Faculty Bibliography

Acetylcholine receptor (AChR) genes are transcribed selectively in synaptic nuclei of skeletal muscle fibers, leading to accumulation of the mRNAs encoding AChR subunits at synaptic sites. The signals that regulate synapse-specific transcription remain elusive, though Neuregulin-1 is considered a favored candidate. Here, we show that motor neurons and terminal Schwann cells express neuregulin-2, a neuregulin-1-related gene. In skeletal muscle, Neuregulin-2 protein is concentrated at synaptic sites, where it accumulates adjacent to terminal Schwann cells. Neuregulin-2 stimulates AChR transcription in cultured myotubes expressing ErbB4, as well as ErbB3 and ErbB2, but not in myotubes expressing only ErbB3 and ErbB2. Thus, Neuregulin-2 is a candidate for a signal that regulates synaptic differentiation

Use of a parallel imaging technique to improve temporal and spatial resolution at three-dimensional contrast-enhanced magnetic resonance (MR) angiography was investigated. Thirty experiments were performed in five groups of healthy subjects. In groups 1-3, the technique was used to improve imaging speed by a factor of two or four while maintaining spatial resolution. Contrast agent concentration was two to four times higher than at standard MR angiography, to take advantage of the faster imaging speed. In groups 4 and 5, the technique was used to double spatial resolution in the phase-encoding direction while maintaining imaging speed and contrast agent concentration. At a two to four times faster imaging speed, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) almost equaled those at standard MR angiography, likely a result of increased contrast agent concentration. The use of parallel imaging to achieve higher spatial resolution was also proved feasible, but with substantial reduction in SNR and CNR

The major neuropathological lesions defining Alzheimer's disease (AD) include neurofibrillary tangles and amyloid plaques, which are mainly composed of abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous neuropathological and neuroimaging studies indicate that at least one-third of AD cases are complicated by some degree of vascular pathology, whereas in a similar proportion of patients clinically diagnosed with vascular dementia, AD pathology is also present. Many classical vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have recently been shown also to increase the risk of AD. Growing evidence suggests that vascular pathology lowers the threshold for the clinical presentation of dementia at a given level of AD-related pathology and potentially directly promotes AD lesions such as A beta plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid precursor protein (APP), which is the precursor to the amyloid beta peptide and damages the blood-brain barrier (BBB), affecting A beta peptide clearance from the brain. Recognition of the importance of these vascular risk factors for AD-related dementia and their treatment will be beneficial not only for preventing cardiac, cerebral, and peripheral complications of vascular disease, but also will likely have a direct impact on the occurrence of sporadic AD in older subjects. In this paper, we review some of the links between vascular risk factors and AD pathology and present data on the direct effect of ischemia on cognitive function and A beta deposition in a mouse model of AD

In this communication we report the characterization of several transgenic rat lines expressing human AbetaPP carrying the Swedish and Indiana mutations (coded UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19) and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg rats, the AbetaPP and PS1 transgene expression was largely restricted to the hippocampus and neocortex. The PS1 transgenic rats did not produce visible changes in Abeta immunoreactivity. The AbetaPP transgenic rats (both the single Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalbeta accumulation without plaque formation and with no increased immunoreactivity for AbetaPP amino and carboxyl-terminal epitopes. This phenotype was apparent as early as 6 months of age in the transgenic rat lines carrying the human AbetaPP transgene. No senile plaques of aggregated Abeta were observed in any of the transgenic lines generated, up to 24 months of age. The hAbetaPP single homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed differences in the protein profile between this transgenic line and controls

Neurons in primary visual cortex are commonly characterized using linear models, or simple extensions of linear models. Specifically, V1 simple cell responses are often characterized using a rectified linear receptive field, and complex cell responses are often described as the sum of squared responses of two linear subunits. We examined this class of model directly by applying spike-triggered covariance analysis to responses of monkey V1 neurons under binary white noise stimulation. The analysis extracts a low-dimensional subspace of the full stimulus space that is primarily responsible for generation of the neural response, including both excitatory and suppressive components. We found no fewer than two excitatory dimensions in simple cells, and as many as seven dimensions in complex cells. For all cells, we also found suppressive dimensions that were at least equal in number to the excitatory dimensions. These results suggest that extensions to standard models are required to fully describe the response properties of cells in V1. (C) 2004 Published by Elsevier B.V

Technical and experimental advances in microaspiration techniques, RNA amplification, quantitative real-time polymerase chain reaction (qPCR), and cDNA microarray analysis have led to an increase in the number of studies of single-cell gene expression. In particular, the central nervous system (CNS) is an ideal structure to apply single-cell gene expression paradigms. Unlike an organ that is composed of one principal cell type, the brain contains a constellation of neuronal and noneuronal populations of cells. A goal is to sample gene expression from similar cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and noneuronal cells. The unprecedented resolution afforded by single-cell RNA analysis in combination with cDNA microarrays and qPCR-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease states. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models as well as postmortem human brain tissues. This focused review illustrates the potential power of single-cell gene expression studies within the CNS in relation to neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia, respectively

BACKGROUND: About a quarter of familial Mediterranean fever (FMF) patients are partially or totally resistant to colchicine. A previous observation reported that acute attacks may be shortened by administration of interferon alpha (IFN). OBJECTIVE: We designed a double-blind, placebo-controlled trial to test our initial observations of a beneficial response with IFN in FMF attacks. METHODS: We treated 34 acute abdominal attacks with IFN 5 million IU or placebo sc in the early phase of the attack. Leucocytes, thrombocytes, the erythrocyte sedimentation rate, fibrinogen, C-reactive protein (CRP), serum amyloid A protein (SAA), haptoglobin, transferrin, IL-1beta and TNF-alpha were measured at hours 0, 6, 12, 24 and 48. RESULTS: The median time to recovery in those treated with IFN and placebo was not significantly different, while the leucocytosis and high levels of fibrinogen were significantly more prolonged in placebo-treated patients. CRP and SAA were extremely elevated and peaked at 24h, remaining less marked in the IFN-treated patients but the difference was not statistically significant. Observations regarding the other parameters were unremarkable. CONCLUSIONS: Although there were some clues indicating a depressed inflammatory response with IFN, we could not demonstrate a definitive effect of this agent in this double-blind trial. The drug may suppress the acute inflammation of FMF only if administered at the earliest phase. CRP and SAA may be more sensitive indicators of an attack than ESR or fibrinogen.

PURPOSE: To prospectively determine hemodynamic changes in the normal-appearing white matter (NAWM) of patients with relapsing-remitting multiple sclerosis (RR-MS) by using dynamic susceptibility contrast material-enhanced perfusion magnetic resonance (MR) imaging. MATERIALS AND METHODS: Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T1-weighted, fluid-attenuated inversion recovery, and T2-weighted images) and dynamic susceptibility contrast-enhanced T2*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6-56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7-62.5 years). Absolute cerebral blood volume (CBV), absolute cerebral blood flow (CBF), and mean transit time (MTT) (referenced to an arterial input function by using an automated method) were determined in periventricular, intermediate, and subcortical regions of NAWM at the level of the lateral ventricles. Least-squares regression analysis (controlled for age and sex) was used to compare perfusion measures in each region between patients with RR-MS and control patients. Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of brain regions in terms of each perfusion measure. RESULTS: Each region of NAWM in patients with RR-MS had significantly decreased CBF (P <.005) and prolonged MTT (P <.001) compared with the corresponding region in control patients. No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined. In control patients, periventricular NAWM regions had significantly higher CBF (P =.03) and CBV (P =.04) than did intermediate NAWM regions. No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS. CONCLUSION: The NAWM of patients with RR-MS shows decreased perfusion compared with that of controls