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We describe a technique of brain surface matching of single-photon emission CT and MR images in human subjects and document the accuracy of this technique with the use of fiduciary markers. This mismatch averaged 4.3 mm as measured by the fiduciary markers and 2.1 mm as measured by the root mean square distance.
Results of this study document a biphasic activation of protein kinases of the MAP kinase cascade-MEK and MAP kinases-upon interleukin-1 stimulation in human HeLa cells. The specific activities of both MEK and MAP kinases were increased within 1 min, declined rapidly to control levels and increased again after 15 min of interleukin-1 stimulation. Inhibition by okadaic acid of serine/threonine specific phosphatases resulted in a marked increase in interleukin-1 stimulated MEK and MAP kinase activities. Elevation by interleukin-1 of the specific activities of MEK and MAP kinases correlated with suppression of serine/threonine phosphatases in the late phase of stimulation. The data indicate, that enhanced phosphorylation of cellular proteins by enzymes of the MAP kinase cascade might represent a fine balance between activated protein kinases and repressed phosphoprotein phosphatase 2A in interleukin-1 stimulated HeLa cells.
The onset of IgH transcription and rearrangement is a defining characteristic of the progenitor population in which B-lineage commitment occurs. These features were used to better define the earliest stage of B-cell commitment in humans and to determine if these stages differ as a function of human ontogeny. Fetal and adult bone marrow mononuclear cells were sorted into B-lineage subpopulations on the basis of surface expression of the stem cell marker CD34, the pan-B-cell marker CD19, and IgM and analyzed for transcription and rearrangement of the IgH locus. The locus was found to be transcriptionally active before surface expression of CD19, as indicated by the presence of germline I mu, C mu, and D(H)Q52 transcripts in the CD34+ CD19- subpopulation. Transcripts from IgH alleles that had undergone DJC mu rearrangements were also detected in the CD34+ CD19- subpopulation. Within this subpopulation, low levels of DXP-containing DJC mu transcripts were detected in both fetal and adult cells. Although D(H)Q52 DJC mu transcripts were abundant in fetal CD34+ CD19- cells, they were not detected in cells of the same phenotype derived from adult bone marrow. In both fetus and adult, V(H)3-and V(H)6-containing VDJC mu transcripts were detected only in the CD19+ subpopulations. These data indicate that transcription of D(H)Q52-J(H) and DXP-J(H) rearrangements differs during fetal and adult B lymphopoiesis. Moreover, in both fetus and adult, transcription of unrearranged components of the IgH locus and DJ rearrangements can proceed before the surface expression of CD19.
Vinculin phosphorylation by pp60src is stimulated by anionic phospholipids (Ito, S., Richert, N., and Pastan, I. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 4628-4631). We have examined whether vinculin interacts with phospholipids, the specificity of the interactions, and a possible mechanism for the enhancement of vinculin phosphorylation by these phospholipids. 3H-labeled vinculin binds to phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, and phosphatidic acid. No binding to phosphatidylcholine or phosphatidylethanolamine was observed. The phospholipid binding specificity correlated with the ability of these phospholipids to enhance vinculin phosphorylation by the src kinase. Chlorpromazine (0.1 and 0.3 mM) inhibited both vinculin binding to phosphatidylinositol and the enhanced phosphorylation of vinculin by pp60src in the presence of phosphatidylinositol. Tryptic peptide maps of vinculin phosphorylated in the absence of phospholipid revealed three phosphorylated peptides. The same three peptides were phosphorylated in the presence of phospholipid. However, phosphorylation at one site was markedly increased. In the presence of phospholipid proteolysis of vinculin with both chymotrypsin and V8 protease was markedly enhanced and different peptide maps of vinculin were generated. Microheterogeneity of vinculin was observed with isoelectric focusing. All the isoforms (pI 5.45-5.8) were found to bind phospholipids and undergo phosphorylation by the src kinase. These results suggest that one way anionic phospholipids can enhance vinculin phosphorylation is by binding to vinculin and inducing a conformational change in the vinculin molecule.
PURPOSE: To correlate quantification of collateral flow in aortic coarctation with the morphological visualization of the collateral vessels and to compare different approaches to measurement of collateral flow. MATERIALS AND METHODS: Thirteen children with coarctation were examined with T1-weighted spin-echo (T1-W SE) imaging and 3D contrast-enhanced magnetic resonance angiography (MRA). MR velocity mapping was performed at four levels in the descending aorta. RESULTS: The flow immediately above and below the coarctation did not differ significantly. Measuring within the coarctation resulted in flow overestimation. The increase of flow from proximal to distal aorta was 12 +/- 21% in patients with no or uncertain collaterals and 69 +/- 55% in patients with pronounced collaterals. Spin-echo images and MRA were comparable in visualizing collateral vessels. The visual estimation of collaterals correlated reasonably well with flow quantification MR velocity mapping. CONCLUSION: Collateral flow assessment with MR velocity mapping is an accurate technique for evaluating the hemodynamic importance of a coarctation and is recommended if abundant collaterals are not visualized with spin echo or MRA.
The pleasure which some children find in maps and map reading is manifold in origin. Children cathect patterns of configuration and color and derive joy from the visual mastery of these. This gratification is enhanced by the child's knowledge that the map represents something bigger than and external to itself. Likewise, some children take pleasure in the pronunciation of names themselves. The phonetic transcription of multisyllabic names is often a plearurable challenge. The vocalized name has its origin in the self, becomes barely external to self, and is self-monitored. Thus, in children both the configurations and the vocalizations associated with map reading have the properties of "self=objects" (Kohut, 1971). From the author's observation the delight which some children take in sounding out geographic names on a map may, in some instances, indicate pre-existing gratifying sound associations. Childish amusement in punning on cognomens may be an even greater stimulant for learning than visual configurations or artificial cognitive devices.
BACKGROUND: Sentinel lymph node (SLN) mapping for melanoma and breast cancer has greatly enhanced the identification of micrometastases in many patients, thereby upstaging a subset of these patients. The purpose of this study was to see if SLN mapping technique could be used to identify SLNs in colorectal cancer and to assess its impact on pathological staging and treatment. METHODS: At the time of surgery, 1 ml of Lymphazurin 1% was injected subserosally around the tumor without injecting into the lumen. The first to fourth blue nodes identified were considered the SLNs, which have the highest probability to contain metastases. A standard oncological resection of the bowel was then performed. Multilevel microsections of the SLNs, including a detailed pathological examination of the entire specimen, was performed. RESULTS: SLN was successfully identified in 85 (98.8%) of 86 patients. In 85 patients, there were 1,367 (16 per patient) lymph nodes examined, of which 140 (1.6 per patient) were identified as SLNs. In 53 (95%) of 56, of whom the SLNs were without metastases (negative), all other non-SLNs also were negative. In 29 (34% of 85) patients, SLNs were positive for metastases; in 14 of the 29 patients, other non-SLNs also were positive in addition to the SLNs. In the other 15 of the 29 patients (18% of 85 patients), SLNs were the only site of metastases, and all other non-SLNs were negative. In 7 patients (8.2% of 85 patients), micrometastases were identified only in 1 or 2 of the 10 sections of a single SLN. In five of seven patients, such micrometastases were detected by hematoxylin and eosin staining and immunohistochemistry; in the other two patients, it was detected only by immunohistochemistry. In patients with negative SLNs, the rate of occurrence of micrometastases in non-SLNs was 5 (0.4%) of 1,184 lymph nodes. CONCLUSIONS: SLN mapping can be performed easily in colorectal cancer patients, with an accuracy of more than 95%. The identification of submicroscopic lymph node metastases by this technique may have upstaged these patients (18%) from stage I/II to stage III disease, who may then benefit from further adjuvant chemotherapy.
A link between glucose transport and apoptosis was suggested. We studied the mechanisms of glucose transport in human eosinophils by means of the uptake of the positron emitting analogue, 18Fluoro-2-Deoxyglucose (FDG) and apoptosis by means of flow cytometry. FDG uptake was inhibited by antibodies to GLUT1, 3 and 4 and by cytochalasin B. The anti-apoptotic principles IL-5, GM-CSF, IL-3 enhanced the uptake, whereas the apoptosis-inducing principles anti-CD95 (anti-Fas) and exposure to serum-coated Sephadex particles caused a reduction. Also TNF-alpha enhanced the uptake. Other cytokines such as IL-2, IL-4, IL-8, RANTES and MCP-3 had no effect on the glucose uptake. 2-Deoxyglucose, antibodies to GLUT4 and CD95 induced apoptosis. The basal FDG-uptake was unaffected by PKC inhibitors Ro-31-8220, Gö-6983 and Gö-6976, whereas the latter inhibited the IL-5-enhanced uptake possibly due to the inhibition of PKC(mu). Protein tyrosine kinase and PI-3 kinase inhibitors inhibited IL-5-enhanced FDG-uptake only. In contrast MEK inhibitors inhibited the basal uptake only. Inhibitors of p38 MAPkinase inhibited both basal and IL-5 enhanced uptake. We conclude that glucose uptake in eosinophils is governed by specific intracellular mechanisms involving mobilization of GLUTs, Ca2+ and the activation of the MAP kinase pathway and that the IL-5-enhanced uptake uniquely seems to involve PKC(mu) activity. Our results suggest a close link between apoptosis and glucose transport in human eosinophils.
We have documented that the Rous sarcoma virus (RSV) internal enhancer functions in the nontransformed Baby Hamster Kidney (BHK) cell line. The sequences within this region were assayed for their ability to bind to specific factors present in BHK nuclear extracts using the gel retardation assay and DNAse I footprinting. At least two sequences within the internal enhancer which can specifically bind nuclear factors in vitro have been identified. These regions are located between nucleotides 813-850 and 856-877. These sites map within the overall region of the internal enhancer which has been shown to be essential for enhancer activity and within the specific region which can function as an orientation independent enhancer. Using the DNase I footprinting and binding data to design an oligonucleotide, we have demonstrated that an oligonucleotide extending from nucleotides 804-877 will substitute efficiently as an enhancer. We also demonstrate that the SV40 enhancer does not compete for the factors which bind to the RSV internal enhancer, whereas an oligonucleotide to the binding site for EFII in the LTR can compete for factor binding to the internal enhancer.
Nefiracetam has been reported to increase intracellular cyclic AMP levels and enhance calcium channel current. Since the cAMP cascade is involved in the development of drug dependence, we investigated whether nefiracetam attenuates the methamphetamine (MAP)-induced discriminative responses in rats. Nefiracetam (50 mg/kg) inhibited MAP-induced discriminative responses. Furthermore, rolipram, raclopride, and L-745870, all of which can enhance cAMP activity, disrupted MAP-paired lever press of rats. Nifedipine and neomycin, which are blockers of voltage-sensitive calcium channels (VSCCs), decreased MAP-induced discriminative responses. However, pretreatment of these VSCC blockers failed to affect the inhibitory effects of nefiracetam on MAP-induced discriminative responses. Our findings suggested that nefiracetam inhibits MAP-induced discriminative responses, which may be at least partly associated with the changes in intracellular cAMP levels.
The tandemly repeated sea urchin alpha-histone genes are developmentally regulated. These genes are transcribed up to the early blastula stage and permanently silenced as the embryos approach gastrulation. As previously described, expression of the alpha-H2A gene depends on the binding of the MBF-1 activator to the 5' enhancer, while down-regulation relies on the functional interaction between the 3' sns 5 insulator and the GA repeats located upstream of the enhancer. As persistent MBF-1 binding and enhancer activity are detected in gastrula embryos, we have studied the molecular mechanisms that prevent the bound MBF-1 from trans-activating the H2A promoter at this stage of development. Here we used chromatin immunoprecipitation to demonstrate that MBF-1 occupies its site regardless of the transcriptional state of the H2A gene. In addition, we have mapped two nucleosomes specifically positioned on the enhancer and promoter regions of the repressed H2A gene. Interestingly, insertion of a 26 bp oligonucleotide between the enhancer and the TATA box, led to up-regulation of the H2A gene at gastrula stage, possibly by changing the position of the TATA nucleosome. Finally, we found association of histone de-acetylase and de-acetylation and methylation of K9 of histone H3 on the promoter and insulator of the repressed H2A chromatin. These data argue for a role of a defined positioned nucleosome in the promoter and histone tail post-translational modifications, in the 3' insulator and 5' regulatory regions, in the repression of the alpha-H2A gene despite the presence of the MBF-1 activator bound to the enhancer.
Plasma concentrations of the atherogenic lipoprotein(a) (Lp(a)) are predominantly determined by inherited sequences within or closely linked to the apolipoprotein(a) gene locus. Much of the interindividual variability in Lp(a) levels is likely to originate at the level of apo(a) gene transcription. However, the liver-specific apo(a) basal promoter is extremely weak and does not exhibit common functional variations that affect plasma Lp(a) concentrations. In a search for additional apo(a) gene control elements, we have identified two fragments with enhancer activity within the 40-kilobase pair apo(a)-plasminogen intergenic region that coincide with DNase I-hypersensitive sites (DHII and DHIII) observed in liver chromatin of mice expressing a human apo(a) transgene. Neither enhancer exhibits tissue specificity. DHIII activity was mapped to a 600-base pair fragment containing nine DNase I-protected elements (footprints) that stimulates luciferase expression from the apo(a) promoter 10-15-fold in HepG2 cells. Binding of the ubiquitous transcription factor Sp1 plays a major role in the function of this enhancer, but no single site was indispensable for activity. DHIII comprises part of the regulatory region of an inactive long interspersed nucleotide element 1 retrotransposon, raising the possibility that retrotransposon insertion can influence the regulation of adjacent genes. DHII enhancer activity was localized to a 180-base pair fragment that stimulates transcription from the apo(a) promoter 4-8-fold in HepG2 cells. Mutations within an Sp1 site or either of two elements composed of direct repeats of the nuclear hormone receptor half-site AGGTCA in this sequence completely abolished enhancer function. Both nuclear hormone receptor elements were shown to bind peroxisome proliferator-activated receptors and other members of the nuclear receptor family, suggesting that this enhancer may mediate drug and hormone responsiveness.
Abuse of methamphetamine (MAP) and cocaine causes severe medical and social problems throughout the world. Our previous study found that trihexyphenidyl (THP), a muscarinic cholinergic receptor antagonist, specifically suppressed the rewarding properties of MAP but not of cocaine, as measured by conditioned place preference in mice. The present study examined using in vivo microdialysis whether THP differentially affects the extracellular dopamine (DA) levels in the nucleus accumbens and striatum of mice injected with MAP and cocaine in comparison with another antimuscarinic agent, scopolamine (SCP). In addition, locomotor activity was simultaneously measured during microdialysis. In vivo microdialysis experiments revealed that during the initial hour after injection of MAP (1 mg/kg) DA levels increased up to 698% in the nucleus accumbens and 367% in the striatum as compared to the basal level. These increases were reduced to 293% in the nucleus accumbens and 207% in the striatum by treatment with 5 mg/kg THP. However, SCP (3 mg/kg) had no effect on the increases in extracellular DA levels in both regions after MAP injection. Cocaine (10 mg/kg) increased DA levels during the initial hour to 254% in the nucleus accumbens and 220% in the striatum as compared to the basal level. These increases were unaffected by treatment with either THP or SCP. On the contrary, both THP and SCP enhanced the locomotor-stimulant action of MAP and cocaine. These results, together with our previous finding, suggest that THP may specifically antagonize the rewarding properties of MAP through suppression of DA release in the mesolimbic area without retarding locomotor activity.
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Alien was previously identified as a corepressor for the thyroid hormone receptor (TR) and DAX-1 which belong both to the superfamily of nuclear receptors. Here, we isolated the mixed lineage kinase 2 (MLK2) as an interacting partner for the corepressor Alien using a yeast two hybrid screen. MLK2 is an upstream activator of JNKs and activation of MLK2-mediated signaling cascades play roles in neurodegenerative and apoptotic mechanisms in the central nervous system. MLK2 has been shown to be localized both in the cytoplasm and cell nucleus. We confirmed the Alien-MLK2 interaction using GST pull-down experiments and also show that MLK2 is able to phosphorylate Alien in immune-kinase assays. Functional analyses revealed that Alien, DAX-1 and thyroid hormone receptor mediated transcriptional silencing is strongly enhanced in the presence of active MLK2. Since MAP kinase signaling pathways are important mediators of cellular responses to a wide variety of stimuli, our data suggest that signaling pathways not only regulate transactivation but also enhancement of transcriptional silencing. This novel cross-talk may represent a link between MLK2-mediated signaling and transcriptional repression of target genes during neuronal differentiation processes.
The standard B-mode image shows 256 levels of gray, but the human eye can only differentiate 8-16 shades of gray. Color vision theoretically has several advantages in comparison with gray scale, because the human eye can distinguish 128 fully saturated hues and about 350,000 shades. In 1992, B-mode color maps were introduced in our clinical practice, to establish whether this technology was able to detect the smallest contrast differences better than the gray-scale map and therefore to increase diagnostic accuracy. This paper describes our experience with the technique and reports B-mode color images of clinical complications in obstetrics and gynecology. We use the color figures to illustrate this new technology and to demonstrate the advantages of the increased sensitivity of the human eye to color in different clinical situations. We conclude that the use of B-mode color maps does not change the ultrasonic diagnosis, but does enhance our ability to study and evaluate the morphological structure of different tissues, compared to the gray-scale map alone.
Many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) might be mediated by connective tissue growth factor (CTGF). The present study investigates the role of mitogen-activated protein (MAP) kinase in the expression of CTGF mRNA in the human lung fibroblast line, HFL-1. TGF-beta1 enhanced CTGF mRNA levels in a time- and concentration-dependent manner, and this enhancement was also dependent upon transcription. Inhibition of p38 MAP kinase or extracellular signal-regulated kinase (ERK) activation did not affect TGF-beta1-induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-beta1-induced CTGF expression in a concentration-dependent manner. TGF-beta1 activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-beta1-induced JNK, but not p38 MAP kinase activation. Finally, JNK1 and JNK2 antisense oligonucleotides attenuated cellular levels of JNK1 and JNK2 protein, respectively, and repressed TGF-beta1-induced CTGF expression. These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.
PURPOSE: The purpose of this study was to evaluate the cerebral hemodynamic change in the hyperacute stage of cerebral fat embolism induced by triolein emulsion, by using MR perfusion imaging in cat brains. METHODS: By using the femoral arterial approach, the internal carotid arteries of 14 cats were infused with an emulsion of triolein 0.05 mL. T2-weighted (T2WI), diffusion-weighted (DWI), apparent diffusion coefficient (ADC) map, perfusion-weighted (PWI), and gadolinium-enhanced T1-weighted (Gd-T1WI) images were obtained serially at 30 minutes and 2, 4, and 6 hours after infusion. The MR images were evaluated qualitatively and quantitatively. Qualitative evaluation was performed by assessing the signal intensity of the serial MR images. Quantitative assessment was performed by comparing the signal-intensity ratio (SIR) of the lesions to the contralateral normal side calculated on T2WIs, Gd-T1WIs, DWIs, and ADC maps at each acquisition time and by comparing the relative cerebral blood volume (rCBV), cerebral blood flow (CBF), and mean transit times (MTT) of the lesions to the contralateral normal side calculated on PWI. RESULTS: In the qualitative evaluation of the MR images, the lesions showed hyperintensity on T2WIs, enhancement on the Gd-T1WIs, and isointensity on DWIs and the ADC maps. In the quantitative studies, SIRs on the Gd-T1WIs, DWIs, and ADC maps peaked at 2 hours after infusion. The SIRs on the T2WIs peaked at 4 hours after infusion and decreased thereafter. On PWIs, the rCBV, rCBF, and MTT of the lesion showed no significant difference from the contralateral normal side (P = .09, .30, and .13, respectively) and showed no significant change of time course (P = .17, .31, and .66, respectively). CONCLUSION: The embolized lesions induced by triolein emulsion showed no significant difference in cerebral hemodynamic parameters from those on the contralateral normal side. The result may suggest that consideration of the hemodynamic factor of embolized lesions is not necessary in further studies of the blood-brain barrier with triolein emulsion.