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Unlabelled: Accurate anatomic localization of functional abnormalities seen with PET is known to be problematic. Even though nonspecific tracers such as 18F-FDG visualize certain normal anatomic structures, the spatial resolution is generally inadequate for localization of pathology. Combining PET with a high-resolution anatomic imaging modality such as CT can resolve the localization issue, as long as the images from the two modalities are accurately coregistered. However, software-based registration techniques have difficulty accounting for differences in patient positioning and involuntary movement of internal organs, often necessitating labor-intensive nonlinear mapping that may not converge to a satisfactory result. Acquiring both CT and PET images in the same scanner obviates the need for software registration and routinely provides accurately aligned images of anatomy and function in a single scan., Discussion: A CT scanner positioned in tandem with a PET scanner and with a common patient couch and operating console has recently been explored as a solution to anatomic and functional image registration. Axial translation of the couch between the two modalities enables both CT and PET data to be acquired during a single imaging session. In addition, the CT images can be used to generate noiseless attenuation correction factors for the PET emission data. By minimizing patient movement between the CT and PET scans, and after accounting for the axial separation of the two modalities, accurately registered anatomic and functional images can be obtained. Since the introduction of the first PET/CT prototype a little over 5 years ago, several thousand cancer patients have been scanned on combined PET/CT devices. In the past 3 years, a number of commercial designs have become available featuring multidetector spiral CT scanners and high-performance PET devices. Initial experience has demonstrated an increased level of accuracy and confidence in the interpretation of the combined study compared with separate readings, particularly in the ability to distinguish pathology from normal physiologic uptake and to precisely localize abnormal foci., Conclusion: Combined PET/CT scanners represent an important evolution in technology that is helping to bring molecular imaging to the forefront in cancer diagnosis, staging, and therapy monitoring.

Minimally invasive parathyroidectomy (MIP) guided by preoperative sestamibi scanning has been shown to reduce operative time, hospital stay, and cost in treating primary hyperparathyroidism. However, controversy exists over routine preoperative sestamibi scanning. The purpose of this study was to determine the utility of sestamibi scanning at our institution as part of the MIP protocol and to analyze calcium and parathyroid hormone levels as possible predictors of successful sestamibi scanning. Charts of 37 consecutive patients undergoing MIP at our institution were reviewed, and age, sex, preoperative calcium, and parathyroid (PTH) levels, invasiveness of procedure, and pathologic diagnosis were recorded. Sestamibi scans were reviewed and scored by 4 nuclear medicine faculty based on the level of suspicion for parathyroid adenoma. Neither calcium nor PTH correlated significantly with sestamibi scan score (Spearman coefficient, r = 0.075, P = 0.67 and r = 0.277, P = 0.10, respectively). Receiver-operating-characteristic (ROC) analysis showed sestamibi scanning to have sensitivity and specificity in predicting MIP completion (87% and 68%). Logistic regression showed only sestamibi scan (P = 0.038), not calcium or PTH (P = 0.977 and P = 0.767) to be predictive of MIP completion. In conclusion, sestamibi scanning effectively predicted the ability to perform MIP. However, preoperative calcium and PTH predicted neither sestamibi scan results nor completion of MIP.

Spontaneous or traumatic intracerebral hemorrhage (ICH) in the white matter of neonates, children and adults causes significant mortality and morbidity. The detailed biochemical mechanisms through which blood damages white matter are poorly defined. Presently, we tested the hypothesis that ICH induces rapid oxidative stress in white matter. Also, since clot-derived plasma proteins accumulate in white matter after ICH and these proteins can induce oxidative stress in microglia in vitro, we determined whether the blood's plasma component alone induces oxidative stress. Lastly, since heme oxygenase-1 (HO-1) induction is highly sensitive to oxidative stress, we also examined white matter HO-1 gene expression. We infused either whole blood or plasma (2.5 ml) into the frontal hemispheric white matter of pentobarbital-anesthetized pigs ( approximately 1 kg) over 15 min. We monitored and controlled physiologic variables and froze brains in situ between 1 and 24 h after ICH. White matter oxidative stress was determined by measuring protein carbonyl formation and HO-1 gene expression by RT-PCR. Protein carbonyl formation occurred rapidly in the white matter adjacent to both blood and plasma clots with significant elevations (3- to 4-fold) already 1 h after infusion. This increase remained through the first 24 h. HO-1 mRNA was rapidly induced in white matter with either whole blood or plasma infusions. These results demonstrate that not only whole blood but also its plasma component are capable of rapidly inducing oxidative stress in white matter. This rapid response, possibly in microglial cells, may contribute to white matter damage not only following ICH, but also in pathophysiological states in which blood-brain-barrier permeability to plasma proteins is increased., (Copyright 2002 S. Karger AG, Basel)

Intracerebral hemorrhage (ICH) is a devastating stroke sub-type with high mortality and morbidity. ICH frequently occurs in subcortical white matter generating hematomas that contain high heme iron levels. In this study, we examined the consequences of iron-induced oxidation (1-100 microM Fe2+ for 30 min. or 50 microM Fe2+ for 1-120 min.) on the activities of two oxidatively sensitive enzymes, creatine kinase (CK) and glutamine synthetase (GS), and on an oxidative stress marker, protein carbonyl formation, in porcine cerebral cortical white and gray matter. In vitro iron oxidation produced time and concentration dependent decreases in both CK [maximum decreases of 49.3+/-1.2% and 44.3+/-4.1% (average +/- SEM, N=3) for white and gray matter, respectively] and GS activities (maximum decreases of 16.9+/-1.7% and 13.2+/-1.0% for white and gray matter, respectively) and increases in protein carbonyl formation. Interestingly, protein carbonyl concentrations were significantly greater (p<0.05) in white vs. gray matter at 100 microM iron (30 min.) and 50 microM iron (120 min.). Additionally, CK and GS activities were lower for white versus gray matter at several time points and iron concentrations. It is our hypothesis that iron induced oxidative stress contributes to the pathogenesis of perihematomal brain injury following ICH.

Glutathione is able to protect membrane proteins from oxidative stress. In ischemia/reperfusion injury, free radicals cause synaptosomal membrane protein and lipid oxidation that is prevented by the free radical scavenger N-tert-butyl-alpha-phenylnitrone (Hall N. C. et al. (1995) Neuroscience 64, 81-89; 69, 591-600). We wondered if diminution of glutathione would lead to further membrane alterations. Accordingly, the effects of glutathione depletion, by intraperitoneal administration of 2-cyclohexene-1-one, on the physical state of cortical synaptosomal membrane proteins and lipids, with and without global ischemia/reperfusion, were studied in vivo and in vitro in adult and aged gerbils utilizing electron paramagnetic resonance spectrometry. 2-Cyclohexene-1-one (100 mg/kg, i.p.) was administered 30 min prior to 10-min ischemia followed by 1 or 14 h reperfusion. This glutathione reduction agent was also administered to gerbils under the same temporal schedule in the absence of ischemia and compared to untreated controls. Synaptosomal membranes were labeled with a protein-specific spin label, 2,2,6,6-tetramethyl-4-maleimidopiperidine-1-oxyl, or a lipid-specific spin probe, 5-doxylstearic acid. There were no significant changes in the physical state of the lipid portion of synaptosomal membranes when comparing ischemia reperfusion and 2-cyclohexene-1-one-treated ischemia reperfusion in either the adult or aged gerbils. However, glutathione depletion without ischemia/reperfusion caused significant changes in the physical state of the protein portion of cortical synaptosomal membranes in both the adult and aged models. Glutathione depletion, without ischemia/reperfusion, in the adult model showed a maximum change at 3 h that returned to control values by 14 h. In contrast, the aged model showed significant changes at 1 h reperfusion, which did not return to control values by 14 h reperfusion. Glutathione depletion combined with ischemia/reperfusion caused initial protein change in both adult and aged models at 1 h reperfusion, which did not return toward control values by 14 h reperfusion. The results of this study suggest that glutathione depletion increases the severity of membrane protein damage associated with ischemia/reperfusion injury.

Previous studies in our laboratory demonstrated the alteration in the physical state of synaptosomal membrane lipids and proteins in ischemia/reperfusion injury using selective spin labels and electron paramagnetic resonance spectroscopy [Hall et al. (1995) Neuroscience 61, 84-89]. Since many investigations have provided evidence for free radical generation during ischemia/reperfusion injury, we investigated whether a free radical scavenger would prevent the membrane damage, in gerbils. Further, experiments to determine if a secondary effect of polyamine generation at 14 h reperfusion could be blocked by this free radical scavenger or by an inhibitor of ornithine decarboxylase were also carried out. The alterations in synaptosomal membrane integrity observed during ischemia/reperfusion injury were selectively neutralized by treatment with the free radical spin trap N-tert-butyl-alpha-phenylnitrone or an inhibitor of ornithine decarboxylase, difluoromethylornithine. Administration of N-tert-butyl-alpha-phenylnitrone prior to ischemia totally abrogated both lipid and protein alterations observed at 1 and 14 h reperfusion. Pretreatment with difluoromethylornithine neutralized only the 14 h change in lipid label motion. Treatment with N-tert-butyl-alpha-phenylnitrone at 6 h post ischemia showed only a slight attenuation of the 14 h lipid effect and no change in the protein effect. Difluoromethylornithine treatment at 6 h post ischemia negated the 14 h ischemia/reperfusion injury-induced lipid effect and had no effect on the protein change. These data support previous suggestions that free radicals and polyamines play a critical role in neuronal damage and cell loss following ischemia/reperfusion injury and that the polyamine effect is dependent upon free radical generation during ischemia/reperfusion injury.

We have previously reported that ischemia reperfusion injury results from free radical generation following transient global ischemia, and that this radical induced damage is evident in the synaptosomal membrane of the gerbil. [Hall et al, (1995) Neuroscience 64: 81-89]. In the present study we have extended these observations to transient focal ischemia in the cat. We prepared synaptosomal membranes from frontal, parietal-temporal, and occipital regions of the cat cerebral cortex with reperfusion times of 1 and 3 hours following 1 hour right middle cerebral artery occlusion. The membranes were selectively labeled with protein and lipid specific paramagnetic spin labels and analyzed using electron paramagnetic resonance spectrometry. There were significant motional changes of both the protein and lipid specific spin labels in the parietal-temporal and occipital regions with 1 hour reperfusion; but, both parameters returned to control values by 3 hours reperfusion. No significant changes were observed in the normally perfused frontal pole at either reperfusion time. These results support the argument that free radicals play a critical role in cell damage at early reperfusion times following ischemia.

The effects of transient bilateral carotid occlusion on the physical state of synaptosomal membrane proteins and lipids were studied in adult and aged gerbils employing electron paramagnetic resonance. Transient ischemia was produced in adult and aged gerbils by bilateral occlusion of the common carotid arteries with reperfusion times ranging from 0 to 24 h. Synaptosomes of the cerebral cortices were isolated and labeled with a protein-specific spin probe (2,2,6,6-tetramethyl-4-maleimido-piperidine-1-oxyl) and a lipid-specific spin probe (5-doxylstearic acid). Changes in the physical state of the protein peaked at 60 min reperfusion for both adult and aged gerbil models, with a more intense change in aged, but did not return to control values by 24 h. A biphasic change occurred with the lipid-specific label in both the aged and adult models. The onset of the first phase of change occurred at an earlier time (30 min reperfusion) for aged gerbil tissue than for adult tissue (between 3 and 6 h reperfusion), while the second phase of change occurred at 12 h reperfusion for both adult and aged. These results are consistent with the hypothesis that protein oxidation and lipid peroxidation are direct results of free radicals produced during the reperfusion following ischemia and that protein oxidation may be intensified by peroxidation of the surrounding lipids. Phospholipase A2 activation is implicated to cause changes in membrane phospholipid organization as seen in these studies.

Dehydroabietic acid (DHAA) is a major aquatic toxic resin acid usually found in unbleached pulp mill effluents. This compound has been reported to accumulate in the red cells of rainbow trout and to cause hemolysis. To elucidate further understanding to the mechanism of action of this resin, the interaction of DHAA with human erythrocyte membranes has been monitored by electron paramagnetic resonance techniques of spin labeling. Results presented in this paper indicate that DHAA, in a concentration-dependent manner, significantly altered both the motion and order of the lipid bilayer and the physical state of cytoskeletal proteins, while DHAA had no effect on isolated lipids. It is proposed that the increase in the 'fluidity' of the lipid bilayer induced by DHAA is a secondary effect of primary changes in the physical state of the cytoskeletal proteins of the membrane, and that the latter effect is critically associated with the toxicity of DHAA.

The interaction of the amino acid beta-(N-methylamino)-L-alanine, a neurotoxin found in the seed of the false sago palm, with erythrocyte membranes has been monitored by electron paramagnetic resonance techniques of spin labeling. This neurotoxin did not alter the motion or order of bilayer lipids, but a highly-significant and dose-dependent alteration in the physical state of cytoskeletal proteins was observed. These results are discussed in reference to potential mechanisms involved in the neurotoxicity produced by beta-(N-methylamino)-L-alanine and in reference to the unusual neurological disorders among the Chamorro population of Guam and other Marianas Islands.

Approval of a new medical device's safety and effectiveness by the Food and Drug Administration (FDA) is only one step in the typical device's passage into the marketplace. A review of 10 new Class II and III devices found an average of 62 months elapsing between the beginning of FDA-approved clinical trials and the device's final approval for general marketing. However, FDA marketing approval does not mean a new device can be sold because, for many new devices, the Health Care Financing Administration (HCFA) requests a technology assessment from the Office of Health Technology Assessment (OHTA) in order to determine whether the device's use is "reasonable and necessary" and thus appropriate for Medicare payment. The Medicare decision often guides other third parties. OHTA assessments of 93 devices and procedures required an average of 26 months to complete; of 16 FDA-approved Class III devices, OHTA reported to HCFA that insufficient data existed to recommend coverage for 12 (75 percent). Under the Medicare prospective payment system (PPS) for hospital care, a third step has been added to the process, consideration by the Prospective Payment Assessment Commission (ProPAC) and HCFA of the new device's impact on PPS payment rates. Further, under recent legislation, OHTA is mandated also to consider a device's cost effectiveness. Duplicative reviews of new devices should be eliminated, and until they are, medical equipment developers must recognize that delays and conflicting payment rulings may have serious impacts on the ability to market a new device.