration. No significant association was identified between MTXPG and adverse events or responder status. CONCLUSIONS: This is the first study to demonstrate the prospective accumulation of MTXPG(1-5) in patients with psoriasis. The detection of MTXPGs early in therapy and the establishment of a steady state with continuous treatment may offer measuring of MTXPG as a test to monitor patient compliance with therapy. Larger studies are required to determine the role of MTXPG as a potential biomarker of clinical response.

Fecal calprotectin predicts the clinical course of acute severe ulcerative colitis.

OBJECTIVES: Calprotectin is a granulocyte neutrophil-predominant cytosolic protein. Fecal concentrations are elevated in intestinal inflammation and may predict relapse in quiescent inflammatory bowel disease. We aim to investigate fecal calprotectin (FC) as a biomarker in predicting the clinical course of acute severe ulcerative colitis (ASUC). METHODS: In 90 patients with ASUC requiring intensive in-patient medical therapy (January 2005-September 2007), we investigated the discriminant ability of FC to predict colectomy and corticosteroid and infliximab nonresponse. All patients received parenteral corticosteroids as first-line treatment; 21 (23.3%) were also treated with infliximab (5 mg/kg), after failure of corticosteroid therapy. RESULTS: Of 90 patients, 31 (34.4%) required colectomy, including 11 (52.4%) of those treated with infliximab. Overall FC was high (1,020.0 microg/g interquartile range: 601.5-1,617.5). FC was significantly higher in patients requiring colectomy (1,200.0 vs. 887.0; P=0.04), with a trend toward significance when comparing corticosteroid nonresponders and responders (1,100.0 vs. 863.5; P=0.08), as well as between infliximab nonresponders and responders (1,795.0 vs. 920.5; P=0.06). Receiver-operator characteristic curve analysis yielded an area under the curve of 0.65 to predict colectomy (P=0.04), with a maximum likelihood ratio of 9.23, specificity 97.4%, and sensitivity 24.0% at a cutoff point of 1,922.5 microg/g. Kaplan-Meier analyses showed that using 1,922.5 microg/g over a median follow-up of 1.10 years, 87% of patients will need subsequent colectomy. CONCLUSIONS: This is the first data set to demonstrate that FC levels are dramatically elevated in severe UC. These data raise the possibility that this biomarker can predict response to first or second-line medical therapy in this setting.

Environmental risk analysis of ultraviolet phototherapy centres in Ireland.

BACKGROUND: Ultraviolet (UV) radiation is commonly used in the treatment of dermatological conditions such as psoriasis. It is known that high levels of exposure to UV radiation (UVR) will increase the risk of adverse biological effects. Exposure limit values for UVR have been developed by the International Commission on Non-Ionising Radiation Protection (ICNIRP) and occupational exposure to phototherapy staff should be kept within these limits. The use of environmental controls such as warning signs, good ventilation and UV-opaque curtains will significantly reduce the risks to staff, patients and members of the public. AIMS: The aim of the study is to identify hazards in phototherapy centres and present recommendations for reducing risks. METHODS: An environmental risk assessment has been carried out at eleven phototherapy centres in the Republic of Ireland. The study assessed a number of areas such as patient safety, staff safety, room design and UV leakage measurements. RESULTS: The majority of clinics are well designed and there is consistent use of protective equipment. CONCLUSIONS: The results show that on the whole there is a satisfactory level of risk management in phototherapy centres. Recommendations on maintaining good safety standards are presented.

2-Chloro-1-(2,4-dichlorophenyl)-3-(1H-imidazol-1-yl)-2-phenylpropan-1-one hydrochloride, a novel, nonmutagenic antibacterial with specific activity against anaerobic bacteria.

1-(2,4-Dichlorophenyl)-2-phenylpropen-1-one (2) is identified as a potent antibacterial agent. A compound, 2-chloro-1-(2,4-dichlorophenyl)-3-(1H-imidazol-1-yl)-2-phenylpropan++ +-1-one (5) has been designed with the intention of its acting as a pro-drug, liberating the lethal species 2 specifically within the target anaerobic bacterial cell following bioreduction by bacterial ferredoxin or related electron transfer proteins. The synthesis and biological activity of 5 is described and compared with the activities of the analogous alpha-bromo ketone 6 and alpha-fluoro ketone 7. Synthesis of 6, 7, and the corresponding alpha-hydroxy ketone 11 is also described.

The discriminant value of semiquantitative SPECT data in mild Alzheimer's disease.

UNLABELLED: In most semiquantitative SPECT studies, overlap between groups of patients with Alzheimer's disease (AD) and age-matched elderly controls is such that single posterior cortical perfusion measurements lack sensitivity. In the present study, the value of a combination of semiquantitative temporoparietal SPECT parameters was examined. METHODS: Supratentorial transaxial perfusion measurements were obtained in frontal, anterior temporal, posterior temporoparietal and occipital cortical areas in both hemispheres, in a baseline population of 10 healthy elderly controls and 30 mild to moderately impaired AD patients, as well as in a prospective group of 15 patients with mild cognitive impairment, 12 patients with a diagnosis of probable AD and individual cases of multi-infarct dementia, dementia-frontal type and paranoid psychosis. A linear discriminant function (LDF) was calculated from the baseline subjects' data to classify control and AD subjects individually. RESULTS: Highly significant hypoperfusion was noted in both the anterior temporal and posterior temporoparietal regions of interest in the AD group compared with controls, but with significant overlap. Using an LDF incorporating these perfusion measurements in both hemispheres, 10/10 (100%) controls and 26/30 (87%) AD baseline subjects were correctly classified. Using the baseline LDF in the prospective 15 mildly impaired cases, 11/12 new mild AD cases and none of the 3 non-AD cases were classified in the AD group. CONCLUSION: These results support the use of a combination of semiquantitative SPECT perfusion estimates from cortical areas with predictable pathological involvement in AD in a linear discriminant format in the clinical assessment of patients with suspected AD.

Left ventricular performance during exercise: response of ear densitogram derivative.

The peak derivative of the ear densitogram (PD) has been shown to track left ventricular (LV) function during exercise. Measured as percent change in amplitude from resting control, PD in normal subjects slowly and consistently increased throughout exercise and to 2 minutes of recovery, followed by return to control level. In contrast, PD in patients with coronary artery disease rapidly increased only to 1 minute of exercise, with no significant subsequent increase. Expressed as a percent change from control, the response of normal subjects differs significantly from that of patients with coronary artery disease at 1 and 4 minutes of exercise, and 2 minutes of recovery. The PD increase in normal subjects from end-exercise to 2 minutes of recovery may be attributable to the heart rate decreasing faster than venous return, associated with LV ejection time, which is significantly shorter than heart rate-predicted values 2 minutes after exercise.

Evaluation of renal function following treatment with 5-aminosalicylic acid derivatives in patients with ulcerative colitis.

BACKGROUND: A number of cases of nephrotoxicity have been reported in patients with inflammatory bowel disease taking oral 5-aminosalicylic acid (5-ASA). AIM: To evaluate the effects of 9 months of therapy with mesalazine or olsalazine on renal function in patients with ulcerative colitis in remission. METHODS: Forty patients with ulcerative colitis in complete remission for 6 months were randomized to either olsalazine (n=20) or mesalazine (n=20 for nine months). Thirty-six of the 40 patients were on prior salicylate therapy. Disease activity was the measure ofclinical efficacy and was assessed by the Harvey-Bradshaw Index (HBI). Laboratory efficacy measurements included glomerular filtration rate (GFR), microalbuminuria, urinary gluthathione S-transferase (GST) and serum C-reactive protein (CRP). Safety analysis consisted of documentation of adverse events and laboratory values. RESULTS: There was no significant reduction in the GFR overall on therapy. The levels of GFR adjusted for baseline were similar in the two treatment groups after 3, 6 and 9 months. A significantly higher percentage of mesalazine-treated patients experienced drug related adverse events, all of a minor nature. The incidence of adverse events causing early withdrawal was similar in the two treatment groups. CONCLUSION: Treatment with mesalazine or olsalazine for 9 months had no significant impact on GFR.

Noninvasive tracking of peripheral resistance by ear densitography.

Owing to the interaction between the left ventricle and the arterial system, pulse contour during ejection is significantly affected by changes in peripheral resistance. Quantitative description of the pulse configuration as a function of peripheral resistance involves invasive investigation of complex frequency and impedance spectra. The ear densitogram noninvasively yields a pulse wave shown to closely track changes in the central arterial pulse; in this investigation, its decreasing systolic slope responded to changes in the peripheral resistance like those in the central pulse and in arterial models. The decreasing slope of the ear densitogram pulse (RNAD) can reliably track changes in peripheral resistance.

Event-related potential prolongation in Alzheimer's disease signifies frontal lobe impairment: evidence from SPECT imaging.

BACKGROUND: The N2 and P3 components of auditory event-related potentials (ERPs) and single-photon emission computed tomographic (SPECT) images are separate independent biological markers of cerebral function and are abnormal in Alzheimer's disease (AD). The relationship between ERP N2 and P3 latencies and regional cerebral perfusion abnormalities in AD is unknown. METHODS: ERP and SPECT data were obtained one week apart in 18 patients with "probable" AD of mild or moderate severity, and 12 healthy age-matched elderly controls. Average premotor frontal, anterior temporal, inferior parietal, and occipital cortical/cerebellar perfusion ratios were calculated from the SPECT data and correlations with ERP N2 and P3 latencies derived for AD and control groups separately. RESULTS: ERP N2 latency was correlated significantly with the average frontal perfusion ratio (r = -.59; p < .009), but correlations with average temporal, parietal, and occipital ratios were nonsignificant in the AD group. Similarly, ERP P3 latency was correlated significantly with the average frontal perfusion ratio (r = -.65; p < .004), but not with the other perfusion ratios in the AD group. In the control group, a partial correlation between the average frontal perfusion ratio and the ERP N2 latency was noted (r = -.52; p < .09), but no other ERP/SPECT correlations approached statistical significance. CONCLUSION: ERP N2 and P3 latency delay in AD is a function of differential frontal lobe hypoperfusion.

Correlation of end-diastolic pressure and myocardial elasticity with the transit time of the left atrial pressure wave (A-Ar interval).

Contraction of the left atrium in diastole generates a pressure wave that moves along the postero-lateral wall of the left ventricle (LV), rebounds off the LV apex, and is then directed toward the outflow tract. The movement of this atrial pressure wave may be detected with pulsed Doppler echocardiography by placing a sample volume in the LV outflow tract. The resulting spectral profile shows the initial. A velocity wave and also the Ar velocity wave, which is caused by the atrial pressure wave rebounding off the LV apex. The transit time from the inflow tract to the outflow tract of the atrial pressure wave (A-Ar interval) may be determined from the time axis of the spectral profile by measuring the peak-to-peak separation of the A and Ar, velocity waves. It occurs in the range 25 to 80 milliseconds. The primary determinant of the A-Ar interval is the elasticity of the LV myocardium. We correlated ventricular elasticity with the A-Ar interval in 47 patients and found a significant negative linear correlation (r = -0.782, p < 0.001). Because the pressure in a viscoelastic conduit such as the LV is determined by the elasticity of the ventricular wall, we correlated end-diastolic pressure with the A-Ar interval and again showed a significant negative linear correlation (r = -0.701, p < 0.001). The A-Ar interval is an easily measured noninvasive index of the diastolic function of the LV that reflects its intrinsic elasticity and end-diastolic pressure. It is therefore a quantitative measurement of LV wall stiffness and end-diastolic pressure.

Contrast agent CT imaging in variable sized organs using single energy synchrotron radiation.

A theoretical and experimental study has been performed to determine which element, when used as a contrast agent in CT, requires the lowest concentration when delivered to various sized organs. Iodine is at present the primary contrast agent used in contrast enhanced CT imaging. The results presented here show that iodine is not the optimum element to use in terms of concentration needed for visibility. When administered to very small organs, the use of gadolinium reduces the concentration required for visibility by at least a factor of 3 over that required when using iodine.

Development of a quality assurance protocol for peripheral subtraction imaging applications.

Peripheral subtraction scanning is used to trace the blood vessels of upper and lower extremities. In some modern C-arm fluoroscopy systems this function is performed automatically. In this mode the system is programmed to advance and stop in a series of steps taking a mask image at each point. The system then repeats each step after the contrast agent has been injected, and produces a DSA image at each point. Current radiographic quality assurance protocols do not address this feature. This note reviews methods of measuring system vibration while images are being acquired in automated peripheral stepping. The effect on image quality pre- and post-image processing is assessed. Results show that peripheral stepping DSA does not provide the same degree of image quality as static DSA. In examining static test objects, the major cause of the reduction in image quality is misregistration due to vibration of the image intensifier during imaging.

The development of a phantom to determine foetal organ doses from 131I in the foetal thyroid.

Iodine can accumulate in the foetal thyroid from the twelfth week of gestation onwards. If the iodine taken up by the foetal thyroid is in the form of 131I then the thyroid and its proximal tissues and organs will be irradiated. Several mathematical models exist in the literature on foetal/maternal iodine kinetics. However, very few studies have been performed where the foetal thyroid had been physically modelled thus allowing the determination of foetal organ dosimetry from 131I in the foetal thyroid. Here, the development of such a physical model or phantom is described and dosimetry results obtained from the phantom are discussed. The phantom is of Perspex construction, the dimensions of which are sufficient to incorporate models of the foetus at 16, 24 and 36 weeks' gestational age. The dosimetry of two organs is presented, that of the brain and the thymus. The results show that the measured absorbed dose is comparable with that calculated using modified MIRD dosimetry and traditional methods. The results also show that the dose to the thymus is greater than that of the brain by a factor of almost 30 for 16 weeks' gestational age.

Estimation of foetal brain dose from I-131 in the foetal thyroid.

The ingestion of I-131 by pregnant women can have consequences for the developing foetus, in particular brain function. As the foetal thyroid accumulates iodine from the twelfth week of gestation onwards, the determination of foetal brain dose resulting from such I-131 accumulation is essential. Normal dosimetric methods fail to treat the case of foetus. Using an approximation method based on the MIRD approach, a foetal dose estimation scheme is developed to allow the determination of foetal brain dose from foetal thyroid irradiation. Dose values are obtained for the foetus based on the maternal intake of I-131. It was found that the choice of biokinetic model for the mother/foetus has a large impact on the determined dose estimate.

Thyroid dosimetry in Europe following the Chernobyl accident.

Thyroid dose estimates for European populations following the Chernobyl accident in 1986 have been presented in the literature. These dose estimates used standard values for parameters such as thyroid mass, iodine uptake and biological half-life. Previous work has shown that these values are not representative of European populations and that local values should be utilized. Using published data on revised thyroid dose estimates, thyroid dosimetry data arising as a result of the Chernobyl accident are presented for 22 European countries. When these are compared with previously published estimates it is found that in all cases the previous results underestimate the thyroid dose by up to a factor of 4. Risk estimates on the incidence of fatal and non-fatal thyroid cancers are also determined from this new data and, again, the results are underestimated. The results show an increase in the number of fatal cancers, rising from 149 as predicted by the NEA to 310 under the new estimates, and from 180 as predicted by UNSCEAR to the new estimate of 380.

Thyroid dosimetry of adult European populations.

Radioactive iodine, in the form of iodine-131, behaves similarly to stable iodine in small quantities, thus resulting in a radiation dose to the thyroid. Under the Medical Internal Radiation Dosimetry Committee formulation for radiation dose calculation to an organ, the resulting dose to the thyroid gland is dependent on the organ mass, its isotope uptake and the effective half-life of the element in the gland. Traditionally, values have been used for these parameters which, in some cases, were determined some decades previous. Iodine supply is a primary contributor to correct thyroid function and ultimately these values of mass, uptake and half-life. Recently, new data have become available on iodine kinetics throughout Europe. Here, the influence of the highly variable iodine supply in Europe on projected thyroid doses is determined. Thyroid mass values ranged from 9 g (Sweden) to 28 g (Poland) while uptake measurements were found to range from 18% (Finland) to approximately 60% (Germany and Poland). Resulting dose estimates ranged from 0.5 Gy MBq-1 (Finland) injested to 1.3 Gy MBq-1 (Czechoslovakia) injested. It was also found that among European populations the highest dose burden was to those populations with mild iodine deficiency. The results show that the use of generic metabolic data for the thyroid can lead to a misrepresentation of the absorbed dose to the thyroid. Thus, the data presented provide a better reflection of the actual thyroid dose following ingestion of iodine-131 for European countries.

Specification and initial evaluation of a multiple application teleradiology system.

The digitization and transmission of medical images is becoming increasingly more important and available. The selection of appropriate clinical applications for teleradiology systems is an important factor in determining the success of such ventures. In this paper, the selection of such applications and the evaluation of the teleradiology system is described. The system (LIAISON, CAPTEC Ltd, Malahide, Ireland) is PC based and is capable of digitization and transmission of three categories of medical images: (1) plain film radiographs; (2) CT film data and (3) video sequences such as ultrasound scans. A comprehensive technical evaluation was carried out on the acquisition and display station in which various parameters such as spatial resolution, signal-to-noise ratio (SNR), and distortion were investigated. Results showed that the system performed well within specifications. An exploratory clinical evaluation was performed using a case mix of subtle fractures, chests and dislocations, and CT scans. Here the system performed well with a diagnostic accuracy of 95% for the digital image compared with the analogue image.

The outcome of scoliosis surgery in the severely physically handicapped child. An objective and subjective assessment.

STUDY DESIGN: A prospective, functional assessment based on physical ability and independence in daily activities was performed of patients who had severe physical handicaps and spinal deformities and were undergoing scoliosis surgery. OBJECTIVES: To determine whether improving spinal alignment and truncal balance improved the functional abilities of handicapped patients. SUMMARY OF BACKGROUND DATA: Loss of truncal stability compromises the physical independence of children who are severely handicapped. Physiologic function also may be compromised. It is not clear whether improving truncal balance actually improves their level of independence or merely halts further deterioration. METHODS: Twenty patients with significant physical handicaps resulting from neuromuscular disorders or multiple congenital anomalies and significant spinal deformity and truncal imbalance were treated surgically to realign and stabilize their spines. Their level of physical independence was evaluated before surgery, including their ability to sit, ambulate, and complete activities of daily living. Evaluation was done before surgery, 6 months after surgery, and 12 months after surgery. A subjective assessment of cosmesis also was made. RESULTS: Corrective spinal surgery resulted in a deterioration of physical ability for the first 6 months. Most patients subsequently returned to their preoperative level of function. An improvement of function exceeding their preoperative level was not seen after 12 months. The cosmetic results of surgery were excellent. CONCLUSIONS: Corrective spinal surgery in patients with severe physical handicap should be performed early to preserve function and should not be dictated solely by the severity of the curvature. Improvement in the patient's level of independence may not necessarily occur after truncal stabilization. Cosmetic results in these patients with severe disabilities were extremely gratifying to the patients and their caregivers.

Somatostatin and somatostatin analogues in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumour characterized by the production and secretion of calcitonin. MTC tumours may express functional somatostatin receptors (hSSTR). A significant proportion of hSSTR receptor-positive MTC tumours, including metastatic disease, may be visualized in vivo through 111In-pentetreotide scintigraphy. Four patients with recurrent/metastatic disease, who had previously been assessed with 111In-anti-CEA monoclonal antibody fragment [F(ab')2] imaging, were evaluated. 111In-pentetreotide scintigraphy localized all known disease sites. Furthermore, mediastinal disease was detected in one patient with negative conventional, and 111In-anti-CEA F(ab')2 imaging studies. The detection of somatostatin within the tumour (2 patients), or negative octreotide challenges (2 patients), did not affect the outcome of 111In-pentetreotide scintigraphy. In conclusion, 111In-pentetreotide scintigraphy appears at least as effective as 111In-anti-CEA F(ab')2 imaging and should be considered in the diagnostic evaluation of MTC, particularly in the setting of recurrent/metastatic disease not detected by conventional means.

Classification of mild Alzheimer's disease by artificial neural network analysis of SPET data.

An evaluation of the performance of artificial neural networks (ANNs) for the classification of probable Alzheimer's disease (pAD) patients was undertaken using data extracted from four regions of interest constructed on single photon emission tomographic (SPET) cerebral perfusion images. Two studies using feed-forward neural networks (FFNNs) were undertaken. The first was to determine if it would be possible to classify pAD patients and normal subjects in a mixed group, comprising 29 patients diagnosed as having pAD varying in severity from mild, established dementia to moderate dementia and 10 healthy control subjects. The second was to determine if the networks generated in the first study could prospectively classify 15 additional patients with very mild or mild cognitive impairment. The results were compared to those obtained using the same data and discriminant analysis. The relative performances of the two analysis techniques were assessed on the basis of the area under receiver operating characteristics (ROC) curves. The FFNN successfully classified all datasets in the first study, achieving an area under the ROC curve of 1.00, whereas discriminant analysis achieved 0.94. When tested on data from the second group, the areas under the ROC curves varied between 0.86 and 1.00 for the FFNN, whereas that for discriminant analysis was 0.99. We conclude that FFNNs can accurately classify pAD patients with mild to moderate dementia using data obtained from SPET cerebral perfusion images.