Faculty Bibliography

Fragile X Syndrome is the most prevalent genetic cause of mental retardation. Selective deficits in executive function, including inhibitory control and attention, are core features of the disorder. In humans, Fragile X results from a trinucleotide repeat in the Fmr1 gene that renders it functionally silent and has been modeled in mice by targeted deletion of the Fmr1 gene. Fmr1 knockout (KO) mice recapitulate many features of Fragile X syndrome, but evidence for deficits in executive function is inconsistent. To address this issue, we trained wild-type and Fmr1 KO mice on an experimental paradigm that assesses attentional set-shifting. Mice learned to discriminate between stimuli differing in two of three perceptual dimensions. Successful discrimination required attending only to the relevant dimension, while ignoring irrelevant dimensions. Mice were trained on three discriminations in the same perceptual dimension, each followed by a reversal. This procedure normally results in the formation of an attentional set to the relevant dimension. Mice were then required to shift attention and discriminate based on a previously irrelevant perceptual dimension. Wild-type mice exhibited the increase in trials to criterion expected when shifting attention from one perceptual dimension to another. In contrast, the Fmr1 KO group failed to show the expected increase, suggesting impairment in forming an attentional set. Fmr1 KO mice also exhibited a general impairment in learning discriminations and reversals. This is the first demonstration that Fmr1 KO mice show a deficit in attentional set formation.

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment

RATIONALE: Impulsivity is a vulnerability marker for drug addiction in which other behavioural traits such as anxiety and novelty seeking ('sensation seeking') are also widely present. However, inter-relationships between impulsivity, novelty seeking and anxiety traits are poorly understood. OBJECTIVE: The objective of this paper was to investigate the contribution of novelty seeking and anxiety traits to the expression of behavioural impulsivity in rats. METHODS: Rats were screened on the five-choice serial reaction time task (5-CSRTT) for spontaneously high impulsivity (SHI) and low impulsivity (SLI) and subsequently tested for novelty reactivity and preference, assessed by open-field locomotor activity (OF), novelty place preference (NPP), and novel object recognition (OR). Anxiety was assessed on the elevated plus maze (EPM) both prior to and following the administration of the anxiolytic drug diazepam, and by blood corticosterone levels following forced novelty exposure. Finally, the effects of diazepam on impulsivity and visual attention were assessed in SHI and SLI rats. RESULTS: SHI rats were significantly faster to enter an open arm on the EPM and exhibited preference for novelty in the OR and NPP tests, unlike SLI rats. However, there was no dimensional relationship between impulsivity and either novelty-seeking behaviour, anxiety levels, OF activity or novelty-induced changes in blood corticosterone levels. By contrast, diazepam (0.3-3 mg/kg), whilst not significantly increasing or decreasing impulsivity in SHI and SLI rats, did reduce the contrast in impulsivity between these two groups of animals. CONCLUSIONS: This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction.

BACKGROUND AND PURPOSE: Although NAA is often used as a marker of neural integrity and health in different neurologic disorders, the temporal behavior of WBNAA is not well characterized. Our goal therefore was to establish its normal variations in a cohort of healthy adults over typical clinical trial periods. MATERIALS AND METHODS: Baseline amount of brain NAA, Q(NAA), was obtained with nonlocalizing proton MR spectroscopy from 9 subjects (7 women, 2 men; 31.2 +/- 5.6 years old). Q(NAA) was converted into absolute millimole amount by using phantom-replacement. The WBNAA concentration was derived by dividing Q(NAA) with the brain parenchyma volume, V(B), segmented from MR imaging. Temporal variations were determined with 4 annual scans of each participant. RESULTS: The distribution of WBNAA levels was not different among time points with respect to the mean, 12.1 +/- 1.5 mmol/L (P > .6), nor was its intrasubject change (coefficient of variation = 8.6%) significant between any 2 scans (P > .5). There was a small (0.2 mL) but significant (P = .05) annual V(B) decline. CONCLUSIONS: WBNAA is stable over a 3-year period in healthy adults. It qualifies therefore as a biomarker for global neuronal loss and dysfunction in diffuse neurologic disorders that may be well worth considering as a secondary outcome measure candidate for clinical trials

Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/beta-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1-positive cells during development of the prostate gland in human and in the murine model. We show that during human prostate development, LEF1 is restricted to the basal epithelial layer of the urogenital sinus. During mouse development, Lef1 is also present in the urogenital mesenchyme in addition to the basal epithelial layer of the urogenital sinus. In the course of elongation and branching of the prostatic ducts, Lef1 is localized to the proliferating epithelium at the distal tips of the buds. Notably, during branching morphogenesis, domains of Lef1 and AR are mutually exclusive. We further employed the TOPGAL reporter strain to examine the dynamics of Wnt signaling in the context of prostate regression upon a 7-d treatment with a competitive AR inhibitor, bicalutamide. We found that Wnt/Lef1-positive basal cells are not dependent upon androgen for survival. Furthermore, upon bicalutamide treatment, Wnt/Lef1-positive basal progenitors repopulated the luminal compartment. We conclude that Wnt/Lef1 activity identifies an androgen-independent population of prostate progenitors, which is important for embryonic development and organ maintenance and regeneration in the adult

This review critically examines progress in understanding the link between Alzheimer's disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-beta. We present the argument that the AD research field requires more multifaceted analyses into the impacts of Alzheimer's pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, 'systems-level' methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made-highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics

Nephrolithiasis is a common disease across the world that is becoming more prevalent. Although the underlying cause for most stones is not known, a body of literature suggests a role of heat and climate as significant risk factors for lithogenesis. Recently, estimates from computer models predicted up to a 10% increase in the prevalence rate in the next half century secondary to the effects of global warming, with a coinciding 25% increase in health-care expenditures. Our aim here is to critically review the medical literature relating stones to ambient temperature. We have categorized the body of evidence by methodology, consisting of comparisons between geographic regions, comparisons over time, and comparisons between people in specialized environments. Although most studies are confounded by other factors like sunlight exposure and regional variation in diet that share some contribution, it appears that heat does play a role in pathogenesis in certain populations. Notably, the role of heat is much greater in men than in women. We also hypothesize that the role of a significant human migration (from rural areas to warmer, urban locales beginning in the last century and projected to continue) may have a greater impact than global warming on the observed worldwide increasing prevalence rate of nephrolithiasis. At this time the limited data available cannot substantiate this proposed mechanism but further studies to investigate this effect are warranted.Kidney International advance online publication, 30 March 2011; doi:10.1038/ki.2011.76

During the life span of The FASEB Journal, the decline in cardiovascular mortality was astonishing as the fundamental bases of the complex syndromes of cardiovascular disease were illuminated. In this Silver Anniversary Review, we highlight a few pivotal advances in the field and relate them to research in Pasteur's quadrant, the region of investigation driven by both a desire for fundamental understanding and the consideration of its use. In the second half of the 20th century, we advanced from little pathophysiologic understanding to a near-complete understanding and effective, evidence-based therapeutics for vascular disorders and a similar development of pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. In the current era, we have witnessed 'the rise of the machines,' from stents to cardiac resynchronization therapy. The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders. We briefly consider the promise of regenerative medicine and are intrigued by the possibility for the direct reprogramming of resident cardiac fibroblasts into cardiomyocytes. As for the future, genomic profiling should help physicians recommend individualized risk factor modification targeted to prevent specific manifestations of cardiovascular disease. Transcriptional and biomarker analyses will almost surely be used individually to tailor therapy for those at risk of or experiencing cardiovascular disease. Given the ongoing exponential expansion of scientific knowledge, all of human ingenuity will be needed to fully utilize the power of Pasteur's quadrant and to unleash another quarter century in cardiology as scientifically fruitful and effective on human health as the last.-Levin, R. I., Fishman, G. I. The power of Pasteur's quadrant: cardiovascular disease at the turn of the century

PURPOSE: To evaluate the reduced transverse relaxation rate (RR2), a new relaxation index which has been shown recently to be primarily sensitive to intracellular ferritin iron, as a means of detecting short-term changes in myocardial storage iron produced by iron-chelating therapy in transfusion-dependent thalassemia patients. MATERIALS AND METHODS: A single-breathhold multi-echo fast spin-echo sequence was implemented at 3 Tesla (T) to estimate RR2 by acquiring signal decays with interecho times of 5, 9 and 13 ms. Transfusion-dependent thalassemia patients (N = 8) were examined immediately before suspending iron-chelating therapy for 1 week (Day 0), after a 1-week suspension of chelation (Day 7), and after a 1-week resumption of chelation (Day 14). RESULTS: The mean percent changes in RR2, R2, and R2* off chelation (between Day 0 and 7) were 11.9 +/- 8.9%, 5.4 +/- 7.7% and -4.4 +/- 25.0%; and, after resuming chelation (between Day 7 and 14), -10.6 +/- 13.9%, -8.9 +/- 8.0% and -8.5 +/- 24.3%, respectively. Significant differences in R2 and RR2 were observed between Day 0 and 7, and between Day 7 and 14, with the greatest proportional changes in RR2. No significant differences in R2* were found. CONCLUSION: These initial results demonstrate that significant differences in RR2 are detectable after a single week of changes in iron-chelating therapy, likely as a result of superior sensitivity to soluble ferritin iron, which is in close equilibrium with the chelatable cytosolic iron pool. RR2 measurement may provide a new means of monitoring the short-term effectiveness of iron-chelating agents in patients with myocardial iron overload. J. Magn. Reson. Imaging 2011;33:1510-1516. (c) 2011 Wiley-Liss, Inc

PURPOSE: To develop a noncontrast magnetic resonance angiography (MRA) method for comprehensive evaluation of abdominopelvic arteries in a single 3D acquisition. MATERIALS AND METHODS: A noncontrast MRA (NC MRA) pulse sequence was developed using four inversion-recovery (IR) pulses and 3D balanced steady-state free precession (b-SSFP) readout to provide arterial imaging from renal to external iliac arteries. Respiratory triggered, high spatial resolution (1.3 x 1.3 x 1.7 mm(3) ) noncontrast angiograms were obtained in seven volunteers and ten patients referred for gadolinium-enhanced MRA (CE MRA). Images were assessed for diagnostic quality by two radiologists. Quantitative measurements of arterial signal contrast were also performed. RESULTS: NC MRA imaging was successfully completed in all subjects in 7.0 +/- 2.3 minutes. In controls, image quality of NC MRA averaged 2.79 +/- 0.39 on a scale of 0-3, where 3 is maximum. Image quality of NC MRA (2.65 +/- 0.41) was comparable to that of CE MRA (2.9 +/- 0.32) in all patients. Contrast ratio measurements in patients demonstrated that NC MRA provides arterial contrast comparable to source CE MRA images with adequate venous and excellent background tissue suppression. CONCLUSION: The proposed noncontrast MRA pulse sequence provides high-quality visualization of abdominopelvic arteries within clinically feasible scan times. J. Magn. Reson. Imaging 2011;33:1430-1439. (c) 2011 Wiley-Liss, Inc