Evidence from an fMRI study that dessert-flavored e-cigarettes engage taste-related, but not smoking-related, brain circuitry for female daily smokers.

Regulations limiting the sale of flavored e-cigarette products are controversial for their potential to interfere with e-cigarette use as a cessation aid in addition to curbing youth use. Limited research suggests that flavor might enhance the addictive potential of e-cigarettes; however, the acute effects of flavored aerosols on brain function among humans have not been assessed. The present study aimed to isolate and compare the neural substrates of flavored and unflavored e-cigarette aerosols on brain function among nine female daily smokers. Participants inhaled aerosolized e-liquid with 36 mg/mL of nicotine with and without a strawberry-vanilla flavor while undergoing functional magnetic resonance imaging. We used general linear modeling to compare whole-brain mean neural activation and seed-to-voxel task-based functional connectivity between the flavored and unflavored inhalation runs. Contrary to our hypothesis, the flavored aerosol was associated with weaker activation than the unflavored aerosol in the brain stem and bilateral parietal-temporal-occipital region of the cortex. Instead, the flavor engaged taste-related brain regions while suppressing activation of the neural circuits typically engaged during smoking and nicotine administration. Alternatively, functional connectivity between subcortical dopaminergic brain seeds and cortical brain regions involved in motivation and reward salience were stronger during the flavored compared to unflavored aerosol run. The findings suggest that fruity and dessert-flavored e-cigarettes may dampen the reward experience of aerosol inhalation for smokers who initiate e-cigarette use by inhibiting activation of dopaminergic brain circuits. These preliminary findings may have implications for understanding how regulations on flavored e-cigarettes might impact their use as cessation aids. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Room Temperature Magnetoelectric Sensor Arrays For Application of Detecting Iron Profiles in Organs.

Noninvasive measurement of liver iron concentration (LIC) is clinically important. Yet, at the present time, it can only be achieved with SQUID technology. However, SQUID based BLS suffers high costs and cumbersome cryogenic requirements that prevent SQUID BLS from being adopted by clinical applications. Recently, we demonstrated that a single channel ME sensor with piezo-single crystals could detect LIC from only 3cc of mouse liver tissue without any magnetic field shielding. The results demonstrated not only the sensitivity of ME sensor system for LIC but also the feasibility for mapping LIC profiles spatially. This investigation further developed ME sensor arrays, exploiting the compact size and room temperature operation. A Dual-Channel 1-D ME sensor array along the vertical, Z-direction, was developed and shown to be sensitive to the skin-liver distance change which can be utilized to calibrate and eliminate the inter-subject variability of the LIC measurement due to skin-liver distance. With phantom having spatially dependent iron concentrations, the 1-D ME sensor array was capable of mapping the one-dimensional profile of the iron concentration in the horizontal X- and Y-directions. The results of the prototype sensor devices show the feasibility of an array ME-sensors for imaging iron profile.

An Electronic Aerosol Delivery System for Functional Magnetic Resonance Imaging.

BACKGROUND: Public health concerns over the addictive potential of electronic cigarettes (e-cigs) have heightened in recent years. Brain function during e-cig use could provide an objective measure of the addictive potential of new vaping products to facilitate research; however, there are limited methods for delivering e-cig aerosols during functional magnetic resonance imaging (fMRI). The current study describes the development and feasibility testing of a prototype to deliver up to four different e-cig aerosols during fMRI. METHODS: Standardized methods were used to test the devices' air flow variability, nicotine yield, and free radical production. MRI scans were run with and without the device present to assess its safety and effects on MRI data quality. Five daily smokers were recruited to assess plasma nicotine absorption from e-liquids containing nicotine concentrations of 8, 11, 16, 24, and 36 mg/ml. Feedback was collected from participants through a semi-structured interview and computerized questionnaire to assess comfort and subjective experiences of inhaling aerosol from the device. RESULTS: Nicotine yield captured from the aerosol produced by the device was highly correlated with the nicotine concentration of the e-liquids used (R2 = 0.965). Nicotine yield was reduced by a mean of 48% and free radical production by 17% after traveling through the device. The e-liquid containing the highest nicotine concentration tested (36 mg/ml) resulted in the highest plasma nicotine boost (6.6 ng/ml). Overall, participants reported that the device was comfortable to use and inhaling the e-cig aerosols was tolerable. The device was determined to be safe for use during fMRI and had insignificant effects on scan quality. CONCLUSIONS: With the current project, we were able to design a working prototype that safely and effectively delivers e-cig aerosols during fMRI. The device has the potential to be used to assess brain activation during e-cig use and to compare brain reactivity to varying flavors, nicotine concentrations, and other e-cig characteristics.

The exercise pressor reflex and active O2 transport in peripheral arterial disease.

It is unclear if the exaggerated exercise pressor reflex observed in peripheral arterial disease (PAD) patients facilitates Oxygen (O2 ) transport during presymptomatic exercise. Accordingly, this study compared O2 transport between PAD patients and healthy controls during graded presymptomatic work. Seven PAD patients and seven healthy controls performed dynamic plantar flexion in the bore of a 3T MRI scanner. Perfusion, T2 * (an index of relative tissue oxygenation), and SvO2 (a measure of venous oxygen saturation) were collected from the medial gastrocnemius (MG) during the final 10 seconds of each stage. Blood pressure was also collected during the final minute of each stage. As expected, the pressor response to presymptomatic work (4 kg) was exaggerated in PAD patients compared to controls (+14 mmHg ± 4 and +7 mmHg ± 2, P ≤ 0.034). When normalized to changes in free water content (S0 ), T2 * was lower at 2 kg in PAD patients compared to controls (-0.91 Δms/ΔAU ± 0.3 and 0.57 Δms/ΔAU ± 0.3, P ≤ 0.008); followed by a greater increase in perfusion at 4 kg in the PAD group (+18.8 mL/min/100g ± 6.2 vs. -0.21 mL/min/100g ± 3.2 in PAD and controls, P ≤ 0.026). Lastly, SvO2 decreased at 4 kg in both groups (-13% ± 4 and -2% ± 4 in PAD and controls, P ≤ 0.049), suggesting an increase in O2 extraction in the PAD group. Based on these findings, O2 transport appears to be augmented during graded presymptomatic work in PAD patients, and this may be partially mediated by an exaggerated pressor response.

Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer's disease knock-in APP mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized pathologically by amyloid beta (Aß) deposition, microgliosis, and iron dyshomeostasis. Increased labile iron due to homeostatic dysregulation is believed to facilitate amyloidogenesis. Free iron is incorporated into aggregating amyloid peptides during Aß plaque formation and increases potential for oxidative stress surrounding plaques. The goal of this work was to observe how brain iron levels temporally influence Aß plaque formation, plaque iron concentration, and microgliosis. We fed humanized APPNL-F and APPNL-G-F knock-in mice lipophilic iron compound 3,5,5-trimethylhexanoyl ferrocene (TMHF) and iron deficient diets for twelve months. TMHF elevated brain iron by 22% and iron deficiency decreased brain iron 21% relative to control diet. Increasing brain iron with TMHF accelerated plaque formation, increased Aß staining, and increased senile morphology of amyloid plaques. Increased brain iron was associated with increased plaque-iron loading and microglial iron inclusions. TMHF decreased IBA1+ microglia branch length while increasing roundness indicative of microglial activation. This body of work suggests that increasing mouse brain iron with TMHF potentiates a more human-like Alzheimer's disease phenotype with iron integration into Aß plaques and associated microgliosis.

Gamma Knife radiosurgery of saccular aneurysms in a rabbit model.

OBJECTIVEIntracranial aneurysms are vascular abnormalities associated with neurological morbidity and mortality due to risk of rupture. In addition, many aneurysm treatments have associated risk profiles that can preclude the prophylactic treatment of asymptomatic lesions. Gamma Knife radiosurgery (GKRS) is a standard treatment for trigeminal neuralgia, tumors, and arteriovenous malformations. Aneurysms associated with arteriovenous malformations have been noted to resolve after treatment of the malformation. The aim of this study was to determine the efficacy of GKRS treatment in a saccular aneurysm animal model.METHODSAneurysms were surgically produced using an elastase-induced aneurysm model in the right common carotid artery of 10 New Zealand white rabbits. Following initial observation for 4 years, each rabbit aneurysm was treated with a conformal GKRS isodose of 25 Gy to the 50% margin. Longitudinal MRI studies obtained over 2 years and terminal measures obtained at multiple time points were used to track aneurysm size and shape index modifications.RESULTSAneurysms did not rupture or involute during the observation period. Whole aneurysm and blood volume averages decreased with a linear trend, at rates of 1.7% and 1.6% per month, respectively, over 24 months. Aneurysm wall percent volume increased linearly at a rate of 0.3% per month, indicating a relative thickening of the aneurysm wall during occlusion. Nonsphericity of the average volume, aspect ratio, and isoperimetric ratio of whole aneurysm volume all remained constant. Histopathological samples demonstrated progressive reduction in aneurysm size and wall thickening, with subintimal fibrosis. Consistent shape indices demonstrate stable aneurysm patency and maintenance of minimal rupture risk following treatment.CONCLUSIONSThe data indicate that GKRS targeted to saccular aneurysms is associated with histopathological changes and linear reduction of aneurysm size over time. The results suggest that GKRS may be a viable, minimally invasive treatment option for intracranial aneurysm obliteration.

Dietary lipophilic iron accelerates regional brain iron-load in C57BL6 mice.

Impaired brain iron homeostatic mechanisms, independent of pathological hallmarks, are harmful to the brain because excess free iron can cause DNA, protein, and lipid damage via oxidative stress. The goal of this study was to evaluate the longitudinal effect of chronic iron overload and deficiency in the vertebrate brain. Ten-week-old C57BL6 male mice were randomly assigned to one of four unique dietary regiments for 1 year: iron-deficient, normal iron, and two different concentrations of lipophilic iron diet containing 3,5,5-trimethylhexanoyl ferrocene (TMHF). Longitudinal MRI parametrics were used to assess the location and extent of ferric iron distribution. Tissue collected at 12 months was used to directly measure iron-load, protein alterations, and histological metrics. While the iron-deficient diet did not alter brain iron stores, 0.11% TMHF and early exposure with 0.5% TMHF elevated brain iron by roughly 40 and 100%, respectively. R 2 rate increased more in the TMHF groups within iron rich brain regions. Increased brain iron concentration was linearly correlated with an increase in L-ferritin expression, and TMHF diet was found to increase L-ferritin within the olfactory bulb, neocortex, pallidum, thalamus, corpus callosum, CA3 regions of the hippocampus, and substantia nigra. Moreover, gliosis and oxidative stress were detected in the TMHF groups in the regions associated with iron-load. Spatial memory impairment was evident in the iron-loaded mice. This work illustrates that lipophilic iron elevates brain iron in a regionally specific fashion and positions dietary TMHF administration as a model for brain iron overloading.

Default mode network deactivation during odor-visual association.

Default mode network (DMN) deactivation has been shown to be functionally relevant for goal-directed cognition. In this study, the DMN's role during olfactory processing was investigated using two complementary functional magnetic resonance imaging (fMRI) paradigms with identical timing, visual-cue stimulation, and response monitoring protocols. Twenty-nine healthy, non-smoking, right-handed adults (mean age = 26 ± 4 years, 16 females) completed an odor-visual association fMRI paradigm that had two alternating odor + visual and visual-only trial conditions. During odor + visual trials, a visual cue was presented simultaneously with an odor, while during visual-only trial conditions the same visual cue was presented alone. Eighteen of the twenty-nine participants (mean age = 27.0 ± 6.0 years, 11 females) also took part in a control no-odor fMRI paradigm that consisted of a visual-only trial condition which was identical to the visual-only trials in the odor-visual association paradigm. Independent Component Analysis (ICA), extended unified structural equation modeling (euSEM), and psychophysiological interaction (PPI) were used to investigate the interplay between the DMN and olfactory network. In the odor-visual association paradigm, DMN deactivation was evoked by both the odor + visual and visual-only trial conditions. In contrast, the visual-only trials in the no-odor paradigm did not evoke consistent DMN deactivation. In the odor-visual association paradigm, the euSEM and PPI analyses identified a directed connectivity between the DMN and olfactory network which was significantly different between odor + visual and visual-only trial conditions. The results support a strong interaction between the DMN and olfactory network and highlights the DMN's role in task-evoked brain activity and behavioral responses during olfactory processing. Hum Brain Mapp 38:1125-1139, 2017. © 2016 Wiley Periodicals, Inc.

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.

BACKGROUND & AIMS: We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. METHODS: Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. RESULTS: This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8+ T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8+ T cells associated with accumulation of programmed cell death protein 1 (PD-1)hi CD8+ T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. CONCLUSION: Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. LAY SUMMARY: In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.

A large-scale measurement of dielectric properties of normal and malignant colorectal tissues obtained from cancer surgeries at Larmor frequencies.

PURPOSE: Knowledge of dielectric properties of malignant human tissues is necessary for the recently developed magnetic resonance (MR) technique called MR electrical property tomography. This technique may be used in early tumor detection based on the obvious differentiation of the dielectric properties between normal and malignant tissues. However, the dielectric properties of malignant human tissues in the scale of the Larmor frequencies are not completely available in the literature. In this study, the authors focused only on the dielectric properties of colorectal tumor tissue. METHODS: The dielectric properties of 504 colorectal malignant samples excised from 85 patients in the scale of the Larmor frequencies were measured using the precision open-ended coaxial probe method. The obtained complex-permittivity data were fitted to the single-pole Cole-Cole model. RESULTS: The median permittivity and conductivity for the malignant tissue sample were 79.3 and 0.881 S/m at 128 MHz, which were 14.6% and 17.0% higher, respectively, than those of normal tissue samples. Significant differences between normal and malignant tissues were found for the dielectric properties (p < 0.05). CONCLUSIONS: Experimental results indicated that the dielectric properties were significantly different between normal and malignant tissues for colorectal tissue. This large-scale clinical measurement provides more subtle base data to validate the technique of MR electrical property tomography.

A Room Temperature Ultrasensitive Magnetoelectric Susceptometer for Quantitative Tissue Iron Detection.

Iron is a trace mineral that plays a vital role in the human body. However, absorbing and accumulating excessive iron in body organs (iron overload) can damage or even destroy an organ. Even after many decades of research, progress on the development of noninvasive and low-cost tissue iron detection methods is very limited. Here we report a recent advance in a room-temperature ultrasensitive biomagnetic susceptometer for quantitative tissue iron detection. The biomagnetic susceptometer exploits recent advances in the magnetoelectric (ME) composite sensors that exhibit an ultrahigh AC magnetic sensitivity under the presence of a strong DC magnetic field. The first order gradiometer based on piezoelectric and magnetostrictive laminate (ME composite) structure shows an equivalent magnetic noise of 0.99 nT/rt Hz at 1 Hz in the presence of a DC magnetic field of 0.1 Tesla and a great common mode noise rejection ability. A prototype magnetoelectric liver susceptometry has been demonstrated with liver phantoms. The results indicate its output signals to be linearly responsive to iron concentrations from normal iron dose (0.05 mg Fe/g liver phantom) to 5 mg Fe/g liver phantom iron overload (100X overdose). The results here open up many innovative possibilities for compact-size, portable, cost-affordable, and room-temperature operated medical systems for quantitative determinations of tissue iron.

An Ultrasensitive Magnetoelectric Sensor System For the Quantitative Detection of Liver Iron.

Ultrasensitive magnetoelectric (ME) sensors have been developed using magnetostrictive/piezoelectric laminate heterostructures. This paper discusses a highly interdisciplinary design of a room temperature biomagnetic liver susceptometry system (BLS) based on the ME sensors. The ME-sensor based BLS maintains the ultrahigh sensitivity to detect the weak AC biomagnetic signals and introduces a low equivalent magnetic noise. The results reveal a "turning point" and successfully indicate the output signals to be linearly responsive to iron concentrations from normal iron level (0.05 mgFe/gliver phantom) to 5 mgFe/gliver phantom iron overload level (100X overdose). Further, the introduction of the water-bag technique shows the promise on the automatic deduction of the background (tissue) signal, enabling an even higher sensitivity and better signal-to-noise (SNR). With these improvements, it becomes feasible to get improved characterization flexibility and the field distribution mapping potential via signal processing from the correlations of multiple sensors in the system. Considering the wide presence of biomagnetic signals in human organs, the potential impact of such biomagnetic devices on medicine and health care could be enormous and far-reaching.

MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA.

BACKGROUND: Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Rα2), which has been shown to be overexpressed in glioma, can be used as a target moiety. We hypothesized that liposomes conjugated with IL-13 and encapsulating MRI contrast agent are capable of passing through an intact BBB and producing MRI contrast with greater sensitivity. METHODS: The targeted MRI contrast agent was created by encapsulating Magnevist (Gd-DTPA) into liposomes conjugated with IL-13 and characterized by particle size distribution, cytotoxicity, and MRI relaxivity. MR image intensity was evaluated in the brain in normal mice post injection of Gd-DTPA and IL-13-liposome-Gd-DTPA one day apart. The specificity for glioma detection by IL-13-liposome-Gd-DTPA was demonstrated in an intracranial glioma mouse model and validated histologically. RESULTS: The average size of IL-13-liposome-Gd-DTPA was 137 ± 43 nm with relaxivity of 4.0 ± 0.4 L/mmole-s at 7 Tesla. No significant cytotoxicity was observed with MTS assay and serum chemistry in mice. The MRI signal intensity was enhanced up to 15% post injection of IL-13-liposome-Gd-DTPA in normal brain tissue following a similar time course as that for the pituitary gland outside of the BBB. MRI enhanced by IL-13-liposome-Gd-DTPA detected small tumor masses in addition to those seen with Magnevist-enhanced MRI. CONCLUSIONS: IL-13-liposome-Gd-DTPA is able to pass through the uncompromised BBB and detect an early stage glioma that cannot be seen with conventional contrast-enhanced MRI.

The fMRI BOLD response to unisensory and multisensory smoking cues in nicotine-dependent adults.

Given that the vast majority of functional magnetic resonance imaging (fMRI) studies of drug cue reactivity use unisensory visual cues, but that multisensory cues may elicit greater craving-related brain responses, the current study sought to compare the fMRI BOLD response to unisensory visual and multisensory, visual plus odor, smoking cues in 17 nicotine-dependent adult cigarette smokers. Brain activation to smoking-related, compared to neutral, pictures was assessed under cigarette smoke and odorless odor conditions. While smoking pictures elicited a pattern of activation consistent with the addiction literature, the multisensory (odor+picture) smoking cues elicited significantly greater and more widespread activation in mainly frontal and temporal regions. BOLD signal elicited by the multisensory, but not unisensory cues, was significantly related to participants' level of control over craving as well. Results demonstrated that the co-presentation of cigarette smoke odor with smoking-related visual cues, compared to the visual cues alone, elicited greater levels of craving-related brain activation in key regions implicated in reward. These preliminary findings support future research aimed at a better understanding of multisensory integration of drug cues and craving.

Cortical iron regulation and inflammatory response in Alzheimer's disease and APPSWE/PS1ΔE9 mice: a histological perspective.

Disruption of iron homeostasis and increased glial response are known to occur in brains afflicted by Alzheimer's disease (AD). While the APP/PS1 transgenic mouse model recapitulates the hallmark amyloid-beta plaque pathology of AD, it does so in a different neuronal mileu than humans. Understanding the iron characteristics and glial response of the APP/PS1 model is important when testing new treatment procedures and translating these results. Brain tissue from AD patients, APP/PS1 mice, and controls were stained for iron, H- and L-ferritin, microglia, astrocytes, Aß40∕42, and degenerating neurons. The histological data demonstrate differences in ferritin, iron distribution, gliosis, and Aß plaque composition between APP/PS1 and AD tissue. Specifically, an association between focal iron deposition and Aß plaques is found ubiquitously throughout the AD tissue and is not observed in the APP/PS1 mouse model. Ferritin, microglia, and astrocyte staining show differential response patterns to amyloid plaques in AD and the APP/PS1 tissue. Aß 40 and 42 antibody and thioflavin staining demonstrate morphological differences in plaque composition. The histological data support the hypothesis that iron distribution, iron management, and glial response histologically differ between the APP/PS1 and AD brain. Acknowledging the caveat that there are distinct plaque, iron, and glial contrasts between the AD brain and the APP/PS1 mouse is crucial when utilizing this model.

The effect of iron in MRI and transverse relaxation of amyloid-beta plaques in Alzheimer's disease.

Dysregulation of neural iron is known to occur during the progression of Alzheimer's disease. The visualization of amyloid-beta (Aß) plaques with MRI has largely been credited to rapid proton relaxation in the vicinity of plaques as a result of focal iron deposition. The goal of this work was to determine the relationship between local relaxation and related focal iron content associated with Aß plaques. Alzheimer's disease (n=5) and control tissue (n=3) sample slices from the entorhinal cortex were treated overnight with the iron chelator deferoxamine or saline, and microscopic gradient-echo MRI datasets were taken. Subsequent to imaging, the same slices were stained for Aß and iron, and then compared with regard to parametric R2 * relaxation maps and gradient-echo-weighted MR images. Aß plaques in both chelated and unchelated tissue generated MR hypo-intensities and showed relaxation rates significantly greater than the surrounding tissue. The transverse relaxation rate associated with amyloid plaques was determined not to be solely a result of iron load, as much of the relaxation associated with Aß plaques remained following iron chelation. The data indicate a dual relaxation mechanism associated with Aß plaques, such that iron and plaque composition synergistically produce transverse relaxation.

Margin-maximizing feature elimination methods for linear and nonlinear kernel-based discriminant functions.

Feature selection for classification in high-dimensional spaces can improve generalization, reduce classifier complexity, and identify important, discriminating feature "markers." For support vector machine (SVM) classification, a widely used technique is recursive feature elimination (RFE). We demonstrate that RFE is not consistent with margin maximization, central to the SVM learning approach. We thus propose explicit margin-based feature elimination (MFE) for SVMs and demonstrate both improved margin and improved generalization, compared with RFE. Moreover, for the case of a nonlinear kernel, we show that RFE assumes that the squared weight vector 2-norm is strictly decreasing as features are eliminated. We demonstrate this is not true for the Gaussian kernel and, consequently, RFE may give poor results in this case. MFE for nonlinear kernels gives better margin and generalization. We also present an extension which achieves further margin gains, by optimizing only two degrees of freedom--the hyperplane's intercept and its squared 2-norm--with the weight vector orientation fixed. We finally introduce an extension that allows margin slackness. We compare against several alternatives, including RFE and a linear programming method that embeds feature selection within the classifier design. On high-dimensional gene microarray data sets, University of California at Irvine (UCI) repository data sets, and Alzheimer's disease brain image data, MFE methods give promising results.

Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model.

Human glioblastoma tumors selectively express receptors for interleukin 13 (IL-13). In a previous study, we showed that liposomes, when conjugated with IL-13, will deliver chemotherapeutics to a subcutaneous glioma tumor model in mice much more effectively than conventional unconjugated liposomes. Based on this observation, we developed an intracranial brain tumor model in nude mice using human U87 glioma cells. Mice receiving weekly i.p. injections of 15 mg/kg of doxorubicin encapsulated in IL-13-conjugated liposomes had a 5-fold reduction in the intracranial tumor volume over 6 weeks and four of seven animals survived >200 days after tumor implantation. In contrast, the animals receiving unconjugated liposomes with the same doxorubicin concentration did not survive beyond 35 days and there was no evidence of tumor size reduction. The presence of liposomes with doxorubicin in the tumor was shown by taking advantage of the selective expression of IL-13 receptors on the tumor cells and the endogenous fluorescence of doxorubicin. There was no increase in the indices of toxicity in animals receiving the doxorubicin-containing liposomes. Finally, a model of the blood-brain barrier was used to show that the nanovesicles do not harm the endothelial cells yet maintain their toxicity to astrocytoma cells. This approach is necessary to show the efficacy of this targeting platform for tumors in which the blood-brain barrier is not compromised and as a potential use of the nanovesicle system as a surveillance mechanism to prevent recurrence. These data show that IL-13 targeted nanovesicles are a viable option for the treatment of brain tumors.

Developmental shifts in fMRI activations during visuospatial relational reasoning.

To investigate maturational plasticity of fluid cognition systems, functional brain imaging was undertaken in healthy 8-19 year old participants while completing visuospatial relational reasoning problems similar to Raven's matrices and current elementary grade math textbooks. Analyses revealed that visuospatial relational reasoning across this developmental age range recruited activations in the superior parietal cortices most prominently, the dorsolateral prefrontal, occipital-temporal, and premotor/supplementary cortices, the basal ganglia, and insula. There were comparable activity volumes in left and right hemispheres for nearly all of these regions. Regression analyses indicated increasing activity predominantly in the superior parietal lobes with developmental age. In contrast, multiple anterior neural systems showed significantly less activity with age, including dorsolateral and ventrolateral prefrontal, paracentral, and insula cortices bilaterally, basal ganglia, and particularly large clusters in the midline anterior cingulate/medial frontal cortex, left middle cingulate/supplementary motor cortex, left insula-putamen, and left caudate. Findings suggest that neuromaturational changes associated with visuospatial relational reasoning shift from a more widespread fronto-cingulate-striatal pattern in childhood to predominant parieto-frontal activation pattern in late adolescence.