Simultaneous measurements of myocardial glucose metabolism and extracellular volumes with hybrid PET/MRI using concurrent injections of Gd-DTPA and [18F]FDG.

BACKGROUND: The aims of this study were to investigate the application of a constant infusion (CI) to mitigate the issue of constantly changing Gd-DTPA contrast levels in a bolus injection for extracellular volume (ECV) measurements by (a) comparing a CI alone to a bolus alone and a bolus followed by CI in healthy myocardium, (b) evaluating the impact of glucose suppression using heparin on ECV. METHODS: Five healthy canine subjects were imaged to compare three different protocols for injecting Gd-DTPA and FDG: bolus alone, CI alone, bolus followed by CI. Suppression of myocardial glucose uptake was induced using a continuous infusion of 20% lipid at a rate of 0.25 mL·min-1·kg-1 as well as 2000 units of intravenous heparin injected 20 minutes prior to FDG/Gd-DTPA injection. RESULTS: There was no significant effect on ECV measurement when heparin was used for glucose suppression at equilibrium irrespective of infusion protocol). Measurements of ECV in myocardium, regardless of infusion protocol showed no significant difference at all time points (P = 0.21) prior to washout. CONCLUSIONS: The suppression of myocardial uptake of [18F]FDG with heparin did not alter the determination of myocardial ECV though a larger sample size may show differences. Further, the infusion protocol (bolus or constant infusion) had no effect on the calculated ECV.

Tracking the progress of inflammation with PET/MRI in a canine model of myocardial infarction.

BACKGROUND: Following myocardial infarction, tissue undergoes pathophysiological changes involving inflammation and scar tissue formation. However, little is known about the pathophysiology and prognostic significance of any corresponding changes in remote myocardium. The aim of this study was to investigate the potential application of a combined constant infusion of 18F-FDG and Gd-DTPA to quantitate inflammation and extracellular volume (ECV) from 3 to 40 days after myocardial infarction. METHODS: Eight canine subjects were imaged at multiple time points following induction of an MI with a 60-minute concurrent constant infusion of Gd-DTPA and 18F-FDG using a hybrid PET/MRI scanner. RESULTS: There was a significant increase in ECV in remote myocardium on day 14 post-MI (P = .034) and day 21 (P = .021) compared to the baseline. ECV was significantly elevated in the infarcted myocardium compared to remote myocardium at all time points post-MI (days 3, 7, 14, 21, and 40) (P < .001) while glucose uptake was also increased within the infarct on days 3, 7, 14, and 21 but not 40. CONCLUSIONS: The significant increase in ECV in remote tissue may be due to an ongoing inflammatory process in the early weeks post-infarct.

Same day comparison of PET/CT and PET/MR in patients with cardiac sarcoidosis.

BACKGROUND: Inflammatory cardiac disorders, in particular, sarcoidosis, play an important role in left ventricular dysfunction, conduction abnormalities, and arrhythmias. In this study, we compared the imaging characteristics and diagnostic information obtained when patients were imaged sequentially with PET/CT and then with hybrid PET/MRI on the same day following a single 18F-FDG injection. METHODS: Ten patients with known or suspected sarcoidosis underwent imaging in sequence of (a) 99mTc-MIBI, (b) 18F-FDG with PET/CT, and (c) 18F-FDG with 3T PET/MRI. Images were compared quantitatively by determination of SUVmax and SUV on a voxel by voxel basis, and qualitatively by two experienced observers. RESULTS: When both platforms were compared quantitatively, similar data for the evaluation of enhanced 18F-FDG uptake were obtained. Qualitatively, there were (1) several instances of normal perfusion with delayed enhancement and/or focal 18F-FDG uptake, (2) comparable enhanced 18F-FDG uptake on PET/CT vs. PET/MRI, and (3) diversity in disease patterns with delayed enhancement only, increased 18F-FDG uptake only, or both. CONCLUSION: In this limited patient study, PET/CT and PET/MR provided similar diagnostic data for 18F-FDG uptake, and the concurrent acquisition of MR images provided further insight into the disease process.

Hybrid PET/MR imaging in myocardial inflammation post-myocardial infarction.

Hybrid PET/MR imaging is an emerging imaging modality combining positron emission tomography (PET) and magnetic resonance imaging (MRI) in the same system. Since the introduction of clinical PET/MRI in 2011, it has had some impact (e.g., imaging the components of inflammation in myocardial infarction), but its role could be much greater. Many opportunities remain unexplored and will be highlighted in this review. The inflammatory process post-myocardial infarction has many facets at a cellular level which may affect the outcome of the patient, specifically the effects on adverse left ventricular remodeling, and ultimately prognosis. The goal of inflammation imaging is to track the process non-invasively and quantitatively to determine the best therapeutic options for intervention and to monitor those therapies. While PET and MRI, acquired separately, can image aspects of inflammation, hybrid PET/MRI has the potential to advance imaging of myocardial inflammation. This review contains a description of hybrid PET/MRI, its application to inflammation imaging in myocardial infarction and the challenges, constraints, and opportunities in designing data collection protocols. Finally, this review explores opportunities in PET/MRI: improved registration, partial volume correction, machine learning, new approaches in the development of PET and MRI pulse sequences, and the use of novel injection strategies.

Neurophysiological and behavioral effects of a 60 Hz, 1,800 µT magnetic field in humans.

The effects of time-varying magnetic fields (MF) on humans have been actively investigated for the past three decades. One important unanswered question is the potential for MF exposure to have acute effects on human biology. Different strategies have been used to tackle this question using various physiological, neurophysiological and behavioral indicators. For example, researchers investigating electroencephalography (EEG) have reported that extremely low frequency (ELF, <300 Hz) MF can increase resting occipital alpha rhythm (8-12 Hz). Interestingly, other studies have demonstrated that human motricity can be modulated by ELF MF: a reduction of anteroposterior standing balance or a decrease of physiological tremor intensity have been reported as consequences of exposure. However, the main limitation in this domain lies in the lack of results replication, possibly originating from the large variety of experimental approaches employed. Therefore, the present study aimed to investigate the effects of a 60 Hz, 1,800 µT MF exposure on neurophysiological (EEG) and neuromotor (standing balance, voluntary motor function, and physiological tremor) aspects in humans using a single experimental procedure. Though results from this study suggest a reduction of human standing balance with MF exposure, as well as an increase of physiological tremor amplitude within the frequency range associated with central nervous system contribution, no exposure effect appeared on other investigated parameters (e.g., EEG or voluntary motor control). These results suggest that 1 h of 60 Hz, 1,800 µT MF exposure may modulate human involuntary motor control without being detected in the cortical electrical activity.

Sci-Fri AM: Imaging - 06: The role of body mass and gender in atlas construction for attenuation correction in PET/MRI.

Attenuation correction (AC) in PET/MRI is difficult as there is no clear relationship between MR signal and 511 keV attenuation coefficients (µ) as there is with CT. One approach is to register a pre-defined atlas of µ to the PET/MRI for AC. However, the design of the atlas may strongly influence the quantitative accuracy of the AC. Here we compare 3 different atlas design approaches and evaluate their performance in an oncology patient population. The 3 strategies were: use of BMI-dependent atlases; use of gender-dependent atlases, and use of a gender- and sex-independent atlas. Seventeen patients were imaged with FDG PET/CT and subsequently scanned with 3T MRI. MR and PET/CT images were coregistered, CT scans converted to µ-maps, and the resulting MRI/µ-map paired data were used to construct 6 atlases: averaged male and female atlases, averaged BMI-specific atlases (obese >30, overweight 25-29.9, Normal 18.5-24.9), and a single atlas comprised of all patients averaged together. The atlases were then used for PET AC for patients not included in the construction of the atlas in a leave-one-out manner. Resulting PET images were compared to each other and to the gold-standard CT-based PET reconstructions across all voxels and tissue-specific regions (soft-tissue, bone, lung). Sex-specific atlases yielded best results (average relative percent error over the 3 VOIs = 0.4509) & BMI-based atlases yielded highest average relative percent error at 0.9340. In all cases, highest errors were in the VOIs located in the livers.

A comparison of MR-based attenuation correction in PET versus SPECT.

Attenuation correction (AC) is a critical step in the reconstruction of quantitatively accurate positron emission tomography (PET) and single photon emission computed tomography (SPECT) images. Several groups have proposed magnetic resonance (MR)-based AC algorithms for application in hybrid PET/MR systems. However, none of these approaches have been tested on SPECT data. Since SPECT/MR systems are under active development, it is important to ascertain whether MR-based AC algorithms validated for PET can be applied to SPECT. To investigate this issue, two imaging experiments were performed: one with an anthropomorphic chest phantom and one with two groups of canines. Both groups of canines were imaged from neck to abdomen, one with PET/CT and MR (n = 4) and the other with SPECT/CT and MR (n = 4), while the phantom was imaged with all modalities. The quality of the nuclear medicine reconstructions using MR-based attenuation maps was compared between PET and SPECT on global and local scales. In addition, the sensitivity of these reconstructions to variations in the attenuation map was ascertained. On both scales, it was found that the SPECT reconstructions were of higher fidelity than the PET reconstructions. Further, they were less sensitive to changes to the MR-based attenuation map. Thus, MR-based AC algorithms that have been designed for PET/MR can be expected to demonstrate improved performance when used for SPECT/MR.

[PICC: central venous access by the peripheral route. Medical-nursing aspects]. / PICC: accesso venoso centrale per via periferica aspetti medico-infermieristici.

To have access to central vein, for the infant in NICU,often have a role, for their, life-preserving. The increase of survival in the VLBW, and specially in the ELBW,is guaranteed, in the first days of the life also by a safe vascular access, in fact we can, in this way, to supply with parenteral nutrition to all the requirements that these special patients have. In the first approach to the seriously ill newborn, the umbilical vessels, are the first choice to use,we have the way more fast, stable and easy, to guarantee: the emergency therapy, monitoring and caloric requirements. After 6-7 days, however, specially in the ELBW, it is important to find a more stable vascular access, through we can to provide high osmolarity solutions without complications, to supplement the MEF (Minimal Enteral Feeding) with parenteral nutrition optimizing energy intake and caloric. At this time, for the preterm baby is more safe and easy choice the central venous catheter peripherally inserted (PICC). The Authors assess the medical nurse aspects related to this method starting from the choice of vase, the techniques of cannulation and dressing, then linger on the management and prevention of complications. We will, finally, show our data on PICC related to 212 preterms admitted in our NICU with weight <1500 gr and/o E.G. <30 ws.; from the year 2006 to 2009, that correspond to the our precence to the Vermont Oxford Network (VON).

Effects of acute hypoxia on postural and kinetic tremor.

Human physiological tremor is a complex phenomenon that is modulated by numerous mechanical, neurophysiological, and environmental conditions. Researchers investigating tremor have suggested that acute hypoxia increases tremor amplitude. Based on the results of prior studies, we hypothesized that human participants exposed to a simulated altitude of 4,500 m would display an increased tremor amplitude within the 6-12 Hz frequency range. Postural and kinetic tremors were recorded with a laser system in 23 healthy male participants before, during, and after 1 h of altitude-induced hypoxia. A large panel of tremor characteristics was used to investigate the effect of hypoxia. Acute hypoxia increased tremor frequency content between 6 and 12 Hz during both postural and kinetic tremor tasks (P < 0.05, F = 6.142, Eta(2) = 0.24 and P < 0.05, F = 3.767 Eta(2) = 0.14, respectively). Although the physiological mechanisms underlying the observed changes in tremor are not completely elucidated yet, this study confirms that acute hypoxia increases tremor frequency in the 6-12 Hz range. Furthermore, this study indicates that changes in physiological tremor can be detected at lower hypoxemic levels than previously reported (blood saturation in oxygen = 80.9%). The effects of hypoxia mainly result from a cascade of events starting with the activation of the hypothalamic-pituitary-adrenal axis causing in turn an increase in catecholamine release, leading to an augmentation of tremor amplitude in the 6- to 12-Hz interval and heart rate increase.

Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release.

Neurological disorders are among the most challenging medical problems faced by science today. To treat these disorders more effectively, new technologies are being developed by reviving old ideas such as brain stimulation. This review aims to compile stimulation techniques that are currently in use to explore or treat neurological disorders. Transcranial magnetic stimulation is a non-invasive method of modulating neuronal activity with induced electric currents. Other more invasive methods, such as deep brain stimulation and vagal nerve stimulation, use implanted probes to introduce brain activity alterations. Scientific and clinical applications have largely preceded the development of extensive animal models, presenting a challenge for researchers. This has left researchers with information on alleviating symptoms in humans but without solid research as to the mechanisms and neurobiological effects of the devices. This review combines stimulation parameters developed in animal models and stimulation techniques used in human treatment; thus, resulting in a greater understanding of the mechanisms and neurobiological effects of neuromodulation devices.

Changes in human EEG alpha activity following exposure to two different pulsed magnetic field sequences.

The present study investigates the effects of a weak (+/-200 microT(pk)), pulsed, extremely low frequency magnetic field (ELF MF) upon the human electroencephalogram (EEG). We have previously determined that exposure to pulsed ELF MFs can affect the EEG, notably the alpha frequency (8-13 Hz) over the occipital-parietal region of the scalp. In the present study, subjects (n = 32) were exposed to two different pulsed MF sequences (1 and 2, used previously) that differed in presentation rate, in order to examine the effects upon the alpha frequency of the human EEG. Results suggest that compared to sham exposure, alpha activity was lowered over the occipital-parietal regions of the brain during exposure to Sequence 1, while alpha activity over the same regions was higher after Sequence 2 exposure. These effects occurred after approximately 5 min of pulsed MF exposure. The results also suggest that a previous exposure to the pulsed MF sequence determined subjects' responses in the present experiment. This study supports our previous observation of EEG changes after 5 min pulsed ELF MF exposure. The results of this study are also consistent with existing EEG experiments of ELF MF and mobile phone effects upon the brain.

Quantification of pain-induced changes in cerebral blood flow by perfusion MRI.

The purpose of this study was to assess if the functional activation caused by painful stimuli could be detected with arterial spin labeling (ASL), which is a non-invasive magnetic resonance imaging (MRI) technique for measuring cerebral blood flow (CBF). Because ASL directly measures blood flow, it is well suited to pain conditions that are difficult to assess with current functional MRI, such as chronic pain. However, the use of ASL in neuroimaging has been hampered by its low sensitivity. Recent improvements in MRI technology, namely increased magnetic field strengths and phased array receiver coils, should enable ASL to measure the small changes in CBF associated with pain. In this study, healthy volunteers underwent two ASL imaging sessions, during which a painful thermal stimulus was applied to the left hand. The results demonstrated that the ASL technique measured changes in regional CBF in brain regions that have been previously identified with pain perception. These included bilateral CBF changes in the insula, secondary somatosensory, and cingulate cortices, as well as the supplementary motor area (SMA). Also observed were contralateral primary somatosensory and ipsilateral thalamic CBF changes. The average change in CBF for all regions of interest was 3.68ml/100g/min, ranging from 2.97ml/100g/min in ipsilateral thalamus to 4.91ml/100g/min in contralateral insula. The average resting global CBF was 54+/-9.7ml/100g/min, and there was no change in global CBF due to the noxious thermal stimulus.

Associations of the plasma interleukin 6 (IL-6) levels with disability and mortality in the elderly in the Treviso Longeva (Trelong) study.

IL-6 expression is regulated by the interplay of several transcriptional and hormonal factors, including sex steroids and glucocorticoids. In late life IL-6 expression increases as a result from loss of the normally inhibiting sex steroids. IL-6 is one of several proinflammatory cytokines. It has been proposed that many chronic inflammatory diseases are the result of a dysregulation of IL-6 expression. In this work we demonstrate that increased IL-6 levels in elderly are associated with higher disability and mortality, also independently of age and comorbidity.

Interdisciplinary rehabilitation in morbidly obese subjects: an observational pilot study.

BACKGROUND AND AIM: To assess the clinical effectiveness of a interdisciplinary rehabilitation programme (CR), in a population of morbidly obese subjects we have undertaken a observational study. METHODS: The study included fifty-nine adult subjects (18 M, 60+/-10 years, BMI 47+/-8) with sleep-disturbance related symptoms and disabilities. Assessment and correction of sleep disordered breathing (SDB) abnormalities, improvement of exercise tolerance, body weight and associated psychological features were the aims of this CR, which has been carried out over a 1 month period. Lung functions, apnea/hypopnea index (AHI), 6-minute walking distance (6MWD), body weight (BW), quality of life by means of Sat-P questionnaire and serum metabolic data has been recorded at baseline (TO), at the end (Ti) and 6 months after (T2) the CR. RESULTS: The percentage of patients with AHI > 10 declined from 65% (at TO) to 20% (at both T1 and T2). 6MWD and BW significantly improved (p < 0.005) at T1 and still maintained at T2; a significant relationship (r = 0.379, p < 0.01) has been found between changes of BW and 6MWD recorded in between TO and T2. Sat-P item scores dealing with sleep efficiency, problem solving, and social interactions improved (p < 0.01) at T1 and still maintained at T2. CONCLUSIONS: This hospital-based CR provides indication for effectiveness in advanced morbidly obese subjects and warrants further controlled trials to confirm the results.

Exposure to ELF magnetic and ELF-modulated radiofrequency fields: the time course of physiological and cognitive effects observed in recent studies (2001-2005).

In 2002, we published a review of the cognitive and physiological effects of extremely low frequency magnetic fields (ELF MFs) and ELF-modulated radiofrequency fields associated with mobile phones. Since the original preparation of that review, a significant number of studies have been published using techniques such as electroencephalography, event-related potentials and positron emission tomography to investigate electromagnetic field effects upon human physiology and various measures of performance (cognitive, perceptual, behavioral). We review these recent studies, and when effects were observed, we reference the time course of observed effects (immediate or delayed). In our concluding remarks, we discuss a number of variables that are not often considered in human bioelectromagnetics studies, such as personality, individual differences and the specific laterality of ELF MF and mobile phone exposure over the brain. We also consider the sensitivity of various physiological assays and performance measures in the study of biological effects of electromagnetic fields.

Antihypertensive effect of oral potassium aspartate supplementation in mild to moderate arterial hypertension.

BACKGROUND: Previous studies showed that potassium chloride (48-120 mmol/day) supplementation reduced arterial blood pressure (BP) in hypertensive patients. OBJECTIVES: Our aim was to evaluate the effect of a lower dose of potassium aspartate salt on BP in individuals with essential arterial hypertension. METHODS: One hundred and four patients (65 males, age 53 +/- 12 years) with mild to moderate essential hypertension (systolic/diastolic BP 154.2/96.2 +/- 10.8/5.4 mmHg) were allocated in two comparable groups of 52 to receive or not 30 mmol/day per os of potassium aspartate supplementation for four weeks. Office and 24-h BP, as well as serum and urinary electrolytes, were measured at baseline and at the follow-up visit after four weeks. RESULTS: Office and 24-h BP did not change in the control group, while these values were significantly reduced in the potassium supplementation group. Changes in office (systolic BP: 154.4 +/- 8.2 vs. 142.2 +/- 7.6 mmHg; diastolic BP: 95.0 +/- 5.6 vs. 87.2 +/- 4.3 mmHg, P < 0.001 for both) and 24-h BP (systolic BP: 142.7 +/- 8.2 vs. 134.8 +/- 6.3 mmHg; diastolic BP: 90.8 +/- 4.4 vs. 84.6 +/- 3.8 mmHg, P < 0.001 for both) following potassium supplementation were highly significant. The changes in day time and night time BP were similar. The treated group showed significantly increased potassium serum level and 24-h urinary excretion of potassium (P < 0.01 in both cases) after four weeks, while the untreated group showed no significant changes of the same parameters. Urinary Na/K ratio decreased significantly with potassium supplementation (P < 0.001). In the treated group changes in office (r = 0.58, P < 0.001) and 24-h SBP (r = 0.51, P < 0.001), but not in DBP (r = 0.29 and r = 0.25, n.s.), correlated positively with the urinary Na/K ratio at baseline. CONCLUSIONS: A relatively low supplementation of 30 mmol/day of potassium as aspartate lowered office and 24-h ambulatory BP in subjects with mild to moderate essential hypertension. The antihypertensive effect was sustained throughout the day, and was greater in the patients with high basal urinary Na/K ratio.

Modeling (1H) exchange: an estimate of the error introduced in MRI by assuming the fast exchange limit in bolus tracking.

A simulation is presented which calculates the MRI signal expected from a model tissue for a given pulse sequence after a bolus injection of a contrast agent. The calculation assumes two physiologic compartments only, the intravascular and extravascular spaces. The determination of the concentration of contrast in each compartment as a function of time and position has been outlined in a previous publication (Moran and Prato, Magn Reson Med 2001;45:42-45). These contrast agent concentrations are used here to determine the NMR relaxation times as a function of time and position within the tissue. Knowledge of this simulated tissue 'map' of relaxation times as a function of time provides the information required to determine whether the proton exchange rate is fast or slow on the NMR timescale. Since with a bolus injection the concentration of contrast and hence the relaxation time may vary with position along the capillary, some segments of the capillary are allowed to be in fast exchange with the extravascular space, while others may be in slow exchange. Using this information, and parameters specific to a given tissue, the MRI signal for a given pulse sequence is constructed which correctly accounts for differences in proton exchange across the length of the capillary. It is shown that extravascular contrast agents show less signal dependence on water exchange, and thus may be more appropriate for quantitative imaging when using fast exchange assumptions. It is also shown that nondistributed compartment models can incorrectly estimate the water exchange that is occurring at the capillary level if exchange-minimizing pulse sequences are not used.

Results of current surveillance of likely bluetongue virus vectors of the genus Culicoides in Catalonia, Spain.

Following the outbreaks of bluetongue (BT) disease in sheep on the Balearic islands in 2000, a survey was conducted for Culicoides vectors along the eastern Catalonian cost of continental Spain where the presence of only C. obsoletus (Meigen) and C. pulicaris (Linnaeus) was known. Light-trap collections made at eight sites in 2002 yielded nine species of Culicoides, including C. imicola Kieffer (represented by a gravid female caught at Dosrius at a latitude of 41 degrees 35'N) and C. scoticus Downs and Kettle. The following season (2003), C. imicola was captured consistently at all sites and in greater numbers (maximum catch of 46) from August to November. The findings suggest that the distribution of C. imicola is extending northwards into Europe. The presence of four bluetongue vectors (C. imicola, C. obsoletus, C. pulicaris and C. scoticus) in Catalonia is of concern.

Epidemiological surveillance of bluetongue in Sicily.

The authors describe the status of bluetongue (BT) since 13 October 2000, when the first outbreak was reported in Sicily. The results of the epidemiological surveillance programme, based on sentinel animals distributed over the entire region, are also given. In Sicily, the incidence of the disease is relatively low compared to some other areas in the Mediterranean Basin. Seventy-five outbreaks of the disease were recorded in the first three epidemics (October 2000 to May 2003). Overall morbidity was 13.25%, mortality 5.36% and the case fatality rate 41.49%. The Province of Catania seems to have been the worst affected; the incidence rate in August 2002 was 0.8%. The monthly incidence rate was calculated for sentinel animals of which the estimated total was 3 654, distributed in 63 areas. It is important to underline that in the period under consideration, a total of 2 382 animals was examined. During the surveillance period, which extended from September 2001 to May 2003, the incidence of BT peaked in September 2002, at 5.91% -/+ 0.979. The cumulative incidence rate from September 2001 to August 2002 and September 2002 to March 2003 was 4.53% -/+ 0.76 and 20.03% -/+ 1.85, respectively. The circulation of BT virus serotypes 2, 4, 9 and 16 is described, as revealed by seroconversion in sentinel animals.

An investigation of the toxicity of gadolinium based MRI contrast agents using neutron activation analysis.

The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 +/- 0.17 ppm and 0.47 +/- 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 +/- 0.46 ppm for the bolus and 1.24 +/- 0.39 ppm for the bolus/constant infusion strategy and 0.16 +/- 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.