Search PubMed⌕ Search

Biomedical subjects

C Kelley

Publications and source records attributed to C Kelley.

At least 37 records · Page 2Linked to original sources
PubMed1996

Intraspinal epidural sarcoidosis: case report.

OBJECTIVE AND IMPORTANCE: A rare case of lumbar intraspinal epidural sarcoidosis is identified. The rarity of this condition and its clinical presentation are stressed. CLINICAL PRESENTATION: A young Caucasian man presented with the progressive onset of cauda equina syndrome as a result of an expanding mass in the lumbar epidural space compromising the lumbar dural tube from L1 to S1. The patient presented with motor, sensory, and sphincteric dysfunction as a result of this large intraspinal epidural mass. No evidence of systemic illness was noted concomitant with the patient's onset of neurological symptomatology. The patient underwent surgical extirpation of a lumbar intraspinal epidural mass, which was identified histopathologically as sarcoid granuloma. The postoperative work-up included the identification of a mediastinal adenopathy, which was subsequently biopsied and confirmed the diagnosis of sarcoid disease. The patient was treated postoperatively with oral prednisone over a 4-month period. At 7 months postoperatively, the patient had regained gainful employment, the results of his neurological examination were normal, and he was pain-free. INTERVENTION: The patient underwent a multilevel bilateral lumbar laminectomy with facet preservation, extending from L1 to S1, allowing for a gross total removal of the epidural mass. Postoperative oral prednisone was administered as adjuvant therapy for the treatment of multisystem sarcoid disease. CONCLUSION: Aggressive surgical management involving the removal of an extensive epidural mass of the lumbar canal, which was diagnosed as sarcoid disease, coupled with the adjuvant use of oral prednisone has resulted in an excellent outcome for the patient. The results of his clinical examination are now normal, and postoperative radiological imaging reveals no evidence of recurrent or residual disease in the lumbar epidural space. In the unusual case of intraspinal epidural sarcoidosis, the surgical resection of accessible intraspinal epidural masses is recommended, as is the use of oral prednisone postoperatively.

Adult↗
PubMed1996

Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds.

Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predicted and tested active analogs in a Leishmania promastigote assay; thus, we have identified the putative mechanism of action of this class of drugs in Leishmania species. Potentially, this will allow the design of noncarcinogenic, active drugs.

Animals↗
PubMed1995

Evolutionarily conserved alternative pre-mRNA splicing regulates structure and function of the spectrin-actin binding domain of erythroid protein 4.1.

A developmental alternative splicing switch, involving exon 16 of protein 4.1 pre-mRNA, occurs during mammalian erythropoiesis. By controlling expression of a 21-amino acid peptide required for high-affinity interaction of protein 4.1 with spectrin and actin, this switch helps to regulate erythrocyte membrane mechanical stability. Here we show that key aspects of protein 4.1 structure and function are conserved in nucleated erythroid cells of the amphibian Xenopus laevis. Analysis of protein 4.1 cDNA sequences cloned from Xenopus erythrocytes and oocytes showed that tissue-specific alternative splicing of exon 16 also occurs in frogs. Importantly, functional studies with recombinant Xenopus erythroid 4.1 demonstrated specific binding to and mechanical stabilization of 4.1-deficient human erythrocyte membranes. Phylogenetic sequence comparison showed two evolutionarily conserved peptides that represent candidate spectrin-actin binding sites. Finally, in situ hybridization of early embryos showed high expression of 4.1 mRNA in ventral blood islands and in developing brain structures. These results demonstrate that regulated expression of structurally and functionally distinct protein 4.1 isoforms, mediated by tissue-specific alternative splicing, has been highly evolutionarily conserved. Moreover, both nucleated amphibian erythrocytes and their enucleated mammalian counterparts express 4.1 isoforms functionally competent for spectrin-actin binding.

Actins↗
PubMed1995

Metabolism of a candidate 8-aminoquinoline antimalarial agent, WR 238605, by rat liver microsomes.

The in vitro metabolism of the 8-aminoquinoline, 8-(4-amino-1- methylbutylamino-2,6-dimethoxy-4-methyl-5-(3-trifluromethyl- phenoxy)quinoline (WR 238605), by rat liver microsomes was studied. After incubation of WR 238605 with rat liver microsomes, the metabolites were isolated either by direct solvent extraction or by extraction in the presence of ethyl chloroformate. WR 238605 was extensively metabolized to aminophenolic compounds, which underwent air oxidation during the isolation process to a mixture of quinones and quinoneimines. Because of the instability of the metabolites toward air oxidation, most of them could only be isolated as the ethoxycarbonyl derivatives by in situ derivatization with ethyl chloroformate. The metabolism of WR 238605 involved the expected metabolic pathways, such as O-demethylation, N-dealkylation, N-oxidation, and oxidative deamination. In addition, C-hydroxylation involving the 8-aminoalkylamino side chain, which was previously unknown for 8-aminoquinoline analogs, was found to be an important metabolic pathway for WR 238605. Most of the metabolites retained the 5-(m-trifluoromethyl)phenoxy group of WR 238605. Direct and indirect supporting evidence for the structure of the metabolites of WR 238605 came from the concomitant study of the in vitro metabolism of six other compounds that are putative metabolites of WR 238605.

Aminoquinolines↗
PubMed1994

Ventral expression of GATA-1 and GATA-2 in the Xenopus embryo defines induction of hematopoietic mesoderm.

The early embryonic events involved in the commitment of mesoderm to form blood have not been studied in detail for lack of molecular markers. We have studied the expression of the hematopoietic transcription factors GATA-1 and GATA-2 during Xenopus embryogenesis. During development GATA-1 expression is localized to the ventral region of the embryo and precedes the expression of embryonic globins. GATA-2 is highly expressed in the ventral region of the embryo by the end of gastrulation and later is expressed in the blood island region and the central nervous system. Lithium-induced dorsalization of embryos abrogates GATA-2 expression, and uv-induced ventralization of embryos leads to a radially symmetrical expression of GATA-2. Therefore, GATA-2 expression reflects the ventral character of the embryo. The expression of the GATA-binding proteins and globin in ventral marginal zone explants demonstrates that hematopoiesis is programmed as early as the blastula stage. GATA-1 and GATA-2 are also expressed in cultured animal cap explants, suggesting that these cells have hematopoietic potential. The developmental expression of GATA-1 and GATA-2 is consistent with their role in hematopoiesis in higher organisms and defines the ventral regions of the early embryo that give rise to hematopoietic progenitors. Our studies indicate that these genes will be useful in defining the inductive events that lead to the formation of hematopoietic mesoderm.

Animals↗
PubMed1993

Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis.

Mitogen-activated protein (MAP) kinases comprise an evolutionarily conserved family of proteins that includes at least three vertebrate protein kinases (p42, p44, and p55 MAPK) and five yeast protein kinases (SPK1, MPK1, HOG1, FUS3, and KSS1). Members of this family are activated by a variety of extracellular agents that influence cellular proliferation and differentiation. In Saccharomyces cerevisiae, there are multiple physiologically distinct MAP kinase activation pathways composed of structurally related kinases. The recently cloned vertebrate MAP kinase activators are structurally related to MAP kinase activators in these yeast pathways. These similarities suggest that homologous kinase cascades are utilized for signal transduction in many, if not all, eukaryotes. We have identified additional members of the MAP kinase activator family in Xenopus laevis by a polymerase chain reaction-based analysis of embryonic cDNAs. One of the clones identified (XMEK2) encodes a unique predicted protein kinase that is similar to the previously reported activator (MAPKK) in X. laevis. XMEK2, a highly expressed maternal mRNA, is developmentally regulated during embryogenesis and expressed in brain and muscle. Expression of XMEK2 in yeast cells suppressed the growth defect associated with loss of the yeast MAP kinase activator homologs, MKK1 and MKK2. Partial sequence of a second cDNA clone (XMEK3) identified yet another potential MAP kinase activator. The pattern of expression of XMEK3 is distinct from that of p42 MAPK and XMEK2. The high degree of amino acid sequence similarity of XMEK2, XMEK3, and MAPKK suggests that these three are related members of an amphibian family of protein kinases involved in the activation of MAP kinase. Discovery of this family suggests that multiple MAP kinase activation pathways similar to those in yeast cells exist in vertebrates.

Amino Acid Sequence↗
PubMed1993

GATA-4 is a novel transcription factor expressed in endocardium of the developing heart.

We have isolated and characterized Xenopus cDNA clones for a new transcription factor that represents an early marker for the developing heart. The cDNAs encode a protein that we have designated GATA-4; it contains the highly conserved DNA-binding domain that characterizes this family of cell-type restricted transcriptional activators. Whole-embryo in situ analysis of Xenopus embryos demonstrates that the GATA-4 gene is transcribed in presumptive cardiac ventral mesoderm at the time that bilateral progenitors fuse and form the cardiac tube. GATA-4 is therefore the earliest molecular marker of cardiogenesis yet characterized. By stage 30, the GATA-4 mRNA is expressed in the developing atria and ventricles; at stage 38, cross-sections reveal that the gene is active in the endocardial layer, but not in myocardium. By stage 40, GATA-4 message is detected in the great vessels. In the adult frog, the GATA-4 gene is highly transcribed in heart and gut; lower levels of message are detected in various endoderm-derived tissues and gonads. Expression in the stomach is largely confined to the epithelium. The GATA-4 gene is first activated at stage 11; mRNA is initially present throughout the marginal zone of explants and later partially localized to the ventral marginal zone. GATA-4 mRNA is also detected at high levels in cultured endodermal explants derived from the vegetal region of early embryos. In mesoderm induction experiments, GATA-4 transcription is not induced in animal caps treated with activin or bFGF. The GATA-4 gene may provide a new early marker for studying the inductive processes that lead to the formation of the cardiovascular system and for the specification of the endocardial lineage.

Amino Acid Sequence↗
PubMed1988

Vasoactive hormones and cAMP affect pericyte contraction and stress fibres in vitro.

Pericytes are contractile cells of the microvascular wall that may influence capillary haemodynamics and permeability. We examined the contractile responses of cultured pericytes to selected vasoactive agents and cAMP agonists. Morphological and biochemical changes associated with these responses were also studied. Pericytes seeded onto silicone rubber contracted when stimulated with histamine or serotonin, relaxed in response to the beta-adrenergic agonist isoproterenol and did not respond to epinephrine. Since hormonal-induced relaxation of vascular smooth muscle involves cAMP, we investigated the ability of cAMP, to modulate pericyte contraction. Dibutyryl cAMP and forskolin (an adenylate cyclase activator) both induced pericyte relaxation and elevated intracellular cAMP levels. Isoproterenol increased cAMP levels but epinephrine had no effect. However, when epinephrine and isoproterenol were co-incubated with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), cAMP was increased to levels above those elicited by these agonists alone. Serotonin and histamine in the presence of IBMX did not affect cAMP levels. These results suggest that certain vasoactive agents may relax pericytes by cAMP-dependent processes. We have shown previously that stress fibres are also involved in pericyte contraction. Hence, changes in the staining patterns of stress fibres in response to these selected agonists were studied. Histamine, serotonin and epinephrine had no apparent effect on stress fibre staining. Dibutyryl cAMP, forskolin, and isoproterenol, which relax pericytes and increase cAMP, disassembled fibres. In summary, the results demonstrate that the contractile activity of cultured pericytes in vitro can be regulated by vasoactive agonists and that changes in cAMP and stress fibres may mediate the regulation.

Actin Cytoskeleton↗
PubMed1987

Microvascular pericyte contractility in vitro: comparison with other cells of the vascular wall.

Collagen lattices containing bovine retinal pericytes (RPs), vascular smooth muscle cells (VSMCs), pulmonary microvessel endothelial cells (PMECs), or aortic endothelial cells (AECs) were prepared and contraction was quantitated by measuring the resulting change in lattice area. VSMCs were the most efficient at lattice contraction followed by RPs and then PMECs. AECs did not contract the lattices. To document further that these observations represent contraction, cells were grown on inert silicone rubber sheets. Substratum wrinkling was indicative of tension development and quantitated as percent of cells contracted. RPs were more contractile than PMECs, and AECs were incapable of developing tension. VSMCs were less contractile than RPs, unlike the comparative contractility observed with the lattice system. Alteration of actin-containing filaments by cytochalasin B significantly reduced RP contraction of silicone rubber and inhibited their contraction of collagen lattices in a dose-dependent manner. Rhodamine-phalloidin staining of contracting RPs revealed microfilament bundle orientations that suggested their association in the force applied for contraction. RP, VSMC and PMEC contraction of collagen lattices was directly proportional to the concentration of fetal calf serum. Also, RP contraction was greater in calf serum than calf plasma-derived serum, an indication that RPs respond to substances that appear continuously and episodically in blood. These in vitro findings support the theory that pericytes in vivo are contractile but that endothelial cells may also contribute to microvascular tonus.

Animals↗
PubMed1985

Femoral mycotic aneurysm presenting as arthritis and purpura.

A case is described with recurrent arthritis and skin rash confined to the right lower limb and exacerbated on each occasion by exercise. Investigation established this to be due to a mycotic aneurysm of the right common femoral artery. Treatment with excision and grafting and antibiotics resulted in full recovery. Mycotic aneurysm and the unusual presenting features in this case are discussed.

Aneurysm, Infected↗
PubMed1983

The role of drugs in adolescent suicide attempts.

Drug histories of 46 adolescent suicide attempters and their parents are described. In addition, these attempters and their parents are compared with a group of non-attempters and their parents on selected measures of drug use. Findings indicate that adolescent drug use is closely related to and perhaps symptomatic of suicidal behaviors and overall pathology. The relationship between adolescent suicidal behaviors and parental drug use is unclear because of the discrepancy between parent-adolescent responses.

Adolescent↗
PubMed1982

Carbon-7 substituted actinomycin D analogues as improved antitumor agents: synthesis and DNA-binding and biological properties.

7-(2,3-Epoxypropoxy)actinomycin D has been synthesized along with its major companion product, 7-(2,3-dihydroxypropoxy)actinomycin D. They were characterized by UV-visible and CD spectra and by NMR studies. According to UV-visible absorptiometry, circular dichroism, and thermal denaturation studies, they bind to DNA in a manner that is comparable to actinomycin D. The analogues are, like actinomycin D, extremely cytotoxic to human lymphoblastic leukemic cells (CCRF-CEM) in vitro but are significantly less toxic than actinomycin D to normal CDF1 mice is vivo. Unlike actinomycin, these analogues are metabolized in rats, and the metabolites are excreted in rat urine at a rapid rate. Compared to actinomycin D, the antitumor activity of the 7-(2,3-epoxypropoxy)actinomycin analogue against P-388 leukemia in mice is decidedly superior, and the therapeutic index is improved several fold.

Animals↗
PubMed1982

Adolescent suicide. A comparison of attempters and nonattempters in an emergency room population.

Forty-six adolescent suicide attempters and their parents were compared with 46 adolescent nonattempters and their parents using various measures of family conflict, family cohesion, and parenteral maladaptive behavior. Data analysis indicated several significant differences between these two family groups in these dependent measures of family functioning, suggesting that the family milieu plays an important role in the etiology of adolescent suicidal behavior.

Adolescent↗
PubMed1981

Reliability of the behavior problem checklist with institutionalized male delinquents.

Interrater and 2-week test-retest reliability coefficients were determined for subscales of the Behavior Problem Checklist on 50 males incarcerated in a state receiving facility for delinquent adolescents. Raters were 22 dormitory counselors, 2 of whom rated each child after 1 week and again after 3 weeks of observing the boys. Interrater reliability ranged from .06 to .68 on the various BPC subscales and was .50 overall, reflecting wide variation in the agreement of raters in rating boys on different dimensions. Test-retest reliability coefficients for the same rater at 2-week intervals were higher (.71 overall) and also varied among subscales. Raters were able to agree best on aggressive, acting-out behaviors. Other personality dimensions tapped by the BPC were rated with less reliability in this particular setting.

Adolescent↗
PubMed1979

The interaction of stressors in the induction of increased levels of fluctuating asymmetry in the laboratory rat.

Recent studies on fluctuating dental asymmetry have isolated single stressors as causative agents. Since most stressors are composite in nature, the present study was designed to determine the effects of the interaction of stressors in the induction of fluctuating dental asymmetry. Pregnant rats were assigned to one of six treatment groups and stressed with various combinations of heat, cold, noise and protein deprivation. The levels of fluctuating dental asymmetry were assessed and it was found that all protocols produced higher levels of asymmetry than found for control animals. Noise and reduced protein exhibited an additive effect and the interaction of stressors produced a reduction in litter size. Suggestions were offered for further research in this expanding field.

Animals↗
PubMed1979

Subtotal-skin electron-beam therapy once a week for inflammatory breast carcinoma.

Subtotal-skin electron-beam therapy (SSEB) was employed once a week in the treatment of 22 patients with recurrent inflammatory breast carcinoma between 1971 and 1976. The entire upper torso received 400 rad once a week for 6 consecutive weeks, using 3.5-MeV electrons from a 6-MeV linear accelerator. Seventeen patients (77%) obtained complete response and 3 (14%) had partial response, for a total response rate of 91%. Remission lasted for six months or longer in 35% of those exhibiting complete response. Treatments were tolerated well. The authors suggest that this is an excellent palliative method of treating this rapidly progressive disease.

Adult↗