UNLABELLED: Although hemoglobin-based oxygen carriers (HBOC) are now being investigated, the effects of HBOC solutions during regional anesthesia have never been analyzed. Therefore, we investigated the hemodynamic changes after HBOC infusion during general anesthesia and thoracic epidural anesthesia. Sheep were assigned to three different groups: a) a control group with six unanesthetized sheep; b) six sheep with a halothane anesthesia (2.0 vol.% in oxygen); and c) six awake sheep with a thoracic epidural anesthesia with bupivacaine. After a period of stabilization, all 18 animals received 100 mg/kg of the HBOC pyridoxalated hemoglobin polyoxyethylene conjugate. The infusion of the HBOC caused a significant increase in mean arterial pressure and pulmonary artery pressure in both the control and epidural anesthesia groups. Anesthesia with halothane reduced the effects of the HBOC-solution on mean arterial pressure but did not abolish the increase in pulmonary artery pressure. Our results demonstrate that vasoconstriction caused by HBOC solutions is not abolished by epidural anesthesia, but halothane anesthesia may alter the hemodynamic effects of HBOC solutions. IMPLICATIONS: We evaluated the effects of epidural anesthesia and halothane anesthesia on the vasoconstrictive properties of a cell-free hemoglobin solution. The vasoconstriction caused by a cell-free hemoglobin solution was similar in unanesthetized sheep and sheep with thoracic epidural anesthesia and was reduced in sheep with halothane anesthesia.

Anesthesia, Epidural↗

PubMed1999

Predictors of adverse outcome 10 years after coronary angioplasty.

UNLABELLED: To determine which factors before percutaneous transluminal coronary angioplasty (PTCA) predict long-term outcome, we evaluated the clinical follow-up data from 535 patients 10 years after single-vessel PTCA. Events were defined as death, myocardial infarction, bypass surgery or repeat PTCA. During the follow-up period 79 patients (15%) died, 59 patients (11%) suffered a myocardial infarction, 107 patients (20%) had coronary artery bypass surgery and 141 patients (26%) underwent a redilatation. To determine the predictors of 10-year follow-up, 12 patient-related and 9 lesion parameters were analyzed by logistic regression analysis. Mortality was independently increased in patients with diabetes, with multi-vessel disease, after a previous myocardial infarction and in smokers. The presence of multi-vessel disease, symptoms of a higher angina class and younger age increased the risk for undergoing bypass surgery. In the statistical model with lesion parameters, the risk of bypass surgery was decreased if the stenosis was located in the distal segment of the coronary vessel and by a higher minimal luminal diameter before PTCA. CONCLUSION: Logistic regression analysis identified multi-vessel disease, diabetes, smoking and a previous myocardial infarction as independent clinical predictors of an adverse outcome 10 years after coronary angioplasty. Lesion parameters before PTCA seem to be less important with regard to the long-term outcome after PTCA.

Angioplasty, Balloon, Coronary↗

PubMed1998

Mapping of the ICAM-5 (telencephalin) gene, a neuronal member of the ICAM family, to a location between ICAM-1 and ICAM-3 on human chromosome 19p13.2.

Intercellular adhesion molecule 5 (ICAM-5, telencephalin) is a cell adhesion molecule expressed on neurons in the most rostral segment of the mammalian brain, the telencephalon. Antibody studies in rodents and rabbits have demonstrated expression of this molecule on the cell body and dendrites of these neurons. We have examined the expression pattern in human brain by Northern blot analysis of 16 human brain segments. This analysis has confirmed the unique expression pattern of this ICAM in human. In addition, we report the mapping of the human ICAM-5 gene to an 80-kb region on chromosome 19p13.2 that also contains ICAM-1 and ICAM-3.

Antigens, CD↗

PubMed1998

Short CAG repeats within the hSKCa3 gene associated with schizophrenia: results of a family-based study.

In a family-based association study we investigated transmission of a multiallelic CAG repeat in a novel neuronal potassium channel gene, hSKCa3, in 59 parent/ offspring trios. In contrast to recent reports of an association of moderately large repeats with schizophrenia in case-control studies, our findings indicate that short CAG repeats (< or=19 repeats) are transmitted at an increased frequency to schizophrenic offspring (p=0.014), particularly among familial cases (p=0.007). No evidence for a parent-of-origin effect was found. Multiallelic TDT procedure showed no association of individual CAG repeats to schizophrenia. Further studies using family-based designs should clarify whether hSKCa3 is a susceptibility factor to schizophrenia or co-segregates with a major disease gene in tight linkage.

Adolescent↗

PubMed1998

Heterologous biosynthesis and characterization of the [2Fe-2S]-containing N-terminal domain of Clostridium pasteurianum hydrogenase.

The primary structure of Clostridium pasteurianum hydrogenase I appears to be composed of modules suggesting that the various iron-sulfur clusters present in this enzyme might be segregated in structurally distinct domains. On the basis of this observation, a gene fragment encoding the 76 N-terminal residues of this enzyme has been expressed in Escherichia coli. The polypeptide thus produced contains a [2Fe-2S]n+ cluster of which the oxidized level (n = 2) has been monitored by UV-visible absorption, circular dichroism, and resonance Raman spectroscopy. This cluster can be reduced by dithionite or electrochemically to the n = 1 level which has been investigated by EPR and by low-temperature magnetic circular dichroism. The redox potential of the +2 to +1 transition is -400 mV (vs the normal hydrogen electrode). The spectroscopic and redox results indicate a [2Fe-2S]2+/+ chromophore coordinated by four cysteine ligands in a protein fold similar to that found in plant- and mammalian-type ferredoxins. Among the five cysteines present in the N-terminal hydrogenase fragment, four (in positions 34, 46, 49, and 62) are conserved in other sequences and are therefore the most likely ligands of the [2Fe-2S] site. The fifth cysteine, in position 39, can be dismissed on the grounds that the Cys39Ala mutation does not alter any of the properties of the iron-sulfur cluster. The spectroscopic signatures of this chromophore are practically identical with some of those reported for full-size hydrogenase. This confirms that C. pasteurianum hydrogenase I contains a [2Fe-2S] cluster and indicates that the polypeptide fold around the metal site of the N-terminal fragment is very similar, if not identical, to that occurring in the full-size protein. The N-terminal sequence of this hydrogenase is homologous to sequences of a number of proteins or protein domains, including a subunit of NADH-ubiquinone oxidoreductase of respiratory chains. From that, it can be anticipated that the structural domain isolated and described here is a building block of electron transfer complexes involved in various bioenergetic processes.

Amino Acid Sequence↗

PubMed1998

Changes of neurohumoral parameters and endothelin-1 in response to exercise in patients with mild to moderate congestive heart failure.

UNLABELLED: Plasma endothelin levels are increased in patients with moderate and severe CHF. Conflicting data exist about the endothelin-1 (ET) level in patients with mild to moderate CHF and the effect of maximal exercise on plasma ET levels. METHODS AND RESULTS: We determined the plasma levels of ET and various neurohumoral parameters in 93 patients with CHF in functional class II and III of the NYHA classification at rest and after maximal bicycle exercise. Baseline ET level was increased compared to an age-matched healthy volunteer group (6.95+/-0.31 vs 3.29+/-0.17 pg/ml, mean+/-S.E.M., P<0.05), without significant differences between NYHA class II and III patients. Maximal exercise did not increase the ET level. In contrast, the neurohumoral parameters were significantly increased with maximal exercise. In conclusion, plasma levels of ET are increased in patients with mild to moderate CHF. However, no further increase in response to exercise was observed. Thus, it is highly unlikely that exercise capacity may be limited by ET-mediated peripheral vasoconstriction.

Aged↗

PubMed1998

The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways.

The alpha-chemokine stromal cell-derived factor (SDF)-1alpha binds to the seven transmembrane G-protein-coupled CXCR-4 receptor and acts to modulate cell migration and proliferation. The signaling pathways that mediate the effects of SDF-1alpha are not well characterized. We studied events following SDF-1alpha binding to CXCR-4 in a model murine pre-B cell line transfected with human CXCR-4. There was enhanced tyrosine phosphorylation and association of components of focal adhesion complexes such as the related adhesion focal tyrosine kinase, paxillin, and Crk. We also observed activation of phosphatidylinositol 3-kinase. Wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase, partially inhibited the SDF-1alpha-induced migration and tyrosine phosphorylation of paxillin. SDF-1alpha treatment selectively activated p44/42 mitogen-activated protein kinase (Erk 1 and Erk 2) and its upstream kinase mitogen-activated protein kinase kinase but not p38 mitogen-activated protein kinase, c-Jun amino-terminal kinase or mitogen activated protein kinase kinase. We also observed that SDF-1alpha treatment increased NF-kappaB activity in nuclear extracts from the CXCR-4 transfectants. Taken together, these studies revealed that SDF-1alpha activates distinct signaling pathways that may mediate cell growth, migration, and transcriptional activation.

Animals↗

PubMed1998

Evidence for opening of hair-cell transducer channels after tip-link loss.

The mechanosensitive transducer channels of hair cells have long been proposed to be gated directly by tension in the tip links. These are thin, elastic extracellular elements connecting the tips of adjacent stereocilia located on the apical surface of the cell. If this hypothesis is true, the channels should close after destruction of tip links. The hypothesis was tested pharmacologically using receptor currents obtained in response to mechanical stimulation of the stereociliary bundle of outer hair cells isolated from the adult guinea pig cochlea. Application of elastase (20 U/ml) or 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetra-acetic acid (BAPTA; 5 mM), both of which are known to disrupt tip links in other hair-cell preparations, led to the expected irreversible loss of receptor currents. However, the cells then displayed a maintained inward current, implying that channels were left permanently open. This current was similar in magnitude to the receptor current before treatment and was reduced reversibly by known blockers of mechanosensitive channels, namely, dihydrostreptomycin (100 microM), amiloride (300 microM), and gadolinium ions (1 mM). These observations suggest that the maintained current flows through the mechanosensitive channels. Electron microscopical analysis of isolated hair cells, exposed to the same concentrations of elastase or BAPTA as in the electrophysiological experiments, demonstrated an almost total loss of tip links in hair bundles that showed no evidence of other mechanical damage. It is concluded that although the tip links are required for mechanoelectrical transduction, the channels are not gated directly by the tip links.

Animals↗

PubMed1998

Extensive ligand rearrangements around the [2Fe-2S] cluster of Clostridium pasteurianum ferredoxin.

The [2Fe-2S] cluster of the ferredoxin from Clostridium pasteurianum is coordinated by cysteines 11, 56, and 60 and by a fourth cysteine, residue 24 in the wild-type protein, located on a flexible and deletable loop around residues 14-30. New mutated forms of this ferredoxin show that the fourth cysteine ligand can be located in any one of positions 14, 16, 21, 24, or 26. Another set of molecular variants has unveiled a new case of ligand swapping on the cysteine 60 ligand site. Replacement of cysteine 60 by alanine and introduction of a cysteine in position 21 yielded a ferredoxin that assembles a [2Fe-2S] cluster of which the ligands are cysteines 11, 21, 24, and 56. This cysteine ligand pattern is similar to that occurring in plant-type or mammalian-type ferredoxins, although the overall sequence similarities are below detection. Moreover, the vibrational and electronic properties of the resulting [2Fe-2S]2+/+ center, as revealed by resonance Raman and EPR studies, are strikingly similar to those of mammalian-type ferredoxins. The extensive set of mutated forms of the C. pasteurianum ferredoxin now available indicates that cysteine ligand exchange may occur on residues 24 and 60, but not on residues 11 and 56. It is thus suggested that cysteines 24 and 60 are part of a solvent accessible aspect of the Fe-S cluster, whereas cysteines 11 and 56 are buried and form the more rigid part of the polypeptide ligand framework. In view of the unprecedented versatility of this [2Fe-2S] cluster and of its polypeptidic environment, the introduction of ligands other than cysteine in various positions has been attempted. These experiments have remained unsuccessful, and even including previous studies, noncysteinyl ligation has been obtained with this protein in only very few cases. The data provide an extensive confirmation that Fe-S clusters have a strong preference for thiolate ligation and rationalize the relatively rare occurrence of noncysteinyl ligation in native Fe-S proteins.

Amino Acid Substitution↗

PubMed1998

NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees.

The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.

Adolescent↗

PubMed1998

Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium.

The Genetics Initiative of the National Institute of Mental Health (NIMH) was a multisite study that created a national repository of DNA from families informative for genetic linkage studies of schizophrenia, bipolar disorder, and Alzheimer's disease. The schizophrenia families were collected by three sites: Washington University, Harvard University, and Columbia University. This article, one in a series that describes the data collected for linkage analysis by the schizophrenia consortium, presents the results for the European-American sample. The European-American sample comprised 43 nuclear families and 146 subjects. Ninety-six of the family members were considered affected by virtue of having received a DSM-III-R diagnosis of schizophrenia (N = 82) or schizoaffective disorder, depressed (N = 14). The families contained a total of 50 independent sib-pairs. Using the significance threshold criteria suggested by Lander and Kruglyak [(1995): Nat Genet 241-247], no region showed statistically significant evidence for linkage; two markers on chromosome 10p showed statistical evidence suggestive of linkage using the criteria of Lander and Kruglyak [(1995): Nat Genet 241-247]: D10S1423 (nonparametric linkage (NPL) Z = 3.4, P = .0004) and its neighbor, D10S582 (NPL Z = 3.2, P = .0006).

Adolescent↗

PubMed1998

Images in cardiovascular medicine. Ectasia and aneurysm of the right coronary artery resulting from a shunt to the coronary sinus.

Explore the source record for details and available documents.

Aged↗

PubMed1998

Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation.

BACKGROUND: This study was performed to analyze the influence of either aspirin, ticlopidine, or their combination on platelet activation and aggregation parameters after stent implantation. METHODS AND RESULTS: Sixty-one patients with successful implantation of a single Palmaz-Schatz stent in a native coronary artery were randomly assigned to either group A (aspirin 300 mg/d+ticlopidine 2X250 mg/d), group B (ticlopidine 2X250 mg/d), or group C (aspirin 300 mg/d). Platelet activation was evaluated on days 1, 7, and 14 by flow cytometry measurement of expression of CD62p (p-selectin) and the binding of fibrinogen to the platelet surface glycoprotein IIb/IIIa receptor. Platelet aggregation was induced by addition of ADP or collagen. Differences between treatment groups were compared by ANOVA. Between days 1 and 14, we observed a significant decrease in collagen-induced platelet aggregation in group A (62.2+/-2.5% versus 36.9+/-3.1%), whereas an increase was seen in group B (58.3+/-2.5% versus 67.7+/-3.2%) and no change was seen in group C (P<.0001). The ADP-induced aggregation declined significantly in group A (74.7+/-1.4% versus 55.3+/-2.6%), whereas a delayed reduction was seen in group B (72.0+/-3.0% versus 52.6+/-4.2%) and no change was seen in group C (P=.0017). The CD62p expression declined significantly in groups A (68.2+/-2.7% versus 41.3+/-2.7%) and B (64.8+/-2.9% versus 39.3+/-3.5%) but not in group C (P<.0001). Moreover, the fibrinogen binding decreased significantly in group A (61.0+/-4.3% versus 36.3+/-4.2%) and with delay in group B (58.3+/-2.2% versus 39.4+/-3.0%), whereas no alterations were seen in group C (P=.012). CONCLUSIONS: Our results demonstrate synergistic and accelerated platelet inhibitory effects of ticlopidine plus aspirin in patients after stent implantation compared with a monotherapy with either ticlopidine or aspirin alone.

Angioplasty, Balloon, Coronary↗

PubMed1998

Carboxyl-truncated STAT5beta is generated by a nucleus-associated serine protease in early hematopoietic progenitors.

Hematopoiesis is tightly controlled by a family of cytokines that signal through a related set of receptors. The pleiotropic and overlapping response of a cell to different cytokines is reflected in the number and complex pattern of activated signal transducers. Of special interest is STAT5, which is stimulated by a large and diverse set of cytokines. In addition to the two highly homologous proteins, STAT5A and STAT5B, encoded by duplicated genes, expression and activation of a dominant-negative, carboxyl-truncated form has also been described in early hematopoietic progenitors. We show here that a protease expressed in early hematopoietic cells cleaves the alpha forms of STAT5A/5B (p96/p94) to generate carboxyl-truncated beta forms (p80/p77). Inhibition studies assigned this protease to the serine class of endopeptidases. Cell fractionation experiments showed that the protease is associated with the nucleus in a constitutively activated form and does not require an activated STAT5 substrate. The ability of a protease to modulate the specificity of an activated transcription factor is unprecedented and underlines the importance of proteases in regulation of cell functions.

Animals↗