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G Nagel

Publications and source records attributed to G Nagel.

At least 19 recordsLinked to original sources
PubMed1997

Endoluminal stent-grafts for infrarenal abdominal aortic aneurysms.

BACKGROUND: The treatment of aortic aneurysms with endovascular stents or stent-graft prostheses is receiving increasing attention as an alternative to major abdominal surgery. To define the clinical value of this technique, we prospectively studied the use of stent-graft endoprostheses made of nitinol and covered with polyester fabric for the treatment of infrarenal abdominal aortic aneurysms. METHODS: We treated a total of 154 patients at three academic hospitals. Twenty-one patients with aortic aneurysms not involving the aortic bifurcation received straight stent-grafts, and 133 patients with aortic aneurysms involving the bifurcation and the common iliac arteries received bifurcated stent-grafts. After a unilateral surgical arteriotomy, the endoprostheses were advanced through the femoral arteries and placed under fluoroscopic guidance. Computed tomography and intraarterial angiography were performed during an average follow-up of 12.5 months. RESULTS: The primary success rate, defined as complete exclusion of the abdominal aortic aneurysm from the circulation, was 86 percent in the group receiving straight grafts and 87 percent in the group receiving bifurcated grafts. In three patients the procedure had to be converted to an open surgical operation. Minor (n=13) or major (n=3) complications associated with the procedure (including 1 death) occurred in 10 percent of the patients. All patients had a postimplantation syndrome, with leukocytosis and elevated C-reactive protein levels. CONCLUSIONS: Our results suggest that endovascular treatment of infrarenal abdominal aortic aneurysms is technically feasible and can effectively exclude abdominal aortic aneurysms from the circulation. With further refinement, endoluminal repair may emerge as an interventional strategy to treat infrarenal aortic aneurysms, especially in patients at high surgical risk.

Adult↗
PubMed1996

Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease.

Allogeneic CD8+ T cells mediate both a graft-vs-leukemia (GVL) effect and graft-vs-host disease (GVHD). To evaluate whether CD8 cells of defined cytokine phenotype differentially mediate these processes, alloreactive donor CD8+ T cells preferentially secreting type I or type II cytokines were generated by alloantigenic priming in vitro in the presence of IL-12 or IL-4, respectively. Both cytokine-secreting subsets lysed allogeneic tumor targets in vitro ("Tc1" and "Tc2" subsets). A transplantation model was established (B6 into B6C3F1, 1050 cGy host irradiation) using the 32Dp210 myeloid line (bcr/abl transfected, H-2k; 1 x 10(4) tumor cells/recipient). Compared with leukemia controls (death at 12.9 days post-bone marrow transplantation), both Tc1 and Tc2 recipients were conferred a survival advantage. At cell doses of 2 to 2.5 x 10(7), the Tc1-mediated GVL effect (mean survival of 34.2 days) was more potent than the Tc2-mediated GVL effect (mean survival of 20.5 days; Tc1 > Tc2, p = 0.009). On day 15, histologic examination showed that Tc1 recipients had undetectable tumor burdens, whereas Tc2 recipients had extensive leukemic infiltrates. However, Tc2 recipients had essentially no histologic evidence of GVHD, whereas Tc1 recipients had mild to moderate GVHD (average GVHD scores of 1/40 and 9.3/40, respectively). In contrast, recipients of uncultured CD8+ donor T cells developed severe GVHD (average GVHD score of 26.7/40). Because in vitro-generated, alloreactive Tc1 and Tc2 populations mediated GVL with reduced GVHD, we conclude that both subsets may improve the therapeutic outcome of allogeneic T cell transfers in patients with leukemia.

Acetylcysteine↗
PubMed1996

Rapid chemical kinetic techniques for investigations of neurotransmitter receptors expressed in Xenopus oocytes.

Xenopus laevis oocytes have been used extensively during the past decade to express and study neurotransmitter receptors of various origins and subunit composition and also to express and study receptors altered by site-specific mutations. Interpretations of the effects of structural differences on receptor mechanisms were, however, hampered by a lack of rapid chemical reaction techniques suitable for use with oocytes. Here we describe flow and photolysis techniques, with 2-ms and 100-microseconds time resolution, respectively, for studying neurotransmitter receptors in giant (approximately 20-microns diameter) patches of oocyte membranes, using muscle and neuronal acetylcholine receptors as examples. With these techniques, we find that the muscle receptor in BC3H1 cells and the same receptor expressed in oocytes have comparable kinetic properties. This finding is in contrast to previous studies and raises questions regarding the interpretations of the many studies of receptors expressed in oocytes in which an insufficient time resolution was available. The results obtained indicate that the rapid reaction techniques described here, in conjunction with the oocyte expression system, will be useful in answering many outstanding questions regarding the structure and function of diverse neurotransmitter receptors.

Animals↗
PubMed1996

A CD66a-specific, activation-dependent epitope detected by recombinant human single chain fragments (scFvs) on CHO transfectants and activated granulocytes.

Antibodies to CD66 recognize at least five members (CD66a-e) of the carcinoembryonic antigen (CEA) family. Recombinant human single-chain Fv fragments (scFvs) that bind specifically to CD66a (biliary glycoprotein) were obtained from a naive human scFv library. The scFvs bound to the N-domain of CD66a on Chinese hamster ovary (CHO) transfectants but did not bind to freshly isolated peripheral granulocytes or to dimethylsulfoxide-treated HL-60 cells. In contrast, scFvs bound well to granulocytes that were short-term activated with N-formyl-Met-Leu-Phe or phorbol 12-myristate 13-acetate and to human HL-60 cells that were treated with all-trans-retinoic acid to induce granulocytic differentiation. Quantification of antigenic sites showed that the activation-dependent CD66a epitopes were expressed on nearly all of the CD66a molecules on CHO-biliary glycoprotein transfectants, but they were detected only on a portion of the molecules on activated polymorphonuclear neutrophils and differentiated HL-60 cells. Binding of CD66a scFvs to their neoepitopes on prestimulated PMNs induced respiratory burst, suggesting that CD66a is capable of delivering transmembrane signals in these cells.

Animals↗
PubMed1996

Na+,K(+)-ATPase pump currents in giant excised patches activated by an ATP concentration jump.

The giant-patch technique was used to study the Na+,K(+)-ATPase in excised patches from rat or guinea pig ventricular myocytes. Na+,K(+)-pump currents showed a saturable ATP dependence with aK(m) of approximately 150 microM at 24 degrees C. The pump current can be completely abolished by ortho-vanadate. Dissociation of vanadate from the enzyme in the absence of extracellular Na+ was slow, with a Koff of 3.10(-4) S-1 (K1 approximately 0.5 microM, at 24 degrees C). Stationary currents were markedly dependent on intracellular pH, with a maximum at pH 7.9. Temperature-dependence measurements of the stationary pump current yielded an activation energy of approximately 100 kJ mol-1. Partial reactions in the transport cycle were investigated by generating ATP concentration jumps through photolytic release of ATP from caged ATP at pH 7.4 and 6.3. Transient outward currents were obtained at pH 6.3 with a fast rising phase followed by a slower decay to a stationary current. It was concluded that the fast rate constant of approximately 200 s-1 at 24 degrees C (pH 6.3) reflects a step rate-limiting the electrogenic Na+ release. Simulating the data with a simple three-state model enabled us to estimate the turnover rate under saturating substrate concentrations, yielding rates (at pH 7.4) of approximately 60 s-1 and 200 s-1 at 24 degrees C and 36 degrees C, respectively.

Adenosine Triphosphate↗
PubMed1995

Functional expression of bacteriorhodopsin in oocytes allows direct measurement of voltage dependence of light induced H+ pumping.

We report on the first successful expression of the light driven H+ pump, bacteriorhodopsin, into the plasma membrane of oocytes from Xenopus laevis. The light induced photocurrents which reflect the pumping of H+ by BR were analysed under voltage clamp conditions. At least 100 active BR molecules per microns 2 were expressed in the plasma membrane so that both the voltage clamp and giant patch clamp method could be applied. We show that H+ pumping by BR is modulated by the membrane potential, i.e. the pump current shows strong voltage dependence in the range measured between -165 mV to +60 mV.

Animals↗
PubMed1995

CD66b, CD66c and carcinoembryonic antigen (CEA) are independently regulated markers in sera of tumor patients.

Non-specific cross-reacting antigens (NCA-95 = CD66b and NCA-50/90 = CD66c) are members of the CEA (carcinoembryonic antigen = CD66e) family. Analysis of mRNA levels of CD66c in colon tumors suggests that this antigen is strongly up-regulated compared to its normal counterpart and could, therefore, be of clinical interest. CD66c is also expressed in normal lung and spleen tissues and, above all, on granulocytes. The appearance of CD66b in serum, the only strictly granulocyte-specific antigen, could point to the involvement of granulocytes in disease. Specific sandwich ELISAs have been established to determine CEA, CD66b and CD66c levels in serum. Controls have been carried out by testing sera from patients with benign tumors or inflammatory diseases and from healthy individuals. In sera of most patients suffering from solid tumors, sensitivities for CD66c are comparable to or lower than those for CEA. CD66c showed a much higher sensitivity in early colon tumor stages. Sensitivities over 40% have been determined for CD66b in sera of patients with uterine and kidney carcinomas. CML patients revealed sensitivities of 84% for CD66c and 47% for CD66b. Investigations of sera from patients with inflammatory colon diseases which are negative for CEA showed high sensitivity for CD66c but not for the granulocyte-specific CD66b. Patients with mastopathy revealed sensitivities of over 40% for both CD66c and CD66b. CD66b, CD66c and CEA are independently regulated proteins in a high percentage of patients. The simultaneous determination of CEA and CD66b/c can increase the sensitivities for malignant tumors but high sensitivities of CD66b/c for benign diseases limit their usefulness as tumor markers. CD66b may be interesting as a marker for kidney and corpus carcinomas, for which good markers are not yet available.

Adult↗
PubMed1995

From genes to proteins: the nonspecific cross-reacting antigens.

The existence of nonspecific cross-reacting antigens (NCAs), following their first description by von Kleist, was regarded as a disadvantage for the characterization and determination of carcinoembryonic antigen (CEA) using monoclonal antibodies or antiserum. Nowadays, after identification of a family of genes highly homologous to the CEA gene and some of the corresponding proteins, there is increasing evidence for important roles of these molecules in cell adhesion, bacterial binding, bile acid transport and other functions. For example, rapid up-regulation of the well-established NCAs (NCA-160, NCA-95 and NCA-90) on the surface of neutrophilic granulocytes by different inflammatory agents and the inhibition of binding of these cells to cytokine-activated endothelial cells by antibodies against NCAs are good indications for an important role in granulocyte functions. The presence of a consensus sequence in the cytoplasmic domains of some transmembrane members of the CEA family, which was first described for subunits of signal transduction complexes of the immune system (e.g. B and T cell receptor), also suggests a role in signal transduction. Additionally, using stably transfected cells expressing members of the CEA family, NCAs could be clustered to the 'cluster of differentiation' (CD) CD66a-d, during the recent 5th Leukocyte Typing Workshop. Therefore, further contributions to our knowledge about NCAs can be expected not only from researchers working in the CEA field but also from scientists working with cells of the hematopoietic system.

Animals↗
PubMed1995

[Thrombosed popliteal aneurysm--a cause of acute lower leg ischemia].

Popliteal artery aneurysms (PAA) frequently remain asymptomatic up to the event of acute thromboembolic occlusion. Acute occlusions in the femoro-popliteal level without cardial source of embolism, a pulsating tumor in the knee pit or preexisting abdominal-or groin aneurysms are suspicious for the disease. Between 01/87 and 07/93 we saw 21 popliteal aneurysms in 14 patients. In 50% of the cases the aneurysms were found bilaterally. Arteriosclerosis was the most frequent cause, in 30% as a generalised dilative angiopathy. 18 aneurysms were operated upon, 11 in the stage of acute ischemia among a total of 190 acute vascular occlusions in the same period. Treatment consisted in total resection and anatomical reconstruction by means of saphenous vein interposition. The patency rate in our patients operated in the stage of acute ischemia was 73% during this observation period; one major amputation was carried out. The postoperative course of all 7 electively operated aneurysms was without complications. PAA is readily diagnosed by ultrasound. Because of the catastrophic consequences of an acute ischemia resulting from thrombosis we also tend to operate asymptomatic cases. For that reason the contra lateral knee of the healthy appearing leg should be included in the examination as well as higher located possible locations of dilatative angiopathy. A thrombotic treatment, PTA, stent implantation or embolectomy cannot be recommended because of remaining wall adhesive thrombi with danger of embolisation.

Adult↗
PubMed1994

Regulation of the gating of cystic fibrosis transmembrane conductance regulator C1 channels by phosphorylation and ATP hydrolysis.

Opening of cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels requires their phosphorylation by protein kinase A followed by exposure to ATP. We examined the interaction between nucleotides and phosphorylated CFTR channels by recording currents in intact cardiac myocytes and in excised patches. We found that, although the hydrolysis-resistant ATP analogue 5'-adenosine(beta,gamma- imino)triphosphate (AMP-PNP) cannot open phosphorylated CFTR channels, it can cause channels opened by ATP to remain open for many minutes. This suggests that ATP action at one site on CFTR is a prerequisite for AMP-PNP action at a second site. However, this action of AMP-PNP is restricted to highly phosphorylated CFTR channels, which, in the presence of ATP, display a relatively high open probability, but is not seen in partially phosphorylated CFTR channels, which have a low open probability in the presence of ATP. Our findings argue that incremental phosphorylation differentially regulates the interactions between nucleotides and the two nucleotide binding domains of CFTR. The nature of those interactions suggests that ATP hydrolysis at one nucleotide binding domain controls channel opening and ATP hydrolysis at the other regulates channel closing.

Adenosine Triphosphate↗
PubMed1994

[Postoperative leakage of silicone oil into the anterior chamber].

BACKGROUND: One reason for complications after silicone oil application is the postoperative entrance of silicone oil into the anterior chamber. In a retrospective study, we tried to define risk factors for oil entrance into the anterior chamber. METHODS: 159 Eyes of 148 patients, vitrectomized and filled with silicone oil between 1988 and 1992 were analysed. In 22 eyes (13.8%) silicone oil entered the anterior chamber postoperatively. Eyes with emulsified oil in the anterior chamber and eyes, where the oil entered the anterior chamber during cataract extraction were not included in this group. Diagnoses, postoperative fundus findings and lens status, intraocular pressure, depth of the anterior chamber and time of the oil entrance were analysed. RESULTS: Risk factors in the first 10 postoperative days (14 eyes = 63.6%) seem to be aphakia and choroidal effusions, especially if combined with buckling procedures (encircling bands). In the late postoperative period, i.e. up to 6.5 months (8 eyes = 36.4%), proliferative vitreoretinopathy was responsible for the entrance of silicone oil into the anterior chamber in all cases. The decreased production of aqueous humour combined with hypotony seems also to play an important role in this process. CONCLUSIONS: It seems that in the early postoperative period the frequency of oil entrance into the anterior chamber can only be lowered by a subtotal oil filling in aphakic eyes with accompanying encircling procedures. It remains open if radical amputation of the vitreous base can avoid peripheral reproliferations.

Anterior Chamber↗
PubMed1994

[Blue nevi of the conjunctiva].

PATIENT AND METHODS: A 54-year-old man presented with multifocal pigmentations of the left bulbar and palpebral conjunctiva. He had first noticed these changes 5 years ago without any evidence of progression. The pigmented lesions were located in the plica, caruncle, the lower fornix and the mucocutaneous junction of the lower lid. The right cornea showed a focal superficial scar paracentrally due to a herpes simplex keratitis in 1970. Visual acuity was 20/20, otherwise the eyes were unremarkable. Biopsies were performed in all areas. One year after surgery, there was no recurrence of the lesions. MICROSCOPY: Histopathologically, the conjunctival epithelium is essentially unremarkable. The substantia propria display mostly uniformly pigmented spindle-shaped melanocytic cells. Many cells contain coarsely clumped melanin granules. Other areas reveal poorly pigmented to unpigmented melanocytic cells, some of them with Schwannian features. Intranuclear vacuoles are commonly present. The tumor cells are often located in stromal areas displaying increased amounts of collagen. A few polyhydral melanophages are present within the lesion. DIAGNOSIS: Biopsy A (plica)--blue nevus with areas of cellular blue nevus. Biopsy B (caruncle)--cellular blue nevus. Biopsy C (lower fornix)--cellular blue nevus. Biopsy D (mucocutaneous junction of left lower lid)--Blue nevus.

Biopsy↗
PubMed1994

Regulation of CFTR channel gating.

Findings outlined here support a complex model for the regulation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel gating that incorporates incremental protein kinase A (PKA) phosphorylation of CFTR at multiple sites which, in turn, differentially control the activity of CFTR's two nucleotide-binding domains (NBDs). The NBDs are functionally distinct: only one can respond to the non-hydrolyzable ATP analogue AMP-PNP, and then only after ATP has acted at the other. Moreover, the nature of the responses to AMP-PNP, and to the inorganic phosphate analogue orthovanadate, argues that ATP hydrolysis normally occurs at both NBDs, at one to initiate channel opening and at the other to initiate closing.

Adenosine Triphosphate↗
PubMed1994

Expression of the CEA gene family members NCA-50/90 and NCA-160 (CD66) in childhood acute lymphoblastic leukemias (ALLs) and in cell lines of B-cell origin.

The carcinoembryonic antigen (CEA) and the classical non-specific cross-reacting antigens (NCAs) belong to the CEA gene family which is part of the immunoglobulin superfamily. In normal hematopoiesis, CEA gene family members (CGMs) have only been reported on cells of myeloid and monocytic origin. In the present study, we analyzed 62 childhood acute lymphoblastic leukemias (ALLs) and seven surface immunoglobulin positive (sig+) B-cell lines for the expression of the CEA family members CEA, NCA-50/90, NCA-95, NCA-160, CGM1 and CGM7. We demonstrated that members of the CEA family were present in 76% of childhood ALLs of B- and T-cell origin. In ALLs of B-cell origin, 82% of the samples expressed at least one CEA subgroup member: 38% NCA-50/90 (CD66c), 31% NCA-160 (CD66a), and 13% both. Six of seven B-cell lines solely expressed NCA-160. In seven ALL of T-cell origin, sole NCA-160 expression was present in 29% of the cases. CEA and CGM1 were not expressed in childhood ALLs or in the sIg+ B-cell lines. In 15 ALLs and seven B-cell lines which could be analyzed for CGM7 expression, the antigen was not detected. NCA-95 was not expressed in 91% of the B-lineage ALLs, in T-lineage ALLs and in the B-cell lines. However, five B-lineage ALLs showed conflicting data on the binding patterns of two, on leukocytes specifically NCA-95 recognizing antibodies suggesting either expression of unknown forms of NCA-95 or NCA-50/90 or of a yet unknown member of the CEA family in these ALL cells. The expression of CEA subgroup members in childhood ALL cells might have prognostic impacts, as an inverse correlation exists between NCA expression on leukemic blasts and the risk factor white blood count at diagnosis.

Adolescent↗
PubMed1993

Determination of the specificities of monoclonal antibodies recognizing members of the CEA family using a panel of transfectants.

Carcinoembryonic antigen (CEA), one of the most clinically important tumor markers, is mainly used in the post-surgical surveillance of patients with colorectal carcinomas. CEA belongs to a large protein family, which includes cross-reacting antigens, e.g., non-specific cross-reacting antigens (NCAs) and biliary glycoprotein (BGP) as well as pregnancy-specific glycoproteins (PSGs). The genes encoding these proteins can be subdivided into the CEA and PSG subgroups. The members of the subgroups share antigenic determinants and show high similarity in amino-acid sequences. Their derived secondary structures show them to belong to the immunoglobulin superfamily. Due to the close relationship of the members of the CEA subgroup, it is very difficult to distinguish between the individual members with MAbs. Here we have used flow cytometric analysis of transfectants expressing individual members of the CEA subgroup as an alternative approach to determine the specificities of 13 MAbs. This allows us to examine the specificities of these antibodies for members of the CEA family, even of those which have not yet been characterized at the protein level. In addition, binding of the MAbs to NCAs expressed by polymorphonuclear cells (PMN) was tested by Western-blot analysis, immunoprecipitation and flow cytometry. Four antibodies bound exclusively to NCA-50/90 and one MAb (80H3) only to NCA-95. MAb 4/3/17 recognizes CEA and BGP on the surface of transfectants and NCA-160 from granulocytes. We assume that NCA-160 is a product of the BGP gene. On granulocytes, which do not express CEA, MAb 4/3/17 is specific for NCA-160 (BGP). Mutual inhibition of the MAbs binding to NCA-50/90 revealed 3 different epitope groups.

Antibodies, Monoclonal↗
PubMed1993

Genomic organization, splice variants and expression of CGM1, a CD66-related member of the carcinoembryonic antigen gene family.

The tumor marker carcinoembryonic antigen (CEA) belongs to a family of proteins which are composed of one immunoglobulin variable domain and a varying number of immunoglobulin constant-like domains. Most of the membrane-bound members, which are anchored either by a glycosylphosphatidylinositol moiety or a transmembrane domain, have been shown to convey cell adhesion in vitro. Here we describe two splice variants of CGM1, a transmembrane member of the CEA family without immunoglobulin constant-like domains. CGM1a and CGM1c contain cytoplasmic domains of 71 and 31 amino acids, respectively. The cytoplasmic region of CGM1a is encoded by four exons (Cyt1-Cyt4). Differential splicing of the Cyt1 exon (53 bp) leads to the formation of CGM1c. The presence or absence of potential protein kinase phosphorylation sites in the cytoplasmic domains and a sequence consensus motif involved in signal transduction in multichain immune recognition receptors indicates that this splice event is of functional importance. CGM1a mRNA, the predominant CGM1 transcript, was found in the granulocytic lineage, but not in monocytes, lymphocytes nor in a number of tumors derived from all three germ layers. Weak staining using monoclonal antibodies Tu2 and 73 in fluorescence-activated cell scan analyses indicate low concentrations of CGM1 protein on the surface of granulocytes. The CGM1 protein is also recognized by CD66 antibodies. Therefore, the granulocyte-specific CD66 epitope is present on at least four CEA family members: CGM1, CEA, NCA-50/90 and NCA-160.

Amino Acid Sequence↗