Five-year point prevalence survey of healthcare-associated infections and antimicrobial use in a Japanese university hospital.

BACKGROUND: Periodic point prevalence surveys (PPSs) provide a method for assessing changes in healthcare-associated infections (HAIs) and antimicrobial use over time. Following the introduction of an antimicrobial stewardship programme at Nagoya University Hospital (Aichi, Japan) a five-year PPS study was performed to highlight any epidemiological changes. METHODS: One-day PPSs were performed annually in July at Nagoya University Hospital. Data on patient characteristics, medical devices, active HAIs and antimicrobial use were collected using a standard data-collection form. RESULTS: A total of 4339 patients were included. Over the five-year study period the median patient age was 62 years, median duration of hospital admission was nine days, 9% of patients had an HAI and 35.2% received at least one antimicrobial. Overall there were 406 HAIs (95% confidence interval, 369-447) with surgical site infection, pneumonia and febrile neutropenia occurring most frequently. Enterobacterales were the most common pathogens (N = 78, 28.6%) and 32.1% were third-generation cephalosporin-resistant. Meropenem was the most frequently prescribed antimicrobial for HAIs. Surgical antimicrobial prophylaxis changed drastically, with shorter durations and a marked reduction in oral cephalosporin use. However, antimicrobials for medical prophylaxis gradually increased. CONCLUSIONS: This five-year PPS study shows consistent data for patient background, HAIs and causative pathogens and highlights changes in antimicrobial use during the era of the National Action Plan on Antimicrobial Resistance. To describe the epidemiology of Japanese hospitals by PPS, multicentre PPSs including in community hospitals should be performed annually.

The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

[Silent myocardial ischemia and exercise-induced arrhythmia detected by the exercise test in the total health promotion plan (THP)].

We investigated the prevalence and characteristics of ischemic heart disease especially silent myocardial ischemia (SMI) and arrhythmia in need of careful observation in the exercise stress tests in the Total Health Promotion Plan (THP), which was conducted between 1994-96 for the purpose of measuring cardiopulmonary function. All workers (n = 4,918, 4,426 males) aged 18-60 yr old in an occupational field were studied. Exercise tests with an ergometer were performed by the LOPS protocol, in which the maximal workload was set up as a presumed 70-80% maximal oxygen intake, or STEP (original multistage protocol). ECG changes were evaluated with a CC5 lead. Two hundred and fifteen people refused the study because of a common cold, lumbago and so on. Of 4,703 subjects, 17 with abnormal rest ECG and 19 with probable anginal pain were excluded from the exercise tests. Of 4,667 who underwent the exercise test, 37 (0.79%) had ischemic ECG change, and 155 (3.32%) had striking arrhythmia. These 228 subjects then did a treadmill exercise test with Bruce protocol. Twenty-two (0.47% of 4,703) showed positive ECG change, 9 (0.19%) of 22 had abnormal findings on a 201Tl scan. 8 (0.17%) were diagnosed as SMI (Cohn I), in which the prevalence of hypertension, hyperlipidemia, diabetes mellitus, smoker and positive familial history of ischemic heart disease was greater than that of all subjects. In a 15-30 month follow up, none has developed cardiac accidents. Exercise-induced arrhythmia was detected in 11 (0.23%) subjects. Four were non-sustained ventricular tachycardia without any organic disease, 4 were ventricular arrhythmia based on cardiomyopathy detected by echocardiography, 2 were atrial fibrillation and another was WPW syndrome. It is therefore likely that the ergometer exercise test in THP was effective in preventing sudden death caused by ischemic heart disease or striking arrhythmia.

[Influence of the radioactive strontium (89Sr) using for nuclear medical radiation therapy upon radioactive draining-water system].

PURPOSE: Strontium-89 chloride (89Sr) is a new radiopharmaceutical that provides effective pain relief for metastatic bone lesions, and is expected to be available soon in the palliative management for metastatic bone pain in Japan. Because of relatively long physical half life (50.5 days), 89Sr may affect to the radioactive draining-water system by exceeding the limits of activity concentration for radioactive drain. In this article, the influence of 89Sr use on the radioactive drainage system was simulated. METHODS: The standard tank capacity of drainage and draining frequency was determined from the results of questionnaire carried out for the nationwide medical and research institutes where radioisotope treatment are performed. On the assumption that 89Sr of 148 MBq for one therapy was used twice a week and several common radionuclides were used as the same activity as used at Chiba Cancer Center, the influence of 89Sr was estimated. The calculation was performed using the activity contamination ration into the draining-water system of each radionuclide of 0.01, which was legally determined. RESULTS: The simulation revealed that the sum of the contamination ratios of individual radionuclides exceeded a legal value of 1.0 in standard drainage with the capacity of 5 m3 and 10 m3 and draining frequency of 7 times per year. The actual contamination ratios of common radiopharmaceuticals measured at Chiba Cancer Center ranged from 1/100 to 1/1000 of the legal values. CONCLUSION: It is necessary that the legal value of activity contamination ratios into the draining-water system should be reassessed before starting 89Sr therapy.

[Quantitative evaluation for scatter and attenuation correction in 99mTc SPECT--multicenter cooperation phantom study].

A multicenter cooperation phantom study was conducted to evaluate the accuracy of a triple energy window scatter correction technique in combination with various attenuation correction methods for 99mTc single photon emission computed tomography (SPECT) imaging. Six centers participated in this research and the data obtained with seven SPECT instruments were analyzed. The phantom used in the experiment was a 20 x 10 cm cylinder filled with homogeneous 99mTc solution, containing two kinds of cold spots (cold rod phantoms). One had a water-filled cylinder 5.5 cm in diameter positioned 2.5 cm from the center. The other contained 6 water-filled cylinders of various sizes. Contrasts of cold regions were in the range from 74% to 120% (true 100%). Another phantom had the shape of a pie-chart divided into six chambers symmetrically positioned in a cylinder 20 cm in diameter and 10 cm in height. Each chamber had volume of 480 ml and contained homogeneous 99mTc solution of different concentrations. This phantom was used to test for linearity between the radio activity concentration and reconstructed count density (linearity phantom). The intercept of the regression line obtained from the linearity phantom was 8.4 kBq ml-1 without scatter correction and -6.8 kBq ml-1 with scatter correction. Contrast was in the range from 78% to 132% (true 100%). The mean relative error for the measured activity concentration was 4.9% +/- 3.5% (mean +/- sd).

Effects of low-intensity aerobic training on the high-density lipoprotein cholesterol concentration in healthy elderly subjects.

The concentration of high-density lipoprotein cholesterol (HDL-C) is inversely correlated with the risk of coronary heart disease. The effects of low-intensity aerobic training on serum HDL-C and other lipoprotein concentrations were examined in healthy elderly subjects. The subjects were randomly assigned to two groups matched for sex, age, height, and weight. The training group (n = 20, 10 men and 10 women aged 67 +/- 4 years) participated in a supervised physical exercise regimen using a bicycle ergometer at an intensity of 50% estimated maximal oxygen consumption (VO2max) for 60 minutes two to four times per week for 5 months. In contrast, the control group (n = 20, 10 men and 10 women aged 68 +/- 4 years) did not perform any particular physical training. The training protocol resulted in significant increases in the VO2max (P < .05), HDL-C, HDL2-C, and HDL2-C/HDL3-C ratio (P < .01). The change in HDL2-C (r = .57, P < .01) and HDL2-C/HDL3-C (r = .63, P < .01) was positively associated with an increase in the total exercise duration per week. In addition, the total weekly exercise duration also showed a significant positive relationship with HDL-C (r = .75, P < .01), HDL2-C (r = .81, P < .01), and HDL2-C/HDL3-C (r = .71, P < .01) after the training period. The changes in body weight and the VO2max were not significantly correlated with any lipid parameters. Low-intensity aerobic training may improve the profile of HDL-C and its subfractions in healthy elderly subjects. Also, the total exercise duration may be an important factor for improving HDL-C and HDL2-C in elderly subjects.

67Ga planar imaging with a low-energy collimator and scatter correction using the triple energy window method.

To improve the spatial resolution and contrast of 67Ga planar imaging, we used a low-energy collimator and two lower-energy windows with a triple-energy-window (TEW) scatter compensation method. The spatial resolution is better than with a medium-energy collimator, and the TEW method can correct for scattered photons and reduce the background counts. In a phantom study and a clinical study involving 44 patients, the images obtained by the proposed method were compared with the images obtained with a medium-energy collimator and three energy windows without scatter compensation (the conventional method). The spatial resolution and the counts were measured. Two nuclear medicine physicians interpreted the images and clinical usefulness was evaluated. The spatial resolution and contrast were improved by our proposed method. It enabled the detection of lesions in five locations in the clinical study. The counts were reduced but misreadings were not seen. We conclude that our proposed method shows a clinical advantage over the conventional method. It can be used easily and quickly with commercially available equipment and is useful in clinical practice.

[Investigation of radiation safety management of nuclear medicine facilities in Japan; contamination of radioactivity in the draining-water system. A Working Group of Japanese Society of Nuclear Medicine for the Guidelines of Nuclear Medicine Therapy].

Radiation safety management condition in Japanese nuclear medicine facilities were investigated by the questionnaire method. The first questionnaire was asked in all Japanese 1,401 Nuclear Medicine facilities. Answers from 624 institutes (44.5%) were received and analyzed. The radiation-safety management in nuclear medicine institutes was considered to be very well performed everyday. Opinion for the present legal control of nuclear medicine institutes was that the regulation in Japan was too strict for the clinical use of radionuclides. The current regulation is based on the assumption that 1% of all radioactivity used in nuclear medicine institutes contaminates into the draining-water system. The second questionnaire detailing the contamination of radioactivity in the draining-water system was sent to 128 institutes, and 64 answers were received. Of them, 42 institutes were considered to be enough to evaluate the contamination of radioactivity in the draining-water system. There was no difference between 624 institutes answered to the first questionnaire and 42 institutes, where the radioactivity in the draining-water system was measured, in the distribution of the institute size, draining-water system equipment and the radioactivity measuring method, and these 42 institutes seemed to be representative of Japanese nuclear medicine institutes. Contamination rate of radioactivity into the draining system was calculated by the value of radioactivity in the collecting tank divided by the amount of radionuclides used daily in each institute. The institutes were divided into two categories on the basis of nuclear medicine practice pattern; type A: in-vivo use only and type B: both in-vivo and in-vitro use. The contamination rate in 27 type A institutes did not exceed 0.01%, whereas in 15 type B institutes the contamination rate distributed widely from undetectable to above 1%. These results indicated that the present regulation for the draining-water system, which assumed that 1% of all radioactivity used in nuclear medicine institutes contaminated into draining-water system, should be reconsidered in nuclear medicine facilities where radionuclides are used only in in-vivo studies.

Investigation of hepatic cytochrome P-450 enzyme induction and DNA adduct formation in male CD/1 mice following oral administration of toxaphene.

Exposure of experimental animals to toxaphene induces hepatic cytochrome P-450 (CYP). Although chronic administration of toxaphene to mice was found to cause an increased incidence of liver tumors, a mechanism for its carcinogenicity has yet to be elucidated. We investigated two potential mechanisms of toxaphene-induced carcinogenicity: peroxisomal proliferation and DNA binding. Peroxisomal proliferation was evaluated by measuring the level of immunodetectable CYP 4A1, an isozyme of CYP that is specifically induced by peroxisomal proliferators, in hepatic microsomes from CD1 mice that were treated by oral gavage for seven consecutive days with corn oil vehicle or 10, 25, 50 or 100 mg kg(-1) toxaphene. In comparison to control mice, toxaphene-treated mice had increased liver weight, increased liver/body weight ratios and increased levels of total hepatic CYP and cytochrome b5. No increase in the level of immunodetectable levels of CYP 4A1 was found in hepatic microsomes from toxaphene-treated mice when compared to controls. In contrast, increases in immunodetectable CYP 4A1 were detected in hepatic microsomes from mice treated with the peroxisomal proliferator clofibrate. These findings suggest that toxaphene-induced induction of CYP may not involve CYP 4A1 and that peroxisomal proliferation may not be involved in toxicity. Significant increases in immunodetectable levels of CYP 2B were, however, detected in toxaphene-treated mice, and are consistent with earlier reports demonstrating that toxaphene, like many other pesticides, induces the phenobarbital-inducible subfamily of CYP. Analysis of DNA adduct levels in the livers of toxaphene-treated mice by DNA 32P-post-labeling showed no evidence of DNA adduct formation.

Blood pressure lowering effect of low intensity aerobic training in elderly hypertensive patients.

PURPOSE: The purpose of this investigation was to determine the effect of 9 months of low intensity aerobic training on blood pressure in elderly hypertensive patients who were receiving antihypertensive medication. METHODS: The training group (N = 13; mean age 75.4 +/- 5.4 yr) agreed to take part in physical training using a treadmill with an exercise intensity at the blood lactate threshold (LT) for 30 min three to six times a week for 9 months. The rest (N = 13; mean age 73.1 +/- 4.2 yr) served as controls. RESULTS: The resting systolic (-15 +/- 8 mm Hg), mean (-11 +/- 6 mm Hg), and diastolic blood pressures (-9 +/- 9 mm Hg) decreased significantly after 3 months of training and the blood pressure of all participants stabilized at a significantly lower level by the end of the study (9 months) in the training group, whereas no significant changes in blood pressure were found in the control group. Both the pretraining systolic and diastolic blood pressure of those recruited patients negatively correlated with those changes after the training (SBP: P < 0.01; DBP: P < 0.05, respectively). After 1 month of detraining in five patients, the blood pressure levels were similar to those in the pretraining state. The LT increased significantly in the training group (P < 0.01). CONCLUSION: In conclusion, an additional antihypertensive effect of mild aerobic training at the LT was confirmed in elderly patients receiving antihypertensive medication. The cessation of such training in five patients, however, resulted in a relatively rapid return to pretraining levels within a month.

[Frameless registration for chest SPECT and X-ray CT image by volume matching].

Image registration of functional (SPECT) and morphological (X-ray CT/MRI) images has been studied in order to improve the accuracy and the quality of the image diagnosis. This paper describes a new registration method for chest SPECT and X-ray CT images. Presented method is a frameless and automatic registration method which calculates a transformation matrix between two coordinate systems of image data by an optimization method. This registration method uses similar physical characteristics of X-ray CT and transmission CT image. The three-dimensional overlap of the body region is used for image matching. Precision evaluation and visual image evaluation were conducted. The result of the precision evaluation with a phantom and clinical data suggested the clinically acceptable robustness in registration procedure. Visual evaluation of registered images confirmed the usefulness of this method in clinical applications.

Absent myocardial accumulation of two different radioiodinated pentadecanoic acids.

This article presents two cases with preserved myocardial 201Tl uptake and absent uptake of two kinds of radioiodinated fatty acids: iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and iodine-123-labeled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA). Although coronary angiography showed no stenotic lesion and left ventriculography revealed no wall motion abnormality, no myocardial uptake of BMIPP and 9MPA was observed in the first case. In the second case, no myocardial accumulation was recognized even in the initial phase of dynamic SPECT acquired soon after the injection of 9MPA. The results suggest that the non-visualized myocardium was not specific for BMIPP imaging and that rather than the early back diffusion of the tracers from the myocardium, abnormality of the myocardial cell membrane was a possible mechanism accounting for the phenomenon.

Thallium-201 single-photon emission tomography in the treatment follow-up of nasopharyngeal carcinoma.

In order to assess the usefulness of thallium-201 single-photon emission tomography (SPET) in the treatment follow-up of nasopharyngeal carcinoma (NPC), a total of 75 201T1 SPET studies were performed in 18 patients with histologically proven NPC. The findings were compared with those of magnetic resonance imaging (MRI) before and after therapy. Four patients received radiotherapy alone while the other 14 received concurrent chemo-radiotherapy. Treatment response was classified as complete (CR) or partial (PR) based on the findings of MRI and 201T1 SPET. Intense 201T1 uptake by the tumour was seen in all 18 patients before treatment. After treatment, MRI showed seven CRs and 11 PRs, whereas 201T1 SPET showed 13 CRs and five PRs. In 12 patients, the results of 201T1 SPET were in agreement with those of MRI. In six patients MRI showed PR but 201T1 showed CR. Follow-up (mean 10.6 months) MRI and 201T1 SPET studies of these six patients revealed that tumour gradually decreased and finally vanished in three patients. This preliminary study indicates that 201T1 SPET has potential in the assessment of early response to treatment of patients with NPC when compared with MRI.

Quantitative evaluation in tumor SPECT and the effect of tumor size: fundamental study with phantom.

An experimental study with phantoms was performed in order to evaluate the effect of the tumor volume on the quantitative estimation in tumor SPECT. The ratio of mean count/pixel in the phantom to that of the background (T/N ratio) was well correlated with the size of the phantom: even when the concentration of the Tc-99m O-4 solution of globular phantoms with diameters of 29, 37 and 46 mm was constant, the greater the size of the phantom, the higher was the T/N ratio. This study showed that we should understand that the T/N ratio was certainly affected by the reduction of the tumor size itself whenever we evaluate treatment-response or assess tumor viability after treatment by reference to the T/N ratio.

[Quantitative measurement of cerebral blood flow by the microsphere model with super-early 123I-IMP brain SPECT].

Cerebral blood flow (CBF) was quantitatively measured in 6 healthy young volunteers based on "super-early" acquisition of N-isopropyl-p-[123I]iodoamphetamine (IMP) brain SPECT obtained 4-6 min after IMP injection with a three-head rotating gamma camera and the microsphere (MS) model. The ratio of radioactivity (count/pixel/min) in the conventional early SPECT image (taken 25-55 min after IMP injection) to that in the "super-early" image for each brain region negatively correlated with regional CBF value obtained with the "super-early" MS method. This indicates that wash-out of IMP from the regions with higher CBF is faster than that from the regions with lower CBF and that CBF values are underestimated with the conventional MS method in regions with higher CBF. Regional CBF was quantitatively measured with the "super-early" MS method and the ARG method, a recently developed method based on two-compartment model. The mean cortical CBF was 52.5 +/- 7.0 (ml/100 g/min, mean +/- SD) with the "super-early" MS method and 47.5 +/- 3.3 with the ARG method. The CBF values obtained with the "super-early" MS method agreed with those previously reported with positron emission tomography. Since the MS method is theoretically the simplest model, the "super-early" MS method can be applied various disorders of the central nervous system where the behavior of IMP is not fully understood.

A new approach to the safety assessment of pharmaceutical excipients. The Safety Committee of the International Pharmaceutical Excipients Council.

This article presents a set of proposed guidelines for the safety assessment of new pharmaceutical excipients. These guidelines were developed by the Safety Committee of the International Pharmaceutical Excipients Council and represent a new, scientifically based approach to establishing conditions for the safe use of proposed pharmaceutical excipients utilizing various routes of human exposure. They are based upon the best currently available toxicological science and have taken the deliberations of the International Conference on Harmonization into consideration. These guidelines were developed because there are no regulatory agency guidelines currently available which specifically address the toxicological testing of a material intended for use as an excipient in pharmaceutical preparations. Only materials which have been previously permitted for use in a pharmaceutical preparation or which have been permitted for use in foods may be considered safe under current practices. If implemented, these guidelines should expedite the review of a proposed new excipient by regulatory agencies.

Thyroid function and thyroid tumors in toxaphene-treated rats.

Historically, a direct and irreversible genotoxic reaction of a xenobiotic with DNA has been considered to be a universal and obligatory initiating event in the etiology of neoplasia, and it was assumed therefore that (1) there was no threshold other than zero exposure for cancer initiation, and (2) like radiation, exposure was additive over a lifetime. Human exposure to xenobiotics causing neoplasia in laboratory rodents has been regulated in many countries on that basis. In the last decade evidence has accumulated indicating that some neoplasia in laboratory rodents may not be caused by a direct and irreversible interaction of xenobiotics with DNA. In addition, it has been found that some neoplasia caused in laboratory rodents by xenobiotics may not be relevant for biochemical/physiological reasons. This has raised the question whether human exposure to these xenobiotics should be regulated by the no-threshold philosophy used for direct-acting genotoxic xenobiotics or whether they can be regulated by the threshold philosophy used for classical xenobiotic-induced toxic effects. In a bioassay carried out by the National Cancer Institute and published in 1979, toxaphene was found to cause an increase in the occurrence of two spontaneously occurring tumors in laboratory rodents that since have been found to have both genotoxic and nongenotoxic etiologies in laboratory rodents. Experiments described in this paper are part of a program to help elucidate whether the increased incidence of these two neoplasms in laboratory rodents could have had a nongenotoxic origin, and thus whether toxaphene could be regulated by a threshold approach. Forty male rats were orally intubated with 100 mg/kg/day technical grade toxaphene in corn oil for 3 days. The dose was reduced to 75 mg/ kg/day on Day 4 due to toxicity. This lower dose was administered daily for 25 days. Another group of 40 male rats was orally gavaged daily with equivalent volumes of corn oil. After 0, 7, 14, and 28 doses, 10 test and 10 vehicle control animals were sacrificed for gross and histopathological examination of thyroid, parathyroid, and pituitary glands. Weights of these endocrine organs, body weights, and brain weights were determined. Prior to sacrifice, a blood sample was obtained from each animal for preparation of serum for analyses of thyroid stimulating hormone (TSH), thyroxine (T4), thyroid hormone (T3), and reverse T3 (rT3). Thyroid glands were evaluated microscopically for follicular cell hypertrophy, hyperplasia, and colloid storage. There were significant time-related increases in serum TSH in the test animals after 7, 14, and 28 doses of toxaphene. The serum levels of T3, T4, rT3, and corrected T3 (CrT3) in the test group were not significantly different from controls at each interval. Thyroid gland weights and thyroid to brain weight ratios were not significantly (p > 0.05) increased in the test group at each sacrifice interval. Pituitary weight, brain weight, and the ratios of these organ weights to body weights were similar in the test and control groups at each sacrifice interval. Thyroid follicular cell hypertrophy and intrafollicular hyperplasia increased and thyroid follicular cell colloid stores decreased with duration of treatment with toxaphene. The hormonal and histopathologic changes seen in the test group were consistent with increased excretion of T3 and/or T4 resulting from cytochrome P450 enzyme induction in the liver. This mechanism for thyroid neoplasia is not known to occur in humans.

The effect of steroid on thallium-201 uptake by malignant gliomas.

In order to assess the effect of steroid on thallium-201 uptake by glioma, 201Tl single-photon emission tomography was performed before and after steroid administration in four patients with recurrent malignant glioma. After steroid administration the 201Tl index, expressed as the ratio of 201Tl uptake in the tumour to that in the contralateral cerebral hemisphere, was 0.77+/-0.11 of the value before steroid (mean+/-SD: P<0.05 by paired t test). The 201Tl index has been used as a possible indicator for the differentiation of malignant gliomas from relatively benign tumours or radiation necrosis. The present results indicate that the effect of steroid has to be taken into account when semi-quantitative analysis, e.g. by means of the 201Tl index, is used in patients with brain tumours.

The activity and expression of thymidine phosphorylase in human solid tumours.

Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has angiogenic activity. Since dThdPase seems to have an important role in angiogenesis of tumours, we measured the activity and expression of dThdPase in various tumours and the adjacent non-neoplastic tissues. We assayed dThdPase activity by spectrophotometric means, and the expression of dThdPase was examined by immunoblotting and by immunohistochemical staining using a monoclonal antibody against dThdPase. In the oesophagus, stomach, colorectum, pancreas, and lung, dThdPase activity in carcinomas was significantly higher (P < 0.05) than that in the adjacent non-neoplastic tissues. The expression level of dThdPase detected by immunoblotting correlated well with the activity of dThdPase. In the oesophagus, stomach, colorectum, gall bladder, pancreas and lung, the proportion of dThdPase-positive tumours was significantly higher (P < 0.05 or 0.01) than that of the dThdPase-positive adjacent normal tissues. In oesophageal, gastric colorectal and lung carcinomas, the proportion of dThdPase positivity in advanced carcinomas was significantly higher (P < 0.01) than that in early carcinomas. Tumour-infiltrative macrophages or lymphocytes in the lymph node, alveolar macrophages and Kupffer cells expressed high levels of dThdPase. The results indicate that dThdPase activity and expression level in many tumours are higher than those in the adjacent non-neoplastic tissues, and that dThdPase may have an important role in the proliferation of these solid tumours.

Protein tyrosine kinase inhibitors promote amylase secretion and inhibit ornithine decarboxylase induction in sialagogue-stimulated rat parotid explants.

Three sialagogues, isoproterenol (IPR), carbachol, and methoxamine, caused induction of ornithine decarboxylase (ODC) in cultured rat parotid explants. All the protein tyrosine kinase inhibitors tested suppressed this ODC induction but enhanced sialagogue-dependent amylase secretion. Sodium orthovanadate showed the reverse effects as the kinase inhibitors. Immunoblot analysis with anti-phosphotyrosine antibody revealed that herbimycin A depresses IPR-stimulated tyrosine phosphorylation of parotid proteins. Herbimycin A did not affect the IPR- or dibutyryl cAMP-induced surge of the parotid cAMP level but inhibited these agonist-dependent ODC inductions. These results suggest that sialagogue-induced ODC induction and amylase secretion are mediated by different signal transduction pathways and that protein tyrosine kinase participates in IPR-dependent ODC induction and amylase secretion in the process subsequent to the cAMP surge.