Value of SiPM PET in myocardial perfusion imaging using Rubidium-82.

BACKGROUND: PET scanners using silicon photomultipliers with digital readout (SiPM PET) have an improved temporal and spatial resolution compared to PET scanners using conventional photomultiplier tubes (PMT PET). However, the effect on image quality and visibility of perfusion defects in myocardial perfusion imaging (MPI) is unknown. Our aim was to determine the value of a SiPM PET scanner in MPI. METHODS: We prospectively included 30 patients who underwent rest and regadenoson-induced stress Rubidium-82 (Rb-82) MPI on the D690 PMT PET (GE Healthcare) and within three weeks on the Vereos SiPM PET (Philips Healthcare). Two expert readers scored the image quality and assessed the existence of possible defects. In addition, interpreter's confidence, myocardial blood flow (MBF), and myocardial flow reserve (MFR) values were compared. RESULTS: Image quality improved (P = 0.03) using the Vereos as compared to the D690. Image quality of the Vereos and the D690 was graded fair in 20% and 10%, good in 60% and 50%, and excellent in 20% and 40%, respectively. Defect interpretation and interpreter's confidence did not differ between the D690 and the Vereos (P > 0.50). There were no significant differences in rest MBF (P ≥ 0.29), stress MBF (P ≥ 0.11), and MFR (P ≥ 0.51). CONCLUSION: SiPM PET provides an improved image quality in comparison with PMT PET. Defect interpretation, interpreter's confidence, and absolute blood flow measurements were comparable between both systems. SiPM PET is therefore a reliable technique for MPI using Rb-82. TRIAL REGISTRATION: ToetsingOnline NL63853.075.17. Registered 13 November, 2017.

Minimal rest activity for SPECT myocardial perfusion imaging in a one-day stress-first protocol.

PURPOSE: Guidelines propose different rest-stress activity ratios (RSAR) for one-day stress-first SPECT myocardial perfusion imaging (MPI), but evidence is limited. Our aim was to determine and validate the minimal RSAR resulting in the same diagnostic outcome in one-day stress-first SPECT MPI. METHODS: Forty-seven patients referred for rest after stress CZT-SPECT/CT MPI were prospectively included. Rest acquisitions were performed 3 h after stress. In addition to the stress and rest acquisitions, the first 22 patients underwent an additional acquisition prior to the rest injection to determine the remaining stress activity. Next, we simulated six RSARs varying from 1.0 to 3.5 in both patients and a phantom and compared the images to those using the reference RSAR of 4.0. Differences in summed difference score (SDS) >2 or ischemic defect interpretation were considered to significantly influence diagnostic outcome. After deriving the minimal RSAR, it was validated in 25 additional patients by comparing it to a RSAR of 4.0. RESULTS: After 3 h only 26% of the stress activity was still present in the myocardium. SDS differences >2 were found in one (4%) patient using RSAR of 3.5, 2.5 and 2.0, in three (12%) using 1.5 and in five (20%) using SRAR of 1.0. These results were consistent with the phantom study showing SDS differences >2 for RSARs ≤1.5 and with the visual interpretation which showed an increased number of deviating scans for RSAR 1.0. Validating the RSAR of 2.0 resulted in a different SDS in one patient (SDS of 30 versus 11). Moreover, two scans were interpreted as ischemic instead of normal when using RSAR 2.0 and in two other scans the opposite was the case. CONCLUSIONS: A RSAR of 2.0 in one-day stress-first MPI SPECT seems sufficient to obtain accurate diagnostic outcomes and is therefore recommended to reduce radiation exposure.

Value of attenuation correction in stress-only myocardial perfusion imaging using CZT-SPECT.

BACKGROUND: Attenuation correction (AC) improves the diagnostic outcome of stress-only myocardial perfusion imaging (MPI) using conventional SPECT. Our aim was to determine the value of AC using a cadmium zinc telluride-based (CZT)-SPECT camera. METHODS AND RESULTS: We retrospectively included 107 consecutive patients who underwent stress-optional rest MPI CZT-SPECT/CT. Next, we created three types of images for each patient; (1) only displaying reconstructed data without the CT-based AC (NC), (2) only displaying AC, and (3) with both NC and AC (NC + AC). Next, two experienced physicians visually interpreted these 321 randomized images as normal, equivocal, or abnormal. Image outcome was compared with all hard events over a mean follow-up time of 47.7 ± 9.8 months. The percentage of images interpreted as normal increased from 45% using the NC images to 72% using AC and to 67% using NC + AC images (P < .001). Hard event hazard ratios for images interpreted as normal were not different between using NC and AC (1.01, P = .99), or NC and NC + AC images (0.97, P = .97). CONCLUSIONS: AC lowers the need for additional rest imaging in stress-first MPI using CZT-SPECT, while long-term patient outcome remained identical. Use of AC reduces the need for additional rest imaging, decreasing the mean effective dose by up to 1.2 mSv.

Visual estimation of coronary calcium on computed tomography for attenuation correction.

BACKGROUND: The coronary calcium score (CCS) provides independent diagnostic and prognostic information on top of myocardial perfusion imaging (MPI) in patients suspected for coronary artery disease, but requires an additional computed tomography (CT) scan. OBJECTIVE: We investigated the accuracy and inter-reader reproducibility of visual estimation of the CCS on the CT used for attenuation correction. METHODS: 250 patients undergoing single photon emission computed tomography MPI and Agatston CCS were included. The CCS was also visually estimated on the CT for attenuation correction by two separate readers blinded to the Agatston CCS, and was categorized into a six-point scale (0, 1-10, 11-100, 101-400, 401-1000 and > 1000). RESULTS: The median Agatston CCS was 82 [25th-75th percentile: 0-562], with a range from 0 to 7287. Of the visually estimated CCS, 60% (reader 1) and 65% (reader 2) were classified correctly into the 6 categories. 93% (reader 1) and 88% (reader 2) of the visually estimated CCS did not vary by more than one category from the Agatston CCS. The intraclass correlation coefficient for agreement between the Agatston CCS and the visually estimated CCS was 0.95 for reader 1 and 0.94 for reader 2. The intraclass correlation coefficient for inter-reader reproducibility of the visually estimated CCS was 0.96. CONCLUSION: The CCS can be accurately estimated on the CT for attenuation correction, as high agreement is demonstrated with the Agatston CCS and inter-reader reproducibility is excellent. If no traditional Agatston CCS is performed, the degree of atherosclerosis should be assessed by means of estimating CCS on the CT for attenuation correction.

A practical approach for a patient-tailored dose protocol in coronary CT angiography using prospective ECG triggering.

To derive and validate a practical patient-specific dose protocol to obtain an image quality, expressed by the image noise, independent of patients' size and a better radiation dose justification in coronary CT angiography (CCTA) using prospective ECG triggering. 43 patients underwent clinically indicated CCTA. The image noise, defined as the standard deviation of pixel attenuation values in a homogeneous region in the liver, was determined in all scans. Subsequently, this noise was normalized to the radiation exposure. Next, three patient-specific parameters, body weight, body mass index and mass per length (MPL), were tested for the best correlation with normalized image noise. From these data, a new dose protocol to provide a less variable image noise was derived and subsequently validated in 84 new patients. The normalized image noise increased for heavier patients for all patients' specific parameters (p < 0.001). MPL correlated best with the normalized image noise and was selected for dose protocol optimization. This new protocol resulted in image noise levels independent of patients' MPL (p = 0.28). A practical method to obtain CCTA images with noise levels independent of patients' MPL was derived and validated. It results in a less variable image quality and better radiation exposure justification and can also be used for CT scanners from other vendors.

Development and validation of a patient-tailored dose regime in myocardial perfusion imaging using conventional SPECT.

BACKGROUND: The decreasing image quality in heavier patients can be compensated by administration of a patient-specific dose in myocardial perfusion imaging (MPI) using a cadmium zinc telluride-based SPECT camera. Our aim was to determine if the same can be achieved when using a conventional SPECT camera. METHODS: 148 patients underwent SPECT stress MPI using a fixed Tc-99m tetrofosmin tracer dose. Measured photon counts were normalized to administered tracer dose and scan time and were correlated with body weight, body mass index, and mass per length to find the best predicting parameter. From these data, a protocol to provide constant image quality was derived, and subsequently validated in 125 new patients. RESULTS: Body weight was found to be the best predicting parameter for image quality and was used to derive a new dose formula; A admin (MBq) = 223·body weight (kg)(0.65)/T scan (min). The measured photon counts decreased in heavier patients when using a fixed dose (P < .01) but this was no longer observed after applying a body-weight-dependent protocol (P = .20). CONCLUSIONS: Application of a patient-specific protocol resulted in an image quality less depending on patient's weight. The results are most likely independent of the type of SPECT camera used, and, hence, adoption of patient-specific dose and scan time protocols is recommended.

El regadenosón como nuevo agente de estrés para la adquisición de imágenes SPECT de perfusión miocárdica. Experiencia inicial en Holanda / Regadenoson as a new stress agent in myocardial perfusion imaging. Initial experience in The Netherlands

Objetivo. El regadenosón es un agonista selectivo para los receptores adenosínicos-2A recién aprobado para inducir estrés farmacológico con una sola inyección en bolo para la adquisición de imágenes SPECT de perfusión miocárdica (IPM). Material y Métodos. Se incluyeron 123 pacientes sucesivos referidos para IPM por sospecha de enfermedad arterial coronaria (EAC). A 66 pacientes se les hizo una prueba de estrés con regadenosón y a 57 con adenosina, ambas seguidas por SPECT de manera estándar. A los técnicos, médicos y los pacientes mismos se les pidió que reportaran sus experiencias mediante cuestionarios. Resultados. En comparación con la adenosina, el regadenosón no produjo ningún bloqueo auriculoventricular (frente al 10% tras adenosina), pero produjo una taquicardia menor y cambios de la presión arterial pequeños. Todos los síntomas tras el regadenosón fueron más leves y de duración más corta. Hubo menos pacientes que tenían síntomas graves tras el regadenosón (17% vs. 32%, p < 0,01). El efecto secundario reportado más frecuentemente fue la disnea, seguido por rubefacción y angina, pero todos estos efectos se resolvieron rápidamente. La puntuación global de los síntomas, que incluye tanto la severidad como la duración, fue significativamente más baja después del regadenosón que después de la adenosina (6,7 ± 6,3 vs. 10,0 ± 7,9, respectivamente, p < 0,01). Las imágenes SPECT fueron similares. El procedimiento con el regadenosón fue más rápido y práctico. Conclusión. El regadenosón es un nuevo agente de estrés conveniente para IPM con un perfil muy favorable para los pacientes y los departamentos de cardiología nuclear (AU)

Objective. Regadenoson is a recently approved selective adenosine-2A receptor agonist to induce pharmacological stress in myocardial perfusion imaging (MPI) procedures using a single bolus injection. Material and Methods. We included 123 patients referred for MPI because of suspected coronary arterial disease (CAD). Of these, 66 patients underwent a regadenoson stress test and 57 patients underwent an adenosine stress test preceding standard myocardial SPECT imaging. Technicians, physicians and patients were asked to report their experience using questionnaires. Results. As compared to adenosine, regadenoson did not produce any atrio-ventricular block (0 vs. 10% with adenosine), but did produce minor tachycardia and minimal blood pressure changes while all other side effects were milder and shorter. There were fewer patients with severe complaints after taking regadenoson than adenosine (17% vs. 32%, respectively, p < 0.01). The most frequent complaint reported was dyspnea, followed by flushing and chest pain. However, when they did occur, they usually disappeared rapidly. The overall symptom score, including severity and duration of side effects, was significantly lower after regadenoson than after adenosine (6.7 ± 6.3 vs. 10.0 ± 7.9, respectively; p < 0.01.) SPECT imaging results were similar. The regadenoson procedure was faster and more practical. Conclusion. Regadenoson, the new selective adenosine-2A receptor agonist, is a stress agent for MPI with a patient- and department friendly profile (AU)

[Regadenoson as a new stress agent in myocardial perfusion imaging. Initial experience in The Netherlands]. / El regadenosón como nuevo agente de estrés para la adquisición de imágenes SPECT de perfusión miocárdica. Experiencia inicial en Holanda.

OBJECTIVE: Regadenoson is a recently approved selective adenosine-2A receptor agonist to induce pharmacological stress in myocardial perfusion imaging (MPI) procedures using a single bolus injection. MATERIAL AND METHODS: We included 123 patients referred for MPI because of suspected coronary arterial disease (CAD). Of these, 66 patients underwent a regadenoson stress test and 57 patients underwent an adenosine stress test preceding standard myocardial SPECT imaging. Technicians, physicians and patients were asked to report their experience using questionnaires. RESULTS: As compared to adenosine, regadenoson did not produce any atrio-ventricular block (0 vs. 10% with adenosine), but did produce minor tachycardia and minimal blood pressure changes while all other side effects were milder and shorter. There were fewer patients with severe complaints after taking regadenoson than adenosine (17% vs. 32%, respectively, p<0.01). The most frequent complaint reported was dyspnea, followed by flushing and chest pain. However, when they did occur, they usually disappeared rapidly. The overall symptom score, including severity and duration of side effects, was significantly lower after regadenoson than after adenosine (6.7±6.3 vs. 10.0±7.9, respectively; p<0.01.) SPECT imaging results were similar. The regadenoson procedure was faster and more practical. CONCLUSION: Regadenoson, the new selective adenosine-2A receptor agonist, is a stress agent for MPI with a patient- and department friendly profile.

Death and venous thromboembolism after lower extremity amputation.

BACKGROUND: Lower extremity amputation is often performed in patients with end-stage vascular disease and is considered a high-risk procedure. Uncertainty exists about the rate of venous thromboembolism (VTE) in these patients. OBJECTIVES: To establish the incidence of death and venous thromboembolism after lower extremity amputation. METHODS: A prospective cohort study was performed to establish the incidences of death and VTE after lower extremity amputation, as detected by bilateral complete compression ultrasonography and ventilation-perfusion scintigraphy performed preoperatively and around day 14 postoperatively. Standard low-molecular-weight heparin thromboprophylaxis was given during the study period. A secondary outcome was the incidences of mortality and symptomatic venous thromboembolic complications during 8 weeks of postoperative follow-up. RESULTS: Forty-nine patients (53 amputations) were ultimately included in the intention-to-treat analysis. Five patients died within the 2-week period and an additional seven patients died during the 8 weeks clinical follow-up period. The total mortality rate therefore was 12 of 53 amputations [22.6%; 95% confidence interval (CI), 12.3-36.2%]. Six patients developed pulmonary embolisms (of which two were fatal) and one patient developed an asymptomatic contralateral distal deep venous thrombosis, resulting in a total VTE rate of 7 out of 53 amputations (13.2%; 95% CI, 5.47-25.3%). CONCLUSION: Lower extremity amputation is accompanied by a high mortality rate from sepsis, and respiratory and vascular causes. This study shows that VTE substantially contributes to the morbidity and mortality after lower extremity amputation despite adequate pharmacological thromboprophylaxis in this vulnerable population of patients.

Differential effects of CRH infusion into the central nucleus of the amygdala in the Roman high-avoidance and low-avoidance rats.

Roman-high (RHA/Verh) and low (RLA/Verh) avoidance rats are selected and bred for rapid learning versus non-acquisition of two-way, active avoidance behavior in a shuttle box. RHA/Verh rats generally show a more active coping style than do their RLA/Verh counterparts when exposed to various environmental challenges. The central nucleus of the amygdala (CeA) is known to be involved in the regulation of autonomic, neuroendocrine and behavioural responses to stress and stress-free conditions, and it is considered in relation to coping strategies. Corticotropin-releasing hormone (CRH) seems to be a key factor in the control of the CeA output. Neuroanatomical studies have revealed that the majority of CRH fibers from the CeA have direct connections with autonomic regulatory nuclei in the brainstem, e.g. lateral parabrachial nucleus (lPB), ventrolateral periaquaductal gray (vlPAG). The modulating effects of CRH (30 ng) on CeA activity were studied by infusion of CRH into the CeA in freely moving male RHA/Verh and RLA/Verh rats under stress-free conditions. Heart-rate and behavioural activities were repeatedly measured before, during and after local administration of CRH or vehicle, after which early gene product FOS immunocytochemistry and CRH-mRNA in situ hybridisation were carried out in selected brain areas. CRH infusion into the CeA caused a long lasting increase in heart-rate and behavioural activation in the RHA/Verh rats, leaving the RLA/Verh rats unaffected. As a result of CRH infusion, the number of FOS positive cells in the CeA and lPB of RLA/Verh rats was increased whereas an opposite response was found in the RHA/Verh rats. However, CRH into the CeA of the Roman rat lines induced no pronounced effects on FOS staining in the vlPAG and CRH mRNA levels in the CeA. These results indicate that the CRH system of the CeA, connected with the output brainstem areas, is differentially involved in cardiovascular and behavioural responses.

Long-term food restriction, deprenyl, and nimodipine treatment on life expectancy and blood pressure of stroke-prone rats.

We determined whether food restriction or the drugs nimodipine (Ca2+ antagonist) and deprenyl (a MAO-B inhibitor) prevent the development of stroke in the spontaneously hypertensive stroke-prone rat (SHR-SP). Forty male SHR-SP rats, in the age of 34 weeks, were exposed to various treatments. During a period of 27 weeks, survival and blood pressure were followed. In the control and deprenyl group, the blood pressure values remained unchanged; 50% had died after 27 weeks. All rats that were treated with nimodipine survived. After food restriction, 7/8 rats survived and showed a lower blood pressure. This study in SHR-PR rats shows the superiority of nimodipine on survival, and the potential of food restriction as a stroke-preventing measure.

Metyrapone reduces rat brain damage and seizures after hypoxia-ischemia: an effect independent of modulation of plasma corticosterone levels?

Hypoxia-ischemia is accompanied by abundant corticosterone secretion that could exacerbate brain damage after the insult. The authors demonstrate that the steroid synthesis inhibitor metyrapone (150 mg/kg subcutaneously) suppresses the hypoxia-ischemia-induced rise of plasma corticosterone levels (17.3 +/- 3.6 micrograms/dL) when compared with corticosterone-treated animals (72.2 +/- 4.8 micrograms/dL) immediately after hypoxia-ischemia. In parallel, metyrapone reduced brain damage (P < 0.05). Moreover, none of the metyrapone-treated animals displayed seizures, whereas seven of eight corticosterone-treated animals had seizures after hypoxia-ischemia. Although corticosterone administration in metyrapone-treated animals elevated plasma corticosterone levels (39.0 +/- 5.3 micrograms/dL), this did not result in a subsequent increase in brain damage and seizures when compared with metyrapone-treated animals. The authors conclude that metyrapone reduces brain damage and the incidence of seizures after hypoxia-ischemia but that this effect might partially be independent from its effect on modulating plasma corticosterone levels.

Dynamics of cerebral tissue injury and perfusion after temporary hypoxia-ischemia in the rat: evidence for region-specific sensitivity and delayed damage.

BACKGROUND AND PURPOSE: Selective regional sensitivity and delayed damage in cerebral ischemia provide opportunities for directed and late therapy for stroke. Our aim was to characterize the spatial and temporal profile of ischemia-induced changes in cerebral perfusion and tissue status, with the use of noninvasive MRI techniques, to gain more insight in region-specific vulnerability and delayed damage. METHODS: Rats underwent 20 minutes of unilateral cerebral hypoxia-ischemia (HI). We performed combined repetitive quantitative diffusion-weighted, T2-weighted, and dynamic susceptibility contrast-enhanced MRI from before HI to 5 hours after HI. Data were correlated with parallel blood oxygenation level-dependent MRI and laser-Doppler flowmetry. Finally, MRI and histology were done 24 and 72 hours after HI. RESULTS: Severe hypoperfusion during HI caused acute reductions of the apparent diffusion coefficient (ADC) of tissue water in the ipsilateral hemisphere. Reperfusion resulted in dynamic perfusion alterations that varied spatially. The ADC recovered completely within 1 hour in the hippocampus (from 0.68 +/- 0.07 to 0.83 +/- 0.09 x 10[-3] mm2/s), cortex (from 0.56 +/- 0.06 to 0.77 +/- 0.07 x 10[-3] mm2/s), and caudate putamen (from 0.58 +/- 0.06 to 0.75 +/- 0.06 x 10[-3] mm2/s) but only partially or not at all in the thalamus (from 0.65 +/- 0.07 to 0.68 +/- 0.12 x 10[-3] mm2/s) and substantia nigra (from 0.80 +/- 0.08 to 0.76 +/- 0.10 x 10[-3] mm2/s). Secondary ADC reductions, accompanied by significant T2 elevations and histological damage, were observed after 24 hours. Initial and secondary ADC decreases were observed invariably in the hippocampus, cortex, and caudate putamen and in approximately 70% of the animals in the thalamus and substantia nigra. CONCLUSIONS: Region-specific responses and delayed ischemic damage after transient HI were demonstrated by MRI. Acute reperfusion-induced normalization of ADCs appeared to poorly predict ultimate tissue recovery since secondary, irreversible damage developed eventually.

Cobalt-57 as a SPET tracer in the visualization of ischaemic brain damage in patients with middle cerebral artery stroke.

In PET studies we have shown the usefulness of cobalt radionuclides for the visualization and quantification of ischaemic damage in stroke. In the present study, we explored 57Co2+ as a SPET tracer. Uptake of radioactivity was estimated by using a cobalt enhancement ratio defined as the ratio of cobalt uptake in the affected region versus a similar volume in the non-affected contralateral side. Clinical status was assessed with the Orgogozo stroke score at the time of scanning and at least 60 days after admission. Nineteen patients (11 men, 8 women) with a middle cerebral artery stroke were examined with 57Co2+ SPET 0-30 days after stroke onset. Our investigations show enhanced cobalt uptake in the infarcted brain tissue in patients with a major stroke and little clinical improvement. There was a significant correlation between the cobalt enhancement ratio and the Orgogozo score at the time of scanning and discharge. Our results suggest that 57Co2+ SPET is suitable for determining the extent of (possibly calcium-mediated) damage in stroke and in the assessment of potential therapeutic interventions.

Corticotropin-releasing hormone modulation of a conditioned stress response in the central amygdala of Roman high (RHA/Verh)-avoidance and low (RLA/Verh)-avoidance rats.

Roman high (RHA/Verh)- and low (RLA/Verh)-avoidance rats are selected and bred for rapid versus nonacquisition of two-way, active avoidance behavior in the shuttle box. RHA/Verh rats generally show a more active coping style than do their RLA/Verh counterparts when exposed to various environmental challenges. The central nucleus of the amygdala (CeA) is known to be involved in the regulation of autonomic, neuroendocrine, and behavioral responses to stress. Its involvement in the selection of coping strategies has also been suggested. Corticotropin-releasing hormone (CRH) seems to be one of the key neurohormones in the control of CeA output. Neuroanatomical studies have revealed that the majority of CRH fibers from the CeA have direct connections with autonomic regulatory nuclei in the brain-stem, e.g. lateral parabrachial nucleus (lPB). The effects of CRH (30 ng) on modulating CeA activity were studied by infusion of CRH into the CeA during conditioned stress (inescapable foot-shocks) in RHA/Verh and RLA/Verh male rats. Heart-rate responses after CRH treatment were not changed in either line. However, distinctly different behavioral responses were seen after CRH infusion into the CeA of both rat lines. A decrease in immobility responses was seen in both RHA/Verh and RLA/Verh rats, while an increase in exploration was observed in RHA/Verh rats only in the conditioned stress situation. Rearing levels were increased in the RHA/Verh rats, whereas they were decreased in the RLA/Verh animals. As a result of CRH infusion, the number of FOS immunoreactive cells in the lPB of RLA/Verh rats was decreased, whereas an opposite response was found in RHA/Verh rats. These results indicate that the CRH system of the CeA connected with output brain-stem areas is differentially involved in the cardiovascular and behavioral responses of these rats having different coping styles.

Pharmacokinetics and dosimetry of cobalt-55 and cobalt-57.

UNLABELLED: The isotopes 55Co and 57Co have been evaluated for PET and SPECT imaging in several clinical brain studies. For clinical application of cobalt, it is important to know the delivered radiation dose. The biodistribution of 55Co in both rat and humans after intravenous (bolus)-administration was studied. Based on pharmacokinetic data, radiation dose calculations according to the MIRD system are presented. By combining present measurements with literature data on 60CoCl2, the radiation dose delivered by 56CoCl2 (T1/2 78.8 days) and 57CoCl2 (T1/2 = 270 days) could be assessed. METHODS: Whole-body Co-PET was performed in two healthy volunteers and one rat after intravenous injection of 37 and 3.7 MBq (1 resp. 0.1 mCi) 55Co, respectively. Blood samples were withdrawn during 300 min in humans. In seven rats the 55Co-biodistribution was determined by postmortem analysis. The residence time of the liver (critical organ) was determined in rats and humans. Blood partition-data of 55Co were assessed resulting in basic pharmacokinetic data in humans. Based on these kinetic data, radiation dose was calculated using the MIRD protocol. RESULTS: In both the humans and the rat, the liver and bladder retained the highest fractions of 55Co (about 50% resp. 40% of the administered dose). The liver residence time in humans was 8.6 hr. The free fraction 55Co in the human plasma was at maximum 12%. The total-body mean transit time was 152 min. The volume of the central compartment = 2.8 liter and the steady-state distribution volume = 48 liter. CONCLUSION: From these results, according to the WHO recommendations for class II studies, 22.2 MBq (0.6 mCi) 55Co and 14.8 MBq (0.4 mCi) 57Co (excluding any radionuclide contamination) can be used.

Immunolocalization of glutathione reductase in the murine brain.

Free radical species arise from the univalent reduction of oxygen. The cytosolic agent H2O2, produced during enzymatic scavenging of the superoxide radical (O2-) is in turn removed predominantly via the oxidation of reduced glutathione (GSH) to the oxidized form (GSSG) by glutathione peroxidase. Subsequently GSSG is recycled back to GSH by glutathione reductase (GSH-red). Little is known about the distribution of this enzyme in the brain. The aim of this study was to determine the distribution of this enzyme in the brain of different murine species by means of immunocytochemical techniques, although most attention was given to the distribution of GSH-red in the forebrain. In most brain areas GSH-red positive neurons were detected, but the regional intracellular staining intensity differed markedly. The pre-piriform and piriform cortices, the pyramidal cell layers of the hippocampus, and the dentate gyrus were heavily stained. The caudate nucleus displayed a progressive increase in the intracellular staining intensity from the rostral to the caudolateral parts. Furthermore, in the thalamus, there was a gradual decrease in GSH-red staining from the medial to the lateral parts. The mesencephalon was poor in immunopositive cells, and in the substantia nigra pars reticulata, almost no labeling was detected. However, the substantia nigra pars compacta showed an intense GSH-red immunoreactivity. The results show a specific localization of glutathione reductase in distinct brain regions, suggesting a variable potency of different brain areas in dealing with the damaging oxidative actions of free radicals. Also, differential GSH-red expression patterns were found in the various murine species. Some species showed a pronounced GSH-red immunoreactivity in glial cells, specifically in regions that lacked neuronal GSH-red immunoreactivity.

L-deprenyl reduces brain damage in rats exposed to transient hypoxia-ischemia.

BACKGROUND AND PURPOSE: L-Deprenyl (Selegiline) protects animal brains against toxic substances such as 1-methyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine. Experiments were conducted to test whether L-deprenyl prevents or reduces cerebral damage in a transient hypoxia/ischemia rat model. METHODS: Rats were treated for 14 days with 2 mg/kg and 10 mg/kg L-deprenyl or saline. After surgery a 20-minute hypoxia/ischemia period was induced by simultaneous occlusion of the left common carotid artery and reduction of the percentage of oxygen in the gas mixture to 10%. Rats were killed 24 hours later. Silver staining was used to reveal damage in several brain regions. RESULTS: In the brain, both L-deprenyl dosages reduced damage up to 78% compared with the controls. Total brain damage was decreased from 23%-31% to 5%-9% with the L-deprenyl treatment (2 mg/kg: F1.13 = 6.956, P < .05; 10 mg/kg: F1.13 = 5.731, P < .05). In the striatum, significant treatment effects were found between both the L-deprenyl groups (2 mg/kg and 10 mg/kg, respectively) and the saline group (F1.13 = 14.870, P < .005; and F1.13 = 8.937, P = .01; respectively). In the thalamus, significant treatment effects were seen in the 2-mg/kg L-deprenyl group (F1.13 = 11.638, P < .005) and the 10-mg/kg group (F1.13 = 8.347, P < .05) compared with the control group. No significant damage decrease was seen in the hippocampus and the cortex. CONCLUSIONS: The results show that L-deprenyl is effective as a prophylactic treatment for brain tissue when it is administered before hypoxia/ischemia. Mechanisms responsible for the observed protection remain unclear. The regional differences in damage, however, are in accordance with the reported regional increase in superoxide dismutase and catalase activities after L-deprenyl treatment, suggesting the involvement of free radicals and scavenger enzymes.

Down-regulation of the hypothalamo-pituitary-adrenal axis reduces brain damage and number of seizures following hypoxia/ischaemia in rats.

Several reports suggest that the activity of the hypothalamo-pituitary-adrenal axis (HPA-axis) is increased following hypoxia/ischaemia and that this might be associated with increased neuronal vulnerability. The main goal of this study was to examine the effects of down-regulation of the HPA-axis on the hypoxia/ischaemia-induced (1) rise of plasma corticosterone levels, (2) seizures, and (3) brain damage. Down-regulation of the HPA-axis was induced by prolonged corticosterone treatment lasting until 24 h before hypoxia/ischaemia exposure. When compared to 8 days vehicle (sesame oil)-treated animals (CONT), 8 days daily corticosterone (40 mg/animal)-treated animals (CORT) showed significantly reduced adrenal-and thymus weight. Shortly after hypoxia/ischaemia plasma corticosterone levels in CORT animals were significantly reduced (17.30 micrograms/dl +/- 3.50) when compared to CONT animals (54.80 micrograms/dl +/- 7.78). This correlated with the brain damage which is expressed as the ratio between the damaged area and the total area. The total brain damage was significantly less in CORT-treated animals (28% +/- 11%) than in CONT animals (69% +/- 2%). Following hypoxia/ischaemia the number of seizures was significantly reduced in CORT animals (56 +/- 26) when compared to CONT animals (217 +/- 50). We conclude that prolonged corticosterone treatment resulting in down-regulation of the HPA-axis leads to (1) lower plasma corticosterone levels during hypoxia/ischaemia, (2) a reduction in brain damage following hypoxia/ischaemia, and (3) less hypoxia/ischaemia-induced seizures.