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Background Generalized anxiety disorder (GAD) is a common, chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically-informative research has examined the potential sources of reported brain differences.

A common approach to quantify gadolinium (Gd) contrast agents involves measuring the post-contrast change in T1 rate and then using the constant T1 relaxivity R to determine the contrast agent concentration. Because this method is fast and non-invasive, it could be potentially valuable in many areas of brain research. However, to accurately measure contrast agent concentrations in the brain, the T1 relaxivity R of the specific agent must be accurately known. Furthermore, the macromolecular content and compartmentalization of the brain extracellular space (ECS) are expected to significantly alter R from values measured in aqueous solutions. In this study, the T1 relaxivity R of gadolinium-diethylene-triamine penta-acetic acid (Gd-DTPA) was measured following direct interstitial infusions of three different contrast agent concentrations to the parenchyma of rat brains. Changes in magnetic resonance (MR) T1 values were compared to brain slice concentrations determined with inductively coupled plasma atomic emission spectroscopy (ICP-AES) to determine R in 15 rats. Additionally, samples of cerebrospinal fluid, blood and urine were analyzed to evaluate possible Gd-DTPA clearance from the brain. The T1 relaxivity R of Gd-DTPA in the brain ECS was measured to be 5.35 (mM s)(-1) in a 2.4 T field. This value is considerably higher than estimations used in studies by other groups. Measurements of brain Gd-DTPA tissue concentrations using MRI and ICP-AES demonstrated a high degree of coincidence. Clearance of Gd-DTPA was minimal at the time point immediately after infusion. These results suggest that the environment of the brain does in fact significantly affect Gd T1 relaxivity, and that MRI can accurately measure contrast agent concentrations when this relaxivity is well characterized.

The water soluble poly(ethylene glycol) (PEG) functionalized and hydroxylated endohedral trimetallic nitride metallofullerene derivatives, Gd3N@C80[DiPEG(OH)x], have been synthesized and characterized. The 1H MRI relaxivities in aqueous solution were measured for the derivatives with four different molecular weights of PEG (350–5000 Da) at 0.35 T, 2.4 T and 9.4 T. The 350/750 Da PEGs derivatives were found to have the highest relaxivities values among the derivatives, 237/232 mM−1s−1 for r1 and 460/398 mM−1s−1 for r2 (79/77 mM−1s−1 and 153/133 mM−1s−1 based on Gd3+ ion) respectively, at a clinical-range magnetic field of 2.4 T. These represent some of the highest relaxivities reported in the literatures for any commercial or investigational MRI contrast agent. Dynamic light scattering results confirm a larger size distribution for 350/750 Da PEGs derivatives (95/96 nm) relative to longer chain length derivatives, 5000 Da PEG derivatives (37nm). Direct infusion of the optimized 350 Da PEG derivatives into live tumor-bearing rat brains demonstrated an initial uniform distribution and hence, the potential for effective brachytherapy applications when the encapsulated Gd3+ ions are replaced with radioactive 177Lu.

A new magnetic resonance imaging (MRI) contrast agent based on the trimetallic nitride templated (TNT) metallofullerene Gd(3)N@C(80) was synthesized by a facile method in high yield. The observed longitudinal and transverse relaxivities r(1) and r(2) for water hydrogens in the presence of the water-soluble gadofullerene 2 Gd(3)N@C(80)(OH)(approximately 26)(CH(2)CH(2)COOM)(approximately 16) (M = Na or H) are 207 and 282 mM(-1) s(-1) (per C(80) cage) at 2.4 T, respectively; these values are 50 times larger than those of Gd(3+) poly(aminocarboxylate) complexes, such as commercial Omniscan and Magnevist. This high (1)H relaxivity for this new hydroxylated and carboxylated gadofullerene derivative provides high signal enhancement at significantly lower Gd concentration as demonstrated by in vitro and in vivo MRI studies. Dynamic light scattering data reveal a unimodal size distribution with an average hydrodynamic radius of ca. 78 nm in pure water (pH = 7), which is significantly different from other hydroxylated or carboxylated fullerene and metallofullerene derivatives reported to date. Agarose gel infusion results indicate that the gadofullerene 2 displayed diffusion properties different from those of commercial Omniscan and those of PEG5000 modified Gd(3)N@C(80). The reactive carboxyl functionality present on this highly efficient contrast agent may also serve as a precursor for biomarker tissue-targeting purposes.

Targeting tumor vasculature by colchicine site microtubule inhibitors is a new approach in cancer therapy. Here we investigate cis-3, 4′, 5-trimethoxy-3′-aminostilbene (stilbene 5c) in its effect on tumor vascular perfusion, pharmacokinetics, toxicity and therapeutic efficacy in a mouse xenograft model. Tumor xenograft model was established with subcutaneous injection of UCI-101 ovarian cancer cells into nude mice. Tumor blood perfusion was investigated by dynamic contrast-enhanced (DCE) MRI studies. Pharmacokinetic studies were performed by LC/MS/MS to quantify the concentrations of stilbene 5c in plasma. Tumor size was measured by the long and short axes of tumor to calculate tumor volume. Mouse cardiac function study was determined by Doppler echocardiography using the Vevo770TM imaging system. Microvascular density was determined by CD34 staining of tissue sections. Stilbene 5c selectively suppresses tumor perfusion without damaging normal organ perfusion in DCE-MRI studies. Histological sections of normal organs treated with stilbene 5c do not reveal any major toxicity in H&E staining. Microvascular density determined by CD34 staining is unchanged in normal organs, but significantly decreased in tumor after stilbene 5c treatment. Biodistribution study shows that stilbene 5c is not detectable in heart and lung, rapidly decreased in brain, liver, and kidney, but remains high in tumor for more than 3 h after IV injection of stilbene 5c, suggesting preferential accumulation in tumor. Mice treated with 5 days of stilbene 5c had negligible cardiac toxicity based on their normal left ventricular ejection fraction. In vivo efficacy study of stilbene 5c showed that it only suppresses tumor growth by 40% if used alone, but combination with bevacizumab is significantly better. Stilbene 5c is a useful vascular disrupting agent and combination with bevacizumab could be a promising therapy for cancer.

Aim To determine the absorbed radiation dose to the female breast during chest computed tomography (CT), and whether a custom-designed breast shield can reduce that dose. Materials and methods Bilateral breast phantoms were combined with an anthropomorphic torso phantom. Each breast phantom contained 20 thermoluminescent dosimeter (TLD) cavities. Eight cavities were used per phantom. Absorbed radiation was measured using TLD 100s. Three-stacked TLDs comprised a set. Three sets of three TLDs were positioned at eight designated locations and three depths (surface; 1 cm; 4 cm). One set of three TLDs was positioned at eight additional designations, 1 cm deep. Each breast was divided anatomically into quadrants. In total, 32 TLD sets/96 TLDs were deployed. The breast–torso phantom was consecutively imaged using a 16-detector array CT machine. Subsequently, 32 new TLD sets were similarly placed, the phantom re-imaged in a likewise manner, but with the application of a tungsten–antimony composite breast shield. TLD readings were averaged and calculated. Results Average absorbed radiation doses for unshielded right and left breast phantoms ranged from 13.83–19.36 mGy, and 14–20.47 mGy, respectively. The absorbed dose in the shielded right and left breast was reduced to 6.64–8.12 mGy, and 6.7–8.03 mGy, respectively. Average absorbed radiation doses based on the depth for the unshielded breasts ranged from 15.4–18.3 mGy. Shielding reduced this dose to 7–7.9 mGy. Unshielded absorbed radiation doses based on anatomic quadrants ranged from 17.5–18.9 mGy. Shielding reduced this dose to 7–7.5 mGy. Conclusions The average absorbed radiation dose to the unshielded female breast phantom is approximately 14–20 mGy. An externally applied shield can reduce this absorbed dose by 56–61%.

A new magnetic resonance imaging contrast agent containing organophosphonate functional groups was synthesized in high yield by a simple synthesis procedure. This molecule exhibits much higher longitudinal water proton relaxivity (37.0 mM−1 s−1) than commercial Omniscan (Gd-DTPA BMA, 5.7 mM−1 s−1) at 0.35 T. Notably, the relaxivity is larger than that of carboxylated Gd@C82 (16.0 mM−1 s−1) under the same conditions, indicating that the functional groups have an important role on the image contrast enhancement. In addition, the introduction of phosphonate substituents may provide bone-targeting MRI contrast agents.

Enhanced ferrite nanoparticles are a new class of contrast agents for magnetic resonance imaging (MRI). The enhanced ferrites are synthesized by reverse micelles technique to form iron core and oxide or ferrite shell preventing further oxidation of the nanoparticles. The nanoparticles are further functionalized using dopamine and PEG-600 to increase the solubility of the high magnetic moment nanoparticles. 1 H relaxation measurements of aqueous solutions of the nanoparticles were conducted at 2.4 T. The relaxivities r 1 and r 2 , representing the slopes of these curves, are 7.19 and 9.96 s −1 mM −1 , respectively. These values should be compared with relaxivities of 4–5 s −1 mM −1 corresponding to commonly used commercial contrast agents in human MR examinations.

Object The edema associated with brain swelling after traumatic brain injury (TBI) has been thought to be vasogenic in origin, but the results of previous laboratory studies by the authors have shown that a cellular form of edema is mainly responsible for brain swelling after TBI. In this study the authors used magnetic resonance (MR) imaging techniques to identify the type of edema that occurs in patients with TBI. Methods Diffusion-weighted MR imaging was used to evaluate the apparent diffusion coefficient (ADC) in 44 patients with TBI (Glasgow Coma Scale Score < 8) and in eight healthy volunteers. Higher ADC values have been associated with vasogenic edema, and lower ADC values with a predominantly cellular form of edema. Regional measurements of ADC in patients with focal and diffuse injury were computed. The water content of brain tissue was also assessed in absolute terms by using MR imaging to measure the percentage of water per gram of tissue. Cerebral blood flow (CBF) was measured using stable Xe–computerized tomography (CT) studies to rule out ischemia as a cause of cellular edema. The mean ADC value in the healthy volunteers was 0.82 ± 0.05 × 10−3 mm2/second. The ADC values in the patients with diffuse brain injury without swelling were close to the mean for the healthy volunteers. In contrast, the patients with brain swelling had increased brain water content and low ADC values (mean 0.74 ± 0.05 × 10−3 mm2/second). The ADC values correlated with CT classifications. In all patients with low ADC values, the CBF values were outside the range for ischemia. Conclusions The brain swelling observed in patients with TBI appears to be predominantly cellular, as signaled by low ADC values in brain tissue with high levels of water content.

Object. The goal of this study was to validate a simple, inexpensive, and robust model system to be used as an in vitro surrogate for in vivo brain tissues in preclinical and exploratory studies of infusion-based intraparenchymal drug and cell delivery. Methods. Agarose gels of varying concentrations and porcine brain were tested to determine the infusion characteristics of several different catheters at flow rates of 0.5 and 1 µl per minute by using bromophenol blue (BPB) dye (molecular weight [MW] ∼690) and gadodiamide (MW ∼573). Magnetic resonance (MR) imaging and videomicroscopy were used to measure the distribution of these infusates, with a simultaneous measurement of infusion pressures. In addition, the forces of catheter penetration and movement through gel and brain were measured. Agarose gel at a 0.6% concentration closely resembles in vivo brain with respect to several critical physical characteristics. The ratio of distribution volume to infusion volume of agarose was 10 compared with 7.1 for brain. The infusion pressure of the gel demonstrated profiles similar in configuration and magnitude to those of the brain (plateau pressures 10–20 mm Hg). Gadodiamide infusion in agarose closely resembled that in the brain, as documented using T1-weighted MR imaging. Gadodiamide distribution in agarose gel was virtually identical to that of BPB dye, as documented by MR imaging and videomicroscopy. The force profile for insertion of a silastic catheter into agarose gel was similar in magnitude and configuration to the force profile for insertion into the brain. Careful insertion of the cannula using a stereotactic guide is critical to minimize irregularity and backflow of infusate distribution. Conclusions. Agarose gel (0.6%) is a useful surrogate for in vivo brain in exploratory studies of convection-enhanced delivery.

We report on some extensions and further developments of a well-known microcalcification detection algorithm based on adaptive noise equalization. Tissue equivalent phantom images with and without labeled microcalcifications were subjected to this algorithm, and analyses of results revealed some shortcomings in the approach. Particularly, it was observed that the method of estimating the width of distributions in the feature space was based on assumptions which resulted in the loss of similarity preservation characteristics. A modification involving a change of estimator statistic was made, and the modified approach was tested on the same phantom images. Other modifications for improving detectability such as downsampling and use of alternate local contrast filters were also tested. The results indicate that these modifications yield improvements in detectability, while extending the generality of the approach. Extensions to real mammograms and further directions of research are discussed.

N-acetyl-aspartate (NAA) measured by proton nuclear magnetic resonance spectroscopy (1H-NMR) has been used as a marker of neuronal injury in many cerebral pathologies. Therefore, we evaluate the roles of microdialysis vs. 1H-NMR as techniques to assess NAA (NAAd; NAA/Creatine ratio) in the living brain, and compare the results with whole brain NAA (NAAw), analyzed by HPLC after diffuse traumatic brain injury (TBI). Acute (4 h post-injury survival) and late (48 h survival) changes were studied in a sham-operated group (Sham, n = 4), and two injured groups (TBI/4 h, n = 8; TBI/48 h, n = 7). Baseline NAAd was 8.17 +/- 1 microM, and there was no significant difference between groups. There was only a small (twice of control), but transient increase in NAAd in the TBI/4 h group after trauma. Baseline NAA/Cr ratio was 1.35 +/- 0.2, which did not change significantly between baseline, 1, 2, 3, 4 and 48 h or between groups after TBI. Whole brain NAAw (baseline 8.5 +/- 0.5 mmol kg-1 wet weight) did not differ significantly between groups before and after TBI. Diffuse TBI did not produce long-term changes in NAA, assessed by three different methods. These results may indicate that NAA is not a sensitive marker of the severity of diffuse axonal damage. However, further studies are needed to evaluate whether confounding factors such as microdialysis probe, voxel position and non-regional tissue homogenization might have influenced our data.

Object. The pathogenesis of traumatic brain swelling remains unclear. The generally held view is that brain swelling is caused primarily by vascular engorgement and that edema plays a relatively minor role in the swelling process. The goal of this study was to examine the roles of cerebral blood volume (CBV) and edema in traumatic brain swelling.Methods. Both brain-tissue water and CBV were measured in 76 head-injured patients, and the relative contribution of edema and blood to total brain swelling was determined. Comparable measures of brain-tissue water were obtained in 30 healthy volunteers and CBV in seven volunteers. Brain edema was measured using magnetic resonance imaging, implementing a new technique for accurate measurement of total tissue water. Measurements of CBV in a subgroup of 31 head-injured patients were based on consecutive measures of cerebral blood flow (CBF) obtained using stable xenon and calculation of mean transit time by dynamic computerized tomography scanning after a rapid bolus injection of iodinated contrast material. The mean (± standard deviation) percentage of swelling due to water was 9.37 ± 8.7%, whereas that due to blood was −0.8 ± 1.32%.Conclusions. The results of this study showed that brain edema is the major fluid component contributing to traumatic brain swelling. Moreover, CBV is reduced in proportion to CBF reduction following severe brain injury.

We measured serial changes in diffusion-weighted magnetic resonance imaging (DW) and in apparent diffusion coefficient (ADC) 1 to 3 hours after induction of acute subdural hematoma (ASDH) in rats, to assess the rate of development of cytotoxic edema and ischemic brain damage observed in this model. Cortical ADC values underneath the hematoma in ASDH rats (n = 12) were significantly lower than those in sham-operated rats (n = 5) at 1 hour. By 3 hours, the area of ADC abnormality had further increased. The lesion areas, as percentage of hemispheric areas on 1- and 3-hour ADC maps, correlated significantly with those on the histologic sections stained with hematoxylin and eosin. The results indicate that DWI with ADC mapping may provide a valuable diagnostic tool for monitoring of early pathologic changes following subdural hematoma in head-injured patients.

Evaluation of mammograms for artifacts is essential for mammographic quality assurance. A variety of mammographic artifacts (i.e., variations in mammographic density not caused by true attenuation differences) can occur and can create pseudolesions or mask true abnormalities. Many artifacts are readily identified, whereas others present a true diagnostic challenge. Factors that create artifacts may be related to the processor (eg, static, dirt or excessive developer buildup on the rollers, excessive roller pressure, damp film, scrapes and scratches, incomplete fixing, power failure, contaminated developer), the technologist (eg, improper film handling and loading, improper use of the mammography unit and related equipment, positioning and darkroom errors), the mammography unit (eg, failure of the collimation mirror to rotate, grid inhomogeneity, failure of the reciprocating grid to move, material in the tube housing, compression failure, improper alignment of the compression paddle with the Bucky tray, defective compression paddle), or the patient (e.g., motion, superimposed objects or substances [jewelry, body parts, clothing, hair, implanted medical devices, foreign bodies, substances on the skin]). Familiarity with the broad range of artifacts and the measures required to eliminate them is vital. Careful attention to darkroom cleanliness, care in film handling, regularly scheduled processor maintenance and chemical replenishment, daily quality assurance activities, and careful attention to detail during patient positioning and mammography can reduce or eliminate most mammographic artifacts.

Object. The authors present a quantitative in vivo magnetic resonance (MR) imaging method and propose its use for the accurate assessment of brain water in humans.Methods. With this technique, a pure T1-weighted image of a selected brain slice in a patient is generated, and the image is subsequently converted to a pure water image by means of an equation derived from a tissue relaxation model. The image intensity in the resulting water map directly yields absolute measures of water expressed in grams of water per gram of tissue at a given anatomical location. The method has been validated previously in a series of phantom experiments and in an infusion model of brain edema in cats. In this report, the authors evaluate the method by using samples of tissue harvested from patients who underwent surgery for brain tumor removal and apply the technique to a series of normal volunteers, providing average regional brain water content (fw) values for a range of tissues. Application of the method in pathological conditions such as head trauma, tumor, and hydrocephalus allows quantification of regional or global increases in fw that result from edema.Conclusions. It is now possible to obtain accurate brain water measurements with the anatomical resolution of MR imaging. This permits monitoring of the development and resolution of edema in a variety of clinical circumstances, thus enhancing understanding of the underlying pathophysiological processes.

✓ The contribution of brain edema to brain swelling in cases of traumatic brain injury remains a critical problem. The authors believe that cellular edema, the result of complex neurotoxic events, is the major contributor to brain swelling and that vasogenic edema, secondary to blood-brain barrier compromise, may be overemphasized. The objective of this study, therefore, was to quantify temporal water content changes and document the type of edema that forms during the acute and late stages of edema development following closed head injury (CHI). The measurement of brain water content was based on magnetic resonance imaging—determined values of tissue longitudinal relaxation time (T1-weighted imaging) and their subsequent conversion to percentage of water, whereas the differentiation of edema formation (cellular vs. vasogenic) was based on the measurement of the apparent diffusion coefficient (ADC) by diffusion-weighted imaging. A new impact-acceleration model was used to induce CHI. Thirty-six adult Sprague—Dawley rats were separated into two groups: Group I, control (six animals); and Group II, trauma (30 animals). Fast ADC measurements (localized, single-voxel) were obtained sequentially (every minute) up to 1 hour postinjury. The T1-weighted images, used for water content determination, and the diffusion-weighted images (ADC measurement with conventional diffusion-weighted imaging) were obtained at the end of the 1st hour postinjury and on Days 1, 3, 7, 14, 28, and 42 in animals from the trauma and control groups. In the animals subjected to trauma, the authors found a significant increase in ADC (10 ± 5%) and brain water content (1.3 ± 0.9%) during the first 60 minutes postinjury. This is consistent with an increase in the volume of extracellular fluid and vasogenic edema formation as a result of blood-brain barrier compromise. This transient increase, however, was followed by a continuing decrease in ADC that began 40 to 60 minutes postinjury and reached a minimum value on Days 7 to 14 (10 ± 3% reduction). Because the water content of the brain continued to increase during the first 24 hours postinjury (1.9 ± 0.9%), it is suggested that the decreased ADC indicated cellular edema formation, which started to develop soon after injury and became dominant between 1 and 2 weeks postinjury. The study provides supportive evidence that cellular edema is the major contributor to posttraumatic swelling in diffuse CHI and defines the onset and duration of the increase in cellular volume.

Background and Purpose The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke. Methods Seventeen adult cats were allocated to control (n=7) and CP101,606-treated groups (n=10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)–stained section, with and without neuroprotective agents, was used to determine the value of these potential “surrogate markers” of ischemic damage. Results The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P Conclusions CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.

Background and Purpose Knowledge of cerebral blood volume (CBV) is invaluable in identifying the primary cause of brain swelling in patients with stroke or severe head injury, and it might also help in clinical decision making in patients thought to have hemodynamic transient ischemic attacks (TIAs). This investigation is concerned with the development and clinical application of a new method for quantitative regional CBV measurements. Methods The technique is based on consecutive measurements of cerebral blood flow (CBF) by xenon/CT and tissue mean transit time (MTT) by dynamic CT after a rapid iodinated contrast bolus injection. CBV maps are produced by multiplication of the CBF and MTT maps in accordance with the Central Volume Principle: CBV=CBF×MTT. The method is rapid and easily implemented on CT scanners with the xenon/CBF capability. It yields CBV values expressed in milliliters of blood per 100 grams of tissue. Results The method was validated under controlled physiological conditions causing changes that were determined both with our technique and from pressure-volume index (PVI) measurements. The two independent estimates of CBV changes were in agreement within 15%. CBV measurements using this method were carried out in normal volunteers to establish baseline values and to compare with values using the ratio-of-areas method for calculating both CBF and CBV from the dynamic study alone. Average CBV was 5.3 mL/100 g. The method was also applied in 71 patients with severe head injuries and in 1 patient with hemodynamic TIAs. Conclusions The primary conclusions from this study were (1) the proposed method for measuring CBV accurately determines changes in CBV; (2) the MTT×CBF determinations are in agreement with the ratio-of-areas method for CBV measurements in normal volunteers and are consistent with other methods reported in the literature; (3) MTTs are significantly prolonged early after severe head injury, which when combined with the finding of decreased CBF and increased arteriovenous difference of oxygen indicates increased cerebrovascular resistance due to narrowing of the microcirculation consistent with the presence of early ischemia; and (4) CBV in the patient with TIAs was increased in the hemisphere with the occluded internal carotid artery, indicating compensatory vasodilation and probable hemodynamic cause.

Fullerenes are used across scientific disciplines because of their diverse properties gained by altering encapsulated or surface-bound components. In this study, the recently developed theranostic agent based on a radiolabeled functionalized metallofullerene ((177)Lu-DOTA-f-Gd(3)N@C(80)) was synthesized with high radiochemical yield and purity. The efficacy of this agent was demonstrated in two orthotopic xenograft brain tumor models of glioblastoma multiforme (GBM). A dose-dependent improvement in survival was also shown. The in vivo stability of the agent was verified through dual label measurements of biological elimination from the tumor. Overall, these results provide evidence that nanomaterial platforms can be used to deliver effective interstitial brachytherapy.

The current report describes the development of a dual modality tomographic agent for both positron emission tomography and magnetic resonance imaging (PET/MRI). The dual-modality agent in this study was based on a 124I (PET) radiolabeled tri-gadolinium endohedral metallofullerene Gd3N@C80 (MRI) nanoprobe platform. The outer surface of the fullerene cage of the Gd3N@C80 metallofullerenes was surface functionalized with carboxyl and hydroxyl groups (f-Gd3N@C80) using previously developed procedures and subsequently iodinated with 124I to produce 124I-f-Gd3N@C80 nanoprobe. Orthotopic tumor-bearing rats were infused intratumorally by convection-enhanced delivery (CED) with the 124I-f-Gd3N@C80 agent and imaged by MRI or micro PET. The anatomical positioning and distribution of the 124I-f-Gd3N@C80 agent were comparable between the MRI and PET scans. The 124I-f-Gd3N@C80_ dual-agent distribution and infusion site within the tumor was clearly evident in both T1- and T2-weighted MR images. The results demonstrate the successful preparation of a dual-modality imaging agent, 124I-f-Gd3N@C80, which could ultimately be used for simultaneous PET/MR imaging. Published version

The pathogenesis of hepatic encephalopathy(HE) is unclear. However gut flora changes, inflammation and neuro-glial injury have been implicated. The aim was to evaluate factors that were associated with HE recurrence after lactulose withdrawal by analyzing the clinical phenotype, stool microbiome and systemic metabolome longitudinally. HE patients on a standard diet who were adherent on lactulose underwent characterization of their phenotype [cognition, inflammatory cytokines, in-vivo brain MR spectroscopy(MRS)], gut microbiome (stool Multitag Pyrosequencing) and metabolome (urine/serum ex-vivo MRS) analysis while on lactulose and on days 2, 14 and 30 post-withdrawal. Patients whose HE recurred post-withdrawal were compared to those without recurrence. We included seven men (53 ± 8 years) who were adherent on lactulose after a precipitated HE episode were included. HE recurred in three men 32 ± 6 days post-withdrawal. In-vivo brain MRS showed increased glutamine+glutamate (Glx) and decreased myoinositol with a reduction in stool Faecalibacterium spp., post-withdrawal. HE recurrence was predicted by poor baseline inhibitory control and block design performance and was associated with a shift of choline metabolism from tri-methylamine oxide formation towards the development of di-methylglycine, glycine and creatinine. This was accompanied by a mixed effect on the immune response (suppressed IL-10 and Th1/Th2/Th17 response). The correlation network showed Prevotella to be linked to improved cognition and decreased inflammation in patients without HE recurrence. We conclude that lactulose withdrawal results in worsening cognition, mixed inflammatory response effect, lowered stool Faecalibacterium and increase in MR-measurable brain Glx. HE recurrence post-lactulose withdrawal can be predicted by baseline cognitive performance and is accompanied by disrupted choline metabolism.

At the present time dental X-rays are the best method to locate carious lesions, however, small lesions can be detected only with difficulty. Even though investigations in the past have shown that light imaging systems are more sensitive to small lesions than X-rays it is difficult to determine the characteristics of these lesions with any of these systems. We developed a new light imaging technique that makes it much easier to determine the size and depth of these lesions on most areas of the teeth even though modifications on the present setup will still be necessary to detect them as easily on occlusal surfaces. This technique is based on raster scans of the teeth with narrow collimated light beams. The results of this investigation show that the areas ( greater than 0.1 mm 2) of small incipient lesions can be measured and their depths estimated.

To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd₃N@C₈₀) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (¹⁷⁷Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (¹⁷⁷Lu-DOTA-f-Gd₃N@C₈₀), provide an anchor to deliver effective brachytherapy.All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd₃N@CC₈₀ alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of ¹⁷⁷Lu-DOTA-f-Gd₃N@CC₈₀. Survival data were evaluated by using Kaplan-Meier statistical methods.MR imaging showed extended tumor retention (25.6% ± 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f-Gd₃N@CC₈₀ nanoplatform, which enabled longitudinal imaging. Successful coupling of ¹⁷⁷Lu to the f-Gd₃N@CC₈₀ surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage.The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe retention, biodistribution, and extended survival in an orthotopic xenograft brain tumor model.

In traditional transillumination of the breast (diaphanography), the abundance of diffuse light resulting from the use of extended noncollimated sources reduces the visibility of deep seated lesions. A prototype scanning imaging system has been developed to investigate the effectiveness of thin collimated light beams (1.5 mm cross section) synchronized with a similarly collimated detector to increase contrast in lesions normally lost due to the detection of diffuse light. The study demonstrates that detection of opaque 1.5 mm details is possible in phantoms simulating breast tissues 6 mm thick regardless of depth. This is about 10 times better than images obtained on the same samples using present transillumination methods. Furthermore, this study indicates that internal structures (lesions, cysts) in up to 12 mm thick excised breast sections can be visualized by exploiting their frequency-dependent attenuation. This is accomplished by inserting 50 nm interference filters in the input light path, which can be varied in a stepwise manner in the range of 400 nm to 1000 nm. These results demonstrate for the first time that images of lesion-bearing 1 cm or larger tissues can be obtained, thus opening promising possibilities for whole-breast imaging. >

Single-walled carbon nanohorns (SWNHs) are new carbonaceous materials. In this paper, we report the first successful preparation of SWNHs encapsulating trimetallic nitride template endohedral metallofullerenes (TNT-EMFs). The resultant materials were functionalized by a high-speed vibration milling method and conjugated with CdSe/ZnS quantum dots (QDs). The successful encapsulation of TNT-EMFs and external functionalization with QDs provide a dual diagnostic platform for in vitro and in vivo biomedical applications of these new carbonaceous materials.

Convection-enhanced delivery (CED) could have clinical application in the delivery of neuroprotective agents following ischemic stroke. However, ischemic brain tissue changes such as cytotoxic edema, in which cellular swelling decreases the fractional volume of the extracellular space, would be expected to significantly alter the distribution of neuroprotective agents delivered by CED. We sought to predict and characterize these effects using the magnetic resonance contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a model therapeutic agent. CED was observed using MRI in a normal rat brain and in a middle cerebral artery (MCA) occlusion rat model of brain ischemia. Gd-DTPA was infused to the caudate putamen in the normal rat (n = 6) and MCA occlusion model (n = 6). In each rat, baseline apparent diffusion coefficient images were acquired prior to infusion, and T1 maps were then acquired 13 times throughout the duration of the experiment. These T1 maps were used to compute Gd-DTPA concentrations throughout each brain. In the MCA occlusion group, CED delivered Gd-DTPA to a comparatively larger volume with lower average tissue concentrations. Following the infusion, the total content of Gd-DTPA decreased more slowly in the MCA occlusion group than in the normal group. This quantitative characterization confirms that edematous ischemic tissue changes alter the distribution of agents by CED. These findings may have important implications for CED in the treatment of brain injury, and will assist in future efforts to model the distribution of therapeutic agents.

✓ The role of cerebral ischemia in the pathophysiology of traumatic brain injury is unclear. Cerebral blood flow (CBF) measurements with 133Xe have thus far revealed ischemia in a substantial number of patients only when performed between 4 and 12 hours postinjury. But these studies cannot be performed sooner after injury, they cannot be done in patients with intracranial hematomas still in place, and they cannot detect focal ischemia. Therefore, the authors performed CBF measurements in 35 comatose head-injured patients using stable xenon-enhanced computerized tomography (CT), simultaneously with the initial CT scan (at a mean (± standard error of the mean) interval of 3.1 ± 2.1 hours after injury). Seven patients with diffuse cerebral swelling had significantly lower flows in all brain regions measured as compared to patients without swelling or with focal contusions; in four of the seven, cerebral ischemia (CBF ≤ 18 ml/100 gm · min−1) was present. Acute intracranial hematomas were associated with decreased CBF and regional ischemia in the ipsilateral hemisphere, but did not disproportionately impair brain-stem blood flow. Overall, global or regional ischemia was found in 11 patients (31.4%). There was no correlation between the presence of hypoxia or hypertension before resuscitation and the occurrence of ischemia, neither could ischemia be attributed to low pCO2. Ischemia was significantly associated with early mortality (p < 0.02), whereas normal or high CBF values were not predictive of favorable short-term outcome. These data support the hypothesis that ischemia is an important secondary injury mechanism after traumatic brain injury, and that trauma may share pathophysiological mechanisms with stroke in a large number of cases; this may have important implications for the use of hyperventilation and antihypertensive drugs in the acute management of severely head-injured patients, and may lead to testing of drugs that are effective or have shown promise in the treatment of ischemic stroke.

Quantitative MR phase imaging is frequently used to measure spin velocities. A potential difficulty may arise, however, when in-plane phase images are acquired of a vessel carrying laminar flow, for which the fluid velocity profile is parabolic. In that case, depending on the flow velocity (v), the vessel diameter (D), and the chosen MR slice thickness (ST), a spin velocity gradient will be present to some extent within each intraluminal voxel. The resulting intravoxel phase dispersion may be expected to affect the net pixel phase value, and hence compromise the assumed linear correlation between phase shift and velocity. In this study, the effects of alterations of v, D, and ST on the apparent image phase are investigated for the case of laminar flow directed parallel to the sequence read gradient. A theoretical model is developed and the conclusions experimentally tested using a flow phantom. The data demonstrate that when quantitating inplane phase-flow images, significant velocity underestimations may occur when the net flow-induced phase shifts are small and the MR slice thickness is an appreciable fraction of the vessel diameter.

This work is concerned with the accurate quantification of brain water content under routine clinical conditions. Gelatin solutions of varying water content are first employed as a model of an edematous brain and longitudinal relaxation measurements are performed at proton Larmor frequencies of 5, 41, 63, and 100 MHz. These are followed with in vivo measurements in an experimental animal model of brain edema at 41 MHz. The results underscore the dominant role of total water content W in the relaxation process and verify the expected linearity between 1/T1 and 1/W. A scheme is presented and experimentally verified at 41 MHz for deducing the exact relationship of 1/T1 vs 1/W at any frequency. Knowledge of this relationship along with precise measurements of 1/T1 at a given field strength permits quantitative in vivo measures of brain water content to be obtained with a precision of about 0.01. It is concluded that routine, accurate, and noninvasive brain water measurements are possible by magnetic resonance imaging in a clinical environment.

Water-soluble gadofullerides exhibited high efficiency as magnetic resonance imaging (MRI) contrast agents. In this paper, we report the conjugation of the newly synthesized gadofulleride, Gd@C82O6(OH) 16(-)(NHCH2CH2COOH)8, with the antibody of green fluorescence protein (anti-GFP), as a model for "tumor targeted" imaging agents based on endohedral metallofullerenes. In this model system, the activity of the anti-GFP conjugate can be conveniently detected by green fluorescence protein (GFP), leading to in vitro experiments more direct and facile than those of tumor antibodies. Objective-type total internal reflection fluorescence microscopy revealed that each gadofulleride aggregate conjugated on average five anti-GFPs, and the activity of anti-GFPs was preserved after conjugation. In addition, the gadofulleride/antibody conjugate exhibited higher water proton relaxivity (12.0 mM (-1) s (-1)) than the parent gadofulleride aggregate (8.1 mM (-1) s (-1)) in phosphate buffered saline at 0.35 T, as also confirmed by T1-weighted images of phantoms. These observations clearly indicate that the synthesized gadofulleride/antibody conjugate not only has targeting potential, but also exhibits higher efficiency as an MRI contrast agent.

Object The goal of this study was to demonstrate the posttraumatic neurochemical damage in normal-appearing brain and to assess mitochondrial dysfunction by measuring N-acetylaspartate (NAA) levels in patients with severe head injuries, using proton (1H) magnetic resonance (MR) spectroscopy. Methods Semiquantitative analysis of NAA relative to creatine-containing compounds (Cr) and choline (Cho) was carried out from proton spectra obtained by means of chemical shift (CS) imaging and single-voxel (SV) methods in 25 patients with severe traumatic brain injuries (TBIs) (Glasgow Coma Scale scores ≤ 8) using a 1.5-tesla MR unit. Proton MR spectroscopy was also performed in 5 healthy volunteers (controls). Results The SV studies in patients with diffuse TBI showed partial reduction of NAA/Cho and NAA/Cr ratios within the first 10 days after injury (means ± standard deviations 1.59 ± 0.46 and 1.44 ± 0.21, respectively, in the patients compared with 2.08 ± 0.26 and 2.04 ± 0.31, respectively, in the controls; nonsignificant difference). The ratios gradually declined in all patients as time from injury increased (mean minimum values NAA/Cho 1.05 ± 0.44 and NAA/Cr 1.05 ± 0.30, p < 0.03 and p < 0.02, respectively). This reduction was greater in patients with less favorable outcomes. In patients with focal injuries, the periphery of the lesions revealed identical trends of NAA/Cho and NAA/Cr decrease. These reductions correlated with outcome at 6 months (p < 0.01). Assessment with multivoxel methods (CS imaging) demonstrated that, in diffuse injury, NAA levels declined uniformly throughout the brain. At 40 days postinjury, initially low NAA/Cho levels had recovered to near baseline in patients who had good outcomes, whereas no recovery was evident in patients with poor outcomes (p < 0.01). Conclusions Using 1H-MR spectroscopy, it is possible to detect the posttraumatic neurochemical damage of the injured brain when conventional neuroimaging techniques reveal no abnormality. Reduction of NAA levels is a dynamic process, evolving over time, decreasing and remaining low throughout the involved tissue in patients with poor outcomes. Recovery of NAA levels in patients with favorable outcomes suggests marginal mitochondrial impairment and possible resynthesis from vital neurons.

Background We believe that in traumatic brain injury (TBI), the reduction of N-acetyl aspartate (NAA) occurs in the presence of adequate cerebral blood flow (CBF) which would lend support to the concept of mitochondrial impairment. The objective of this study was to test this hypothesis in severely injured patients (GCS 8 or less) by obtaining simultaneous measures of CBF and NAA. Methods Fourteen patients were studied of which six patients presented as diffuse injury at admission CT, while focal lesions were present in eight patients. CBF using stable xenon method was measured at the same time that NAA was measured by magnetic resonance proton spectroscopy (1HMRS) in the MR suite. Additionally, diffusion weighted imaging (DWI) and maps of the apparent diffusion coefficient (ADC) were assessed. Findings In diffuse injury, NAA/Cr reduction occurred uniformly throughout the brain where the values of CBF in all patients were well above ischemic threshold. In focal injury, we observed ischemic CBF values in the core of the lesions. However, in areas other than the core, CBF was above ischemic levels and NAA/Cr levels were decreased. Conclusions Considering the direct link between energy metabolism and NAA synthesis in the mitochondria, this study showed that in the absence of an ischemic insult, reductions in NAA concentration reflects mitochondrial dysfunction.

A bolus-tracking magnetic resonance imaging (MRI) method has been employed to measure velocity profiles for oscillatory flow with and without a steady flow component as well as pulsatile flow in an axisymmetric tube model. A range of flow conditions within normal physiological limits was tested. The imaged velocity profiles were observed to be generally in accord with theoretical predictions. Instantaneous flow rates calculated from the MR images agreed well with those assessed using an ultrasonic flowmeter. Because MRI is noninvasive and poses few risks to subjects, this technique is potentially useful for studying vascular hemodynamics in vivo.

To evaluate the effectiveness of a functionalized trimetallic nitride endohedral metallofullerene nanoparticle as a magnetic resonance (MR) imaging proton relaxation agent and to follow its distribution for in vitro agarose gel infusions and in vivo infusions in rat brain.The animal study was approved by the animal care and use committee. Gd(3)N@C(80) was functionalized with poly(ethylene glycol) units, and the carbon cage was hydroxylated to provide improved water solubility and biodistribution. Relaxation rate measurements (R1 = 1/T1 and R2 = 1/T2) of water solutions of this contrast agent were conducted at 0.35-, 2.4-, and 9.4-T MR imaging. Images of contrast agent distributions were produced following infusions in six agarose gel samples at 2.4 T and from direct brain infusions into normal and tumor-bearing rat brain at 2.4 T. The relaxivity of a control functionalized lutetium agent, Lu(3)N@C(80), was also determined.Water hydrogen MR imaging relaxivity (r1) for this metallofullerene nanoparticle was markedly higher than that for commercial agents (eg, gadodiamide); r1 values of 102, 143, and 32 L . mmol(-1) . sec(-1) were measured at 0.35, 2.4, and 9.4 T, respectively. In studies of in vitro agarose gel infusion, the use of functionalized Gd(3)N@C(80) at concentrations an order of magnitude lower resulted in equivalent visualization in comparison with commercial agents. Comparable contrast enhancement was obtained with direct infusions of 0.013 mmol/L of Gd(3)N@C(80) and 0.50 mmol/L of gadodiamide in live normal rat brain. Elapsed-time studies demonstrated lower diffusion rates for Gd(3)N@C(80) relative to gadodiamide in live normal rat brain tissue. Functionalized metallofullerenes directly infused into a tumor-bearing brain provided an improved tumor delineation in comparison with the intravenously injected conventional Gd(3+) chelate. A control lutetium functionalized Lu(3)N@C(80) nanoparticle exhibited very low MR imaging relaxivity.The new functionalized trimetallic nitride endohedral metallofullerene species Gd(3)N@C(80)[DiPEG5000(OH)(x)] is an effective proton relaxation agent, as demonstrated with in vitro relaxivity and MR imaging studies, in infusion experiments with agarose gel and in vivo rat brain studies simulating clinical conditions of direct intraparenchymal drug delivery for the treatment of brain tumors.

The objective of this study was to confirm the nature of the edema, cellular or vasogenic, in traumatic brain injury in head-injured patients using magnetic resonance imaging techniques. Diffusion-weighted imaging methods were quantified by calculating the apparent diffusion coefficients (ADC). Brain water and cerebral blood flow (CBF) were also measured using magnetic resonance and stable Xenon CT techniques. After obtaining informed consent, 45 severely injured patients rated 8 or less on Glasgow Coma Scale (32 diffuse injury, 13 focal injury) and 8 normal volunteers were entered into the study. We observed that in regions of edema, the ADC was reduced, signifying a predominantly cellular edema. The ADC values in diffuse injured patients without swelling were close to normal and averaged 0.89 ± 0.08. This was not surprising, as ICP values for these patients were low. In contrast, in patients with significant brain swelling ADC values were reduced and averaged 0.74 ± 0.05 (p < 0.0001), consistent with a predominantly cellular edema. We also found that the CBF in these regions was well above ischemic threshold at time of study. Taking these findings in concert, it is concluded that the predominant form of edema responsible for brain swelling and raised ICP is cellular in nature.

Introduction Previous studies have shown that edema formation after diffuse traumatic brain injury (TBI) with secondary insult is cytotoxic and not vasogenic. This assumption is based on observations of reduced apparent diffusion coefficient (ADC) and lack of significant accumulation of intravascular tracer in brain tissue. However, ADC reduction does not exclude vasogenic edema, and intravascular tracer can only accumulate when it reaches the tissue and is not perfusion limited. This study aims to confirm tissue delivery of intravascular tracer and lack of BBB opening during a phase of rapid brain swelling after diffuse TBI.

Relatively little is known regarding the water content of brain tissue in idiopathic normal-pressure hydrocephalus (NPH) patients. The objective of our study was to determine absolute water content non-invasively in hydrocephalic patients, particularly in the anterior and posterior ventricular horns and in the periventricular white matter.

The aim of this study was to evaluate the extent of mitochondrial injury by assessing N-Acetyl-Aspartate by MR spectroscopy in head injured patients and relating the extent of mitochondrial injury to outcome. The study population (n = 15) consisted of head injured patients (GCS < 8) in whom legal consent was obtained for MRS studies. Studies were performed on a 1.5 Tesla Vision/Siemens system. Size of Voxel equaled 8 cm3 with location determined from T1 images. Voxels were positioned adjacent to the lesion and in the contralateral hemisphere for focal and bilateral for diffuse. Mitochondrial impairment was considered as percent reduction in NAA/Cr ratio compared to matched controls. Mitochondrial impairment gradually increases soon after injury reaching a nadir at 10 days. Subsequently, mitochondria recover in patients with favorable outcome, but remains impaired in patients with poor outcome. The prognostic value of NAA/Cr to assist in management and also to serve as a surrogate endpoint for clinical trials appears promising.

The purpose of the award was to provide funding for the development of a multimodality prostate cancer clinical trial. A clinical protocol was developed along with a supporting infrastructure to begin the trial. A submission for funding under the DOD Prostate Cancer Clinical Trial Award mechanism; however the project was not funded. Submission under an alternative funding mechanism is pending collection of more preliminary data and optimization of C-11 acetate synthesis method.

Object. After traumatic brain injury (TBI), S100B protein is released by astrocytes. Furthermore, cerebrospinal fluid (CSF) and serum S100B levels have been correlated to outcome. Given that no data exist about the temporal profile of cerebral S100B levels following TBI and their correlation to serum levels, the authors examined whether proton magnetic resonance (MR) spectroscopy is capable of measuring S100B. Methods. Results of in vitro proton MR spectroscopy experiments (2.35-tesla magnet, 25 G/cm, point-resolved spatially localized spectroscopy) revealed an S100B-specific peak at 4.5 ppm and confirmed a positive correlation between different S100B concentrations (10 nM–1 µM) and the area under the curve (AUC) for the S100B peak (r = 0.991, p < 0.001). Thereafter, proton MR spectroscopy was performed in male Sprague—Dawley rats (7 × 5 × 5—mm voxel in each hemisphere, TR 3000 msec, TE 30 msec, 256 acquisitions). Exogenously increased CSF S100B levels (∼ 200 ng/ml) through the intraventricular infusion of S100B increased the AUC of the S100B peak from 0.06 ± 0.02 to 0.44 ± 0.06 (p < 0.05), whereas serum S100B levels remained normal. Two hours after lateral fluid-percussion injury, serum S100B levels increased to 0.61 ± 0.09 ng/ml (p < 0.01) and rapidly returned to normal levels, whereas the AUC of the S100B peak increased to 0.19 ± 0.04 at 2 hours postinjury and 0.41 ± 0.07 (p < 0.05) on Day 5 postinjury. Conclusions. Proton MR spectroscopy proves a strong correlation between the AUC of the S100B peak and S100B concentrations. Following experimental TBI, serum S100B levels increased for only a very short period, whereas cerebral S100B levels were increased up to Day 5 postinjury. Given that experimental data indicate that S100B is actively released following TBI, proton MR spectroscopy may represent a new tool to identify increased cerebral S100B levels in patients after injury, thus allowing its biological function to be better understood.

Management of cerebral perfusion pressure (CPP) is thought to be important for the treatment of traumatic brain injury (TBI). Vasopressors have been advocated as a method of increasing mean arterial blood pressure (mABP) and cerebral perfusion pressure (CPP) in the face of rising intracranial pressure (ICP). There are unresolved issues and theoretical risks about this therapy. This study therefore examined the effects of dopamine on physiological and MRI/MRS parameters in (1) a rodent model of rapidly rising intracranial pressure, caused by diffuse injury with secondary insult and (2) a model of cortical contusion. Dopamine was capable of restoring CPP in the model of rapidly rising ICP. This CPP restoration was associated with a partial restoration of CBF. Two profiles of change in the Apparent Diffusion Coefficient of water (ADCw) were seen; one in which ADCw recovered to baseline, and one in which ADCw remained persistently low. Dopamine did not alter these profiles. MRI assessed tissue water content was increased four hours after injury and dopamine increased cerebral water content in both subgroups of injury; significantly in the group with a persistently low ADCw (p0.01). In contusional injury, dopamine significantly worsened edema in both the ipsi- and contralateral hippocampus and temporal cortex. This occurred in the absence of ADCw changes, except in the contralateral hippocampus, where both water content and ADCw values rose with treatment, suggesting extracellular accumulation of water. In conclusion, although dopamine is capable of partially restoring CBF after injury, situations exist in which dopamine therapy worsens the swelling process. It is possible therefore that subgroups of patients exist who experience adverse effects of vasopressor treatment, and consequently the effects of vasopressor therapy in the clinical setting need to be more carefully evaluated.

Neurochemical damage following brain injury can be assessed non-invasively by measurement of N-Acetyl-Aspartate (NAA) using Proton Magnetic Resonance Spectroscopy (*HMRS). This report documents results of applying Chemical Shift Imaging (CSI) postprocessing for measuring NAA in traumatically injured brain.

In this communication, we describe the successful encapsulation of (177)Lu into the endohedral metallofullerene (177)Lu(x)Lu(3-x)N@C(80) (x = 1-3) starting with (177)LuCl(3) in a modified quartz Kraschmer-Huffman electric generator. We demonstrate that the (177)Lu (beta-emitter) in this fullerene cage is not significantly released for a period of up to at least one-half-life (6.7 days). We also demonstrate that this agent can be conjugated with an interleukin-13 peptide that is designed to target an overexpressed receptor in glioblastoma multiforme tumors. This nanoparticle delivery platform provides flexibility for a wide range of radiotherapeutic and radiodiagnostic multimodal applications.

Having determined that edema and not vascular engorgement is the major factor leading to traumatic brain swelling, the objective of this study was to determine which type of edema, cellular or vasogenic, is responsible for increased tissue water in patients with focal lesions. Severely head injured patients (GCS 8 or less) were transported to imaging suites for measurement of brain water and apparent diffusion coefficient (ADC) using magnetic resonance technique. Cerebral blood flow by stable Xenon method was also measured in the regions of interest. Brain water was increased significantly in the hemisphere with lesion. The increase in water was associated with reduced ADC signifying a predominant cellular edema. The ADC in the contralateral hemisphere was near normal value. Cerebral blood flow values in the regions of interest were above ischemic levels suggesting that factors other than ischemia are responsible for the cytotoxic swelling in patients with focal injury.

This work investigates the accuracy of an in vivo estimation of absolute N-acetyl aspartate (NAA) concentrations by magnetic resonance spectroscopy (MRS) using cerebral water as an internal reference standard. Single-voxel, proton spectroscopy was carried out in two groups of rats (normal and diffuse head injury), using a PRESS sequence with TR = 3 s, TE = 135 ms. Fully relaxed water spectra and water-suppressed proton spectra were obtained from a 7 x 5 x 5 mm3 volume of tissue. MRI-based brain water content measurements were also performed. Following MRS, HPLC determinations of NAA were carried out. In the normal rats the MRS yielded 10.98 ± 0.83 mmol/kg w.w. vs 10.76 ± 0.76 for HPLC with a mean absolute difference of 0.8. In the injured rats the corresponding results were 9.41 ± 1.78 (MRS) and 8.16 ± 0.77 (HPLC) with a mean absolute difference of 1.66. The in vivo absolute method accurately documented the temporal NAA changes compared to the NAA/Cr approach.

It is traditionally believed that edema associated with brain contusion is vasogenic. The objective of this study was to quantify and characterize the edema in cortical contusion coupled with early hypoxia and hypotension.