Air, hand wipe, and surface wipe sampling for Bisphenol A (BPA) among workers in industries that manufacture and use BPA in the United States.

For decades, bisphenol A (BPA) has been used in making polycarbonate, epoxy, and phenolic resins and certain investment casting waxes, yet published exposure data are lacking for U.S. manufacturing workers. In 2013-2014, BPA air and hand exposures were quantified for 78 workers at six U.S. companies making BPA or BPA-based products. Exposure measures included an inhalable-fraction personal air sample on each of two consecutive work days (n = 146), pre- and end-shift hand wipe samples on the second day (n = 74 each), and surface wipe samples (n = 88). Potential determinants of BPA air and end-shift hand exposures (after natural log transformation) were assessed in univariate and multiple regression mixed models. The geometric mean (GM) BPA air concentration was 4.0 µg/m3 (maximum 920 µg/m3). The end-shift GM BPA hand level (26 µg/sample) was 10-times higher than the pre-shift level (2.6 µg/sample). BPA air and hand exposures differed significantly by industry and job. BPA air concentrations and end-shift hand levels were highest in the BPA-filled wax manufacturing/reclaim industry (GMAir = 48 µg/m3, GMHand-End = 130 µg/sample) and in the job of working with molten BPA-filled wax (GMAir = 43 µg/m3, GMHand-End = 180 µg/sample), and lowest in the phenolic resins industry (GMAir = 0.85 µg/m3, GMHand-End = 0.43 µg/sample) and in the job of flaking phenolic resins (GMAIR = 0.62 µg/m3, GMHand-End = 0.38 µg/sample). Determinants of increased BPA air concentration were industry, handling BPA containers, spilling BPA, and spending ≥50% of the shift in production areas; increasing age was associated with lower air concentrations. BPA hand exposure determinants were influenced by high values for two workers; for all other workers, tasks involving contact with BPA-containing materials and spending ≥50% of the shift in production areas were associated with increased BPA hand levels. Surface wipe BPA levels were significantly lower in eating/office areas (GM = 9.3 µg/100 cm2) than in production areas (GM = 140 µg/100 cm2). In conclusion, worker BPA exposure was associated with tasks and conditions affecting both inhalation and dermal exposure. The potential for BPA-related health effects among these workers is unknown.

Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis.

BACKGROUND: The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. METHODS AND RESULTS: Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001). CONCLUSIONS: Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Jury panel member perceptions of interpersonal-affective traits of psychopathy predict support for execution in a capital murder trial simulation.

Recent research with college undergraduate mock jurors suggests that how psychopathic they perceive a criminal defendant to be is a powerful predictor of whether they will support a death verdict in simulated capital murder trials. Perceived affective and interpersonal traits of psychopathy are especially predictive of support for capital punishment, with perceived remorselessness explaining a disproportionate amount of variance in these attitudes. The present study attempted to extend these findings with a more representative sample of community members called for jury duty (N = 304). Jurors reviewed a case vignette based on an actual capital murder trial, provided sentencing verdicts, and rated the defendant on several characteristics historically associated with the construct of psychopathy. Consistent with prior findings, remorselessness predicted death verdicts, as did the affective and interpersonal features of psychopathy - though the latter effect was more pronounced among jurors who were Caucasian and/or who described their political beliefs as moderate rather than conservative or liberal. Results are discussed in terms of the potentially stigmatizing effects of psychopathy evidence in capital cases.

Detection of DNA damage in workers exposed to JP-8 jet fuel.

The genotoxicity of jet propulsion fuel 8 (JP-8) was assessed in the leukocytes of archived blood specimens from U.S. Air Force personnel using the comet assay. No differences in mean comet assay measurements were found between low, moderate, and high exposure groups before or after a 4h work shift. Before the work shift, mean tail DNA and mean tail (Olive) moment increased as the concentration of benzene measured in end-exhaled breath increased, indicating that prior environmental or work-related exposures to benzene produced DNA damage. The number of cells with highly damaged DNA decreased as the pre-shift benzene concentration in breath increased. It is not clear why the decrease is occurring. Mean tail DNA and mean tail (Olive) moment decreased as the concentrations of benzene and naphthalene measured in breath immediately after the work shift increased. These inverse relationships may reflect a slower rate of absorption or a faster rate of expiration of benzene in the lung. The number of cells with highly damaged DNA increased as the concentration of urinary (2-methoxyethoxy)acetic acid (MEAA) increased. This relationship was not seen in urinary MEAA adjusted for creatinine. MEAA is a metabolite of the deicing agent 2-(2-methoxyethoxy)ethanol contained in JP-8. MEAA or a component of JP-8 correlated with MEAA may have a toxic effect on DNA.

Occupational exposure to acrylamide in closed system production plants: air levels and biomonitoring.

The aim of this study was to evaluate biomarkers of acrylamide exposure, including hemoglobin adducts and urinary metabolites in acrylamide production workers. Biomarkers are integrated measures of the internal dose, and it is total acrylamide dose from all routes and sources that may present health risks. Workers from three companies were studied. Workers potentially exposed to acrylamide monomer wore personal breathing-zone air samplers. Air samples and surface-wipe samples were collected and analyzed for acrylamide. General-area air samples were collected in chemical processing units and control rooms. Hemoglobin adducts were isolated from ethylenediamine teraacetic acid (EDTA)-whole blood, and adducts of acrylamide and glycidamide, at the N-terminal valines of hemoglobin, were cleaved from the protein chain by use of a modified Edman reaction. Full work-shift, personal breathing zone, and general-area air samples were collected and analyzed for particulate and acrylamide monomer vapor. The highest general-area concentration of acrylamide vapor was 350 µg/cm(3) in monomer production. Personal breathing zone and general-area concentrations of acrylamide vapor were found to be highest in monomer production operations, and lower levels were in the polymer production operations. Adduct levels varied widely among workers, with the highest in workers in the monomer and polymer production areas. The acrylamide adduct range was 15-1884 pmol/g; glycidamide adducts ranged from 17.8 to 1376 p/mol/g. The highest acrylamide and glycidamide adduct levels were found among monomer production process operators. The primary urinary metabolite N-acetyl-S-(2-carbamoylethyl) cysteine (NACEC) ranged from the limit of detection to 15.4 µg/ml. Correlation of workplace exposure and sentinel health effects is needed to determine and control safe levels of exposure for regulatory standards.

Evaluation and comparison of urinary metabolic biomarkers of exposure for the jet fuel JP-8.

A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S-benzylmercapturic acid (BMA), S-phenylmercapturic acid (PMA), and (2-methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and MEAA urinary levels were determined by gas chromatography-mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method's limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 µ g/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine.

(2-methoxyethoxy)acetic acid: a urinary biomarker of exposure for jet fuel JP-8.

PURPOSE: To demonstrate the utility of the urinary metabolite (2-methoxyethoxy)acetic acid (MEAA) as a biomarker of exposure. 2-(2-methoxyethoxy)ethanol [diethylene glycol monomethyl ether] is an anti-icing agent used in the formulation of JP-8, and it is added at a known uniform 0.1% (v/v) concentration to each batch lot. JP-8 is a kerosene-based fuel containing different compounds that vary in the content of every batch/lot of fuel; thus, MEAA has the potential to be a more specific and a consistent quantitative biomarker for JP-8 exposure. METHODS: MEAA was used to measure exposure of jet propulsion fuel 8 (JP-8) in United States Air Force (USAF) personnel working at six airbases within the United States. Post-shift urine specimens from various personnel including high (n = 98), moderate (n = 38), and low (n = 61) exposure workgroup categories were collected and analyzed by a gas chromatographic-mass spectrometric test method. The three exposure groups were evaluated for the number per group positive for MEAA, and a statistical analysis consisted of pair-wise t-tests for unequal variances was used to test for the differences in mean MEAA concentrations between the exposure groups. RESULTS: The number of samples detected as positive for MEAA exposure, that is, those above the test method's limit of detection (LOD = 0.1 µg/ml), were 92 (93.9%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure workgroup categories, respectively. The mean urinary MEAA level was significantly greater in the high exposure category (6.8 µg/ml), compared to the moderate (0.42 µg/ml) and the low (0.07 µg/ml) exposure categories. The maximum concentration of urinary MEAA was 110 µg/ml for the high exposure category, while 4.8 µg/ml and 0.2 µg/ml maximum levels were found in the moderate and low exposure categories, respectively. CONCLUSION: This study demonstrated that urinary MEAA can be used as an accurate biomarker of exposure for JP-8 workers and clearly distinguished the differences in JP-8 exposure by workgroup category.

A pilot respiratory health assessment of nail technicians: symptoms, lung function, and airway inflammation.

BACKGROUND: Recent surveys suggest nail technicians, particularly artificial nail applicators, have increased respiratory symptoms and asthma risk. METHODS: We examined lung function (n = 62) and a marker of airway inflammation, i.e., exhaled nitric oxide (ENO) (n = 43), in a subset of nail technician and control participants in a pilot health assessment. RESULTS: Bivariate analysis of technicians demonstrated that job latency was inversely correlated with FEV1 percent predicted (FEV1PP) (r = -0.34, P = 0.03) and FVCPP (r = -0.32, P = 0.05). Acrylic gel contact hours were inversely correlated with FEV1PP (r = -0.38, P = 0.02) and FVCPP (r = -0.47, P = 0.003). Current smoking was inversely and significantly (P

Automated synthesis of the generic peptide labelling agent N-succinimidyl 4-[(18)F]fluorobenzoate and application to (18)F-label the vasoactive transmitter urotensin-II as a ligand for positron emission tomography.

INTRODUCTION: The objectives of this work were to develop an automated production of N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]-SFB) and to test whether the vasoactive peptide urotensin-II (U-II) could be labelled by conjugation with [(18)F]-SFB. METHODS: A TRACERlab MX(FDG) synthesizer including an HPLC unit was used. The MS Excel synthesis sequence and the standard disposable FDG cassette were modified to allow the synthesis of [(18)F]-SFB. U-II was subsequently conjugated with [(18)F]-SFB, and the resulting (18)F-labelled peptides were characterised using in vitro ligand binding assays. RESULTS: [(18)F]-SFB was successfully synthesised in the TRACERlab MX(FDG) in 44.3+/-2.5% (n=25) radiochemical yield in 98 min. [(18)F]-SFB (8-12 GBq) has been produced with specific activities in the range of 250-350 GBq/mumol and a radiochemical purity >95%. [(18)F]-SFB was subsequently used to label U-II. Two radiolabelled products, [(18)F]-(Glu(1))-U-II and [(18)F]-(Lys(8))-U-II, were formed in an isolated radiochemical yield from [(18)F]-SFB of 5.2+/-0.3% and 29.0+/-3.7%, respectively (n=7). Radioligand binding assays revealed that [(18)F]-(Glu(1))-U-II had retained subnanomolar affinity. Binding to human skeletal muscle (n=3) was concentration dependent and saturable with K(d)=0.84+/-0.51 nM, B(max)=0.69+/-0.14 fmol/mg protein and Hill slope (nH)=1.03+/-0.12. CONCLUSIONS: [(18)F]-SFB has been synthesised using the TRACERlab MX(FDG) module, allowing production of up to 8-12 GBq of [(18)F]-SFB with specific activities of 250-350 GBq/mumol. [(18)F]-SFB was used for the labelling of U-II. In vitro characterisation demonstrated that [(18)F]-(Glu(1))-U-II had retained desirable binding properties and may be suitable as a positron emission tomography radioligand for the imaging of the U-II receptor.

Imaging of brain hypoxia in permanent and temporary middle cerebral artery occlusion in the rat using 18F-fluoromisonidazole and positron emission tomography: a pilot study.

In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. Previous human studies using 18F-fluoromisonidazole and positron emission tomography (18F-FMISO PET) have shown high tracer retention indicative of tissue hypoxia, which had normalized at repeat scan >48 h later. In the only validation study of 18F-FMISO, using ex vivo autoradiography in thread middle cerebral artery occluded (MCAo) rats, there was unexpected high uptake as late as 22 h after reperfusion, raising questions about the use of 18F-FMISO as a hypoxia tracer. Here we report a pilot study of 18F-FMISO PET in experimental stroke. Spontaneous hypertensive rats were subjected to distal clip MCAo. Three-hour dynamic PET was performed in 7 rats: 3 normals, 1 with permanent MCAo (two sessions: 30 mins and 48 h after clip), and 3 with temporary MCAo (45 mins, n=1; 120 mins, n=2; scanning started 30 mins after clip removal). Experiments were terminated by perfusion-fixation for standard histopathology. Late tracer retention was assessed by both compartmental modelling and simple side-to-side ratios. In the initial PET session of the permanent MCAo rat, striking trapping of 18F-FMISO was observed in the affected cortex, which had normalized 48 h later; histopathology revealed pannecrosis. In contrast, there was no demonstrable tracer retention in either temporary MCAo models, and histopathology showed ischemic changes only. These results document elevated 18F-FMISO uptake in the stroke area only in the early phase of MCAo, but not after early reperfusion nor when tissue necrosis has developed. These findings strongly support the validity of 18F-FMISO as a marker of viable hypoxic tissue/penumbra after stroke.

Strategy for improved [(11)C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [(11)C]DAA1106.

INTRODUCTION: The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [(11)C]DAA1106 ([(11)C]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide) is a promising positron emission tomography (PET) radioligand for imaging PBRs. METHODS: A four-step synthetic route was devised to prepare DAA1123, the precursor for [(11)C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [(11)C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [(11)C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [(11)C]CH(3)I trapped. Evaluation of [(11)C]DAA1106 for in vivo imaging was performed in a rabbit model with microPET, and the presence of PBR receptor in the target organ was further corroborated by immunohistochemistry. RESULTS: The standard solution method produced 2.6-5.2 GBq (n=19) of [(11)C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [(11)C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/micromol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [(11)C]DAA1106. In vivo microPET [(11)C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 micromol) produced considerable displacement of the radioactive signal in this region. The presence of PBR in kidney cortex was further corroborated by immunohistochemistry. CONCLUSIONS: A robust, high yielding captive solvent method of [(11)C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model.

Urinary Bisphenol A (BPA) Concentrations among Workers in Industries that Manufacture and Use BPA in the USA.

Background: Bisphenol A (BPA) toxicity and exposure risk to humans has been the subject of considerable scientific debate; however, published occupational exposure data for BPA are limited. Methods: In 2013-2014, 77 workers at six US companies making BPA, BPA-based resins, or BPA-filled wax provided seven urine samples over two consecutive work days (151 worker-days, 525 samples). Participant information included industry, job, tasks, personal protective equipment used, hygiene behaviors, and canned food/beverage consumption. Total (free plus conjugated) BPA, quantified in urine by mass spectrometry, was detected in all samples. Results: The geometric mean (GM) creatinine-adjusted total BPA (total BPACR) concentration was 88.0 µg g-1 (range 0.78-18900 µg g-1), ~70 times higher than in US adults in 2013-2014 (1.27 µg g-1). GM total BPACR increased during Day 1 (26.6-127 µg g-1), decreased by pre-shift Day 2 (84.4 µg g-1) then increased during Day 2 to 178 µg g-1. By industry, baseline and post-baseline total BPACR was highest in BPA-filled wax manufacturing/reclaim (GM = 111 µg g-1) and lowest in phenolic resin manufacturing (GM = 6.56 µg g-1). By job, total BPACR was highest at baseline in maintenance workers (GM = 157 µg g-1) and post-baseline in those working with molten BPA-filled wax (GM = 441 µg g-1). Workers in the job of flaking a BPA-based resin had the lowest concentrations at baseline (GM = 4.81 µg g-1) and post-baseline (GM = 23.2 µg g-1). In multiple regression models, at baseline, industry significantly predicted increased total BPACR (P = 0.0248); post-baseline, handling BPA containers (P = 0.0035), taking ≥3 process/bulk samples with BPA (P = 0.0002) and wearing a Tyvek® coverall (P = 0.0042) significantly predicted increased total BPACR (after adjusting for total BPACR at baseline, time point, and body mass index). Conclusion: Several work-related factors, including industry, job, and certain tasks performed, were associated with increased urinary total BPACR concentrations in this group of manufacturing workers. The potential for BPA-related health effects among these workers is unknown.

Intersubject variability and reproducibility of 15O PET studies.

Oxygen-15 positron emission tomography (15O PET) can provide important data regarding patients with head injury. We provide reference data on intersubject variability and reproducibility of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolism (CMRO2) and oxygen extraction fraction (OEF) in patients and healthy controls, and explored alternative ways of assessing reproducibility within the context of a single PET study. In addition, we used independent measurements of CBF and CMRO2 to investigate the effect of mathematical correlation on the relationship between flow and metabolism. In patients, intersubject coefficients of variation (CoV) for CBF, CMRO2 and OEF were larger than in controls (32.9%+/-2.2%, 23.2%+/-2.0% and 22.5%+/-3.4% versus 13.5%+/-1.4%, 12.8%+/-1.1% and 7.3%+/-1.2%), while CoV for CBV were lower (15.2%+/-2.1% versus 22.5%+/-2.8%) (P<0.001). The CoV for the test-retest reproducibility of CBF, CBV, CMRO2 and OEF in patients were 2.1%+/-1.5%, 3.8%+/-3.0%, 3.7%+/-3.0% and 4.6%+/-3.5%, respectively. These were much lower than the intersubject CoV figures, and were similar to alternative measures of reproducibility obtained by fractionating data from a single study. The physiological relationship between flow and metabolism was preserved even when mathematically independent measures were used for analysis. These data provide a context for the design and interpretation of interventional PET studies. While ideally each centre should develop its own bank of such data, the figures provided will allow initial generic approximations of sample size for such studies.

Imaging endothelin ET(B) receptors using [18F]-BQ3020: in vitro characterization and positron emission tomography (microPET).

The endothelin (ET) receptor system has been shown to play a role in a number of vascular diseases. We have synthesized 18F-and 11C-labeled radioligands to enable in vivo imaging of the fundamental processes involved in ET receptor pharmacology in normal and diseased tissue using positron emission tomography (PET). One aim is to elucidate the proposed role of the ET(B) subtype as clearing receptor, removing ET-1 from the circulation, and whether this is an important mechanism to limit the detrimental effects caused by upregulated ET-1 in disease. To image ET(B) receptors we have labeled the selective agonist BQ3020 with 18F. In vitro characterization verified that [18F]-BQ3020 bound with a single subnanomolar affinity (K(D) = 0.34 +/- 0.10 nM, B(max) = 9.23 +/- 3.70 fmol/mg protein) to human left ventricle. Binding of [18F]-BQ3020 to human kidney was inhibited by ET-1 and unlabeled BQ3020 but not by the ET(A) selective antagonist FR139317, confirming that selectivity for the ET(B) receptor was retained. In vitro autoradiography revealed, as expected, high levels of ET(B) receptor densities in lung and kidney medulla, whereas kidney cortex and heart showed lower levels of ET(B) receptor densities. Furthermore, a high level of [18F]-BQ3020 binding was found to colocalize to macrophages in atherosclerotic coronary arteries. MicroPET studies demonstrated high uptake of [18F]-BQ3020 in ET(B) receptor-rich tissue, including lung, liver and kidney. The in vivo biodistribution of [18F]-BQ3020 was comparable to that previously obtained for [18F]-ET-1, supporting our hypothesis that the ET(B) receptor plays a significant role in the uptake of ET-1. In conclusion, [18F]-BQ3020 has retained high affinity and selectivity, allowing imaging of ET(B) receptor distributions in vitro and in vivo in human and animal tissue. Furthermore, in vitro data suggest that [18F]-BQ3020 potentially can be used to image atherosclerotic lesions in vivo using PET.

Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Carotid endarterectomy is currently guided by angiographic appearance on the assumption that the most stenotic lesion visible at angiography is likely to be the lesion from which future embolic events will arise. However, risk of plaque rupture, the most common cause of atherosclerosis-related thromboembolism, is dictated by the composition of the plaque, in particular the degree of inflammation. Angiography may, therefore, be an unreliable method of identifying vulnerable plaques. In this study, plaque inflammation was quantified before endarterectomy using the combination of 18F fluorodeoxyglucose positron (FDG)-emission tomography (PET) and high-resolution MRI (HRMRI). METHODS: Twelve patients, all of whom had suffered a recent transient ischemic attack, had a severe stenosis in the ipsilateral carotid artery, and were awaiting carotid endarterectomy underwent FDG-PET and HRMRI scanning. A semiquantitative estimate of plaque inflammation was calculated for all of the lesions identified on HRMRI. RESULTS: In 7 of 12 patients (58%), high FDG uptake was seen in the lesion targeted for endarterectomy. In the remaining 5 patients, FDG uptake in the targeted lesion was low. In these 5 patients, 3 had nonstenotic lesions identified on HRMRI that exhibited a high level of FDG uptake. All 3 of the highly inflamed nonstenotic lesions were located in a vascular territory compatible with the patients' presenting symptoms. CONCLUSIONS: Our data suggest that angiography may not always identify the culprit lesion. Combined FDG-PET and HRMRI can assess the degree of inflammation in stenotic and nonstenotic plaques and could potentially be used to identify lesions responsible for embolic events.

Positron emission tomography using 18F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ET B receptors in vivo.

Our aim was to synthesise an (18)F analogue of endothelin-1 (ET-1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ET(B) subtype as a clearing receptor in organs expressing high densities including kidney and lung.[(18)F]-ET-1 was characterised in vitro and bound with a single subnanomolar affinity (K(D)=0.43+/-0.05 nM, B(max)=27.8+/-2.1 fmol mg(-1) protein) to human left ventricle (n=4). The in vivo distribution of [(18)F]-ET-1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis. Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [(125)I]-ET-1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements.[(18)F]-ET-1 binding in lungs could not be displaced by the ET(B) selective antagonist BQ788, in agreement with the proposed internalisation of ET-1 by ET(B) receptors. In contrast, infusion of BQ788 prior to injecting [(18)F]-ET-1 significantly reduce the amount of radioligand visualised in the ET(B) rich lung and kidney by 85% (P< 0.05, n=3) and 55% (P<0.05, n=3), respectively. Under conditions of ET(B) receptor blockade, the heart could be visualised by microPET imaging.These results suggest that clearance by ET(B) receptors in the lung and kidney prevents binding of ET-1 to receptors in the heart.

Positron emission tomography in the quantification of cellular and biochemical responses to intrapulmonary particulates.

Inhaled mineral dusts and fibres can cause chronic pulmonary inflammation, often leading to permanent scarring with loss of function, but the mechanisms involved remain obscure. There are currently no good methods for monitoring inflammatory processes in situ. Positron emission tomography (PET) of suitable intravenously injected radiolabelled markers provides non-invasive and repeatable methods of quantifying biochemical and cellular responses. We have developed animal models of fibrotic and non-fibrotic pulmonary response to particulate instillation and characterised these by histology. Different components of the inflammatory response have been investigated by PET: (1) [(18)F]-labelled fluoro-deoxyglucose, a positron emitting glucose analogue, accumulates in cells in proportion to their glucose uptake; ex vivo microautoradiography indicates that neutrophils are the cells responsible for an increased signal during pulmonary inflammation; a persistently high uptake is associated with lung scarring. (2) The radioligand [(11)C]-R-PK11195 binds to benzodiazepine-like receptors abundant in macrophages; following particulate instillation, the [(11)C]-R-PK11195 PET signal tracks with lung macrophage accumulation and also localises to regions consistent with macrophage clearance; poor macrophage clearance is associated with fibrosis. (3) [(18)F]-fluoroproline is likely a substrate for extracellular matrix production, especially proline-rich collagen; during active scarring, the rate of lung uptake of fluoroproline is elevated. Localisation of radioactivity in the lung has been validated ex vivo by microautoradiography of tritium analogues of each of the positron emitting tracers. The use of PET to monitor different inflammatory processes by repeated scanning of the same animal or individual is helping to identify key events in the fibrotic process.

Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2) and oxygen extraction fraction (OEF) using 15O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 +/- 4 to 90 +/- 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO2 were associated with the greatest reduction in OEF (r2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 +/- 16 to 5 +/- 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 +/- 1.5 versus 4.3 +/- 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO2 and neuronal electrical function will require further study.

Monte Carlo simulation and scatter correction of the GE advance PET scanner with SimSET and Geant4.

For Monte Carlo simulations to be used as an alternative solution to perform scatter correction, accurate modelling of the scanner as well as speed is paramount. General-purpose Monte Carlo packages (Geant4, EGS, MCNP) allow a detailed description of the scanner but are not efficient at simulating voxel-based geometries (patient images). On the other hand, dedicated codes (SimSET, PETSIM) will perform well for voxel-based objects but will be poor in their capacity of simulating complex geometries such as a PET scanner. The approach adopted in this work was to couple a dedicated code (SimSET) with a general-purpose package (Geant4) to have the efficiency of the former and the capabilities of the latter. The combined SimSET+Geant4 code (SimG4) was assessed on the GE Advance PET scanner and compared to the use of SimSET only. A better description of the resolution and sensitivity of the scanner and of the scatter fraction was obtained with SimG4. The accuracy of scatter correction performed with SimG4 and SimSET was also assessed from data acquired with the 20 cm NEMA phantom. SimG4 was found to outperform SimSET and to give slightly better results than the GE scatter correction methods installed on the Advance scanner (curve fitting and scatter modelling for the 300-650 keV and 375-650 keV energy windows, respectively). In the presence of a hot source close to the edge of the field of view (as found in oxygen scans), the GE curve-fitting method was found to fail whereas SimG4 maintained its performance.

Assessment of cerebrovascular autoregulation in head-injured patients: a validation study.

BACKGROUND AND PURPOSE: Cerebrovascular autoregulation is frequently measured in head-injured patients. We attempted to validate 4 bedside methods used for assessment of autoregulation. METHODS: PET was performed at a cerebral perfusion pressure (CPP) of 70 and 90 mm Hg in 20 patients. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) were determined at each CPP level. Patients were sedated with propofol and fentanyl. Norepinephrine was used to control CPP. During PET scanning, transcranial Doppler (TCD) flow velocity in the middle cerebral artery was monitored, and the arterio-jugular oxygen content difference (AJDo2) was measured at each CPP. Autoregulation was determined as the static rate of autoregulation based on PET (SROR(PET)) and TCD (SROR(TCD)) data, based on changes in AJDo2, and with 2 indexes based on the relationship between slow waves of CPP and flow velocity (mean velocity index, Mx) and between arterial blood pressure and intracranial pressure (pressure reactivity index, PRx) RESULTS: We found significant correlations between SROR(PET) and SROR(TCD) (r2=0.32; P<0.01) and between SROR(PET) and PRx (r2=0.31; P<0.05). There were no significant associations between PET data and autoregulation as assessed by changes in AJDo2. Global CMRo2 was significantly lower at the higher CPP (P<0.01). CONCLUSIONS: Despite some variability, SROR(TCD) and PRx may provide useful approximations of autoregulation in head-injured patients. At least with our methods, CMRo2 changes with the increase in CPP; hence, flow-metabolism coupling may affect the results of autoregulation testing.