Transient acantholytic dermatosis in a postoperative febrile patient.
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Acantholysis↗
Biomedical subjects
L S Davis
Publications and source records attributed to L S Davis.
Assessment of a positive selection technique using an avidin column to isolate human peripheral blood T cell subsets.
The current studies were designed to assess a new technique for positively selecting human T cells from whole peripheral blood mononuclear cells using the minimal amount of monoclonal antibody required to bind the T cell to an avidin column indirectly via a biotin-conjugated secondary antibody. Positive selection of T cells has previously been avoided because the saturating amounts of antibodies required for other isolation procedures can lead to aberrant results in assays of T cell activation and function. The avidin column technique for obtaining purified T cell subsets was compared to a multi-step procedure that included negative selection panning. The positive selection technique was easily performed within 4 h whereas the negative selection technique required a minimum of 12 h to complete. The avidin column technique proved to be a rapid and simple method for isolating T cell subsets of high purity and normal functional capabilities. Since minimal amounts of monoclonal antibodies were used for the purification protocol, no consistent inhibitory or stimulatory effect of the residual antibody was noted in assays of activation and proliferation of positively selected T cells compared to T cells isolated by negative selection panning.
Adult↗
Rheumatoid synovium is enriched in mature antigen-presenting dendritic cells.
Monocytes and dendritic cells (DC) can be purified from fresh peripheral blood (PB) based on their expression of CD33, CD13, and CD14. Whereas DC can be identified as CD33+ CD14dim or CD13+CD14dim cells, monocytes can be identified as CD33+CD14bright or CD13+CD14bright cells. Rheumatoid synovial fluid (SF) and synovial tissue (ST) non-T cells were found to be enriched in CD33+CD14dim cells compared with PB. Whereas 4 to 14% of normal or rheumatoid PB non-T cells were CD33+ and CD14dim, in rheumatoid SF or ST these cells comprised 20 to 45% of non-T mononuclear cells. Synovial CD33+CD14dim cells assumed a typical dendritic morphology on in vitro culture. Freshly isolated CD33+CD14dim PB DC precursors express low levels of HLA-DQ, CD40, and B7, which increase after in vitro incubation. In contrast, freshly isolated SF DC constitutively expressed these markers, and increased densities of HLA-DR and MHC class I molecules. Rheumatoid SF DC showed a specifically enhanced ability to stimulate autologous PB T cells compared with PB DC, or PB or SF monocytes. PB DC or monocytes preincubated in granulocyte-macrophage-CSF, TNF-alpha, or both cytokines exhibited enhanced expression of HLA-DR. Furthermore, DC preincubated in both granulocyte-macrophage-CSF and TNF-alpha were better stimulators of the autologous MLR than DC preincubated in medium, or in either cytokine alone. The data indicate that DC are enriched in rheumatoid SF and ST, and display a more differentiated phenotype than PB DC. These results suggest that PB DC accumulate in the synovium where they undergo phenotypic and functional differentiation in situ, which may be mediated by local cytokines. DC may play an important role in the ongoing presentation of antigen to autoreactive T cells in RA synovium.
Adult↗
Alternative splicing generates multiple isoforms of a rabbit prostaglandin E2 receptor.
Four cDNA clones homologous with a murine prostaglandin E2 receptor have been isolated from a rabbit kidney cortex cDNA library. These cDNAs encode related proteins that differ only in their COOH-terminal sequences. Southern blot analysis of rabbit genomic DNA indicates that these receptor cDNAs represent alternatively spliced variants derived from a single gene. This was confirmed by isolation and sequence analysis of genomic clones containing common region exons and unique 3'-coding exons, which contained intron/exon boundaries at the predicted splice junctions. Transient expression of a novel full-length cDNA in COS1 cells confirmed the ligand binding profile typical of an EP3 receptor subtype. Ribonuclease protection assays indicate that the gene encoding these receptors is most highly expressed in kidney, adrenal, and stomach with lower but significant expression in uterus, lung, heart, ileum, spleen, and brain. Moreover, each of the cloned isoforms is expressed in the kidney. In situ hybridization analyses of rabbit kidney demonstrated that the level of expression is highest in the outer medulla with lesser expression in the cortex and no detectable expression in the inner medulla. The ligand binding profile and tissue distribution of these receptors is consistent with a functional role for this family of EP3 receptors in mediating the renal actions of prostaglandins as well as the effects of prostaglandins on gastric acid secretion and adrenal function.
Alternative Splicing↗
Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1.
OBJECTIVE: To assess the safety and efficacy of a monoclonal antibody (MAb) to intercellular adhesion molecule 1 (ICAM-1; CD54) in rheumatoid arthritis (RA). METHODS: A phase I/II, open-label, dose-escalation study of 32 patients. RESULTS: During treatment, a peripheral CD3+/CD4+ lymphocytosis was noted, and several patients demonstrated transient cutaneous anergy, which suggests that therapy modified T cell recirculation. Thirteen of the 23 patients who received 5 days of treatment demonstrated clinical improvement through day 29, and 9 of 23 through day 60. Adverse effects were minor and transient. CONCLUSION: Anti-ICAM-1 MAb therapy was well tolerated, resulted in a transient alteration in T lymphocyte recirculation, and effected clinical improvement in some RA patients.
Adult↗
Hypertonic saline destruction of multiple glomus tumors.
BACKGROUND: Multiple glomus tumors are uncommon cutaneous neoplasms. Therapeutic destructive alternatives include excision, argon or CO2 laser treatment, and sclerotherapy with sodium tetradecyl sulphate. OBJECTIVE: A case report is presented using a previously unreported technique of therapy, specifically hypertonic saline. METHODS: 23.4% NaCl was injected intraluminally in four sessions over a 6-month period. CONCLUSION: Serial hypertonic saline injections should be added to the list of effective treatment alternatives for multiple glomus tumors.
Adult↗
Congenital papule on the finger of a child.
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Child↗
Effects of selective endothelin antagonists on the hemodynamic response to cyclosporin A.
Cyclosporin A (CsA) treatment is associated with hypertension and renal dysfunction. Increased circulating endothelin (ET) has been implicated in this renal dysfunction, which is secondary to renal vasoconstriction and decreases in RBF. The effects of the selective blockade of ETA receptors or the combined blockade of ETA and ETB receptors on the acute hemodynamic response to CsA in anesthetized rats were examined. Rats were pretreated with vehicle, BQ-123 (selective ETA receptor antagonist; 0.6 micron/kg per minute), or BQ-123 and PD 142893 (combined ETA/ETB receptor antagonist; 0.6 micron/kg per minute) to achieve both ETA and ETB receptor blockade. After a 10-min pretreatment, CsA (20 mg/kg over 10 min) was administered; mean arterial blood pressure, RBF, and iliac blood flow were monitored continuously. Hemodynamic responses to exogenous endothelin-1 (ET-1, 0.3 and 1 nmol/kg) with and without antagonist pretreatment were measured in separate groups to demonstrate effective receptor blockade. CsA elevated blood pressure 17 to 20% in all three groups; renal resistance maximally increased 23, 20, and 23% in vehicle, BQ-123, and BQ-123 and PD 142893 pretreated groups, respectively. In contrast, the combination of BQ-123 and PD 142893 blocked systemic pressor responses to 0.3 and 1 nmol of ET-1 approximately 50 and 37%, respectively; changes in renal resistance were blocked 81 and 89%, respectively. In conclusion, the elevation in systemic blood pressure and the renal vasoconstrictor activity of CsA do not appear to be mediated through ETA or ETB receptors.
Animals↗
Comparative accessory cell function of human peripheral blood dendritic cells and monocytes.
The capacity of human peripheral blood (PB) dendritic cells (DC) and monocytes to facilitate T cell activation and the interaction molecules employed were compared. We have shown that precursors of DC constitute 2 to 3% of circulating PBMC, and can be isolated as CD33+CD14dim cells, whereas monocytes are CD33+CD14bright. Freshly obtained DC expressed similar densities of HLA-DR and the accessory molecules LFA-3, ICAM-1, and B7 as monocytes; after a 36-h incubation the expression of HLA-DR, ICAM-1, and B7 increased on both APC. Accessory cell function was examined in PB T cell cultures stimulated by suboptimal concentrations of immobilized mAb to CD3, and by stimulation of an allospecific T cell line. Freshly isolated monocytes and DC were comparable accessory cells in these assays, but their accessory function was increased by in vitro preincubation, although cultured DC and monocytes were comparably active. In contrast, DC were much more effective stimulators of freshly isolated allogeneic T cells than monocytes. DC were much more effective stimulators of freshly isolated allogeneic PB CD4+ naive and memory T cells than monocytes, whereas DC and monocytes were comparable accessory cells for memory and naive T cells stimulated with immobilized anti-CD3. The accessory molecules ICAM-1, LFA-3, and B7 were used comparably by DC and monocytes for accessory function in the presence of immobilized anti-CD3 and in the MLR, and none was unique for either APC population. These accessory molecules costimulated T cells in an additive fashion. Although immature blood DC and monocytes expressed minimal B7 and did not utilize it as an accessory molecule, B7 played an important role in the increased accessory function of differentiated APC. The results indicate that PB DC and monocytes function most efficiently after differentiation into mature cells that express increased amounts of MHC and other accessory molecules. Because DC and monocytes exhibit comparable accessory function in anti-CD3 T cell stimulation, differences in the expression of MHC molecules and/or their bound peptides are likely to explain the markedly enhanced capacity of DC to stimulate allogeneic PB T cells.
Adult↗
Isolation and characterization of human peripheral blood dendritic cells.
Dendritic cells (DC) are potent APC that can be purified from cultured peripheral blood non-T cells. Because no specific cell surface marker has been found, the lineage of DC remains obscure. The purpose of these studies was to determine the circulating blood cells that could give rise to functional human DC. DC were enriched when purified by standard techniques from non-T cells that were treated with L-leucyl-L-leucine methyl ester, known to be toxic to monocytes and cytolytic cells. To determine whether monocytes or B cells could give rise to DC, fresh non-T cells were sorted into CD14+ monocytes, CD19+ B cells, and CD14- and CD19- cells. Although there was some enrichment for APC function by cultured nonadherent CD14- or CD19- cells, a marked enrichment for cells with dendritic morphology and potent APC function was found in the population that was sorted by the absence of expression of CD14, CD19, CD3, and CD16. More than 90% of the CD14-CD19-CD16-CD3- sorted cells, and of control DC, expressed the myeloid markers CD13 and CD33. Therefore, fresh non-T cells were sorted based on the expression of these myeloid markers. In comparison with CD33-CD14- B cells, some of the CD33+ cells expressed CD14 dimly. However, they were easily distinguished from monocytes, which intensely expressed CD14. CD33+CD14dim cells developed dendritic processes and were more potent APC than control DC, CD33+CD14+, or CD33-CD14- cells. Although freshly isolated CD33+CD14dim DC expressed a number of cell surface molecules also expressed by CD14+ monocytes, they demonstrated lower levels of lysosomal enzymes and a lack of FcR-mediated phagocytosis in comparison with monocytes. Differentiation of morphology and phenotype of CD33+CD14dim cells occurred within 6 to 36 h in culture. However, the CD33+CD14dim cells could effectively function as APC without prolonged preincubation to develop dendritic morphology. These data indicate that human blood DC arise from precursors that express the myeloid lineage markers CD13 and CD33, but are functionally distinct from classic CD14+ monocytes.
Antigen-Presenting Cells↗
Raf-1 is required for T cell IL2 production.
Engagement of the T cell receptor/CD3 complex activates the serine/threonine kinase, Raf-1, but the physiologic consequences of its activation have not been determined. The effects of Raf-1 on interleukin 2 (IL2) production in T cells were examined using activated and inhibitory forms of Raf-1. A truncated active form of Raf-1 was expressed constitutively from the metallothionein promoter in a malignant T cell line, Jurkat. Treatment of the cells with zinc and cadmium greatly increased active Raf-1 expression. This increase in Raf-1 expression allowed antibodies to CD3 and to CD28 to stimulate IL2 production in the absence of phorbol myristate acetate (PMA) and enhanced IL2 production stimulated by these antibodies in the presence of PMA. The action of active Raf-1 was to increase IL2 gene transcription as it enhanced transcription of a reporter gene linked to IL2 promoter. Finally, the dominant negative form of Raf-1 inhibited transcription directed by the IL2 promoter that was induced by the mitogen phytohemagglutinin (PHA) and PMA. We conclude that Raf-1 activity is necessary for IL2 gene transcription and secretion. These data indicate a role for Raf-1 in the immune response.
CD28 Antigens↗
Tolerance induction of human CD4+ T cells: markedly enhanced sensitivity of memory versus naive T cells to peripheral anergy.
We have previously demonstrated that freshly isolated highly purified normal human peripheral blood CD4+ T cells pulsed with an IgM anti-CD3 mAb, 38.1, or the calcium ionophore, ionomycin, retained the phenotype of normal resting T cells but exhibited markedly reduced proliferative responses upon subsequent stimulation. Using this model of anergy, the sensitivity of naive (CD45RA+) and memory (CD45RO+) T cells was examined. CD4+ T cells were separated into memory or naive subsets based on their relative expression of CD45 isoforms. The memory T cells were found to be much more susceptible than naive T cells to anergy induction. After tolerance induction, memory T cells were inhibited in the ability to respond to the recall antigen, tetanus toxoid, and PHA. Anergy appeared to result from an inability to produce sufficient IL2 and proliferative responses could be restored by large numbers of accessory cells. T cell clones could also be anergized in a similar manner, but their capacity to produce IL2 could not be restored by accessory cells. In contrast to memory cells and T cell clones, the responses of naive T cells were only minimally inhibited by tolerogen. These results suggest that tolerance induced by occupancy of the TCR/CD3 complex in the absence of appropriate costimulation may be an effective means to limit the responses of memory T cells, but that such interactions are unable to limit the subsequent responses of naive T cells.
Adult↗
Proinflammatory cytokines enhance human synoviocyte expression of functional intercellular adhesion molecule-1 (ICAM-1).
We determined the ability of proinflammatory cytokines to enhance ICAM-1 (CD54) expression on, and PBMC adhesion to, human synoviocytes. Surface molecules were characterized by cell ELISA and by flow cytometry. Adhesion of PBMC to synoviocyte monolayers was measured by direct counting or by colorimetric staining. Most cytokines upregulated ICAM-1 expression (IL-1 beta > TNF alpha > IFN-gamma >> PDGF-bb, IL-6), but not GM-CSF or TGF beta. A similar concentration-dependent increase was observed for synoviocytes derived from patients with rheumatoid or osteoarthritis. Kinetic studies of ICAM-1 expression differed among several cytokines: an early rise with IL-1 beta or TNF alpha stimulation, a gradual increase with IFN-gamma, a transient increase with PDGF-bb, and a plateau with IL-6. Adhesion of PBMC to synoviocytes was increased by IL-1 beta or TNF alpha and reduced by MAb to CD54 or CD18. Increased synoviocyte adhesiveness may promote interactions with infiltrating inflammatory cells.
Arthritis, Rheumatoid↗
In situ hybridization and localization of mRNA for the rabbit prostaglandin EP3 receptor.
The physiological effects of PGE2 appear to be mediated by at least three different "E-prostanoid" receptors designated EP1,EP2, and EP3. These receptors are differentially activated by structural PGE analogs (such as misoprostol) and each couples to a different signal transduction mechanism. Studies demonstrating that inhibition of water absorption in the collecting duct is mediated by a Gi coupled mechanism, suggests that an EP3 receptor is involved the renal effects of PGE2. We used in situ hybridization to determine the tissue distribution of the rabbit EP3 receptor. [alpha-35S] UTP labeled antisense RNA, comprising transmembrane domains IV through VII, was hybridized to tissue sections. Specific labeling of kidney, stomach and adrenal was observed. In the kidney, medullary thick ascending limb and cortical and medullary collecting ducts were intensely labeled, while no labeling of glomeruli, proximal tubules, or cortical thick ascending limbs was observed. The adrenal gland labeled exclusively in the medulla. In the stomach the gastric epithelial crypts were the predominant site of hybridization, without evidence of labeling of the smooth muscle. These results suggest an important role for the EP3 receptor in mediating PGE2 effects in these tissues.
Adrenal Glands↗
In vitro and in vivo studies with a series of hexapeptide endothelin antagonists.
The effects of different amino acids incorporated into the 16 and 17 positions of the C-terminal hexapeptide of ET-1 were examined. Structure-activity relationships (SAR) of the ET receptor antagonists PD 142893 [Ac-(D-Dip16-L-Leu17-L-Asp-L-Ile-L-Ile-L-Trp) (D-Dip = 3,3-D-diphenylalanine)] and PD 145065 [Ac-(D-Bhg16-L-Leu17-L-Asp-L-Ile-L-Ile-L-Trp) (D-Bhg = 5H-dibenzyl[a,d]cycloheptene-10,11-dihydro-glycine)] uncovered certain requirements for high potency. The disodium salt of PD 145065 has 4.0 and 15 nM binding affinity (IC50 values) for the ETA (rabbit renal artery vascular smooth-muscle cells) and ETB receptor (rat cerebellum), respectively. The compound is also an antagonist of ET-1- and SRTX-6c-stimulated vasoconstrictor activity, with pA2 values of 6.9 (rabbit femoral artery, ETA assay) and 7.1 (rabbit pulmonary artery, ETB assay). The tripeptidic ETA antagonist FR 139317 was found to be less active in the rabbit femoral artery, with a pA2 value of 6.0, and inactive in the rabbit pulmonary artery. Substitution of acidic and basic residues at position 17 in PD 142893 and PD 145065 indicates differences in selectivity. Incorporation of bulky non-natural amino acids at position 16 has led to potent nonselective analogues, including Ac-D-Bheg16-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp [D-Bheg (5H-dibenzo[a,d]cycloheptene glycine)]. The in vivo effects of single-bolus doses of selected ET antagonists on depressor and pressor responses to ET-1 in anesthetized ganglion-blocked rats were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Why big endothelin-1 lacks a vasodilator response.
The biphasic arterial blood pressure response to endothelin-1 (ET-1) results from a transient decrease, followed by a longer-lasting increase, in systemic vascular resistance. In contrast to ET-1, big endothelin-1 (bET-1) produces monophasic increases in systemic vascular resistance and arterial blood pressure. This is somewhat surprising, because bET-1 activity is reportedly due to ET-1, bET-1 being converted to ET-1 by a putative converting enzyme. In this study we tested two hypotheses that could explain the singular effect of bET-1 on the arterial vasculature: that bET-1 vasoconstriction, mediated by ETA receptors at the level of the smooth muscle, masks the release of endothelial derived vasodilators, and/or that the endothelium develops tachyphylaxis owing to prolonged activation of endothelial ETB receptors. In anesthetized rats, blockade of the vasoconstrictor activity of bET-1 with BQ-123, an ETA-receptor antagonist, did not reveal a masked bET-1 vasodilator component in the rat hindquarter. Furthermore, in the presence of bET-1 (after 3.0 nmol/kg bET-1 i.v.), low doses of ET-1 (0.03-0.3 nmol/kg) produced dose-dependent hindquarter vasodilation, indicating activation of endothelial ETB and therefore no tachyphylaxis. Collectively, these experiments suggest that i.v. administration of bET-1 results in little or no activation of endothelial ETB receptors and therefore lacks a vasodilator response.
Animals↗
Occupational exposure to bloodborne diseases and universal precautions: measurement of health care workers' self reported attitudes.
1. As the numbers of persons infected with bloodborne diseases continues to increase, it is paramount that all health care workers exhibit behaviors reflecting unerring compliance with universal precautions. 2. Physicians and RNs who are highly trained in bloodborne diseases and universal precautions, who have the tools available for universal precautions, and who are exposed to people with bloodborne diseases, are overwhelmingly not complying with universal precautions. 3. To better understand how attitudes impact behaviors, a valid and reliable tool was developed which measured health care workers' attitudes toward bloodborne diseases and universal precautions. 4. Training programs addressing attitudes and knowledge may help change health care workers' non-compliant behaviors into behaviors reflecting compliance with universal precautions.
Blood-Borne Pathogens↗
Amelioration of antigen-induced arthritis in rabbits treated with monoclonal antibodies to leukocyte adhesion molecules.
OBJECTIVE: To examine the effects of treatment of antigen-induced arthritis in rabbits with a monoclonal antibody against CD18, the common beta chain of the leukocyte adhesion molecules. Intraarticular injection of antigen into primed rabbits elicits an acute inflammatory response followed by chronic arthritis in this model. METHODS: Anti-CD18 was given at the time of intraarticular antigen administration, and effects on the acute and chronic arthritis were investigated. Twenty-four rabbits were examined (11 controls, 3 receiving normal mouse IgG, and 10 receiving anti-CD18). RESULTS: Flow cytometry of blood leukocytes at anti-CD18 administration showed saturating amounts of mouse Ig coating all the circulating cells. Treatment effects on the acute arthritis (measured by quantitating the synovial cell exudate 24 hours after arthritis induction) were a profound reduction in the number of inflammatory cells and a striking decrease in the proportion of polymorphonuclear leukocytes recovered from the synovial cavity, indicating a decrease in acute inflammation. Treatment effects on the chronic synovitis (2 and 4 weeks later) compared with controls showed a significant decrease in synovial fluid cell counts at 2 weeks (1.7 versus 21.0 x 10(6)/joint, P less than 0.03) and at 4 weeks (7.4 versus 22.6 x 10(6)/joint, P less than 0.05). Histologic evaluation of the synovium (0-3+ scale, scored "blindly") of anti-CD18-treated rabbits and controls showed marked decreases in subsynovial cell infiltration and lymphoid follicle formation both at 2 weeks (1.0 versus 2.25, P less than 0.005; and 0 versus 1.75, P less than 0.001) and at 4 weeks (1.48 versus 2.17, P less than 0.01; and 0.75 versus 2.08, P less than 0.02). Quantitation of cartilage-bound immune complexes, and of synovial synthesis of Ig and specific antibody showed no differences between groups. CONCLUSION: These findings indicate that treatment with monoclonal antibody to CD18 not only modifies the initial acute arthritis, but also results in significant amelioration of the subsequent chronic inflammation in this animal model of rheumatoid arthritis.
Animals↗