Faculty Bibliography

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 embryogenesis, the rhombic lip of the fourth ventricle is the germinal origin of a diverse collection of neuronal populations that ultimately reside in the brainstem and cerebellum. Rhombic lip neurogenesis requires the bHLH transcription factor Atoh1 (Math1), and commences shortly after neural tube closure (E9.5). Within the rhombomere 1 - isthmus region, the rhombic lip first produces brainstem and deep cerebellar neurons (E9.5-E12), followed by granule cell precursors after E12. While Atoh1 function is essential for all of these populations to be specified, the downstream genetic programs that confer specific properties to early and late born Atoh1 lineages are not well characterized. We have performed a comparative microarray analysis of gene expression within early and later born cohorts of Atoh1 expressing neural precursors purified from E14.5 embryos using a transgenic labeling strategy. We identify novel transcription factors, cell surface molecules, and cell cycle regulators within each pool of Atoh1 lineages that likely contribute to their distinct developmental trajectories and cell fates. In particular, our analysis reveals new insights into the genetic programs that regulate the specification and proliferation of granule cell precursors, the putative cell of origin for the majority of medulloblastomas

This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high distress

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.

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

By application of the MRI method of diffusional kurtosis imaging, a substantially increased diffusional kurtosis was observed within the cerebral ischemic lesions of three stroke subjects, 13-26 h following the onset of symptoms. This increase is interpreted as probably reflecting a higher degree of diffusional heterogeneity in the lesions when compared with normal-appearing contralateral tissue. In addition, for two of the subjects with white matter infarcts, the increase had a strong fiber tract orientational dependence. It is proposed that this effect is consistent with a large drop in the intra-axonal diffusivity, possibly related to either axonal varicosities or alterations associated with the endoplasmic reticulum.

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

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

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