Faculty Bibliography

Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. The purpose of this study was to prospectively evaluate sensitivity and specificity of various estimated perfusion parameters at three-dimensional (3D) perfusion magnetic resonance (MR) imaging of the liver in the diagnosis of advanced liver fibrosis (stage >or= 3), with histologic analysis, liver function tests, or MR imaging as the reference standard. Whole-liver 3D perfusion MR imaging was performed in 27 patients (17 men, 10 women; mean age, 55 years) after dynamic injection of 8-10 mL of gadopentetate dimeglumine. The following estimated perfusion parameters were measured with a dual-input single-compartment model: absolute arterial blood flow (F(a)), absolute portal venous blood flow (F(p)), absolute total liver blood flow (F(t)) (F(t) = F(a) + F(p)), arterial fraction (ART), portal venous fraction (PV), distribution volume (DV), and mean transit time (MTT) of gadopentetate dimeglumine. Patients were assigned to two groups (those with fibrosis stage <or= 2 and those with fibrosis stage >or= 3), and the nonparametric Mann-Whitney test was used to compare F(a), F(p), F(t), ART, PV, DV, and MTT between groups. Receiver operating characteristic curve analysis was used to assess the utility of perfusion estimates as predictors of advanced liver fibrosis. There were significant differences for all perfusion MR imaging-estimated parameters except F(p) and F(t). There was an increase in F(a), ART, DV, and MTT and a decrease in PV in patients with advanced fibrosis compared with those without advanced fibrosis. DV had the best performance, with an area under the receiver operating characteristic curve of 0.824, a sensitivity of 76.9% (95% confidence interval: 46.2%, 94.7%), and a specificity of 78.5% (95% confidence interval: 49.2%, 95.1%) in the prediction of advanced fibrosis

PURPOSE: To retrospectively compare diffusion-weighted (DW) magnetic resonance (MR) imaging with standard breath-hold T2-weighted MR imaging for focal liver lesion (FLL) detection and characterization, by using consensus evaluation and other findings as the reference standard. MATERIALS AND METHODS: Approval for this retrospective HIPAA-compliant study was obtained from the institutional review board; informed consent was waived. Fifty-three consecutive patients (30 men, 23 women; mean age, 60.7 years) with at least one FLL of 1 cm or greater in diameter were evaluated. Two independent observers reviewed DW (b values of 0, 50, and 500 sec/mm(2)) and T2-weighted images for FLL detection and characterization. Reference standard for diagnosis was obtained from consensus review by the two observers of DW, T2-weighted, and dynamic contrast material-enhanced images, pathologic data, and follow-up imaging results. Apparent diffusion coefficient (ADC) was measured for FLLs identified at consensus review. DW and T2-weighted images were compared for FLL detection and characterization by using a binary logistic regression model. Receiver operating characteristic curve analyses were conducted to evaluate the utility of ADC for diagnosis of malignancy. RESULTS: Two hundred eleven FLLs (136 malignant, 75 benign) were detected at consensus review. Overall detection rate (averaged for two observers) was significantly higher for DW (87.7%) versus T2-weighted (70.1%) imaging (P < .001). FLL characterization was not significantly different between DW (89.1%) and T2-weighted (86.8%) imaging (P = .51). ADCs of malignant FLLs were significantly lower than those of benign FLLs (P < .001). The area under the curve for diagnosis of malignancy was 0.839, with sensitivity of 74.2%, specificity of 77.3%, positive predictive value of 85.5%, negative predictive value of 62.3%, and accuracy of 75.3%, by using a threshold ADC of less than 1.60 x 10(-3) mm(2)/sec. CONCLUSION: DW MR imaging was better than standard breath-hold T2-weighted imaging for FLL detection and was equal to breath-hold T2-weighted imaging for FLL characterization

The agyria (lissencephaly)/pachygyria phenotypes are catastrophic developmental diseases characterized by abnormal folds on the surface of the brain and disorganized cortical layering. In addition to mutations in at least four genes-LIS1, DCX, ARX and RELN-mutations in a human alpha-tubulin gene, TUBA1A, have recently been identified that cause these diseases. Here, we show that one such mutation, R264C, leads to a diminished capacity of de novo tubulin heterodimer formation. We identify the mechanisms that contribute to this defect. First, there is a reduced efficiency whereby quasinative alpha-tubulin folding intermediates are generated via ATP-dependent interaction with the cytosolic chaperonin CCT. Second, there is a failure of CCT-generated folding intermediates to stably interact with TBCB, one of the five tubulin chaperones (TBCA-E) that participate in the pathway leading to the de novo assembly of the tubulin heterodimer. We describe the behavior of the R264C mutation in terms of its effect on the structural integrity of alpha-tubulin and its interaction with TBCB. In spite of its compromised folding efficiency, R264C molecules that do productively assemble into heterodimers are capable of copolymerizing into dynamic microtubules in vivo. The diminished production of TUBA1A tubulin in R264C individuals is consistent with haploinsufficiency as a cause of the disease phenotype

Classically, neurons communicate by anterograde conduction of action potentials. However, information can also pass backward along axons, a process that is essential during the development of the nervous system. Here we propose a role for such 'retroaxonal' signals in adult learning. We hypothesize that strengthening of a neuron's output synapses stabilizes recent changes in the same neuron's inputs. During learning, the input synapses of many neurons undergo transient changes, resulting in altered spiking activity. If this in turn promotes strengthening of output synapses, the recent synaptic changes will be stabilized; otherwise they will decay. A representation of sensory stimuli therefore evolves that is tailored to the demands of behavioral tasks. We describe a candidate molecular mechanism for this process involving the activation of CREB by retrograde neurotrophin signals

It is often suggested that during development the brain barriers are immature. This argument stems from teleological interpretations and experimental observations of the high protein concentrations in fetal cerebrospinal fluid (CSF) and decreases in apparent permeability of passive markers during development. We argue that the developmental blood-CSF barrier restricts the passage of lipid-insoluble molecules by the same mechanism as in the adult (tight junctions) rendering the paracellular pathway an unlikely route of entry. Instead, we suggest that both protein and passive markers are transferred across the epithelium through a transcellular route. We propose that changes in volume of distribution can largely explain the decrease in apparent permeability for passive markers and that developmentally regulated cellular transfer explains changes in CSF protein concentrations. The blood-CSF tight junctions are functionally mature from very early in development, and it appears that transfer from blood into embryonic brain occurs predominately via CSF rather than the vasculature.

MYH9 encodes a class II nonmuscle myosin heavy chain-A (NMHC-IIA), a widely expressed 1960 amino acid polypeptide, with a translated molecular weight of 220 kDa. The relatively large number of exons (40) that encode NMHC-IIA and the splice variants that have been documented for its two isoforms, MYH10 and MYH14, strongly suggest existence of alternative splicing for MYH9. In the current study, we perform a targeted search for Myh9 splice variants in two separate regions of the heavy chain that encode loop 1 and loop 2 subdomains within which alternative exons in MYH10 and MYH14 splice variants have been identified. The splice variant search was conducted using two strategies: amplification across the suspected exons directly or by amplification of putative splice variants identified through conserved sequence analysis of suspected intronic regions. Within loop 1, two separate insertions of 12 and 41 nucleotides were identified using conserved sequence analysis only. Each of these insertions, located within intron 4, resulted in premature termination of the variant transcript. Within loop 2, a 63-nucleotide-long in-frame insertion was identified using both strategies. The insertion is identical in length and displays 65% sequence identity with its Myh10 counterpart, but differs greatly from the 123-nucleotide-long insertion within Myh14 transcript identified in this study. Both loop 1 and loop 2 variants of Myh9 were detected in the cochlea, with the latter being most abundant in the brain. Expression of loop 1 variants with premature termination codon may reflect an alternate mode of regulating Myh9 expression, while the conserved sequence and selective expression of the loop 2 variant highlight its potential biological importance

This study examined empirical and theoretical differences and similarities between attention deficit hyperactivity disorder (ADHD) and child temperament in 32 ADHD children aged 6-11 years, and a comparison group of 23 children with similar sociodemographic characteristics. Children were assessed for ADHD symptoms (hyperactivity, impulsivity, and inattention) and dimensions of child temperament (negative reactivity, task persistence, activity, attentional focusing, impulsivity, and inhibitory control) using standardized parent reports and interviews. Symptoms of ADHD and temperament dimensions were correlated; children in the ADHD group had significantly higher scores on negative reactivity, activity and impulsivity, and lower scores on task persistence, attentional focusing and inhibitory control than normative samples. Results indicate that although the constructs of ADHD and temperament have been regarded as two separate bodies of knowledge, theoretical and empirical overlaps exist. Applied implications are discussed. (C) 2007 Elsevier Inc. All rights reserved

Cystinuria is an inherited disorder characterized by the impaired reabsorption of cystine in the proximal tubule of the nephron and the gastrointestinal epithelium. The only clinically significant manifestation is recurrent nephrolithiasis secondary to the poor solubility of cystine in urine. Although cystinuria is a relatively common disorder, it accounts for no more than 1% of all urinary tract stones. Thus far, mutations in 2 genes, SLC3A1 and SLC7A9, have been identified as being responsible for most cases of cystinuria by encoding defective subunits of the cystine transporter. With the discovery of mutated genes, the classification of patients with cystinuria has been changed from one based on phenotypes (I, II, III) to one based on the affected genes (I and non-type I; or A and B). Most often this classification can be used without gene sequencing by determining whether the affected individual's parents have abnormal urinary cystine excretion. Clinically, insoluble cystine precipitates into hexagonal crystals that can coalesce into larger, recurrent calculi. Prevention of stone formation is the primary goal of management and includes hydration, dietary restriction of salt and animal protein, urinary alkalinization, and cystine-binding thiol drugs