Application of Delayed Contrast Extravasation Magnetic Resonance Imaging for Depicting Subtle Blood-Brain Barrier Disruption in a Traumatic Brain Injury Model.

The blood-brain barrier (BBB) is composed of brain microvasculature that provides selective transport of solutes from the systemic circulation into the central nervous system to protect the brain and spinal microenvironment. Damage to the BBB in the acute phase after traumatic brain injury (TBI) is recognized as a major underlying mechanism leading to secondary long-term damage. Because of the lack of technological ability to detect subtle BBB disruption (BBBd) in the chronic phase, however, the presence of chronic BBBd is disputable. Thus, the dynamics and course of long-term BBBd post-TBI remains elusive. Thirty C57BL/6 male mice subjected to TBI using our weight drop closed head injury model and 19 naïve controls were scanned by magnetic resonance imaging (MRI) up to 540 days after injury. The BBB maps were calculated from delayed contrast extravasation MRI (DCM) with high spatial resolution and high sensitivity to subtle BBBd, enabling depiction and quantification of BBB permeability. At each time point, 2-6 animals were sacrificed and their brains were extracted, sectioned, and stained for BBB biomarkers including: blood microvessel coverage by astrocyte using GFAP, AQP4, ZO-1 gaps, and IgG leakage. We found that DCM provided depiction of subtle yet significant BBBd up to 1.5 years after TBI, with significantly higher sensitivity than standard contrast-enhanced T1-weighted and T2-weighted MRI (BBBd volumes main effect DCM/T1/T2 p < 0.0001 F(2,70) = 107.3, time point p < 0.0001 F(2,133, 18.66) = 23.53). In 33% of the cases, both in the acute and chronic stages, there was no detectable enhancement on standard T1-MRI, nor detectable hyperintensities on T2-MRI, whereas DCM showed significant BBBd volumes. The BBBd values of TBI mice at the chronic stage were found significantly higher compared with age matched naïve animals at 30, 60, and 540 days. The calculated BBB maps were histologically validated by determining significant correlation between the calculated levels of disruption and a diverse set of histopathological parameters obtained from different brain regions, presenting different components of the BBB. Cumulative evidence from recent years points to BBBd as a central component of the pathophysiology of TBI. Therefore, it is expected that routine use of highly sensitive non-invasive techniques to measure BBBd, such as DCM with advanced analysis methods, may enhance our understanding of the changes in BBB function after TBI. Application of the DCM technology to other CNS disorders, as well as to normal aging, may shed light on the involvement of chronic subtle BBBd in these conditions.

Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote.

Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.

Brain Motor Region Diffusion Tensor Imaging in Patients with Catatonic Schizophrenia: A Case-Control Study.

BACKGROUND: Only a small proportion of schizophrenia patients present with catatonic symptoms. Imaging studies suggest that brain motor circuits are involved in the underlying pathology of catatonia. However, data about diffusivity dysregulation of these circuits in catatonic schizophrenia are scarce. OBJECTIVES: To assess the involvement of brain motor circuits in schizophrenia patients with catatonia. METHODS: Diffusion tensor imaging (DTI) was used to measure white matter signals in selected brain regions linked to motor circuits. Relevant DTI data of seven catatonic schizophrenia patients were compared to those of seven non-catatonic schizophrenia patients, matched for sex, age, and education level. RESULTS: Significantly elevated fractional anisotropy values were found in the splenium of the corpus callosum, the right peduncle of the cerebellum, and the right internal capsule of the schizophrenia patients with catatonia compared to those without catatonia. This finding showed altered diffusivity in selected motor-related brain areas. CONCLUSIONS: Catatonic schizophrenia is associated with dysregulation of the connectivity in specific motoric brain regions and corresponding circuits. Future DTI studies are needed to address the neural correlates of motor abnormalities in schizophrenia-related catatonia during the acute and remitted state of the illness to identify the specific pathophysiology of this disorder.

Trends in Percutaneous Embolization Procedures by Radiologists and Other Specialists.

PURPOSE: To evaluate utilization trends in percutaneous embolization among radiologists and nonradiologist providers. MATERIALS AND METHODS: The nationwide Medicare Part B fee-for-service databases for 2005-2016 were used to evaluate percutaneous embolization codes. Six codes describing embolization procedures were reviewed. Physician providers were grouped as radiologists, vascular surgeons, cardiologists, nephrologists, other surgeons, and all others. RESULTS: The total volume of Medicare percutaneous embolization procedures increased from 20,262 in 2005 to 45,478 in 2016 (+125%). Radiologists performed 13,872 procedures in 2005 (68% of total volume) and 33,254 in 2016 (73% of total volume), a 140% increase in volume. While other specialists also increased the number of cases performed from 2005 to 2016, radiologists strongly predominated, performing 87% of arterial and 30% of venous procedures in 2016, more than any other single specialty. In 2014 and 2015, a sharp increase in venous embolization cases performed by nonradiologists preceded a sharp decrease in 2016, likely the result of complicated billing codes for venous procedures. Radiologists maintained a steady upward trend in the number of cases they performed during those years. CONCLUSIONS: The volume of percutaneous embolization procedures performed in the Medicare population increased from 2005 to 2016, reflecting a trend toward minimally invasive intervention. In 2016, radiologists performed nearly 10 times more arterial embolization procedures than the second highest specialty and more venous embolization procedures than any other single specialty.

Recent Trends in Endovascular and Surgical Treatment of Peripheral Arterial Disease in the Medicare Population.

OBJECTIVE. Although radiologists developed endovascular treatment of peripheral arterial disease (PAD) in the 1960s, vascular surgeons and cardiologists have become increasingly involved in its application. The purpose of this study was to examine utilization trends in endovascular and surgical treatment of PAD in recent years in the Medicare population. CONCLUSION. Surgical treatment of PAD has decreased each year from 2011 to 2016, whereas endovascular treatment has increased each year. By 2016, Medicare patients who needed revascularization for PAD were more than four times as likely to undergo endovascular as they were to undergo surgical treatment. Between 2011 and 2016, radiologists, vascular surgeons, and cardiologists all increased their endovascular volume, but by 2016, vascular surgeons and cardiologists performed three of every four endovascular procedures for the Medicare population. While only 12% of the total endovascular procedures for PAD were performed in 2016, radiology has grown its procedural volume each year from 2011 through 2016.

The application of point source electroporation and chemotherapy for the treatment of glioma: a randomized controlled rat study.

The prognosis of Glioblastoma Multiforme patients is poor despite aggressive therapy. Reasons include poor chemotherapy penetration across the blood-brain barrier and tumor infiltration into surrounding tissues. Here we studied the effects of combined point-source electroporation (EP) and systemic chemotherapy in glioma-bearing rats. 128 rats were studied. Treatment groups were administered systemic Cisplatin/Methotrexate before EP (either 90 or 180 pulses). Control groups were treated by EP, chemotherapy, or no treatment. Tumor volumes were determined by MRI. Tumors growth rates of the EP + Methotrexate group (1.02 ± 0.77) were significantly lower (p < 0.01) than the control (5.2 ± 1.0) 1-week post treatment. No significant difference was found compared to Methotrexate (1.7 ± 0.5). Objective response rates (ORR) were 40% and 57% for the Methotrexate and EP + Methotrexate groups respectively. Tumor growth rates and ORR of the EP + Cisplatin groups (90 pulses 0.98 ± 0.2, 57%, 180 pulses 1.2 ± 0.1, 33%) were significantly smaller than the control (6.4 ± 1.0, p < 0.01, p < 0.02, 0%) and Cisplatin (3.9 ± 1.0, p < 0.04, p < 0.05, 13%) groups. No significant differences were found between the control groups. Increased survival was found in the EP + Cisplatin group, Χ2 = 7.54, p < 0.006 (Log Rank). Point-source EP with systemic chemotherapy is a rapid, minimal-invasive treatment that was found to induce significant antineoplastic effects in a rat glioma model.

Transient blood-brain barrier disruption is induced by low pulsed electrical fields in vitro: an analysis of permeability and trans-endothelial electric resistivity.

The blood-brain barrier (BBB) is limiting transcellular and paracellular movement of molecules and cells, controls molecular traffic, and keeps out toxins. However, this protective function is the major hurdle for treating brain diseases such as brain tumors, Parkinson's disease, Alzheimer's disease, etc. It was previously demonstrated that high pulsed electrical fields (PEFs) can disrupt the BBB by inducing electroporation (EP) which increases the permeability of the transcellular route. Our goal was to study the effects of low PEFs, well below the threshold of EP on the integrity and function of the BBB. Ten low voltage pulses (5-100 V) were applied to a human in vitro BBB model. Changes in permeability to small molecules (NaF) were studied as well as changes in impedance spectrum and trans-endothelial electric resistivity. Viability and EP were evaluated by Presto-Blue and endogenous Lactate dehydrogenase release assays. The effect on tight junction and adherent junction protein was also studied. The results of low voltage experiments were compared to high voltage experiments (200-1400 V). A significant increase in permeability was found at voltages as low as 10 V despite EP only occurring from 100 V. The changes in permeability as a function of applied voltage were fitted to an inverse-exponential function, suggesting a plateau effect. Staining of VE-cadherin showed specific changes in protein expression. The results indicate that low PEFs can transiently disrupt the BBB by affecting the paracellular route, although the mechanism remains unclear.

In vivo MRI assessment of bioactive magnetic iron oxide/human serum albumin nanoparticle delivery into the posterior segment of the eye in a rat model of retinal degeneration.

BACKGROUND: Retinal degeneration diseases affect millions of patients worldwide and lead to incurable vision loss. These diseases are caused by pathologies in the retina and underlying choroid, located in the back of the eye. One of the major challenges in the development of treatments for these blinding diseases is the safe and efficient delivery of therapeutics into the back of the eye. Previous studies demonstrated that narrow size distribution core-shell near infra-red fluorescent iron oxide (IO) nanoparticles (NPs) coated with human serum albumin (HSA, IO/HSA NPs) increase the half-life of conjugated therapeutic factors, suggesting they may be used for sustained release of therapeutics. In the present study, the in vivo tracking by MRI and the long term safety of IO/HSA NPs delivery into the suprachoroid of a rat model of retinal degeneration were assessed. RESULTS: Twenty-five Royal College of Surgeons (RCS) pigmented rats received suprachoroidal injection of 20-nm IO/HSA NPs into the right eye. The left eye was not injected and used as control. Animals were examined by magnetic resonance imaging (MRI), electroretinogram (ERG) and histology up to 30 weeks following injection. IO/HSA NPs were detected in the back part of the rats' eyes up to 30 weeks following injection by MRI, and up to 6 weeks by histology. No significant differences in retinal structure and function were observed between injected and non-injected eyes. There was no significant difference in the weight of IO/HSA NP-injected animals compared to non-injected rats. CONCLUSIONS: MRI could track the nanoparticles in the posterior segment of the injected eyes demonstrating their long-term persistence, and highlighting the possible use of MRI for translational studies in animals and in future clinical studies. Suprachoroidal injection of IO/HSA NPs showed no sign of adverse effects on retinal structure and function in a rat model of retinal degeneration, suggesting that suprachoroidal delivery of IO/HSA NPs is safe and that these NPs may be used in future translational and clinical studies for extended release drug delivery at the back of the eye.

Inference by exclusion in the red-tailed black cockatoo (Calyptorhynchus banksii).

Inference by exclusion is the ability to select a given option by excluding the others. When designed appropriately, tests of this ability can reveal choices that cannot be explained by associative processes. Over the past decade, exclusion reasoning has been explored in several non-human taxonomic groups, including birds, mainly in Corvids and Parrots. To increase our understanding of the taxonomic distribution of exclusion reasoning and, therefore, its evolution, we investigated exclusion performances in red-tailed black cockatoos (Calyptorhynchus banksii), an Australian relative of the Goffin cockatoo (Cacatua goffini), using a food-finding task. Cockatoos were required to find a food item hidden in 1 of the 2 experimenter's hands. Following training sessions in which they reliably selected the closed baited hand they had just been shown open, each individual was tested on 4 different conditions. Critical to demonstrating exclusion reasoning was the condition in which they were shown the empty hand and then offered a choice of both closed hands. The performance of all birds was above chance on all experimental conditions but not on an olfactory and/or cuing control condition. The results suggest that the birds might be able to infer by exclusion, although an explanation based on rule learning cannot be excluded. This first experiment in red-tailed black cockatoo highlights the potential of this species as a model to study avian cognition and paves the pathway for future investigations.

Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model.

BACKGROUND: Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. With drug treatment only partially efficient, new treatments are being developed. OBJECTIVES: The goal of this study was to demonstrate the feasibility of non-thermal focused-ultrasound (FUS) to induce tremor-suppression in an ET rat model. METHODS: Harmaline-induced tremor rats were treated with FUS along the inferior olivary (IO) system. EMG was recorded continuously during treatment in order to quantify FUS-induced tremor suppression. T2-weighted MRI was performed immediately following treatment and periodically thereafter. RESULTS: FUS treatment at an intensity of 27.2 W/cm2 (Isppa) induced significant reduction of tremor in 12 out of 13 ET rats. Tremor frequency was reduced from 6.2 ±â€¯2.8 to 2 ±â€¯1 Hz, p < 0.0003. In 6 of the 12 responding rats, tremor was completely suppressed. Response duration was 70 ±â€¯61s, on average. FUS induced motor response, depicted as movement of the tail and/or the limbs synchronized with the FUS sonication, was also demonstrated both in ET rats and in naïve rats when treated in the medulla oblongata region. CONCLUSIONS: These results demonstrate the feasibly for obtaining significant tremor reduction or tremor suppression induced by non-thermal, non-invasive, reversible focused-ultrasound.

Radiation-induced vascular malformations in the brain, mimicking tumor in MRI-based treatment response assessment maps (TRAMs).

•Of 310 brain tumors patients recruited, histology of 99 lesions was available.•Of those, 5 were histologically confirmed as radiation-induced malformations.•TRAMs cannot differentiate active tumor from vascular malformation.

Magnetic resonance imaging for prenatal estimation of birthweight in pregnancy: review of available data, techniques, and future perspectives.

Fetuses at the extremes of growth abnormalities carry a risk of perinatal morbidity and death. Their identification traditionally is done by 2-dimensional ultrasound imaging, the performance of which is not always optimal. Magnetic resonance imaging superbly depicts fetal anatomy and anomalies and has contributed largely to the evaluation of high-risk pregnancies. In 1994, magnetic resonance imaging was introduced for the estimation of fetal weight, which is done by measuring the fetal body volume and converting it through a formula to fetal weight. Approximately 10 studies have shown that magnetic resonance imaging is more accurate than 2-dimensional ultrasound imaging in the estimation of fetal weight. Yet, despite its promise, the magnetic resonance imaging technique currently is not implemented clinically. Over the last 5 years, this technique has evolved quite rapidly. Here, we review the literature data, provide details of the various measurement techniques and formulas, consider the application of the magnetic resonance imaging technique in specific populations such as patients with diabetes mellitus and twin pregnancies, and conclude with what we believe could be the future perspectives and clinical application of this challenging technique. The estimation of fetal weight by ultrasound imaging is based mainly on an algorithm that takes into account the measurement of biparietal diameter, head circumference, abdominal circumference, and femur length. The estimation of fetal weight by magnetic resonance imaging is based on one of the 2 formulas: (1) magnetic resonance imaging-the estimation of fetal weight (in kilograms)=1.031×fetal body volume (in liters)+0.12 or (2) magnetic resonance imaging-the estimation of fetal weight (in grams)=1.2083×fetal body volume (in milliliters)ˆ0.9815. Comparison of these 2 formulas for the detection of large-for-gestational age neonates showed similar performance for preterm (P=.479) and for term fetuses (P=1.000). Literature data show that the estimation of fetal weight with magnetic resonance imaging carries a mean or median relative error of 2.6 up to 3.7% when measurements were performed at <1 week from delivery; whereas for the same fetuses, the relative error at 2-dimensional ultrasound imaging varied between 6.3% and 11.4%. Further, in a series of 270 fetuses who were evaluated within 48 hours from birth and for a fixed false-positive rate of 10%, magnetic resonance imaging detected 98% of large-for-gestational age neonates (≥95th percentile for gestation) compared with 67% with ultrasound imaging estimates. For the same series, magnetic resonance imaging applied to the detection of small-for-gestational age neonates ≤10th percentile for gestation, for a fixed 10% false-positive rate, reached a detection rate of 100%, compared with only 78% for ultrasound imaging. Planimetric measurement has been 1 of the main limitations of magnetic resonance imaging for the estimation of fetal weight. Software programs that allow semiautomatic segmentation of the fetus are available from imaging manufacturers or are self-developed. We have shown that all of them perform equally well for the prediction of large-for-gestational age neonates, with the advantage of the semiautomatic methods being less time-consuming. Although many challenges remain for this technique to be generalized, a 2-step strategy after the selection of a group who are at high risk of the extremes of growth abnormalities is the most likely scenario. Results of ongoing studies are awaited (ClinicalTrials.gov Identifier # NCT02713568).

Focused Ultrasound-Induced Suppression of Auditory Evoked Potentials in Vivo.

The goal of this study was to determine the feasibility of focused ultrasound-based neuromodulation affecting auditory evoked potentials (AEPs) in animals. Focused ultrasound-induced suppression of AEPs was performed in 22 rats and 5 pigs: Repetitive sounds were produced, and the induced AEPs were recorded before and repeatedly after FUS treatment of the auditory pathway. All treated animals exhibited a decrease in AEP amplitude post-treatment in contrast to animals undergoing the sham treatment. Suppression was weaker for rats treated at 2.3 W/cm2 (amplitudes decreased to 59.8 ± 3.3% of baseline) than rats treated at 4.6 W/cm2 (36.9 ± 7.5%, p <0.001). Amplitudes of the treated pigs decreased to 27.7 ± 5.9% of baseline. This effect lasted between 30 min and 1 mo in most treated animals. No evidence of heating during treatment or later brain damage/edema was observed. These results demonstrate the feasibility of inducing significant neuromodulation with non-thermal, non-invasive, reversible focused ultrasound. The long recovery times may have clinical implications.

Inferior Vena Cava Filter Placement and Retrieval Rates among Radiologists and Nonradiologists.

PURPOSE: To evaluate inferior vena cava (IVC) filter placement and retrieval rates among radiologists, vascular surgeons, cardiologists, other surgeons, and all other health care providers for Medicare fee-for-service beneficiaries in the years 2012-2015. MATERIALS AND METHODS: The nationwide Medicare Physician/Supplier Procedure Summary Master Files were used to determine the volume and utilization rate of IVC filter placement, IVC filter repositioning, and IVC filter retrieval, which correspond to procedure codes 37191, 37192, and 37193, respectively. Procedural code 37193 was not available before 2012, so data were reviewed for the years 2012-2015. RESULTS: The total volume of Medicare IVC filter placement decreased from 57,785 in 2012 to 44,378 in 2015, with radiologists responsible for 60% of all filter placements. Volume of IVC filter placement declined across all specialties, including radiologists, who placed 33,744 in 2012 and 27,957 in 2015. In contrast, total retrieval of IVC filters increased from 4,060 removals in 2012 to 6,166 in 2015. Retrieval rate per 100,000 Medicare beneficiaries increased from 11 in 2012 to 16 in 2015. Radiologists removed the bulk of the filters: 64% in both 2012 and 2015. Vascular surgeons, cardiologists, and other surgeons retrieved, respectively, 20%, 10%, and 5% of all IVC filters in 2012 and 22%, 9%, and 5% in 2015. CONCLUSIONS: From 2012 to 2015, IVC filter placement steadily decreased across all specialties. Retrieval rate of IVC filters continued to rise over the same period. Radiologists were responsible for the majority of IVC filter placements and retrievals.

A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma.

Data from human biopsies, in-vitro and in-vivo models, strongly supports the role of thrombin, and its protease-activated receptor (PAR1) in the pathology and progression of glioblastoma (GBM), a high-grade glial tumor. Activation of PAR1 by thrombin stimulates vasogenic edema, tumor adhesion and tumor growth. We here present a novel six amino acid chloromethyl-ketone compound (SIXAC) which specifically inhibits PAR1 proteolytic activation and counteracts the over-activation of PAR1 by tumor generated thrombin. SIXAC effects were demonstrated in-vitro utilizing 3 cell-lines, including the highly malignant CNS-1 cell-line which was also used as a model for GBM in-vivo. The in-vitro effects of SIXAC on proliferation rate, invasion and thrombin activity were measured by XTT, wound healing, colony formation and fluorescent assays, respectively. The effect of SIXAC on GBM in-vivo was assessed by measuring tumor and edema size as quantified by MRI imaging, by survival follow-up and brain histopathology. SIXAC was found in-vitro to inhibit thrombin-activity generated by CNS-1 cells (IC50 = 5 × 10-11M) and significantly decrease proliferation rate (p < 0.03) invasion (p = 0.02) and colony formation (p = 0.03) of these cells. In the CNS-1 GBM rat animal model SIXAC was found to reduce edema volume ratio (8.8 ± 1.9 vs. 4.9 ± 1, p < 0.04) and increase median survival (16 vs. 18.5 days, p < 0.02 by Log rank Mental-Cox test). These results strengthen the important role of thrombin/PAR1 pathway in glioblastoma progression and suggest SIXAC as a novel therapeutic tool for this fatal disease.

Incorporation of relative cerebral blood flow into CT perfusion maps reduces false 'at risk' penumbra.

PURPOSE: The region defined as 'at risk' penumbra by current CT perfusion (CTP) maps is largely overestimated. We aimed to quantitate the portion of true 'at risk' tissue within CTP penumbra and to determine the parameter and threshold that would optimally distinguish it from false 'at risk' tissue, that is, benign oligaemia. METHODS: Among acute stroke patients evaluated by multimodal CT (NCCT/CTA/CTP) we identified those that had not undergone endovascular/thrombolytic treatment and had follow-up NCCT. Maps of absolute and relative CBF, CBV, MTT, TTP and Tmax as well as summary maps depicting infarcted and penumbral regions were generated using the Intellispace Portal (Philips Healthcare, Best, Netherlands). Follow-up CT was automatically co-registered to the CTP scan and the final infarct region was manually outlined. Perfusion parameters were systematically analysed - the parameter that resulted in the highest true-negative-rate (ie, proportion of benign oligaemia correctly identified) at a fixed, clinically relevant false-negative-rate (ie, proportion of 'missed' infarct) of 15%, was chosen as optimal. It was then re-applied to the CTP data to produce corrected perfusion maps. RESULTS: Forty seven acute stroke patients met selection criteria. Average portion of infarcted tissue within CTP penumbra was 15%±2.2%. Relative CBF at a threshold of 0.65 yielded the highest average true-negative-rate (48%), enabling reduction of the false 'at risk' penumbral region by ~half. CONCLUSIONS: Applying a relative CBF threshold on relative MTT-based CTP maps can significantly reduce false 'at risk' penumbra. This step may help to avoid unnecessary endovascular interventions.

Liposomal temozolomide drug delivery using convection enhanced delivery.

Even though some progress in diagnosis and treatment has been made over the years, there is still no definitive treatment available for Glioblastoma multiforme (GBM). Convection-enhanced delivery (CED), a continuous infusion-mediated pressure gradient via intracranial catheters, studied in clinical trials, enables in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. We hypothesized that the currently limited efficacy of CED could be enhanced by a liposomal formulation, thus achieving enhanced drug localization to the tumor site with minimal toxicity. We hereby describe a novel approach for treating GBM by CED of liposomes containing the known chemotherapeutic agent, temozolomide (TMZ). A new technique for encapsulating TMZ in hydrophilic (PEGylated) liposomes, characterized by nano-size (121nm), low polydispersity index (<0.13) and with near-neutral charge (-ʒ,0.2mV), has been developed. Co-infusion of PEGylated Gd-DTPA liposomes and TMZ-liposomes by CED in GBM bearing rats, resulted in enhanced tumor detection with longer residence time than free Gd-DTPA. Treatment of GBM-bearing rats with either TMZ solution or TMZ-liposomes resulted in greater tumor inhibition and significantly higher survival. However, the longer survival and smaller tumor volumes exhibited by TMZ liposomal treatment in comparison to TMZ in solution were insignificant (p<0.053); and only significantly lower edema volumes were observed. Thus, there are no clear-cut advantages to use a liposomal delivery system of TMZ via CED over a drug solution.

Automated and Manual Measurements of the Aortic Annulus with ECG-Gated Cardiac CT Angiography Prior to Transcatheter Aortic Valve Replacement: Comparison with 3D-Transesophageal Echocardiography.

RATIONALE AND OBJECTIVES: Multimodality evaluation of the aortic annulus is generally advocated to plan for transcatheter aortic valve replacement (TAVR). We compared aortic annular measurements by cardiac computed tomography angiography (cCTA) to three-dimensional transesophageal echocardiography (3D-TEE), and also evaluated the use of semi-automated software for cCTA annular measurements. MATERIALS AND METHODS: A retrospective cohort of 74 patients underwent 3D-TEE and electrocardiogram-gated cCTA of the heart within 30 days for TAVR planning. 3D-TEE measurements were obtained during mid-systole; cCTA measurements were obtained during late-systole (40% of R-R interval) and mid-diastole (80% of R-R interval). Annular area was measured independently by manual planimetry and with semi-automated software. RESULTS: cCTA measurements in systole and diastole were highly correlated for short-axis diameter (r = 0.91), long-axis diameter (r = 0.92), and annular area (r = 0.96), although systolic measurements were significantly larger (P < 0.001), most notably for the short-axis diameter. Good correlation was observed between 3D-TEE and cCTA for short-axis diameter (r = 0.84-0.90), long-axis diameter (r = 0.77-0.79), and annular area (r = 0.89-0.90). As compared to 3D-TEE, annular area is overmeasured by 28 mm2 on systolic phase cCTA (P < 0.008), but nearly identical with 3D-TEE on diastolic phase cCTA. Semi-automated and manual cCTA annulus measurements were highly correlated in systole (r = 0.94) and diastole (r = 0.93), although the semi-automated annular area measured 11-30 mm2 greater than manual planimetry. Of note, the 95% limits of agreement in our Bland-Altman analysis suggest that the variability in annular area estimates for individual patients between cCTA and 3D-TEE (-100.9 to 99.6 mm2), as well as the variability between manual and automated measurements with cCTA (-105.9 to 45.2 mm2), may be sufficient to alter size selection for an aortic prosthesis. CONCLUSIONS: Although all cCTA measurements are highly correlated with measurements by 3D-TEE, diastolic phase cCTA measurements tend to be closer to standard mid-systolic 3D-TEE measurements. Semi-automated measurement of the aortic annulus with cCTA is highly correlated with manual planimetry. Nonetheless, annular contours derived by semi-automated software should be visually inspected, as the variability in area estimates for individual cases between manual and automated measurements may alter the sizing of an aortic prosthesis.

Adjusting foraging strategies: a comparison of rural and urban common mynas (Acridotheres tristis).

Establishment in urbanized environments is associated with changes in physiology, behaviour, and problem-solving. We compared the speed of learning in urban and rural female common mynas, Acridotheres tristis, using a standard visual discrimination task followed by a reversal learning phase. We also examined how quickly each bird progressed through different stages of learning, including sampling and acquisition within both initial and reversal learning, and persistence following reversal. Based on their reliance on very different food resources, we expected urban mynas to learn and reversal learn more quickly but to sample new contingencies for proportionately longer before learning them. When quantified from first presentation to criterion achievement, urban mynas took more 20-trial blocks to learn the initial discrimination, as well as the reversed contingency, than rural mynas. More detailed analyses at the level of stage revealed that this was because urban mynas explored the novel cue-outcome contingencies for longer, and despite transitioning faster through subsequent acquisition, remained overall slower than rural females. Our findings draw attention to fine adjustments in learning strategies in response to urbanization and caution against interpreting the speed to learn a task as a reflection of cognitive ability.