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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; Aadmin (MBq) = 223·body weight (kg)0.65/Tscan (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.

Summary. 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.

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 behaviour 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. © 1998 Elsevier Science Ltd. All rights reserved.

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.

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. (C) 1998 Elsevier Science Inc.

The role of glucocorticoids in neuronal viability is controversial. Most studies which describe the effects of glucocorticoids on ischemic brain damage use surgical adrenalectomy to induce a reduction in plasma corticosterone levels. In the present study we used metyrapone, a corticosterone synthesis inhibitor, to examine the effects of acute manipulation of corticosterone levels on neuronal damage and seizures. Shortly before transient hypoxia/ischemia, animals were subcutaneously injected with sesame oil, metyrapone, corticosterone or corticosterone + metyrapone. Both the neuronal damage and the percentage animals with seizures were found to correlate well with plasma corticosterone levels. This relation between affected area, seizures and corticosterone levels was confirmed when the rats were re-arranged into animals with and without seizures. However, Corticosterone administration in metyrapone treated rats did not result (compared to MET treatment) in an increased neuronal damage. This suggests that the beneficial effects of metyrapone may be regulated by a corticosterone independent mechanism.

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.

Ebselen, a synthetic selenium-containing compound which exhibits glutathione peroxidase-like activity in vivo, is known for its beneficial effects on inflammation and tissue injury. Experiments were conducted to test whether ebselen dissolved in DiMethylSulfOxide (DMSO) could prevent damage in a rat model for transient unilateral hypoxia/ischemia.Results indicate that ebselen dissolved in DMSO reduced damage in the caudate putamen, the thalamus and the cortex compared to the saline controls. The average damage in the Caudate putamen was also significantly lower in the ebselen group when compared to the DMSO treated rats. Total brain damage in the ebselen group was decreased by 76%. DMSO alone did not reduce damage significantly in any of the analyzed areas. Some protective effects of ebselen, however, may be due to the solvent DMSO. In the caudate putamen ebselen alone was responsible for the observed protection. This protective effect of ebselen might be explained by its actions as a glutathione peroxidase mimic.

The deduced structure of the rat melanin-concentrating hormone (MCH) precursor predicted the existence of at least two peptides that may be processed from it, one similar to teleost MCH and a second novel neuropeptide, NEI. Cellular localization studies confirmed that prepro-MCH (ppMCH) mRNA and the MCH and NEI peptides are expressed predominantly in cells in the zona incerta and caudal lateral hypothalamic area with minor contingents seen in the olfactory tubercle and pons. A moderate MCH-and NEI-immunoreactive axonal projection to the median eminence and, particularly, to oxytocin-rich regions of the posterior pituitary suggested some anatomical heterogeneity of ppMCH-expressing neurons in the hypothalamus, and an involvement in neuroendocrine function. In the present study, immunohistochemical and hybridization histochemical methods were used to follow MCH gene and peptide expression as a function of reproductive status in female rats. Nursing dams sacrificed after 8 to 21 days of lactation consistently displayed ppMCH mRNA and MCH and NEI immunoreactivity in a discrete and contiguous band, encompassing the ventral aspect of the medial part of the medial preoptic nucleus, the periventricular preoptic nucleus, and the most rostral aspects of the paraventricular nucleus of the hypothalamus (PVH). Combined immunohistochemical (for oxytocin) and hybridization histochemical (for ppMCH mRNA) staining failed to reveal a significant degree of congruence in the two chemically-specified cell populations in the PVH of lactating dams. The apparent induction of ppMCH-derived peptides and mRNA in the preoptic area and PVH was not apparent in animals sacrificed 4 to 8 days after weaning, during late pregnancy, or at any point in the estrous cycle. Moreover, no frank alterations in ppMCH mRNA were evident in the principal sites at which ppMCH is expressed at constitutively high levels, i.e. in the lateral hypothalamic area and zona incerta, as a function of reproductive status. The loci and apparent state-dependency of the induction of ppMCH mRNA and peptide expression suggests a role for these gene products in the control of lactation.

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 Co-57(2+) 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 Co-57(2+) 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 Co-57(2+) SPET is suitable for determining the extent of (possibly calcium-mediated) damage in stroke and in the assessment of potential therapeutic interventions. ((C) 1998 Lippincoft-Raven Publishers).

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±0.09×10 −3 mm 2 /s), cortex (from 0.56±0.06 to 0.77±0.07×10 −3 mm 2 /s), and caudate putamen (from 0.58±0.06 to 0.75±0.06×10 −3 mm 2 /s) but only partially or not at all in the thalamus (from 0.65±0.07 to 0.68±0.12×10 −3 mm 2 /s) and substantia nigra (from 0.80±0.08 to 0.76±0.10×10 −3 mm 2 /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.

Transient cerebral hypoxia/ischemia triggers a differential sequence of damage development, which can be distinguished on the basis of the duration of both the period of oxygen shortage and the post-ischemic reperfusion period (figure 1). Development of neuronal damage can be divided into three main patterns; Acute(infarction), early and delayed neuronal damage. Long ischemic periods cause acute (after 3 hours) neuronal and astroglial cell death (1,2), possibly as a consequence of high intracellular acidosis by ionic pump failure. Early damage occurs after 3 hours and is characterized by selective neuronal degeneration most likely a consequence of progressing depolarization events due to a decreased activity of the enzyme Na+/K+ ATP-ase (3,4). Delayed damage becomes apparent between 24 and 72 hours and is also selective neuronal (5,6).

In our experimental hypoxia/ischemia (Levine) model several potential protective pretreatments (1—3) were tested on their ability to reduce damage and L-deprenyl (selegiline) proved to be a very effective neuroprotective agent as it is in reducing brain damage when it is applied for 14 days prior to hypoxia/ischemia (4,5). The mechanism through which L-deprenyl diminishes damage is unclear. However, a few obvious possibilities for the protective effects of L-deprenyl should be taken into consideration. First of all the regional differences in damage protection by L-deprenyl (4) is in agreement with MAO-B independent effects of L-deprenyl on free radical scavenger enzymes i.e. catalase and SOD (6,7). The ability of these scavenger enzymes to protect against ischemia induced damage has been described by numerous studies. Especially intrinsically increased expression of the scavenger enzymes had beneficial effects on damage outcome. For instance an increased SOD-expression in transgenic mice offered protection against radicals generated through ischemia (8,9) and/or MPTP (10).

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: F 1.13 =6.956, P 1.13 =5.731, P l -deprenyl groups (2 mg/kg and 10 mg/kg, respectively) and the saline group (F 1.13 =14.870, P 1.13 =8.937, P =.01; respectively). In the thalamus, significant treatment effects were seen in the 2-mg/kg l -deprenyl group (F 1.13 =11.638, P 1.13 =8.347, P 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.

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.

During an active human cytomegalovirus (HCMV) infection, leukocytes harbouring the HCMV lower matrix protein pp65 (ppUL83) are present in the peripheral blood and can be detected with the HCMV antigenaemia assay. In the present study, it was investigated whether the presence of pp65 in these cells was due to transcription of the virus genome or might be the result of uptake of this viral protein. Peripheral blood leukocytes of transplant recipients and AIDS patients with an active HCMV infection were investigated for the presence of HCMV immediate early (IE) antigen and pp65 using well characterized monoclonal antibodies, and for the presence of the corresponding mRNAs using non-radioactive in situ hybridization. Both mononuclear and polymorphonuclear cells were found to contain IE antigen and pp65. However, only mRNAs encoding IE antigen were found in these cells, whereas mRNAs encoding pp65 were not detected. In contrast, both IE antigen and pp65, as well as their corresponding mRNAs, were detected in the circulating late-stage HCMV-infected endothelial cells that were also present in the leukocyte fractions. These findings demonstrate that a restricted viral gene expression (transcription of IE genes) does occur in mononuclear and poly-morphonuclear leukocytes. However, the abundant presence of the early antigen pp65 without detectable presence of the corresponding mRNA in these cells strongly indicates uptake of this protein by the phagocytic leukocytes, rather than de novo synthesis.