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Objectives: To quantify the barrier sterols and image the lipid structures in the matrix of acquired cholesteatoma and compare the distribution with that found in stratum corneum from normal skin, with the goal to resolve their potential influence on cholesteatoma growth., Methods: High-performance thin-layer chromatography (HPTLC) was used to achieve a quantitative biochemical determination of the sterols. The intercellular lipids were visualized by Coherent Anti-Stokes Raman scattering (CARS) microscopy, which enables label-free imaging of the lipids in intact tissue samples., Results: The results show that the total lipid content of the cholesteatoma matrix is similar to that of stratum corneum from skin and that the cholesteatoma matrix unquestionably contains cholesterol. The cholesterol content in the cholesteatoma matrix is increased by over 30% (w/w dry weight) compared to the control. The cholesterol sulfate content is below 1% of the total lipids in both the cholesteatoma and the control. Cholesterol ester was reduced by over 30% when compared to the control., Conclusions: The content of cholesterol in the cholesteatoma matrix is significantly different from that in stratum corneum from skin, and we confirm that the main structure of the cholesteatoma resembles very thick stratum corneum., (© The Author(s) 2016.)

Unlabelled: The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10-2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850., (© 2016 The Authors.)

Background and Purpose: A number of parameters derived from dynamic contrast-enhanced MR imaging and separate histologic features have been identified as potential prognosticators in high-grade glioma. This study evaluated the relationships between dynamic contrast-enhanced MRI-derived parameters and histologic features in glioblastoma multiforme., Materials and Methods: Twenty-eight patients with newly presenting glioblastoma multiforme underwent preoperative imaging (conventional imaging and T1 dynamic contrast-enhanced MRI). Parametric maps of the initial area under the contrast agent concentration curve, contrast transfer coefficient, estimate of volume of the extravascular extracellular space, and estimate of blood plasma volume were generated, and the enhancing fraction was calculated. Surgical specimens were used to assess subtype and were graded (World Health Organization classification system) and were assessed for necrosis, cell density, cellular atypia, mitotic activity, and overall vascularity scores. Quantitative assessment of endothelial surface area, vascular surface area, and a vascular profile count were made by using CD34 immunostaining. The relationships between MR imaging parameters and histopathologic features were examined., Results: High values of contrast transfer coefficient were associated with the presence of frank necrosis (P = .005). High values of the estimate of volume of the extravascular extracellular space were associated with a fibrillary histologic pattern (P < .01) and with increased mitotic activity (P < .05). No relationship was found between mitotic activity and histologic pattern, suggesting that the correlation between the estimate of volume of the extravascular extracellular space and mitotic activity was independent of the histologic pattern., Conclusions: A correlation between the estimate of volume of the extravascular extracellular space and mitotic activity is reported. Further work is warranted to establish how dynamic contrast-enhanced MRI parameters relate to more quantitative histologic measurements, including markers of proliferation and measures of vascular endothelial growth factor expression., (© 2016 by American Journal of Neuroradiology.)

Context: Left ventricular hypertrophy (LVH) and myocardial fibrosis are considered common findings of the acromegaly cardiomyopathy in echocardiography studies., Objective: To evaluate the frequency of LVH, systolic dysfunction and myocardial fibrosis was undertaken in patients with acromegaly using cardiac magnetic resonance imaging (CMRi) before and after 12 months of octreotide long-acting repeatable treatment., Patients and Methods: Consecutive patients with active acromegaly submitted to biochemical analysis and CMRi before and after 12 months of treatment. Additionally, echocardiography was performed before treatment., Results: Forty consecutive patients were evaluated using CMRi at baseline and 30 patients were reevaluated after 12 months of treatment. Additionally, 29 of these patients were submitted to echocardiography. Using CMRi, the frequency of LVH was 5%. The mean left ventricular mass index (LVMi) was 61.73 ± 18.8 g/m(2). The mean left ventricular ejection fraction (LVEF) was 61.85 ± 9.2%, and all patients had normal systolic function. Late gadolinium enhancement was present in five patients (13.5%), and one patient (3.5%) had an increased extracellular volume. After treatment, 12 patients (40%) had criteria for disease control. No clinically relevant differences in cardiac variables before and after treatment were observed. Additionally, there was no difference in LVMi and LVEF among patients with and without disease control. Using echocardiography, 31% of the patients had LVH, mean LVMi was 117.8 ± 46.3 g/m(2) and mean LVEF was 67.3 ± 4.4%. All patients had normal systolic function., Conclusions: We demonstrated by CMRi, the gold-standard method, that patients with active acromegaly might have a lower prevalence of cardiac abnormalities than previously reported.

Background: Cardiac involvement determines outcome in patients with systemic amyloidosis. There is major unmet need for quantification of cardiac amyloid burden, which is currently only met in part through semi-quantitative bone scintigraphy or Cardiovascular Magnetic Resonance (CMR), which measures ECVCMR. Other accessible tests are needed., Objectives: To develop cardiac computed tomography to diagnose and quantify cardiac amyloidosis by measuring the myocardial Extracellular Volume, ECVCT., Methods: Twenty-six patients (21 male, 64 ± 14 years) with a biopsy-proven systemic amyloidosis (ATTR n = 18; AL n = 8) were compared with twenty-seven patients (19 male, 68 ± 8 years) with severe aortic stenosis (AS). All patients had undergone echocardiography, bone scintigraphy, NT-pro-BNP measurement and EQ-CMR. Dynamic Equilibrium CT (DynEQ-CT) was performed using a prospectively gated cardiac scan prior to and after (5 and 15 minutes) a standard Iodixanol (1 ml/kg) bolus to measure ECVCT. ECVCT was compared to the reference ECVCMR and conventional amyloid measures: bone scintigraphy and clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area)., Results: ECVCT and ECVCMR results were well correlated (r(2) = 0.85 vs r(2) = 0.74 for 5 and 15 minutes post bolus respectively). ECVCT was higher in amyloidosis than AS (0.54 ± 0.11 vs 0.28 ± 0.04, p<0.001) with no overlap. ECVCT tracked clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area), and bone scintigraphy amyloid burden (p<0.001)., Conclusion: Dynamic Equilibrium CT, a 5 minute contrast-enhanced gated cardiac CT, has potential for non-invasive diagnosis and quantification of cardiac amyloidosis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Post-contrast T1 values are closely related to the degree of myocardial extracellular space expansion. We determined the relationship between post-contrast T1 values and left ventricular (LV) diastolic function, LV remodeling, and neurohormonal activation in patients with dilated cardiomyopathy (DCM)., Materials and Methods: Fifty-nine patients with DCM (mean age, 55 ± 15 years; 41 males and 18 females) who underwent both 1.5T magnetic resonance imaging and echocardiography were enrolled. The post-contrast 10-minute T1 value was generated from inversion time scout images obtained using the Look-Locker inversion recovery sequence and a curve-fitting algorithm. The T1 sample volume was obtained from three interventricular septal points, and the mean T1 value was used for analysis. The N-Terminal pro-B-type natriuretic peptide (NT-proBNP) level was measured in 40 patients., Results: The mean LV ejection fraction was 24 ± 9% and the post-T1 value was 254.5 ± 46.4 ms. The post-contrast T1 value was significantly correlated with systolic longitudinal septal velocity (s'), peak late diastolic velocity of the mitral annulus (a'), the diastolic elastance index (Ed, [E/e']/stroke volume), LV mass/volume ratio, LV end-diastolic wall stress, and LV end-systolic wall stress. In a multivariate analysis without NT-proBNP, T1 values were independently correlated with Ed (β = -0.351, p = 0.016) and the LV mass/volume ratio (β = 0.495, p = 0.001). When NT-proBNP was used in the analysis, NT-proBNP was independently correlated with the T1 values (β = -0.339, p = 0.017)., Conclusion: Post-contrast T1 is closely related to LV remodeling, diastolic function, and neurohormonal activation in patients with DCM.

Objective: The purpose of this study was to determine whether contrast-enhanced CT quantification of the hepatic fractional extracellular space (ECS) correlates with the severity of diffuse liver disease., Materials and Methods: The cases of 70 patients without (46 men, 24 women; mean age, 59.1 years) and 36 patients with (23 men, 13 women; mean age, 63.1 years) cirrhosis who had undergone unenhanced and 10-minute delayed phase contrast-enhanced CT were retrospectively identified. By consensus one experienced radiologist and one trainee measured the CT attenuation of the liver and aorta to estimate the fractional ECS, defined as the ratio of the difference between the attenuation of the liver on 10-minute and unenhanced images to the difference between the attenuation of the aorta on 10-minute and unenhanced images multiplied by 1 minus the hematocrit. Findings were correlated with each patient's Model of End-Stage Liver Disease (MELD) score., Results: The mean MELD score was higher in patients with than in those without cirrhosis (14.3 ± 7.3 versus 7.20 ± 2.4, p < 0.0001). The mean fractional ECS was significantly greater in patients with cirrhosis than in those without cirrhosis (41.0% ± 9.0% versus 23.8% ± 6.3%, p < 0.0001). The fractional ECS correlated with the MELD score (r = 0.572, p < 0.0001) and was predictive of cirrhosis with an area under the receiver operating characteristic curve of 0.953 (p < 0.0001). The sensitivity and specificity of an expanded fractional ECS greater than 30% for the prediction of cirrhosis were 92% and 83%. Multivariate linear regression revealed that the fractional ECS is complementary to the MELD score as a predictor of cirrhosis (p < 0.0001)., Conclusion: Noninvasive contrast-enhanced CT quantification of the fractional ECS correlates with the MELD score, an indicator of the severity of liver disease, and merits further study.

Purpose: Myocardial extracellular volume fraction (ECVF) is a surrogate imaging biomarker of diffuse myocardial fibrosis, a hallmark of pathologic ventricular remodeling. Low dose cardiac CT is emerging as a promising modality to detect diffuse interstitial myocardial fibrosis due to its fast acquisition and low radiation; however, the insufficient contrast in the low dose CT images poses great challenge to measure ECVF from the image., Methods: To deal with this difficulty, the authors present a complete ECVF measurement framework including a point-guided myocardial modeling, a deformable model-based myocardium segmentation, nonrigid registration of pre- and post-CT, and ECVF calculation., Results: The proposed method was evaluated on 20 patients by two observers. Compared to the manually delineated reference segmentations, the accuracy of our segmentation in terms of true positive volume fraction (TPVF), false positive volume fraction (FPVF), and average surface distance (ASD), were 92.18% ± 3.52%, 0.31% ± 0.10%, 0.69 ± 0.14 mm, respectively. The interobserver variability measured by concordance correlation coefficient regarding TPVF, FPVF, and ASD were 0.95, 0.90, 0.94, respectively, demonstrating excellent agreement. Bland-Altman method showed 95% limits of agreement between ECVF at CT and ECVF at MR., Conclusions: The proposed framework demonstrates its efficiency, accuracy, and noninvasiveness in ECVF measurement and dramatically advances the ECVF at cardiac CT toward its clinical use.

The nature of brain interstitial fluid (ISF) has long been a subject of controversy. Most of the previous studies on brain ISF were carried out in vitro. In the present study, a novel method was developed to characterize ISF in the living rat brain by magnetic resonance (MR) imaging using gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) as a tracer. Sprague Dawley rats (n=8) were subjected to MR scanning before and after the introduction of Gd-DTPA into the caudate nucleus. A one-way drainage of brain ISF was demonstrated on the dynamic MR images. According to the traditional diffusion model, the diffusion and clearance rate constants of the tracer within brain extracellular space (ECS) were derived as (3.38+-1.07)×10(-4) mm(2) s(-1) and (7.60±4.18)×10(-5) s(-1). Both diffusion and bulk flow contributed to the drainage of ISF from the caudate nucleus, which demonstrated an ISF-cerebrospinal fluid confluence in the subarachnoid space at the lateral and ventral surface of the brain cortex at 3 h after the injection. By using this newly developed method, the brain ECS and ISF can be quantitatively measured simultaneously in the living brain, which will enhance the understanding of ISF and improve the efficiency of drug therapy via the brain interstitium.

Purpose: In vitro it has been shown that the functional activity of P-glycoprotein (Pgp), an important drug transporter responsible for multidrug resistance, can be strongly increased by extracellular acidosis. Here mitogen-activated protein kinases (MAPK) (p38, ERK1/2) seem to play an important role for signal transduction. However, it is unclear whether these effects are also relevant in vivo., Methods: With the newly developed PET tracer Schiff base-based (68)Ga-MFL6.MZ the functional Pgp activity was visualized under acidic conditions and during inhibition of MAPKs non-invasively by means of microPET in rat tumours. Tumours were acidified either by inspiratory hypoxia (8% O(2)) or by injection of lactic acid. Inhibitors of the MAPK were injected intratumourally., Results: With increasing tumour volume the tumour pH changed from 7.0 to 6.7 and simultaneously the Pgp activity increased almost linearly. When the tumour was acidified by direct lactic acid injection the PET tracer uptake was reduced by 20% indicating a higher transport rate out of the cells. Changing the inspiratory O(2) fraction to 8% dynamically led to a reduction of extracellular pH and in parallel to a decrease of tracer concentration. While inhibition of the p38 pathway reduced the Pgp transport rate, inhibition of ERK1/2 had practically no impact., Conclusion: An acidic extracellular environment significantly stimulates the Pgp activity. The p38 MAPK pathway plays an important role for Pgp regulation in vivo, whereas ERK1/2 is of minor importance. From these results new strategies for overcoming multidrug resistance (e.g. reducing tumour acidosis, inhibition of p38) may be developed.

Bupropion is an effective medication in treating addiction and is widely used as an aid to smoking cessation. Bupropion inhibits striatal dopamine reuptake via dopamine transporter blockade, but it is unknown whether this leads to increased extracellular dopamine levels at clinical doses in man. The effects of bupropion on extracellular dopamine levels in the striatum were investigated using [(11)C]raclopride positron emission tomography (PET) imaging in rats administered saline, 11 or 25 mg/kg bupropion i.p. and in healthy human volunteers administered either placebo or 150 mg bupropion (Zyban Sustained-Release). A cognitive task was used to stimulate dopamine release in the human study. In rats, bupropion significantly decreased [(11)C]raclopride specific binding in the striatum, consistent with increases in extracellular dopamine concentrations. In man, no significant decreases in striatal [(11)C]raclopride specific binding were observed. Levels of dopamine transporter occupancy in the rat at 11 and 25 mg/kg bupropion i.p. were higher than predicted to occur in man at the dose used. Thus, these data indicate that, at the low levels of dopamine transporter occupancy achieved in man at clinical doses, bupropion does not increase extracellular dopamine levels. These findings have important implications for understanding the mechanism of action underlying bupropions' therapeutic efficacy and for the development of novel treatments for addiction and depression., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix, and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is approximately 20% and the tortuosity is approximately 1.6 (i.e., free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge, and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases, and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties is valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.

We report a case of idiopathic opacification of Berger's space in a 68-year-old man. The opacification was in the retrolental space between the crystalline lens and the anterior vitreous in the right eye. Opaque fluid was surgically removed, and chemical analysis detected a high concentration of protein and a low concentration of mucopolysaccharides. No underlying pathology was observed.

FDG-PET is used to measure the metabolic rate of glucose. Transport and phosphorylation determine the amount of hexose analog that is phosphorylated and trapped. Competition occurs for both events, such that extracellular glucose concentration affects the FDG image. This study investigated the effect of glucose concentration on the rate of FDG accumulation in three cell lines. The results show that extracellular glucose concentration has a greater impact on the rate of FDG accumulation than the relative abundance of GLUT transporter subtypes.

Objectives: It has recently been established that patients with nonerosive reflux disease have on biopsy within esophageal epithelium a lesion known as dilated intercellular spaces (DIS)., Methods: To further explore the nature and implications of this lesion, in vitro models of nonerosive acid and acid-pepsin damage were created in Ussing chamber-mounted rabbit esophageal epithelium. Using these models circuit analysis and permeability studies were carried out, the latter using dextran of varying size and human epidermal growth factor (EGF)., Results: Luminal HCl, pH 1.1, or HCl, pH 2.0 + pepsin, 1 mg/ml, for 30 min significantly reduced transepithelial electrical resistance (RT) but produced no gross erosions or histologic evidence of cell necrosis. Transmission electron microscopy, however, documented the presence of DIS. Circuit analysis on healthy esophageal epithelium showed that shunt resistance (RS) was much lower than apical membrane, basolateral membrane and transcellular resistances (Ra, Rb, and Rcell, respectively) and approached that of RT. Further, circuit analysis on acid and acid-pepsin damaged tissues showed that the declines in RT resulted from declines in RS. Moreover, the declines in RT (and so RS) were associated with a linear increase in permeability to 4 kD dextrans as well as an increase in permeability to 6 kD EGF and dextrans as large as 20 kD., Conclusions: In nonerosive acid-damaged esophageal epithelium DIS develop in association with and as a marker of reduced transepithelial resistance and increased shunt permeability. This change in shunt permeability upon acid or acid-pepsin exposure is substantial, permitting dextran molecules as large as 20 kD (33 A) to diffuse across the epithelium. Also, this shunt leak enables luminal EGF at 6 kD to diffuse across the acid-damaged epithelium and by so doing enables it to access its receptors on epithelial basal cells. We hypothesize that the shunt leak of EGF may in part account for the development of a reparative phenomenon on esophageal biopsy in patients with nonerosive reflux disease known as basal cell hyperplasia.

Background and Purpose: Loss of neurons results in a relative increase in extracellular space that may lead to altered apparent diffusion coefficient (ADC) values in the hippocampi of patients with seizures. Our purpose was to determine if ADC values along the long axis of hippocampi are useful in evaluating patients with partial complex seizures., Methods: Hippocampi of 23 patients with partial complex seizures and 25 healthy volunteers were evaluated with MR imaging and ADC maps. MR images were evaluated for loss of volume and/or high signal intensity on T2-weighted images and compared with ADC maps. ADCs were compared between patients and controls, as were ADCs along the length of each hippocampus. Mean and SDs were obtained for each measurement, and level of significance was determined (P <.05). The relationship between clinical lateralization and MR imaging and ADCs was studied., Results: No significant variations were found in the ADCs in controls (side to side and along hippocampi). In patients, abnormalities were seen with MR imaging alone in 16, with ADC in 14, and with both in 21. Of 23 hippocampi with an abnormal MR appearance, 14 had abnormal ADCs. Nine hippocampi with a normal MR appearance had abnormal ADCs. Normal MR appearance and ADCs were seen in 13 hippocampi. Most abnormal ADCs were seen in the anterior aspect of the hippocampi. All differences were statistically significant. Of 19 patients who underwent clinical testing, unequivocal lateralization was established in 10. Concordance between clinical tests and MR imaging, ADC, and MR imaging plus ADC was found in five, five, and seven patients, respectively., Conclusion: Visual assessment was better than ADCs alone for detection of abnormal hippocampi. MR imaging plus ADCs was better than either technique alone. ADCs may be abnormal when MR images are unremarkable. Concordance with clinical lateralization was better when MR imaging and ADC were jointly evaluated than when either technique was evaluated separately.

Unlabelled: Brain edema significantly contributes to the clinical course of human brain tumor patients. There is evidence that an enlargement of the extracellular space (ECS) is involved in the development of brain edema. Although T2-weighted magnetic resonance (T2-MR) images represent brain edema by its increased water content, they do not differentiate ECS enlargement from increased intracellular water content., Methods: On the basis of the known distribution of bromide in the ECS, we used (76)Br-bromide and PET to measure the regional ECS in 9 brain tumor patients. Transport rate constants and the distribution volume (DV) of (76)Br-bromide in normal brain and tumor were derived from dynamic PET scans and the measured (76)Br-bromide concentration in arterial plasma. We evaluated different models regarding their reliability in estimating the ECS., Results: Assuming that the DV of (76)Br-bromide represents the ECS, robust estimates were possible for all investigated regions. In normal brain, ECS was within a narrow range-for example, occipital lobe, 19.9% +/- 3.1%-and was lower in 2 dexamethasone-treated patients compared with untreated patients. In 7 of 9 tumors, increased ECS ranged between 43.8% and 61.1%. ECS increases were confined to the tumor mass and did not extend into peritumoral edematous brain. Two patients with large hyperintense lesions according to T2-MR images showed normal ECS values within the lesion., Conclusion: (76)Br-Bromide PET allows a quantitative measurement of the ECS in brain edema and in normal brain. The discrepancies between lesions shown by T2-MRI and regional ECS enlargement as measured with PET challenge the concept of tumor-induced brain edema.

We developed a method to measure regional permeability of cerebral capillary vessels, extracellular fluid space volume, and vascular bed volume using multi-slice dynamic CT with iodinated contrast medium. We implemented the method as a novel software "BBB study", and evaluated it in four cases of brain tumor. The examination time was about 20 minutes, and the resulting functional maps had quality sufficient to distinguish area of irregular permeability enhancement.

Eight healthy men underwent two positron emission tomography (PET) [11C]raclopride scans, one following placebo, the second following d-amphetamine (0.30 mg/kg, p.o.). PET data were analyzed using: (1) brain parametric maps to statistically generate regions of significant change; and (2) a priori identified regions of interest (ROI) manually drawn on each individual's co-registered magnetic resonance (MR) images. Compared with placebo, d-amphetamine decreased [11C]raclopride binding potential (BP) with significant effects in ventral but not dorsal striatum. Change in BP in the statistically generated cluster correlated with self-reported drug-induced 'drug wanting' (r = 0.83, p =.01) and the personality trait of Novelty Seeking-Exploratory Excitability (r = 0.79, p =.02). The same associations were seen in the manually drawn ROI in ventral striatum but not in dorsal putamen or caudate. Changes in extracellular dopamine (DA) did not correlate with mood. Mesolimbic DA might mediate interest in obtaining reward rather than reward, per se. Individual differences in amphetamine-induced DA release might be related to predispositions to drug and novelty seeking.

Extracellular and/or intracellular aggregates are pathological features of many, if not all, neurodegenerative diseases. In Alzheimer disease (AD), extracellular aggregates of beta-amyloid (Abeta) and intracellular aggregates of tau or a-synuclein are key diagnostic markers of the disease. We report here a method to rapidly detect these protein aggregates that relies on size exclusion filtration and immunostaining of trapped material, a method termed filter trapping. We demonstrate that aggregated forms of Abeta and tau are readily trapped in 0.22 microm cellulose acetate filter membranes, which can then be immunostained with specific antibodies in a manner similar to the standard immunoblot. Coupling this method with serial dilution permits a rapid assessment of relative aggregate burden.

Purpose: Drug delivery to treat diseases of the posterior segment of the eye, such as choroidal neovascularization and its complications, is hampered by poor intraocular penetration and rapid elimination of the drug from the eye. The purpose of this study was to investigate the feasibility and tolerance of suprachoroidal injections of poly(ortho ester) (POE), a bioerodible and biocompatible polymer, as a biomaterial potentially useful for development of sustained drug delivery systems., Methods: After tunnelization of the sclera, different formulations based on POE were injected (100 microL) into the suprachoroidal space of pigmented rabbits and compared with 1% sodium hyaluronate. Follow-up consisted of fundus observations, echography, fluorescein angiography, and histologic analysis over 3 weeks., Results: After injection, POE spread in the suprachoroidal space at the posterior pole. It was well tolerated and progressively disappeared from the site of injection without sequelae. No bleeding or retinal detachment occurred. Echographic pictures showed that the material was present in the suprachoroidal space for 3 weeks. Angiography revealed minor pigment irregularities at the site of injection, but no retinal edema or necrosis. Histology showed that POE was well tolerated in the choroid., Conclusions: POE suprachoroidal injections, an easy, controllable, and reproducible procedure, were well tolerated in the rabbit eye. POE appears to be a promising biomaterial to deliver drugs focally to the choroid and the retina.

The plasma clearance curves of small hydrophilic solutes comprise three exponentials, consistent with a three-compartmental distribution model. A previous comparison between inulin and diethylene triamine penta-acetic acid (DTPA) suggested that these three compartments are in series, the first being plasma and the second and third representing compartments within the extravascular space. Moreover, whilst the total distribution volumes of these two indicators were similar, the volume of the second compartment was higher for DTPA. The purpose of the current study was to investigate whether a solute smaller than DTPA, namely bromide, fits the hypothesis that the second space volume is an inverse function of the size of the solute. Two groups of subjects were studied: group A comprised eight patients undergoing routine diagnostic arteriography and group B, eight patients referred for routine measurement of glomerular filtration rate plus two normal volunteers. (99m)Tc-DTPA and sodium [(77)Br]bromide were intravenously administered simultaneously. In group A, frequent arterial samples were obtained up to 40 min after injection, and antecubital venous samples 30 s after each arterial sample. In group B, frequent venous samples were obtained up to 280 min after injection. Volume measurements based on bromide were corrected for erythrocyte bromide accumulation. In both subject groups, the normalised venous concentration ratio of bromide to DTPA, corrected for red cell bromide uptake, was significantly less than unity in the earliest blood samples, being 0.56 (SD 0.08) at 1 min, consistent with faster diffusion of bromide from plasma to interstitial fluid. Furthermore, the extraction fraction of bromide from plasma to interstitial fluid in the forearm was about 0.6, higher than that of DTPA (about 0.5) in spite of red cell bromide accumulation which equilibrated with plasma bromide within 20 s and resulted in a red cell to plasma concentration ratio of 0.51 (0.09). Nevertheless, the net extraction fractions of the two solutes approached asymptotic values with identical time courses over 20-25 min. The total volume of distribution of bromide in group B was 22.5 (3.8) litres, which was higher than that of DTPA, 18.0 (2.8) litres ( P<0.001). It was assumed that this difference was the result of intracellular bromide accumulation. After correction for this, the combined volume of the first and second spaces was significantly higher for bromide, at 13.9 (2.9) litres, than for DTPA, 12.3 (2.0) litres ( P<0.05), but the volume of the third space, 4.1 (2.8) litres, was less compared with DTPA, for which it was 5.8 (2.2) litres ( P<0.05). The proportion of the total space occupied by the first and second spaces was also higher for bromide, 0.78 (0.14), than for DTPA, for which it was 0.69 (0.09; P<0.05). These data are consistent with a three-in series-compartmental model of solute distribution in which the volume of the second space is an inverse function of solute molecular size while the volume of the third is a positive function of solute size.

Background: Both microgravity and simulated microgravity models, such as the 45HDT (45 degrees head-down tilt), cause a redistribution of body fluids indicating a possible adaptive process to the microgravity stressor. Understanding the physiological processes that occur in microgravity is a first step to developing countermeasures to stop its harmful effects, i.e., (edema, motion sickness) during long-term space flights., Hypothesis: Because of the kidneys' functional role in the regulation of fluid volume in the body, it plays a key role in the body's adaptation to microgravity., Methods: Rats were injected intramuscularly with a radioactive tracer and then lightly anesthetized in order to facilitate their placement in the 45HDT position. They were then placed in the 45HDT position using a specially designed ramp (45HDT group) or prone position (control group) for an experimental time period of 1 h. During this period, the 99mTc-DTPA (technetium-labeled diethylenepentaacetate, MW=492 amu, physical half-life of 6.02 h) radioactive tracer clearance rate was determined by measuring gamma counts per minute. The kidneys were then fixed and sectioned for electron microscopy. A point counting method was used to quantitate intracellular spaces of the kidney proximal tubules., Results: 45HDT animals show a significantly (p=0.0001) increased area in the interstitial space of the proximal tubules., Conclusions: There are significant changes in the kidneys during a 1 h exposure to a simulated microgravity environment that consist primarily of anatomical alterations in the kidney proximal tubules. The kidneys also appear to respond differently to the initial periods of head-down tilt., (c2002 Elsevier Science Ltd. All rights reserved.)

Epidural mass lesions may cause ischemia due to progressive intracranial hypertension. In order to investigate the impact of intracranial pressure on accumulation of neuroactive substances, we gradually raised intracranial pressure in five halothane anesthetized cats by inflation of an epidural balloon. We evaluated in the parietal cortex contralateral to the site of balloon inflation, alterations of extracellular glutamate and purine catabolites and of the lactate/pyruvate ratio in relation to changes of intracranial, cerebral perfusion and mean arterial blood pressure. In a complementary experiment, regional cerebral blood flow was assessed by sequential positron emission tomography. In this simplified mass lesion model, extracellular glutamate increased in all cats at a late, critical stage after tentorial herniation, when intracranial pressure had increased to more than 90 mm Hg, cerebral perfusion pressure had decreased below 40-50 mm Hg. Positron emission tomography assessments revealed that the ischemic threshold for glutamate accumulation was in the range of 15-20 mL/100 g/min. Purine catabolites and the lactate/pyruvate ratio increased somewhat earlier than glutamate, but also after reaching the critical, terminal stage. We conclude that in this model of progressive epidural compression, glutamate-mediated excitotoxic processes at sites remote from the initial focal lesion depend on processes such as delayed ischemia in combination with tentorial herniation and systemic hypotension. These processes seem to be initiated by a decrease of cerebral perfusion pressure below a threshold of 40-50 mm Hg.

Objective: To evaluate interstitial glycerol as a marker of ischaemia by studying the changes in glycerol in direct relation to changes in regional cerebral metabolic rate of oxygen (CMRO(2)), the lactate/pyruvate ratio (LP ratio), and glutamate., Methods: Transorbital 2 hour middle cerebral artery occlusion (MCAO) was performed in eight monkeys, which were studied with continuous microdialysis for 24 hours. Interstitial fluids were collected by microdialysis and analysed for glycerol, lactate, pyruvate, and glutamate with an enzymatic assay and high performance liquid chromatography. Sequential PET studies of cerebral blood flow (CBF), CMRO(2), oxygen extraction ratio (OER), and cerebral blood volume (CBV) were performed. The microdialysis probe regions were classified as severe ischaemia or penumbra, depending on whether the mean CMRO(2) side to side ratio was below or above 60%, respectively., Results: A nine-fold, sustained increase in glycerol was registered after MCAO in severe ischaemia regions. In penumbra regions, the increase in glycerol was five-fold, but the glycerol concentration returned to baseline within 8 hours of clip removal. The difference between severe ischaemia and penumbra glycerol values was statistically significant. As expected from previous studies, the interstitial LP ratio and glutamate increased markedly in severe ischaemia, with a less pronounced change in penumbra regions. There was a time lag between the biochemical changes in severe ischaemia regions, with the LP ratio preceding glutamate, followed by glycerol., Conclusions: A marked, sustained increase in interstitial glycerol is indicative of severe ischaemia in this stroke model. A transient, diminutive increase in interstitial glycerol may reflect a penumbra situation. Interstitial glycerol in combination with other biochemical markers such as the LP ratio and glutamate may be useful for clinical monitoring of the ischaemic brain, reflecting a sequence of secondary pathophysiological events.

Microglia cells are closely associated with compact amyloid plaques in Alzheimer's disease (AD) brains. Although activated microglia seem to play a central role in the pathogenesis of AD, mechanisms of microglial activation by beta-amyloid as well as the nature of interaction between amyloid and microglia remain poorly understood. We previously reported a close morphological association between activated microglia and congophilic amyloid plaques in the brains of APP23 transgenic mice at both the light and electron microscopic levels [25]. In the present study, we have further examined the structural relationship between microglia and amyloid deposits by using postembedding immunogold labeling, serial ultrathin sectioning, and 3-dimensional reconstruction. Although bundles of immunogold-labeled amyloid fibrils were completely engulfed by microglial cytoplasm on single sections, serial ultrathin sectioning and three-dimensional reconstruction revealed that these amyloid fibrils are connected to extracellular amyloid deposits. These data demonstrate that extracellular amyloid fibrils form a myriad of finger-like channels with the widely branched microglial cytoplasm. We conclude that in APP23 mice a role of microglia in amyloid phagocytosis and intracellular production of amyloid is unlikely.

The transdermal extraction of interstitial fluid by low-frequency ultrasound offers a potential minimally invasive method of obtaining a fluid sample for at-home blood glucose monitoring. Here we show that the application of low-frequency ultrasound (20 kHz) enhances the transdermal transport of interstitial fluid across hairless rat skin. Using 3H2O as a tracer injected intravenously, a measurable amount of water (>1 microL) was extracted without producing any histologic evidence of injury, even after repeated exposures. Piezoelectric transducers were imbedded in the extraction chamber and used to correlate ultrasound spectral properties to the amount of fluid extracted. Results indicate that the highest amount of water extracted occurs when the acoustic coupling media on the surface of the skin is cavitating, resulting in mild ablation of the stratum corneum and a reduction in its resistance to water mass transfer.

Purpose: Many mammographic and sonographic features of breast abscess overlap with those of carcinoma. We reviewed the usefulness of interstitial fluid and hypoechoic walls in the sonographic diagnosis of breast abscess., Methods: The sonograms and records of 65 patients with breast infection and 60 contemporaneous patients with breast cancer were retrospectively reviewed., Results: Of 49 abscesses identified in patients with breast infection, 14 (29%) had adjacent interstitial fluid that was sonographically visible, and 15 (31%) had a hypoechoic wall. No patients with breast cancer had either sign. The overall sensitivity of the presence of either sign was 55%, and the specificity was 100%., Conclusions: Two sonographic findings, interstitial fluid and a hypoechoic wall, are relatively specific for breast abscess and may aid in the diagnosis of breast disease., (Copyright 2000 John Wiley & Sons, Inc.)

Elastic arteries consist of three primary components: elastin fibers, extracellular collagen matrix and smooth muscle cells. However, the relative contribution of elastin and collagen fibers to overall ultrasonic scattering from an intact arterial wall is poorly understood. To define the principal source of extracellular scattering from the medial layer of elastic arteries, canine ascending aortas (n = 10) were excised, fixed and sectioned for insonification. Subsequently, aortic specimens were restudied after treatment to dissolve all tissue components except extracellular collagen matrix (n = 5) and elastin fibers (n = 5). Histological staining revealed very few elastin fibers and sparse intact collagen in collagen-isolated and elastin-isolated tissues, respectively. Integrated backscatter, attenuation and backscatter coefficients differentiated these two treated tissues. The backscatter coefficient for elastin-isolated tissue demonstrated a fivefold increase over collagen-isolated tissue, suggesting that elastin fibers represent a primary scattering component within elastic arteries, and the collagen fibers may provide a secondary component of scattering.

The experimental spinal cord edema was produced in a cat by the infusion method of Marmarou. Horseradish peroxidase (HRP) dissolved in autoserum of a cat was used as a tracer. After laminectomy, a 30-gauge needle was inserted into the intumescentia cervicalis. A total amount of 20 microliters of a tracer was infused at a rate of 10 microliters/hr. The structural features were studied immediately and 3 days after infusion. Immediately after infusion, HRP was noted in the infused white and gray matters. Though the perivascular space in the white matter at the infused site was widely distended and filled with HRP, the space in the gray matter was not distended but filled with HRP. HRP which was observed along vessels led to the surface of the spinal cord. Swelling of astrocyte was not observed. Three days after infusion, the extracellular space and the perivascular space in the infused white matter were still expanded but were not filled with HRP. The fine structural features were similar to the findings as seen in Marmarou's infusion type of brain edema. Using this model, it seems to be feasible to study the resolution process of spinal cord edema.

Objectives: To assess the topographic relationship between the pneumatic spaces of the temporal bone and the temporomandibular joint (TMJ) using high-resolution CT., Methods: Findings from 100 consecutive patients who had undergone high-resolution axial CT of the base of the skull were reviewed on a digital imaging workstation. Additional multiplanar reformatted images were created in the sagittal and coronal planes through the TMJ. The extension of the pneumatic spaces of the temporal bone and their relation to the TMJ were determined on both sides., Results: The extent of pneumatisation of the temporal bone varied considerably. The roof of the TMJ fossa was pneumatised in 51 patients. The articular eminence contained air spaces in 12 patients, the root of the zygomatic process in five patients. Air cells in the peritubal area extended into the medial wall of the glenoid fossa 53 patients. In approximately 25% the extent of pneumatisation showed marked asymmetry., Conclusions: Pneumatisation of the temporal bone frequently extends close to the TMJ. Knowledge of these air spaces is helpful for the interpretation of imaging studies such as panoramic radiographs and to understand the spread of pathological processes into the joint.

Objective: To determine the relative distribution of fluid within the extracellular fluid volume (ECFV) after infusing either normal saline or 5% albumin in septic, critically ill patients., Design: Prospective, randomized, unblinded, interventional study., Setting: Intensive care unit in a 450-bed, tertiary care, teaching hospital., Patients: Septic, critically ill patients (n = 18)., Interventions: Infusion of either normal saline or 5% albumin to a hemodynamic end point determined by the patient's clinician., Measurements and Main Results: Plasma volume (PV), ECFV, cardiac index, and arterial oxygen content were measured immediately before (baseline) and after each fluid infusion. PV and ECFV were measured by dilution of 131I-albumin and 35S sodium sulfate, respectively. Interstitial fluid volume (ISFV) was calculated as ECFV - PV. Baseline values for PV, ISFV, ECFV, and oxygen delivery index did not differ between treatment groups. Infusion of normal saline increased the ECFV by approximately the volume infused, and the expansion of the PV to ISFV was in a ratio of 1:3. Infusion of 5% albumin increased the ECFV by double the volume infused, with both the PV and ISFV expanding by approximately equal amounts. Oxygen delivery index did not increase after either infusion due to the effect of hemodilution., Conclusion: Expansion of the ECFV in excess of the volume of 5% albumin infused suggests that fluid may move from the intracellular fluid volume to the ECFV in septic patients who receive this fluid.

It is not uncommon to observe the dilation of the pericerebellar fluid space (PCFS) on CT in patients with chronic subdural hematoma (CSDH). CT scans of 92 patients with CSDH proven by surgery were reviewed with respect to the dilatation of PCFS and we evaluated the incidence of dilated PCFS and the relationship between PCFS and other factors. There were 68 males and 24 females. Patients ranged in age from 20 to 90 years (mean 65.2 years). Another 50 patients without CSDH were also reviewed as a control group. A new PCFS grading based on the CT findings was proposed, divided into 3 grades as follows. In grade 0, no PCFS could be seen on CT scans. In grade 1, PCFS could be detected along the posterior aspect of the petrous pyramid, and in grade 2, PCFS could be seen not only along the posterior aspect of the petrous pyramid but also under the tentorium cerebelli. The dilation of PCFS was seen in 78 patients (84.8%) out of the 92 cases. In 50 patients without CSDH (control group), the dilatation of PCFS was noted only in 6 (12%). The dilatation of PCFS was almost always seen on the same side as the CSDH. Among many factors, the significant factor was the degree of the midline shift, the bigger the midline shift caused by CSDH, the larger was the dilated PCFS. Although the mechanism of the dilated PCFS in patients with CSDH is not clear, it is postulated that the mechanism is caused by CSF flow disturbance, compression or adhesion of the subarachnoid space due to CSDH.(ABSTRACT TRUNCATED AT 250 WORDS)

Radioisotopes were used to study the water spaces of the bone and bone marrow in 47 dogs with a created model of acute osteomyelitis. By the 3rd-5th day of experimental osteomyelitis sharp hyperhydration of the bone marrow and bone proper was revealed which was caused by a 2.5-2.8-fold increase of the volume of intercellular fluid in the zone of the affection, leading to circulatory disorders and necrosis. Dehydration of the tissues is accomplished by inflicting numerous percutaneous osteoperforations (NPO) with Kirschner's wire. The osteoperforations are made not at random but in a regular manner through both walls of the bone in two interperpendicular planes. Circulation in the zone of the affection is restored in this case and osteonecrosis in prevented. Conservative methods of treatment of acute hematogenous osteomyelitis were developed according to the stage of its development and were applied in 168 patients whose ages ranged from 20 days to 14 years; in 75% of patients who were admitted in the early stages of AHO the disease took and abrupt course. In patients with neglected forms of AHO three-fourfold infliction of NPO in the subacute stage produced a stimulating effect on reparative regeneration in the zones of osteonecrosis and the forming sequestra.

One dimensional profile scans with a whole body counter are refocused with a linear space invariant filter in the frequency domain, 'Hanning' window and inverse system transfer function. Artifacts are eliminated in a way that a clinically applicable method is developed. Topographic information is achieved with the highly energetic nuclide 82bromide. The bromide space (extracellular volume) in patients with liver cirrhosis (n = 9) compared to normal subjects (n = 10) is increased most in the upper abdominal thoracic region.