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

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.

Kidney stones affect hypertensive patients disproportionately compared to normotensive individuals. On the other hand, some prospective data suggest that a history of nephrolithiasis was associated with a greater tendency to develop hypertension. Newer epidemiologic data also link obesity and diabetes, features of the metabolic syndrome, with nephrolithiasis. In this review, the association of hypertension, diabetes, and obesity with nephrolithiasis is reviewed, and possible pathogenic mechanisms are discussed. Patients with hypertension may have abnormalities of renal calcium metabolism, but data confirming this hypothesis are inconsistent. Higher body mass index and insulin resistance (i.e., the metabolic syndrome) may be etiologic in uric acid nephrolithiasis as increasing body weight is associated with decreasing urinary pH. The possibility that common pathophysiologic mechanisms underly these diseases is intriguing, and if better understood, could potentially lead to better therapies for stone prevention. Both hypertension and stones might be addressed through lifestyle modification to prevent weight gain. Adoption of a lower sodium diet with increased fruits and vegetables and low-fat dairy products, (for example, the dietary approaches to stop hypertension(DASH) diet), may be useful to prevent both stones and hypertension. In those patients in whom dietary modification and weight loss are ineffective, thiazide diuretics are likely to improve blood pressure control and decrease calciuria.American Journal of Hypertension (2008) doi:10.1038/ajh.2007.62American Journal of Hypertension (2008) doi:10.1038/ajh.2007.62

Voltage-gated Ca(2+) channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system diseases associated with small-cell lung cancer, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia (PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in P/Q-type VGCCs (the extracellular Domain-III S5-S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA

Patients with severe and chronic neurogenic pain are known to exhibit excess EEG oscillations in the 4- to 9-Hz theta frequency band in comparison with healthy controls. The generators of these excess EEG oscillations are localized in the cortical pain matrix. Since cortex and thalamus are tightly interconnected anatomically, we asked how thalamic activity and EEG are functionally related in these patients. During the surgical intervention in ten patients with neurogenic pain, local field potentials were recorded from the posterior part of the central lateral nucleus (CL). The highest thalamocortical coherence was found in the 4- to 9-Hz theta frequency band (median 7.7 Hz). The magnitude of thalamocortical theta coherence was comparable to the magnitude of EEG coherence between scalp electrode pairs. Median thalamocortical theta coherence was 27%, reached up to 68% and was maximal with frontal midline scalp sites. The observed high thalamocortical coherence underlines the importance of the thalamus for the synchronization of scalp EEG. We discuss the pathophysiology within the framework of a dysrhythmic thalamocortical interplay, which has important consequences for the choice of therapeutic strategy in patients with chronic and severe forms of neurogenic pain

Elevated tau expression has been proposed as a possible basis for impaired axonal transport in Alzheimer's disease. To address this hypothesis, we analyzed the movement of pulse radiolabeled proteins in vivo along retinal ganglion cell (RGC) axons of mice that lack tau or overexpress human tau isoforms. Here, we show that the global axonal transport rates of slow and fast transport cargoes in axons are not significantly impaired when tau expression is eliminated or increased. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) do not accumulate in retinas and are distributed normally along optic axons in mice that lack or overexpress tau. Finally, ultrastructural analyses revealed no abnormal accumulations of vesicular organelles or neurofilaments in RGC perikarya or axons in mice overexpressing or lacking tau. These results suggest that tau is not essential for axonal transport and that transport rates in vivo are not significantly affected by substantial fluctuations in tau expression

ABSTRACT: BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised. METHODS: We used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms. RESULTS: Healthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8-12 Hz) and beta (15-30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls. CONCLUSION: Our findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input (e.g., detection of a tactile stimulus, stimulus predictability) and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing

Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca2+ channels. After membrane depolarization, Ca2+ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca2+ channel activity is perturbed in a rare yet devastating disorder known as Timothy syndrome (TS), whose features include autism or autism spectrum disorder along with severe cardiac arrhythmia and developmental abnormalities. Most cases of TS arise from a sporadic single nucleotide change that generates a mutation (G406R) in the pore-forming subunit of the L-type Ca2+ channel Ca(V)1.2. We found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI. The deceleration of VDI was observed when the L-type channels were expressed with beta1 subunits prominent in brain, as well as beta2 subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca2+ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly406. As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. Thus, the TS mutation offers a unique perspective on mechanisms of inactivation as well as a promising starting point for exploring the underlying pathophysiology of autism

BACKGROUND: K+ channels are diverse; both in terms of their function and their molecular composition. Shal subunits were first described in Drosophila. There are three mammalian orthologs, which are members of the Kv4 subfamily. They are involved in neuronal firing patterns as well as control of the cardiac action potential duration. RESULTS: Here, we report the biophysical and pharmacological characterization of zShal3, which is the ortholog of the mammalian Kv4.3 subunit, which in mammals is involved in action potential repolarization and gives rise to neuronal A-type K+ currents involved in somatodendretic signal integration. CONCLUSION: We demonstrate that zShal has similar functional and pharmacological characteristics compared to Kv4.3 and it is similarly regulated by pharmacological agents and by the Kv4 accessory subunit, NCS-1