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Biomedical subjects

T Nagel

Publications and source records attributed to T Nagel.

At least 19 recordsLinked to original sources
PubMed2006

[The endovenous laser therapy of varicose veins--substantial innovation or expensive playing?].

INTRODUCTION: The aim of the study was to evaluate the efficiency of the endovenous use of laser for treatment of varicose veins. In particular the influence of laser energy on the perivenous temperature, the postoperative clinical and duplex ultrasound course was taken into account. METHOD: The patients were divided into two groups. In 33 cases the laser therapy was used without perivenous liquid protection. In 30 cases a 0.9 % NaCl solution has been injected around the vein. The laser used was a 980 nm diode laser (Ceralas D 980, Biolitec AG, Bonn). The pulse-mode procedure has been applied for triggering the laser impulse (1.5 s pulse length, 1.5 s pause with a 3 mm withdrawal of the laser fibre. The laser energy was 15 watt. 20 cm distal to the saphenofemoral or saphenopopliteal junction a thermo unit measured continuously the perivenous temperature. Clinical and duplex ultrasound checks were carried out before and on the day of the operation. Further checks followed on the first and tenth day after the operation and 8 weeks and 6 months afterwards. RESULTS: The perivenous temperature prior to ELT was 31.3 degrees C, then dropping after the injection of the NaCl solution by 3.4 degrees C. During the ELT the temperature rose by 10.0 degrees C without and by 5.5 degrees C with infiltration. The rise in temperature happened only 3 cm before the tip of the laser fibre arrived at the thermo unit and fell quite rapidly. 98 % of the veins showed within the time period of 2 to 14 months an effective occlusion controlled by duplex ultrasound without refluxing segments. All operations were out-patient treatments. The patients were able to take up work after 1 to 7 days. CONCLUSION: The endovenous laser treatment is an innovative method for the treatment of varicose veins. Considering the mid-term subjective and objective outcomes this method can not only compete with the conventional surgery but has proved to be superior as regards the recurrence rate and patient's comfort. The study presented here, did not find a risk of damage to surrounding non-target tissue.

Adolescent↗
PubMed2001

Structure determination and by-product profile of the NK(2) receptor antagonist nepadutant, a bicyclic glycopeptide.

We have synthesized and fully characterized the NK(2) receptor antagonist nepadutant and its by-products using nuclear magnetic resonance (NMR) and restrained molecular dynamics. The agent consists of an active bicyclic hexapeptide combined with a sugar residue. Analysis of the high-performance liquid chromatogram and the mass spectroscopy spectra yields traces of three by-products with the same molecular weight as the main product. The conformation of the molecules in the bicyclic hexapeptide segment, the active region, is well defined, whereas the sugar moiety is disordered. For the peptide region of nepadutant and all of its by-products, the NMR observables can be described by a single backbone conformation, more specifically a betaI, betaII-turn arrangement. The active dipeptide unit Trp-Phe occupies the i+1 and i+2 position of a betaI-turn. The by-product profile is characterized by different forms of sugars which are caused mainly by isomerization in the process of ring opening.

Chromatography, High Pressure Liquid↗
PubMed2001

A novel X chromosome-linked genetic cause of recurrent spontaneous abortion.

OBJECTIVE: Unexplained recurrent spontaneous abortion is a common women's health problem that affects approximately 1 of every 200 women who wish to have children. It has long been assumed that a large proportion of recurrent spontaneous abortion results from genetic problems, but no causative genes have been identified to date. Here, we tested the hypothesis that a subset of women with recurrent spontaneous abortion are carriers of X-linked recessive disorders that result in the loss of male pregnancies. STUDY DESIGN: X chromosome inactivation patterns, an assay used to detect women who are likely to be carriers of X-linked recessive cell-lethal traits, were compared between 105 female patients with idiopathic recurrent pregnancy loss and 101 women (control subjects) with a single successful pregnancy and no history of pregnancy loss. Inheritance patterns and gender of offspring were studied in relevant subsets of participants. RESULTS: Female patients showed a highly statistically significant increase in the frequency of skewed X chromosome inactivation (90%; P < .0005). Female patients with highly skewed X chromosome inactivation showed a significant decrease in male children. Four of 6 families that were studied showed maternal inheritance of the skewed inactivation trait. CONCLUSION: We found the 14% of women with unexplained recurrent pregnancy loss show highly skewed X inactivation, which suggests that they are carriers of X-linked recessive lethal traits. Furthermore, the observed gender bias among women with highly skewed X inactivation suggests selective loss of male conceptions, which is consistent with an X chromosome-linked genetic defect that leads to cell death or growth disadvantage. Identification of such female carriers is important for the reproductive counseling and treatment of these women.

Abortion, Habitual↗
PubMed2001

A parametric study of freezing injury in ELT-3 uterine leiomyoma tumour cells.

Cellular level freeze injury was investigated after controlled freezing of an Eker rat uterine fibroid cell line in both the presence and absence of oestradiol. The connection between thermal history and cell injury in single ELT-3 cells in suspension (without oestradiol) was studied through a two-level, four-parameter (2(4)) experiment with membrane dye exclusion as the end-point. The four parameters considered were cooling rate (CR), end temperature (ET), hold time (HT) and thawing rate (TR). A high and low value of each parameter was selected as follows: CR, 5-25 degrees C/min; ET, -20 to -30 degrees C; HT, 0-5 min; TR 20-200 degrees C/min. The greatest parameter effect on freeze injury in this range was ET followed by HT, then TR and finally CR. In addition, significant parameter interactions and curvature were found. Additional CR results outside the original parameter range showed a reduction in survival at both 1 and 50 degrees C/min suggestive of an inverted U-shaped survival curve. These results show that this tumour system is susceptible to cryoinjury, particularly at temperatures below -30 degrees C with HT of >5 min and slow thawing. In addition, the presence of oestradiol was found to increase the susceptibility of these cells to cryoinjury.

Animals↗
PubMed2000

Co-stimulation of IL-2 production by CD28 is independent of tyrosine-based signaling motifs in a murine T cell hybridoma.

In addition to the antigen-specific stimulus delivered by the TCR, T cells under most circumstances require a co-stimulatory signal for complete activation. CD28 can provide this signal, and the importance of CD28-mediated co-stimulation has been well documented both in vitro and in vivo, but the intracellular pathways downstream of CD28 are less well characterized. So far, maximal co-stimulation of IL-2 production has been attributed to tyrosine-based signaling motifs, either including the first cytoplasmic tyrosine residue that binds phosphatidylinositol 3'-kinase (PI3-K), or the third tyrosine residue. Here we describe results of the expression of murine CD28 receptor mutants in a CD28-deficient murine T cell hybridoma, A1.1. We show that in A1.1 cells co-stimulation of IL-2 production is independent of CD28 cytoplasmic tyrosine residues, since a mutant lacking all four cytoplasmic tyrosines is still able to induce a full co-stimulatory response. Using truncation mutants, this activity can be attributed to amino acids 183 to 194, a sequence containing a conserved diproline motif that may recruit SH3 domains of other signaling molecules like Grb2. Thus we have identified a novel pathway for CD28-mediated co-stimulation of IL-2 production that is independent of PI3-K activity and phosphotyrosine-based signaling motifs.

Amino Acid Sequence↗
PubMed2000

Endothelial dysfunction, hemodynamic forces, and atherogenesis.

Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NF kappa B and Egr-1, to shear-stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up- and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non-laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL-1 beta). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX-2, and Mn-SOD) support vasoprotective (i.e., anti-inflammatory, anti-thrombotic, anti-oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related "atheroprotective genes" in the endothelial lining of lesion-protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.

Animals↗
PubMed2000

[Methods for postoperative evaluation of complete excision of the mesorectum].

This study aimed at a more objective evaluation of the specimen after total mesorectal excision [14]. For this reason, a method yielding a simple stained preparation of the totally excised mesorectum was developed. By postoperative injection of 10 ml of an ink solution into the A. rectalis superior of 15 specimens, the arterial mesorectal vascular tree was filled. All specimens had been collected by means of total mesorectal excision. In two specimens, in wich the mesorectal sheath fascia had been injured due to the surgical manipulation, we observed the leakage of ink from the mesorectum even during the injection. In three further specimens, some ink leakage in the form of dots occurred from small opened arterioles after the injection was performed. No ink leakage was observed in the remaining specimens. Prior to the ink injection, thirteen specimens were macroscopically tested and found intact. Three of the fifteen specimens exhibited minor lesions of the mesorectum that would not have been detected macroscopically without ink tagging. The comparison of the findings provided by the surgeon with the histopathological evaluation showed that those specimens in which no ink leakage occurred had an unimpaired mesorectal sheath fascia. These specimens coorespond to the complete excision of the mesorectum and the removal of the tumor in a cancer-sealed package as long as the circumferential rim of the specimen has not been infiltrated by the tumor.

Coloring Agents↗
PubMed1999

Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors.

The vascular endothelium is exposed to a spectrum of fluid mechanical forces generated by blood flow; some of these, such as fluid shear stress, can directly modulate endothelial gene expression. Previous work by others and in our laboratory, using an in vitro uniform laminar shear stress model, has identified various shear stress response elements (SSREs) within the promoters of certain endothelial genes that regulate their expression by interacting with various transcription factors, including nuclear factor-kappaB (NF-kappaB), early growth response-1 (Egr-1), and activator protein-1 (AP-1, composed of c-Jun/c-Jun and c-Jun/c-Fos protein dimers). In the current study, we have examined the topographical patterns of NF-kappaB, Egr-1, c-Jun, and c-Fos activation in a specially designed in vitro disturbed laminar shear stress model, which incorporates regions of significant spatial shear stress gradients similar to those found in atherosclerosis-prone arterial geometries in vivo (eg, arterial bifurcations, curvatures, ostial openings). Using newly developed quantitative image analysis techniques, we demonstrate that endothelial cells subjected to disturbed laminar shear stress exhibit increased levels of nuclear localized NF-kappaB, Egr-1, c-Jun, and c-Fos, compared with cells exposed to uniform laminar shear stress or maintained under static conditions. In addition, individual cells display a heterogeneity in responsiveness to disturbed flow, as measured by the amount of NF-kappaB, Egr-1, c-Jun, and c-Fos in their nuclei. This differential regulation of transcription factor expression by disturbed versus uniform laminar shear stress indicates that regional differences in blood flow patterns in vivo-in particular, the occurrence of spatial shear stress gradients-may represent important local modulators of endothelial gene expression at anatomic sites predisposed for atherosclerotic development.

DNA-Binding Proteins↗
PubMed1998

Mutational analysis of CD28-mediated costimulation of Jun-N-terminal kinase and IL-2 production.

The accessory molecule CD28 delivers a costimulus that acts in concert with TCR signals to promote T cell activation. Activation of Jun-N-terminal kinases (JNK) requires simultaneous stimulation of the TCR and CD28 and, therefore, likely plays an important role in signal integration during costimulation. We investigated the effects of mutations in the 41-amino acid cytoplasmic domain of murine CD28 on its ability to deliver costimuli for JNK activation and IL-2 production when expressed in Jurkat T cells. Our results indicate that the costimulus for JNK activation requires the membrane-proximal 24 amino acids of the CD28 cytoplasmic domain and is not mediated by the tyrosine-based recruitment of signaling molecules, including phosphatidylinositol 3-kinase. Deletion of the carboxyl-terminal 17 amino acids does not affect the ability of CD28 to augment JNK activation but impairs its ability to enhance TCR-mediated production of IL-2, demonstrating that optimal costimulation of IL-2 production requires CD28 signals in addition to the activation of JNK.

Amino Acid Sequence↗
PubMed1998

[Regulation of T-cell activation by CD28 and CTLA-4].

T CELL RESPONSE: T lymphocytes play a key role in the coordination of the immune response. T helper cells contribute primarily by means of cytokine release, whereas cytotoxic T cells eliminate cells bearing antigens recognized as foreign. Through its T cell receptor each T cell can recognize a specific peptide antigen, which is presented in the context of the major histocompatibility complex (MHC) to T helper cells by specialized antigen-presenting cells or to cytotoxic T cells by nearly all body cells. Upon contact with its specific antigen, the T cell receptor transduces an activation signal into the T cell, leading to proliferation, cytokine production, or efficient cytotoxicity. COSTIMULATION: However, a second costimulatory signal is necessary to achieve complete activation. This can be provided by the accessory T cell molecule CD28 upon binding to its respective ligands B7-1 (CD80) or B7-2 (CD86). The same ligands bind to CTLA-4 (CD152), a receptor expressed at the surface of T cells previously activated for 2 to 3 days and capable of downregulating activation. IMMUNOSUPPRESSION BY CTLA-4Ig: A genetically engineered soluble fusion protein containing the extracellular domain of CTLA-4 and the Fc portion of an immunoglobulin heavy chain (CTLA-4Ig) prevents the interaction of CD28 and CTLA-4 with their B7 ligands, the subsequent activation of T cells and thereby eliminates or reduces unfavorable immune system activation in transplant rejection or autoimmunity. CONCLUSION: The importance of the regulatory system comprising CD28, CTLA-4 and the B7 molecules and its modulation by CTLA-4Ig has been demonstrated in a substantial number of animal models in recent years and holds promise as a novel approach for therapeutic immunomodulation in humans.

Abatacept↗
PubMed1998

Reductionism and antireductionism.

Reductionism is the idea that all of the complex and apparently disparate things we observe in the world can be explained in terms of universal principles governing their common ultimate constituents: that physics is the theory of everything. Antireductionism comes in two varieties: epistemological and ontological. Epistemological antireductionism holds that, given our finite mental capacities, we would not be able to grasp the ultimate physical explantation of many complex phenomena even if we knew the laws governing their ultimate constituents. Therefore we will always need special sciences like biology, which use more manageable descriptions. There may be controversy about which special sciences cannot be replaced by reduction, but that there will be some is uncontroversial. Ontological antireductionism holds, much more controversially, that certain higher-order phenomena cannot even in principle be fully explained by physics, but require additional principles that are not entailed by the laws governing the basic constituents. With respect to biology, the question is whether the existence and operation of highly complex functionally organized systems, and the appearance of self-replicating systems in the universe, can be accounted for in terms of particle physics alone, or whether they require independent principles of order.

Models, Theoretical↗
PubMed1997

Shear stress gradients remodel endothelial monolayers in vitro via a cell proliferation-migration-loss cycle.

Wall shear stress has been implicated in the genesis of atherosclerosis because a strong correlation exists between the location of developing arterial lesions and regions where particular gradients in stress occur. Studying the behavior of endothelial cells in such regions may contribute to our understanding of the disease etiology. We report the detailed migratory history of endothelial cells subjected to large shear stress gradients caused by a surface protuberance in an in vitro model system. The history of cell migration, cell division, and cell loss from the surface was continuously monitored in confluent human umbilical vein endothelial cell monolayers for 48 hours after the onset of flow. Individual cells were tracked using time-lapse video microscopy. In contrast to a uniform laminar flow field in which cells were observed to continually rearrange their relative position with no net migration, in a disturbed flow field there was a net migration directed away from the region of high shear gradient. This organized migration pattern under disturbed flow conditions was accompanied by more than a twofold increase in cell motility. In addition, cell division increased in the vicinity of the flow separation (maximum shear stress gradient of 34 dyne/cm2 per mm) whereas cell loss was increased upstream and downstream in the regions where the shear gradient diminishes. These data suggest a steady cell proliferation-migration-loss cycle and indicate that local shear stress gradient may play a key role in the morphological remodeling of the vascular endothelium in vivo.

Arteriosclerosis↗
PubMed1996

Structural requirements for CD28-mediated costimulation of IL-2 production in Jurkat T cells.

Although under certain conditions an association with phosphatidylinositol 3'-kinase (PI3-K) appears to be critical for CD28 signaling, mutation of the PI3-K binding site (Tyr 170) does not alter the costimulatory ability of murine CD28 (mCD28) in Jurkat T cells. To define the structural requirements for this PI3-K-independent signaling, we expressed a series of mCD28 mutants in Jurkat. Mutation to Phe of all four cytoplasmic Tyr residues together (ALL F mutant) greatly reduced the ability of mCD28 to augment IL-2 production. Isolated re-constitution of Tyr 188, but not 170, 185, or 197, restored the ability of ALL F mCD28 to deliver a costimulus. Thus, a signal based upon Tyr 188 can deliver a costimulus for the enhancement of IL-2 production by Jurkat cells.

Amino Acid Sequence↗
PubMed1996

Introduction of a New Coaxial Falloposcopy System

Coaxial falloposcopy is a transcervical approach to visualizing the entire fallopian tubal lumen from the uterotubal ostium (UTO). To eliminate bulky camera attachments and poor image quality, a new falloposcopy system was developed with a small articulating-tip hysteroscope, stabilizing device to maintain UTO alignment, flexible coaxial catheter and guidewire, and 0.4-mm outer diameter falloposcope with enhanced fiberoptics. We used the instrument in 23 women with a diagnosis of proximal (PTO) or distal (DTO) tubal obstruction (group 1, 16 patients, 30 tubes) or unexplained infertility (group 2, 4 patients, 7 tubes) after previous hysterosalpingogram or laparoscopy. Successful cannulation was achieved in 31 (83.3%) of 37 tubes. Fibrosis of the UTO prevented access to two tubes. In group 1, 14 of 23 tubes with presumed PTO were patent and normal at falloposcopy. In group 2, pathology was present in two of seven tubes. A false positive diagnosis was made in 61% of tubes with presumed PTO and false negative diagnosis in 29% of presumably normal tubes. Coaxial falloposcopy is an effective means of assessing the tubal lumen and should become a more routine part of infertility evaluations.

Journal Article↗