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Manganese (II) bis(glycinate)dichloride (Mn(glycinate)2) is a coordination complex of manganese with application as a contrast enhancement agent for magnetic resonance imaging in the heart. To determine the cardioactivity of the manganese ion in this chelation cage, the effects of Mn(glycinate)2 on Ca channel function in the cultured chick atrial cell was studied. Mn(glycinate)2 decreased amplitude of contraction in chick atrial cells from embryos 14 days in ovo with complete inhibition of beating at 1 mM and half-maximal effect at 0.1 mM. Under control conditions, Bay K 8644, a Ca channel activator increased amplitude of contraction by 86% with a half maximal effect at 3.2 x 10(-7) M. In the presence of 0.025 mM Mn(glycinate)2, a concentration which had no effect on the amplitude of contraction, the maximum response to Bay K 8644 was decreased to 31%. Mn(glycinate)2 had no effect on the EC50 for the response to Bay K 8644, 1.7 +/- 0.1 x 10(-9) M (S.E.M., n = 4) in control cells compared to 2.2 +/- 0.4 x 10(-9) M (S.E.M., n = 4) in cells incubated with Mn(glycinate)2. 45Ca2+ uptake over 5 min in cultured chick atrial cells decreased from 2.0 nmol/mg protein in control cells to 1.5 nmol/mg protein in the presence of 10(-5) M PN200-110, a Ca2+ channel blocker, a decrease of 28%. 45Ca2+ uptake decreased to 0.94 nmol/mg protein (53%) in the presence of 1 nmol Mn(glycinate)2. Effects of Mn(glycinate)2 and PN200 were not additive. These data demonstrate that Mn(glycinate)2 exerts its negative inotropic effect, at least partially, by interfering with the function of the L-type Ca channels at high concentrations.
Myxomas are the most common primary tumors of the heart. These lesions contain a gelatinous, ground-substancelike material which has been described as glycosaminoglycan in nature. Using a newly developed, cartilage-derived hyaluronic acid-binding protein and a modification of the avidin-biotin immunostaining procedure, we demonstrate that hyaluronic acid is contained in the jellylike material of cardiac myxomas.
Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27.3. We identified human YAC clones that span fragile X site-induced translocation breakpoints coincident with the fragile X site. A gene (FMR-1) was identified within a four cosmid contig of YAC DNA that expresses a 4.8 kb message in human brain. Within a 7.4 kb EcoRI genomic fragment, containing FMR-1 exonic sequences distal to a CpG island previously shown to be hypermethylated in fragile X patients, is a fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes. This fragment contains a lengthy CGG repeat that is 250 bp distal of the CpG island and maps within a FMR-1 exon. Localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.
Nineteen of 71 (26%) cases of acute myelogenous leukemia (AML) were found to express CD7, a cell surface marker found early during T lineage differentiation. These myeloid leukemias often expressed other lymphoid markers and frequently had rearranged T-cell receptor beta and immunoglobulin heavy chain genes. We propose that in CD7+ AML, the malignant transformation occurred in a CD7+ progenitor cell. CD7+ myeloid leukemic precursors may be capable of limited differentiation with loss of CD7 during the initial phase of the disease, but this capacity may diminish during the course of treatment such that CD7 expression persists.
Regions within the 5'-flanking sequence of the bovine CYP17 (P-450(17)alpha) gene which are required for cAMP-dependent regulation of transcription have been localized by transient transfection of chimeric reporter gene constructs into mouse adrenal tumor Y1 cells. Two sequences have been found which individually confer cAMP responsiveness to reporter genes; they are located at -243/-225 and -80/-40 base pairs (bp). Obvious sequence homology between these two regions is not apparent. Gel shift competition analysis indicates that nuclear protein(s) binding to the -243/-225-bp region can be competed for by the addition of a double-stranded oligonucleotide containing a consensus cAMP-responsive element (CRE) from the human chorionic gonadotropin alpha gene, whereas addition of this CRE does not abolish protein-DNA complexes formed with fragments containing the -80/-40-bp sequence. Gel shift and Southwestern analysis indicate that the -243/-225-bp region of the P-450(17)alpha gene and the CRE both bind a 47-kDa protein and that the CRE binds additional proteins (43 and 68 kDa) not apparently recognized by the -243/-225-bp sequence. Thus cAMP-dependent regulation of the bovine P-450(17)alpha gene appears to involve two independent cis-regulatory regions, neither of which contains a consensus CRE. Based on protein binding analysis, one of these regions (that including -80/-40 bp) is distinct from the consensus CRE while the other (that containing -243/-225 bp) may be related to the consensus CRE.
Adenosine is an inhibitory neuromodulator in several brain regions. In the nucleus tractus solitarius (NTS), however, adenosine exerts excitatory cardiovascular effects. The purpose of the present study was to elucidate the involvement of other endogenous mechanisms that could contribute to the final hemodynamic response to adenosine in this nucleus. In normotensive Sprague-Dawley rats, intra-NTS microinjection of adenosine (2.3 nmol/60 nl) decreased blood pressure and heart rate. These effects were blocked by prior administration of the specific adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (0.92 nmol) and by the two glutamate receptor antagonists kynurenic acid and glutamic diethylester. The specificity of the adenosine-glutamate interaction in the NTS was demonstrated with adrenergic and angiotensin receptor antagonists that did not affect the adenosine response and by experiments with glutamate receptor antagonists that did not affect nicotine actions in the NTS. Furthermore, an increase in glutamate levels was demonstrated during perfusion of adenosine through a microdialysis probe in the NTS of anesthetized rabbits. These findings indicate that adenosine increases the release of glutamate in the NTS and, thus, are at variance with the concept of a "universal" inhibitory effect of adenosine in the central nervous system.
The sequences of productive T-cell gamma/delta receptor transcripts were compared in different murine fetal tissues. Differences from tissue to tissue suggest that the sequence repertoires are at least in part the products of selection, presumably through interaction of T cells bearing the gamma delta receptor with fetal self-ligands.
Cyclodiene resistance represents 60% of the reported cases of insecticide resistance and is also present in vertebrates. Resistance is due to insensitivity of the cyclodiene/picrotoxinin binding site on the gamma-aminobutyric acid subtype A (GABAA) receptor-chloride ionophore complex. Following isolation of cyclodiene-resistant Drosophila mutants, we report the cloning of the locus conferring resistance via a "chromosomal walk" and rescue of the susceptible phenotype by P-element-mediated germ-line transformation. Amino acid sequence analysis of a cDNA from the locus reveals homology with vertebrate GABAA subunits. To our knowledge, this represents the first cloning of an invertebrate GABA receptor and also allows us to manipulate the resistance status of an insect via germ-line transformation. This gene may be useful as a selectable marker in other insect systems.
The association of the plasma levels of the essential micronutrients, ascorbic acid and beta-carotene, with smoking and human papillomaviruses (HPV) infection has been studied in 75 women referred to a colposcopy clinic for an abnormal Pap smear. Each patient had a repeat Pap smear and a colposcopically directed biopsy of a visually perceived cervix abnormality. Cervicovaginal lavage specimen and peripheral venous blood sample were obtained for HPV DNA hybridization studies and nutrient analyses, respectively. Samples were obtained and analyzed without knowledge of each woman's clinical status. A group of 45 subjects had histopathologically diagnosed dysplasias of varying grades of severity. Among women with dysplasias, 53.3% were smokers. Of subjects with and of subjects without dysplasias, 66 and 34%, respectively, were positive for HPV infection. The mean plasma reduced ascorbic acid, retinol, and beta-carotene levels between the dysplastic groups were comparable. A strong association with smoking history and plasma reduced ascorbic acid level was note independent of cervical dysplasias or HPV status. The findings underscore the importance of smoking, ascorbic acid, and beta-carotene as nutritional variables, and HPV infection in the pathogenesis of cervical dysplasias.
Based on competition analysis of gel shift assays utilizing nuclear extracts from the mouse adrenal Y1 cell line, the cAMP-responsive element of the human CYP21B gene (-129/-96 base pairs (bp] is found to contain two overlapping nuclear protein binding elements. One, -126/-113 bp, interacts specifically with an adrenal-specific protein factor (ASP) while the other, -119/-110 bp, contains a GC boxlike sequence and binds Sp1. The nucleotide replacements (GG----CC at -113 and -112 bp) introduced within the sequence -129/-96 bp greatly decreased the binding affinities of both Sp1 and ASP to the fragment and resulted in a loss of cAMP-enhanced transcription of a reporter gene in transient transfection experiments. When the 14-bp ASP-binding sequence was inserted in front of the reporter gene, induced transcription by cAMP was observed that could be increased by multimerization of this -126/-113-bp sequence. The -126/-113-bp fragment revealed specific binding only with nuclear extracts from adrenal Y1 cells among various types of cells tested, indicating that the protein factor ASP is specifically expressed in adrenal cells. The nucleotide replacement (G----C at -117 bp) of the -126 -113-bp sequence not only abolishes the binding to ASP but also the cAMP-dependent transcription, strongly supporting the hypothesis that ASP is a tissue-specific transacting protein that directly functions as a transcription factor essential to the cAMP-dependent transcription. Furthermore, the -129/-115-bp sequence of the bovine cytochrome P450C21 gene corresponding to the human -126/-113-bp sequence is demonstrated to be functionally conserved with respect to both cAMP-dependent enhancement of transcription and ASP binding.