Metabolic Magnetic Resonance Imaging in Neuroimaging: Magnetic Resonance Spectroscopy, Sodium Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer.

Magnetic resonance (MR) is a powerful and versatile technique that offers much more beyond conventional anatomic imaging and has the potential of probing in vivo metabolism. Although MR spectroscopy (MRS) predates clinical MR imaging (MRI), its clinical application has been limited by technical and practical challenges. Other MR techniques actively being developed for in vivo metabolic imaging include sodium concentration imaging and chemical exchange saturation transfer. This article will review some of the practical aspects of MRS in neuroimaging, introduce sodium MRI and chemical exchange saturation transfer MRI, and highlight some of their emerging clinical applications.

Combined task activation display as an effective method to teach introductory fMRI users.

RATIONALE AND OBJECTIVES: Interpreting functional magnetic resonance imaging (fMRI) can be an overwhelming and challenging task for trainees, particularly when post processing, synthesizing and interpreting data from multiple language paradigms. Currently, there is no established best method for teaching fMRI interpretation to new trainees. The purpose of our study is to compare the use of combined task activation display (CTAD) and conventional display of fMRI language paradigms as an effective method to teach fMRI to the introductory learner. MATERIALS AND METHODS: Following IRB approval, 43 unique cases (with 10 repeat cases to assess intra-reader variability) were identified based on the inclusion/exclusion criteria. Eight radiology trainees, without prior exposure to fMRI, were asked to determine language lateralization based on activation of Wernicke's area, Broca's area, and the pre-supplementary motor area. Prior to trainee interpretation, a 15-minute training session was conducted to describe the expected anatomic locations of the language centers. Trainees were asked to determine language dominance using either the CTAD or conventional methods. Following a 6-week washout period, the same eight trainees were asked to interpret the cases using the opposite interpretation approach. RESULTS: Interpreting fMRI with the CTAD method significantly increased trainee accuracy (85.4% vs 70.9% p < 0.001) and trainee confidence (4.3 vs 3.6 p < 0.001), while decreasing time to interpretation (mean difference of 29 min), and intra-reader variability when compared to the conventional approach. CONCLUSION: Combined task activation display is an effective method to teach fMRI to introductory learners.

Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease.

UNLABELLED: Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, "severe" NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. CONCLUSION: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality.

Effect of donor age on patellar tendon allograft ACL reconstruction.

Anterior cruciate ligament reconstruction with patellar tendon allograft tissue is a common orthopedic procedure. It is unknown what effect, if any, the donor age has on clinical outcomes. Biomechanical studies have shown the strength of cadaveric patellar tendon to be independent of age, but no clinical studies have evaluated patient outcomes related to this variable. The purpose of this study was to evaluate the effect of allograft donor age on clinical outcomes of patients undergoing allograft anterior cruciate ligament reconstruction with patellar tendon allograft. Case logs were reviewed to identify primary anterior cruciate ligament reconstruction with allograft patellar tendon by a single surgeon using a standard endoscopic transtibial technique with interference screw fixation. Revision and multiligamentous surgeries were excluded. Seventy-seven patients who met these criteria were identified. Allografts were fresh-frozen, aseptically harvested patellar tendons from a single tissue bank. The donor age was obtained. Clinical outcomes were obtained by contacting patients by telephone and retrospective chart review. Pre- and postoperative Lysholm and Tegner knee scores were used for comparison.Data from 75 patients with an average follow-up of 24 months were obtained. Average donor age was 44 years (range, 14-65 years), and average patient age was 37 years (range, 18-60 years). Statistical analysis of pre- and postoperative Lysholm scores demonstrated statistically significant improvement (P≤.001). Using donor age as a continuous variable, no effect was found on postoperative improvement in Lysholm score or Tegner score (P=.6).

Biological responses of human mesenchymal stem cells to titanium wear debris particles.

Wear debris-induced osteolysis is a major cause of orthopedic implant aseptic loosening, and various cell types, including macrophages, monocytes, osteoblasts, and osteoclasts, are involved. We recently showed that mesenchymal stem/osteoprogenitor cells (MSCs) are another target, and that endocytosis of titanium (Ti) particles causes reduced MSC proliferation and osteogenic differentiation. Here we investigated the mechanistic aspects of the endocytosis-mediated responses of MSCs to Ti particulates. Dose-dependent effects were observed on cell viability, with doses >300 Ti particles/cell resulting in drastic cell death. To maintain cell viability and analyze particle-induced effects, doses <300 particles/cell were used. Increased production of interleukin-8 (IL-8), but not IL-6, was observed in treated MSCs, while levels of TGF-ß, IL-1ß, and TNF-α were undetectable in treated or control cells, suggesting MSCs as a likely major producer of IL-8 in the periprosthetic zone. Disruptions in cytoskeletal and adherens junction organization were also observed in Ti particles-treated MSCs. However, neither IL-8 and IL-6 treatment nor conditioned medium from Ti particle-treated MSCs failed to affect MSC osteogenic differentiation. Among other Ti particle-induced cytokines, only GM-CSF appeared to mimic the effects of reduced cell viability and osteogenesis. Taken together, these results strongly suggest that MSCs play both responder and initiator roles in mediating the osteolytic effects of the presence of wear debris particles in periprosthetic zones.

Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam.

Many commonly used non-steroidal anti-inflammatory drugs (NSAIDs) also cause gastrointestinal toxicity, including the development of life-threatening peptic ulcers. We report that mast cell-deficient mice have an extremely high incidence of severe peptic ulceration when exposed to the NSAID piroxicam. This enhanced ulcer susceptibility can be reversed by reconstitution with mast cells. Furthermore, wild type mice treated with diphenhydramine hydrochloride, a commonly used antihistamine that blocks histamine H1 receptors, develop a similarly high incidence of peptic ulcers following piroxicam exposure. The protective effect of mast cells is independent of TNF, blockade of H2 receptors, or acid secretion. These data indicate a critical role for mast cells and the histamine that they produce in prevention and/or repair of piroxicam-induced gastric mucosal injury. Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans.

Imprinting evolution and human health.

Genomic imprinting results in parent-of-origin-dependent, monoallelic expression of genes. The functional haploid state of these genes has far-reaching consequences. Not only has imprinting been implicated in accelerating mammalian speciation, there is growing evidence that it is also involved in the pathogenesis of several human conditions, particularly cancer and neurological disorders. Epigenetic regulatory mechanisms govern the parental allele-specific silencing of imprinted genes, and many theories have attempted to explain the driving force for the evolution of this unique form of gene control. This review discusses the evolution of imprinting in Therian mammals, and the importance of imprinted genes in human health and disease.

Inflammatory bowel disease following solid organ transplantation.

Inflammatory bowel disease (IBD) is a T cell driven inflammatory condition of the gut. Following solid organ transplantation (SOT), de novo IBD has been reported despite anti-T cell therapy for the prevention of organ rejection. This paradox is illustrated with a case report, highlighting the difficult diagnostic criteria, the potential role of Damage or Pathogen Associated Molecular Pattern Molecules [DAMPs and PAMPs] that drives aspects of ongoing inflammation within the transplanted organ as well as the intestine, and the therapeutic strategies applied. Recurrent IBD is more common than de novo IBD following transplantation, with cumulative risks ten years after orthotopic liver transplantation of 70% and 30%, respectively. Furthermore, the annual incidence of de novo IBD following solid organ transplantation has been estimated to be 206 cases/100,000 or ten times the expected incidence of IBD in the general population (approximately 20 cases/100,000). The association of IBD with other autoimmune conditions such as primary sclerosing cholangitis and autoimmune hepatitis, both common indications for liver transplantation, may play a contributory role, particularly in view of the observation that IBD is more common following liver transplant than other solid organ transplants. Recurrent IBD following transplant appears to run a more aggressive course than de novo IBD, with a higher proportion requiring colectomy for medically refractory disease. Risk factors that have been associated with development of post-transplant IBD include acute CMV infection and the use of tacrolimus.

Genetic architecture of conspecific sperm precedence in Allonemobius fasciatus and A. socius.

The evolution of barriers to gene exchange is centrally important to speciation. We used the crickets Allonemobius fasciatus and A. socius to investigate the genetic architecture of conspecific sperm precedence (CSP), a postinsemination prezygotic reproductive barrier. With amplified fragment-length polymorphism (AFLP) markers and controlled crosses we constructed linkage maps and estimated positions of QTL associated with CSP. The majority of QTL have low to moderate effects, although a few QTL exist in A. socius with large effects, and the numbers of QTL are comparable to numbers of genes accounting for species differences in other studies. The QTL are spread across many unlinked markers, yet QTL placed with linked markers are on a small number of linkage groups that could reflect the role of the large Allonemobius sex chromosome in prezygotic isolation. Although many QTL had positive effects on conspecific sperm utilization several QTL also exerted negative effects, which could be explained by intraspecific sexual conflict, sperm competition, or epistasis of introgressed genes on novel backgrounds. One unexpected outcome was that A. socius CSP alleles have a stronger effect than those from A. fasciatus in hybrid females, causing hybrids to behave like A. socius with regard to sperm utilization. Implications of this asymmetry in the Allonemobius hybrid zone are discussed.

The genetics of reproductive isolation: a retrospective and prospective look with comments on ground crickets.

An intriguing aspect of the current renaissance in investigations of the genetics of reproductive isolation is that it has been dominated by studies that resemble work done in the 1930s, 1940s, and 1950s. The dominant model organism (Drosophila), research approaches, and traits of interest (sterility and inviability of hybrids) all harken back to this earlier era. Herein, we explore the factors that led to a rebirth of interest in the genetics of reproductive isolation and to the adoption of the approaches of an earlier generation of biologists. At the same time, we appeal for more intensive investigations of traits that reproductively isolate closely related species, inclusion of a greater range of organisms in studies of reproductive isolation, and focus on a broader range of questions surrounding speciation. We end with a description of ongoing quantitative trait loci (QTL) studies of conspecific sperm precedence in the ground crickets Allonemobius fasciatus and Allonemobius socius. We have found several QTL with large effects on variance in patterns of sperm utilization in backcross females. Moreover, some QTL have an antagonistic effect on conspecific sperm, a finding that lends support to the hypothesis that rapid evolution of conspecific sperm precedence is a by-product of sexual conflict.