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PubMed2003

Magnetic resonance imaging and histologic findings of experimental cerebral fat embolism.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine whether cerebral fat embolism demonstrated reversible or irreversible findings in magnetic resonance (MR) imaging over time and to compare the features in MR images with histologic findings in a cat model. MATERIALS AND METHODS: MR images were obtained serially at 2 hours, 1 and 4 days, and 1, 2, and 3 weeks after embolization with 0.05 mL of triolein into the internal carotid artery in 19 cats. Any abnormal signal intensity and change in the signal intensity were evaluated on T2-weighted images, T1-weighted images, diffusion-weighted images (DWIs; including apparent diffusion coefficient [ADC] maps), and gadolinium-enhanced T1-weighted images (Gd-T1WI) over time. After MR imaging at 3 weeks, brain tissue was obtained and evaluated for light microscopic (LM) examination using hematoxylin-eosin and Luxol fast blue staining. For electron microscopic examination, the specimens were obtained at the cortex. The histologic and MR findings were compared. RESULTS: The embolization lesions showed hyperintensity on T2-weighted images, hyperintensity, or isointensity on DWIs, hypointensity, or isointensity on ADC maps and contrast enhancement on Gd-T1WIs at 2 hours. The T2-weighted hyperintensity extended to the white matter at day 1 and decreased thereafter. Contrast enhancement decreased continuously from day 1, and hyperintensity on DWI decreased after day 4. Hypointensity on ADC maps became less prominent after day 4. By week 3, most lesions had reverted to a normal appearance on MR images and were correlated with LM findings. However, small focal lesions remained in the gray matter of 8 cats and in the white matter of 3 cats on MR images, and this correlated with the cystic changes on LM findings. Electron microscopic examination of the cortical lesions that reverted to normal at week 3 in MR images showed that most of these lesions appeared normal but showed sporadic intracapillary fat vacuoles and disruption of the endothelial walls. CONCLUSIONS: The embolized lesions of the hyperacute stage were of 2 types: type 1 lesions, showing hyperintensity on DWIs and hypointensity on ADC maps, have irreversible sequelae, such as cystic changes; whereas type 2 lesions, showing isointensity or mild hyperintensity on DWIs and ADC maps, reverted to a normal appearance in the subacute stage.

Animals↗
PubMedDate not supplied

Secreted beta-APP stimulates MAP kinase and phosphorylation of tau in neurons.

We have previously demonstrated that the secreted form of the beta-amyloid precursor protein (beta-APP) activates mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. beta-APP as well as other treatments that activate MAP kinase also enhance phosphorylation of the microtubule-associated protein tau in these cells. In this study, we extended this analysis to neurons. Using dissociated cultures of cortical neurons, we found that exposure to beta-APP activated MAP kinase 4 and 7 days but not 1 day after plating. Phosphorylation of tau in neurons was measured by immunoreactivity with the AT8 antibody, which recognizes a phosphorylated epitope present in tau from paired helical filaments. We found that activation of MAP kinase in neurons was associated with increased amounts of AT8-reactive tau. These results support a role for MAP kinase in transducing the biological effects of secreted beta-APP on neurons and suggest possible mechanisms by which beta-APP might be involved in the pathogenesis of Alzheimer's disease.

Amyloid beta-Protein Precursor↗
PubMed2026

Multimodal atlas of human atherosclerosis links granular vascular cell states to coronary artery disease risk.

Advances in single-cell and spatial assays have revolutionized the scale and resolution of molecular tissue profiling. Here we present MetaPlaq, a multimodal atlas of human atherosclerotic arterial beds comprising over a million cells across single-cell transcriptomics, epigenomics and high-resolution spatial expression assays. We map granular cell states and disease-relevant transcriptional programs within the native tissue context of coronary arteries. Furthermore, we map cardiovascular GWAS signals to smooth muscle cells (SMCs) and endothelial cells (ECs) and uncover the cis-regulatory architecture governing their phenotypic transitions. Our comprehensive epigenomic reference allowed us to build cell-specific enhancer-gene link maps and multimodal gene regulatory networks (GRNs) underlying disease-relevant states such as osteogenic SMCs and ECs undergoing mesenchymal transition. We also integrate SMC and EC disease-associated gene sets with GRNs to nominate key transcription factors such as PRRX1, BNC2 and ELK3 regulating atherosclerosis-relevant transcriptional programs. Finally, we layer single-cell and spatial modalities to fine-map GWAS variants with improved cell and anatomical context. We highlight candidate cell-specific regulatory mechanisms at less characterized CAD loci, including FGD5 and MCF2L in ECs. Together, this atlas represents an important step towards fully interpreting genetic risk loci and informing new therapeutic strategies for cardiovascular disease.

Journal Article↗
PubMed2000

High-resolution transcript map of the region spanning D12S1629 and D12S312 at chromosome 12q13: triple A syndrome-linked region.

For those searching for human disease-causing genes, information on the position of genes with respect to genetic markers is essential. The physical map composed of ESTs and genetic markers provides the positional information of these markers as well as the starting point of gene identification in the form of genomic clones containing exons. To facilitate the effort of identification of genes in the region spanning D12S1629 and D12S312, we constructed a high-resolution transcript map with PAC/BAC/cosmid clones. The strategy for the construction of such a map involved utilization of STSs for the screening of the large insert bacterial chromosome libraries and a chromosome 12-specific cosmid library by hybridization. The contig was constructed based on the STS contents of the clones. The resulting high-resolution transcript map of the region between P273P14/SP6 and D12S312 spans 4.4 cM from 66.8 to 71.2 cM of the Généthon genetic map and represents approximately 2.4 Mb. It was composed of 81 BAC, 45 PAC, and 91 cosmid clones with a minimal tiling path consisting of 16 BAC and 4 PAC clones. These clones are being used to sequence this part of chromosome 12. We determined the order of 135 STSs including 74 genes and ESTs in the map. Among these, 115 STSs were unambiguously ordered, resulting in one ordered marker per 21 kb. The order of keratin type II locus genes was determined. This map would greatly enhance the positional cloning effort of the responsible genes for those diseases that are linked to this region, including male germ cell tumor as well as palmoplantar keratoderma, Bothnian-type, and triple A syndrome. This transcript map was localized at human chromosome 12q13.

Addison Disease↗
PubMed1991

The physical map of chromosome arm 19q: some new assignments, confirmations and re-assessments.

We have constructed and analysed somatic cell hybrids from cell lines containing balanced reciprocal translocations involving chromosome 19 and providing two new breakpoints on 19q. These and other hybrids have been tested with a series of markers from 19q to enhance the existing map. Several new cloned DNA sequences that map to 19q13.3-19qter are reported; the locus D19Z1 has been analysed by CHEF gel electrophoresis.

Animals↗
PubMed1985

[Topographic mapping of regional cerebral blood flow by xenon-enhanced CT--introducing a simplified method as a routine examination].

Measurement of regional cerebral blood flow (rCBF) has become a routine examinations in the field of clinical neurology and neurosurgery. Therefore, various methods for measuring rCBF have been developed. Among them, xenon-enhanced CT method has many advantages compared with others. An obtainable topographic flow map, high anatomical spatial resolution, and readily available instrument, namely CT scanner, are regarded as the advantages. On the one hand, anesthetic effects of xenon gas on the patients, taking a great expense for a single examination, and a significant dose of radiation delivered to the patients are thought to be the disadvantages. Due to the disadvantages, xenon-enhanced CT is regarded as an unpractical examination. In the paper, we introduce a method with a brief xenon inhalation, named a simplified method, with which the disadvantages can be avoided. Conventional xenon-enhanced CT requires 20 to 25 minute inhalation of xenon gas in order to achieve a saturation of xenon in the cerebral tissue for a calculation of the partition coefficients (L). In the simplified method, instead of using the calculated L, L was given as 1.0 in all the cerebral regions and xenon gas was terminated at 4 minute inhalation. Four minute inhalation of xenon gas did not make any significant anesthetic effects on the patients nor the changes of physiological parameters, such as, PaCO2 and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Volume Determination↗
PubMed1996

Levosimendan potentiates the inotropic actions of dopamine in conscious dogs.

We examined the hemodynamic and left ventricular (LV) functional actions of dopamine with and without levosimendan in dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dtmax, subendocardial segment length, and cardiac output (CO). On different experimental days, dogs were randomly assigned to receive dopamine (2.5, 5.0, and 10.0 micrograms kg-1 min-1) in the absence and presence of levosimendan (0.125, 0.25, and 0.5 microgram kg-1 min-1) or levosimendan alone. Dopamine increased heart rate (HR), CO, stroke volume (SV), and pressure-work index (PWI) and decreased systemic vascular resistance (SVR). Dopamine also increased LV systolic and end-diastolic pressures (LVSP and LVEDP) and mean arterial pressure (MAP). Dopamine caused dose-related positive inotropic [increases in preload recruitable stroke work (Mw) and + dP/ dtmax] and lusitropic effects [decreases in the time constant of isovolumic relaxation (tau) and increases in maximum segment-lengthening velocity (dL/dtmax)]. Dopamine also increased the regional chamber thickness constant (Kp) concomitant with increases in LVEDP. In the presence of levosimendan, dopamine-induced increases in HR, PWI, CO, and SV and decreases in SVR were enhanced. Increases in MAP, LVSP, and LVEDP observed with dopamine alone were attenuated by the addition of levosimendan. Dopamine-induced increases in Mw and +dP/dtmax were enhanced by levosimendan. Reductions in tau and increases in dL/dtmax produced by dopamine were similar with and without levosimendan. However, levosimendan abolished increases in Kp caused by dopamine alone. Levosimendan alone caused dose-related improvements in indices of LV systolic and diastolic function. The results indicate that levosimendan potentiates the positive inotropic effects of dopamine in conscious, unsedated dogs, while attenuating the deleterious action of dopamine on chamber compliance.

Animals↗
PubMed1990

The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions.

The BZLF1 or zta immediate-early gene of Epstein-Barr virus (EBV) encodes a 33-kilodalton phosphorylated nuclear protein that is a specific transcriptional activator of the EBV lytic cycle when introduced into latently infected B lymphocytes. We have shown previously that the divergent EBV DSL target promoter contains two zta-response regions, one within the minimal promoter and the other in an upstream lymphocyte-dependent enhancer region. In this study, we used footprinting and gel mobility retardation assays to reveal that bacterially synthesized Zta fusion proteins bound directly to six TGTGCAA-like motifs within DSL. Four of the Zta-binding sites lay adjacent to cellular TATA and CAAT factor-binding sites within the minimal promoter, and two mapped within the enhancer region. Single-copy oligonucleotides containing these Zta-binding sites conferred Zta responsiveness to heterologous promoters. In addition, the Zta protein, which possesses a similar basic domain to the conserved DNA-binding region of the c-Fos, c-Jun, GCN4, and CREB protein family, proved to bind directly to the consensus AP-1 site in the collagenase 12-O-tetradecanoylphorbol-13-acetate response element. Cotransfection with zta also trans activated a target reporter gene containing inserted wild-type 12-O-tetradecanoylphorbol-13-acetate response element oligonucleotides. Cellular AP-1 binding activity proved to be low in latently EBV-infected Raji cells but was induced (together with the Zta protein) after activation of the lytic cycle with 12-O-tetradecanoylphorbol-13-acetate. We conclude that EBV may have captured and modified a cellular gene encoding a c-jun-like DNA-binding protein during its evolutionary divergence from other herpesviruses and that this protein is used to specifically redirect transcriptional activity toward expression of EBV lytic-cycle genes in infected cells.

Amino Acid Sequence↗
PubMed2006

Enhancing the precision of quantitative water content mapping by optimizing sequence parameters.

This article describes a methodology for determining the precision of a recently published method for quantitative water content mapping using MRI. A framework for calculating the random error component as a function of sequence parameters is provided and predictions are compared with experimental results obtained in a phantom. The experimental and theoretical results are in good agreement and demonstrate that the precision of quantitative water content mapping can be significantly increased by a proper and objective choice of acquisition parameters.

Brain Edema↗
PubMed2005

Phosphorylation of ezrin enhances microvillus length via a p38 MAP-kinase pathway in an immortalized mouse hepatic cell line.

The apical microvilli are closely related with the development and the maintenance of cell polarization, and the length of microvilli varies in a regular way among cell types. Ezrin, a member of the ezrin/radixin/moesin (ERM) family, seems to be involved in the formation and stabilization of the apical microvilli. We found that phosphorylation of ezrin caused elongation of microvilli via a p38 MAP-kinase signaling pathway in an immortalized mouse hepatic cell line. When, in the oncogenic Raf-1-transfected mouse hepatic cell line, epithelial to mesenchymal transition (EMT) indicated as down-regulation of E-cadherin and up-regulation of Snail occurred, loss of microvilli and down-regulation of ezrin but not radixin and moesin were also observed. In the Raf-1 transfectants treated with the MAP-kinase inhibitor PD98059 and the p38 MAP-kinase inhibitor SB203580, the numbers of microvilli and the expression of ezrin, E-cadherin and Snail were recovered. More interestingly, treatment with SB203580 induced elongation of microvilli and increased phosphorylation of ezrin (at Thr-567 and Tyr-353). Phosphorylated ezrin-positive dots were colocalized with actin-positive dots on the surface of some Raf-1 transfectants treated with SB203580. These results suggested that phosphorylation of ezrin via the p38 MAP-kinase signaling pathway might be involved in the formation of microvilli during development of epithelial cell polarization.

Acrylates↗
PubMed2000

A standardized method of generating time-to-peak perfusion maps in dynamic-susceptibility contrast-enhanced MR imaging.

BACKGROUND AND PURPOSE: Perfusion MR imaging, performed as dynamic-susceptibility contrast-enhanced MR imaging, is sensitive to hemodynamic risks for patients with cerebrovascular disease. We sought to define a quantitative parameter for perfusion MR imaging, which shows brain areas at hemodynamic risk and enables direct comparison of different perfusion MR imaging examinations. METHODS: A new standardization procedure for the time-to-peak (TTP) parameter, standardized time to peak (stdTTP), was introduced. The stdTTP automatically calculates a time offset correlated to the earliest enhancing voxels in a section and rescales all TTP values accordingly. Because of a close relation between this offset and stdTTP of early enhancing voxels in central vascular territories (CVTs), stdTTP provides an estimate of the bolus run time between CVTs and related border zones (BZs). The stdTTP in CVTs and BZs was measured in 11 patients without hemodynamic impairment by using high temporal resolution dynamic-susceptibility contrast-enhanced perfusion MR imaging. RESULTS: An excellent comparability of different dynamic susceptibility contrast-enhanced MR imaging studies was found. The stdTTP in CVTs was 0.4 +/- 0.5 s (minimum, 0 s; maximum, 1.3 s) for the anterior, 0.5 +/- 0.3 s (minimum, 0 s; maximum, 1.0 s) for the middle, and 1.4 +/- 0.5 s (minimum, 0.4 s; maximum, 2.4 s) for the posterior cerebral artery. In the anterior BZ, stdTTP was 2.3 +/- 0.4 s (minimum, 1.6 s; maximum, 3.2 s), and in the posterior BZ, stdTTP was 2.8 +/- 0.4 s (minimum, 2.0 s; maximum, 3.4 s). CONCLUSION: The results suggest a limit for stdTTP of approximately 3.5 s in the anterior and posterior BZs. The stdTTP could serve as a quantitative measure for the hemodynamic risk assessment of patients with cerebrovascular disease. Because stdTTP can be directly derived from the measured curves, the hemodynamic situation of a patient can be judged with a minimum of computational effort.

Adult↗
PubMed1993

Mapping of the mouse Rar loci encoding retinoic acid receptors RAR alpha, RAR beta and RAR gamma.

Nuclear retinoic acid receptors RAR alpha, RAR beta and RAR gamma are transcription factors that bind all-trans retinoic acid as their ligand and mediate its action by activating particular set of genes that contain retinoic acid responsive elements in their promoter-enhancers. We have mapped genetic loci for these genes using restriction fragment length variants (RFLVs) in interspecific backcross mice. None of the Rar loci cosegregated with each other or with the new subclass of retinoid receptors, Rxr loci. Rara mapped to mChr 11, Rarb mapped to mChr 14, and Rarg mapped to mChr 15. The results are consistent with the previous reports and the human data in terms of syntenic homology between mouse and human chromosomes.

Animals↗
PubMed2006

Independent component analysis of dynamic contrast-enhanced computed tomography images.

Independent component analysis (ICA) was applied on dynamic contrast-enhanced computed tomography images of cerebral tumours to extract spatial component maps of the underlying vascular structures, which correspond to different haemodynamic phases as depicted by the passage of the contrast medium. The locations of arteries, veins and tumours can be separately identified on these spatial component maps. As the contrast enhancement behaviour of the cerebral tumour differs from the normal tissues, ICA yields a tumour component map that reveals the location and extent of the tumour. Tumour outlines can be generated using the tumour component maps, with relatively simple segmentation methods.

Adult↗
PubMed2003

Wernicke's encephalopathy: is diffusion-weighted MRI useful?

We present the clinical and magnetic resonance imaging (MRI) findings of five patients with acute Wernicke's encephalopathy. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images demonstrated symmetrical hyperintense lesions within the dorsomedial thalami, periaqueductal white matter, and the tectum of the midbrain. None of the lesions enhanced with gadolinium. In addition to conventional MRI sequences, we performed diffusion-weighted imaging (DWI). In all patients, DWI showed symmetrical pathologic thalamic and midbrain signal hyperintensities more distinctly than did conventional T2-weighted or FLAIR sequences. The apparent diffusion coefficient (ADC) map images showed slight signal reductions in four patients, suggesting restricted diffusion within these regions. In one patient, the signal intensity within the affected thalami was isointense with the ipsilateral basal ganglia on ADC map images. For enhanced detection of pathology, we conclude that DWI should be included in the imaging protocols of patients suspected to suffer from Wernicke's encephalopathy.

Acute Disease↗
PubMed1999

Adipose expression of the phosphoenolpyruvate carboxykinase promoter requires peroxisome proliferator-activated receptor gamma and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo.

A putative adipocyte-specific enhancer has been mapped to approximately 1 kilobase pair upstream of the cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene. In the present study, we used transgenic mice to identify and characterize the 413-base pair (bp) region between -1242 and -828 bp as a bona fide adipocyte-specific enhancer in vivo. This enhancer functioned most efficiently in the context of the PEPCK promoter. The nuclear receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and 9-cis-retinoic acid receptor (RXR) are required for enhancer function in vivo because: 1) a 3-bp mutation in the PPARgamma-/RXR-binding element centered at -992 bp, PCK2, completely abolished transgene expression in adipose tissue; and 2) electrophoretic mobility supershift experiments with specific antibodies indicated that PPARgamma and RXR are the only factors in adipocyte nuclear extracts which bind PCK2. In contrast, a second PPARgamma/RXR-binding element centered at -446 bp, PCK1, is not involved in adipocyte specificity because inactivation of this site did not affect transgene expression. Moreover, electrophoretic mobility shift experiments indicated that, unlike PCK2, PCK1 is not selective for PPARgamma/RXR binding. To characterize the enhancer further, the rat and human PEPCK 5'-flanking DNA sequences were compared by computer and found to have significant similarities in the enhancer region. This high level of conservation suggests that additional transcription factors are probably involved in enhancer function. A putative human PCK2 element was identified by this sequence comparison. The human and rat PCK2 elements bound PPARgamma/RXR with the same affinities. This work provides the first in vivo evidence that the binding of PPARgamma to its target sequences is absolutely required for adipocyte-specific gene expression.

Adipocytes↗
PubMed1988

A common trans-acting factor is involved in transcriptional regulation of neurotransmitter genes by cyclic AMP.

Activation of neurotransmitter receptors can regulate transcription in postsynaptic cells through the actions of second messengers. Trans-synaptic regulation of transcription appears to be an important mechanism controlling the synthesis of molecules involved in neuronal signaling, especially neuropeptides. Proenkephalin, vasoactive intestinal polypeptide, and somatostatin have been shown to be transcriptionally regulated by the second messenger, cyclic AMP (cAMP), as has the catecholamine synthesizing enzyme tryosine hydroxylase. cAMP-inducible elements have been mapped within these genes, and trans-acting factors which bind to several such elements have been identified. With the discovery that individual neurons generally contain multiple transmitters within their synaptic terminals, it has become important to understand in detail the mechanisms by which the synthesis of transmitters can be coregulated. Here we compare the structure and function of the proenkephalin cAMP-inducible enhancer with the mapped cAMP-inducible elements of the vasoactive intestinal polypeptide, somatostatin, and tyrosine hydroxylase genes and a putative cAMP-inducible element in the proto-oncogene c-fos. We have previously shown that the proenkephalin enhancer is composed of two different elements, ENKCRE-1 and ENKCRE-2. We show here that one of these, ENKCRE-2, is structurally similar to elements found within the vasoactive intestinal polypeptide, somatostatin, and tyrosine hydroxylase genes and binds a trans-acting factor that is competed for both in cotransfection experiments (in vivo) and in DNase I footprint assays (in vitro) by these other elements. The c-fos element has similar structural requirements to confer transcriptional induction by cAMP but competes less strongly. Protein purified by affinity chromatography with the ENKCRE-2 sequence binds to each of these elements. A second element within the proenkephalin cAMP-inducible enhancer, ENKCRE-1, binds a factor that is not competed for by these other genes and is therefore distinct. This analysis suggests a potential mechanism of transcriptional coregulation of the neuronally expressed genes investigated in this study and also demonstrates that multiple factors are involved in transcriptional activation by cAMP.

Binding, Competitive↗
PubMed1991

Reduced baroreflex changes in muscle sympathetic nerve activity during blood pressure elevation in essential hypertension.

To determine whether the baroreflex control of sympathetic nerve activity is altered in patients with essential hypertension, muscle sympathetic nerve activity (MSNA) was recorded microneurographically from the tibial nerves of 23 normotensive subjects and 23 patients with essential hypertension. When phenylephrine (2 micrograms/kg) was injected intravenously, although the pressor response of mean arterial blood pressure (MAP) was significantly enhanced in the hypertensives as compared with the normotensives, the reflex decrease in MSNA was significantly smaller in the hypertensives. Furthermore, the baroreflex slope for MSNA, used as an index of baroreflex sensitivity and calculated by relating the change in MSNA to the change in MAP, was significantly less in the hypertensives. Following the injection of nitroglycerin (2 micrograms/kg), there were no significant differences between the normotensives and hypertensives in the depressor response, the reflex increase in MSNA or the baroreflex slope for MSNA. These observations suggest that the baroreflex change in sympathetic nerve activity is reduced during phenylephrine-induced blood pressure elevation but not during nitroglycerin-induced hypotension in the hypertensives, and that the blunted response of sympathetic nerve activity occurring during hypertension in these hypertensive patients may underlie the maintenance of high blood pressure in essential hypertension.

Adult↗