7 Tesla Magnetic Resonance Imaging to Detect Cortical Pathology in Multiple Sclerosis

Background

Neocortical lesions (NLs) are an important pathological component of multiple sclerosis (MS), but their visualization by magnetic resonance imaging (MRI) remains challenging.

Objectives

We aimed at assessing the sensitivity of multi echo gradient echo (ME-GRE) T₂ ^*-weighted MRI at 7.0 Tesla in depicting NLs compared to myelin and iron staining.

Methods

Samples from two MS patients were imaged post mortem using a whole body 7T MRI scanner with a 24-channel receive-only array. Isotropic 200 micron resolution images with varying T₂ ^* weighting were reconstructed from the ME-GRE data and converted into R₂ ^* maps. Immunohistochemical staining for myelin (proteolipid protein, PLP) and diaminobenzidine-enhanced Turnbull blue staining for iron were performed.

Results

Prospective and retrospective sensitivities of MRI for the detection of NLs were 48% and 67% respectively. We observed MRI maps detecting only a small portion of 20 subpial NLs extending over large cortical areas on PLP stainings. No MRI signal changes suggestive of iron accumulation in NLs were observed. Conversely, R₂ ^* maps indicated iron loss in NLs, which was confirmed by histological quantification.

Conclusions

High-resolution post mortem imaging using R₂ ^* and magnitude maps permits detection of focal NLs. However, disclosing extensive subpial demyelination with MRI remains challenging.     

Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer

Objective

Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50–60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2^−/− mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC.

Methods

Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2^−/− mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging.

Results

Unlike controls, Mdr2^−/− mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality.

Conclusions

Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.     

X-linked glucose-6-phosphate dehydrogenase deficiency inMus musculus

A mouse with X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency has been recovered in offspring of 1-ethyl-1-nitrosourea-treated male mice. The activity alteration was detected in blood but can also be observed in other tissue extracts. Hemizygous, heterozygous, and homozygous mutants have, respectively, about 15, 60, and 15% G6PD remaining activity in the blood as compared to the wild type. Erythrocyte indices did not show differences between mutants and wild types. The mutation does not affect the electrophoretic migration, the isoelectric point, or the thermal stability. Kinetic properties, such as theK _m for glucose-6-phosphate or for NADP and the relative utilization of substrate analogues, showed no differences between wild types and mutants with the exception of the relative utilization of deamino-NADP which was significantly lower in mutants. This is presently the only animal model for X-linked G6PD deficiency in humans.This research was supported in part by Contract BI6-156-D from the Commission of the European Communities.     

Predicting spatial distribution of human–black bear interactions in urban areas

Human–wildlife interactions are often associated with a myriad of stakeholder groups, intense political scrutiny, and limited biological data, creating complex decision-making situations for wildlife management agencies. Limited research exists on the development and testing of tools (e.g., models to predict the spatial distribution of interactions) to reduce human–black bear (Ursus americanus) interactions (HBI). Available models predicting spatial distribution of HBI are usually developed at scales too large to predict across urban areas, are rarely tested against independent data sets, and usually do not incorporate both landscape and anthropogenic variables. Our objective was to develop a predictive modeling tool that could identify areas of high conflict potential across urban landscapes. We compared locations of HBI in Missoula, MT, recorded by Montana Fish, Wildlife & Parks from 2003 to 2008, to random locations using logistic regression. The final model discriminated the relative spatial probability of HBI within Missoula well, and a second study area moderately. The probability of HBI in Missoula increased when residents lived close to forested patches and major rivers and streams and in intermediate housing densities (approx. 6.59 houses/ha). Our results provide a wildlife management tool and a repeatable statistical framework that predicts spatial distribution of HBI using only a small set of variables. © 2011 The Wildlife Society.     

Long-term starvation in Xenopus laevis Daudin--II. Effects on several organs

1. The effect of starvation for 12 months on organo-somatic indices, glycogen, protein and water contents of several organs and the Na+/K+ ratio in muscle was studied in the South African clawed toad Xenopus laevis Daudin. 2. The liver- and ovary-somatic index were reduced by 30 and 70% of the initial value after 12 months. Fat bodies had disappeared after approximately 6 months of starvation. The indices of heart and kidney were not changed. 3. Glycogen concentration of the liver, ovaries and muscle were depleted nearly totally during the first half of the experimental time, whereas glycogen in the kidney seemed to be unaffected. 4. Protein concentration increased in the liver, decreased in the muscle and remained constant in the kidney. 5. Starvation caused an increase of the water concentration of the whole animal and different organs, especially at the end of the experiment. 6. The Na+/K+ ratio of the muscle increased significantly after 6 months of starvation and reached a maximum after 10 months.     

Sexually mature transgenic American chestnut trees via embryogenic suspension-based transformation

The availability of a system for direct transfer of anti-fungal candidate genes into American chestnut (Castanea dentata), devastated by a fungal blight in the last century, would offer an alternative or supplemental approach to conventional breeding for production of chestnut trees resistant to the blight fungus and other pathogens. By taking advantage of the strong ability of embryogenic American chestnut cultures to proliferate in suspension, a high-throughput Agrobacterium tumefaciens-mediated transformation protocol for stable integration of foreign genes into the tree was established. Proembryogenic masses (PEMs) were co-cultivated with A. tumefaciens strain AGL1 harboring the plasmid pCAMBIA 2301, followed by stringent selection with 50 or 100 mg/l Geneticin. A protocol employing size-fractionation to enrich for small PEMs to use as target material and selection in suspension culture was applied to rapidly produce transgenic events with an average efficiency of four independent transformation events per 50 mg of target tissue and minimal escapes. Mature somatic embryos, representing 18 transgenic events and derived from multiple American chestnut target genotypes, were germinated and over 100 transgenic somatic seedlings were produced and acclimatized to greenhouse conditions. Multiple vigorous transgenic somatic seedlings produced functional staminate flowers within 3 years following regeneration.     

Collective decision‐making promotes fitness loss in a fusion‐fission society

While collective decision‐making is recognised as a significant contributor to fitness in social species, the opposite outcome is also logically possible. We show that collective movement decisions guided by individual bison sharing faulty information about habitat quality promoted the use of ecological traps. The frequent, but short‐lived, associations of bison with different spatial knowledge led to a population‐wide shift from avoidance to selection of agricultural patches over 9 years in and around Prince Albert National Park, Canada. Bison were more likely to travel to an agricultural patch for the first time by following conspecifics already familiar with agricultural patches. Annual adult mortality increased by 12% due to hunting of bison on agricultural lands. Maladaptive social behaviour accordingly was a major force that contributed to a ~50% population decline in less than a decade. In human‐altered landscapes, social learning by group‐living species can lead to fitness losses, particularly in fusion‐fission societies.