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Biomedical subjects

S Schwender

Publications and source records attributed to S Schwender.

At least 19 recordsLinked to original sources
PubMed2002

Genetic risk factors in young adults with 'cryptogenic' ischemic cerebrovascular disease.

Mutations such as factor V Leiden G1691A (FVL), prothrombin G20210A (FIIM), methylenetetrahydrofolate reductase (MTHFR) C677T, cystathionine beta-synthase (CBS) 844ins68 and endothelial cell protein C receptor (EPCR) 4031ins23 are risk factors for thromboembolism. To assess the role of these mutations in young adults with cerebral ischemia of otherwise undetermined etiology, 93 patients younger than 50 years old with thromboembolic strokes or transient ischemic attacks were studied. One hundred and eighty-six healthy age-matched and sex-matched blood donors served as controls. The FVL mutation was detected in 15/93 patients and 13/186 controls. After adjustment for smoking, arterial hypertension, and hyperlipidemia, the association of the FVL mutation with cerebral ischemia [odds ratio (OR), 3.19; 95% confidence interval (CI), 1.38-7.39] remained significant. One of 93 patients and 6/186 controls were carriers of FIIM (OR, 0.33; 95% CI, 0.04-2.75). We detected the MTHFR TT677 genotype in 9/93 patients and 26/186 controls (OR, 0.66; 95% CI, 0.30-1.47), a CBS 844ins68 mutation in 12/93 patients and 19/186 controls (OR, 1.30; 95% CI, 0.60-2.81), and an EPCR 4031ins23 mutation in 1/93 patients and in no control individual (P = 0.33). In conclusion, in younger adults the FVL mutation is a risk factor for cerebrovascular disease. FIIM, the MTHFR TT677 genotype and the CBS 844ins68 mutation did not contribute to the risk in this group of patients. The EPCR 4031ins23 mutation is very rare, its possible role needs further investigation.

Adolescent↗
PubMed2001

Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts.

Aniline Compounds↗
PubMed1999

Recurrent optic nerve head infarctions associated with combined factor V Leiden- and factor II:G20210A-mutation.

PURPOSE: To demonstrate the association of bilateral recurrent optic nerve head infarctions with thrombophilia due to combined factor V:R506Q- and factor II:G20210A-mutation. METHODS: Case report. We examined a 55-year-old man with a two-year history of three segmental optic nerve head infarctions. Visual acuity was 20/80 on the left and 20/25 on the right eye. RESULTS: Ophthalmologic, cardiologic, radiologic, neurologic and hematologic-immunologic examinations were unremarkable except for increased APC-resistance (APC ratio: 1.4; normal value >2) due to heterozygous factor V:R506Q-mutation and high factor II-levels due to factor II:G20210A-mutation. Therapy with coumarin was instituted at INR 2.0-3.0 and no relapse has occurred over the past 1-year period. CONCLUSION: Combined occurrence of thrombogenic factor II:G20210A-mutation and factor V:R506Q-mutation may be causally linked to recurrent optic nerve head infarctions.

Factor V↗
PubMed1999

Modulation of acute coronavirus-induced encephalomyelitis in gamma-irradiated rats by transfer of naive lymphocyte subsets before infection.

Clinical course, recovery of infectious virus from brain tissue and histopathology of the central nervous system were examined in gamma-irradiated Lewis rats reconstituted by naive lymphocytes before infection with coronavirus MHV-4 (strain JHM). Up to 9 days past infection, no differences were seen between immunologically competent and immuno-deficient animals in terms of onset and progression of neurological disease. However, in the latter animals neurological symptoms were dominated by signs of encephalitis instead of paralytic disease as usually seen in immunocompetent animals. Nevertheless, despite high titers of infectious virus in the CNS of immunodeficient animals only mild histopathological changes were noticeable. In contrast, infectious virus in the CNS of immunologically competent animals was below the detection limit of the assay. Paralytic disease and tissue destruction were T lymphocyte mediated because gamma-irradiated rats that were reconstituted by CD4+ or CD8+ T lymphocyte enriched cells in the absence of B lymphocytes revealed an earlier onset of clinical symptoms and a more rapid deterioration of their clinical state compared to fully competent animals. Whereas in CD4+ T cell reconstituted animals infectious virus was moderately reduced and tissue destruction as well as inflammatory changes in the CNS were focal, in CD8+ T cell reconstituted animals vacuolizing white matter inflammation was diffuse without reduction of infectious virus in brain tissue. From the presented data we conclude that in the acute stage of JHMV-induced encephalomyelitis of Lewis rats: (i) tissue destruction and paralytic clinical symptomatology are mainly T cell-mediated; (ii) CD4+ T lymphocytes can directly contribute to reduction of viral load in the brain and (iii) only coordinated action of both, the T and the B cell compartment enables animals to survive the infection and recover from disease.

Animals↗
PubMed1998

Response of the cellular immune system to cardiopulmonary bypass is independent of the applied pump type and of the use of heparin-coated surfaces.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with an activation of leukocytes. The extent of this activation was thought to depend on the applied CPB-circuit set-up. The present study comparatively evaluated the effect of roller pump, centrifugal pump, and uncoated and heparin-coated surfaces. METHODS: 73 patients were included, randomly assigned to 3 groups. In group A a roller pump was used, in group B a centrifugal pump, and in group C a centrifugal pump together with Carmeda heparin-coated surfaces. The quantitative (cell count) and the qualitative changes of leukocyte populations (subpopulations and expression of the CD126-, HLA-DR-, CD45 RO-, CD71 antigens) was comparatively analysed before, during, and following CPB. RESULTS: Groups A and B did not differ in leukocyte counts and the differences between groups B and C were restricted to single time points. Neither groups A and B, nor groups B and C differed significantly in the relative distribution of lymphocyte subpopulations or in the percentage of CD126+, HLA-DR+, CD45 RO+ and CD71+ leukocyte subpopulations. CONCLUSIONS: CPB affects the cellular immune system; however, this effect seems to be a physiological reaction, independent of the applied CPB circuit system.

Adult↗
PubMed1998

Atypical spontaneous factor VIII inhibitor: specific diagnostics and therapy of acute bleeding.

Differentiation of rapidly binding coagulation factor inhibitors from antiphospholipid antibodies is a challenge for the hemostaseologic laboratory, especially with respect to the different therapeutic consequences. Several immunological and functional assays for the diagnosis of these disorders have been proposed. Here we report the clinical and laboratory findings of a 65-year-old man who developed severe bleeding after a tooth extraction. The process leading to the diagnosis of a spontaneous atypical factor VIII inhibitor and the value of different laboratory tests are discussed.

Aged↗
PubMed1997

Response of the cellular immune system to cardiopulmonary bypass in vivo.

Cardiopulmonary bypass (CPB) is known to induce an inflammatory response. Previous studies reported an impairment of the cellular immune response with activation of neutrophils and changes in lymphocyte subpopulations. The objective of the present study was to investigate the effect of CPB on leukocyte activation in vivo. In 27 patients undergoing coronary artery bypass grafting, the quantitative and the qualitative response of leukocyte populations to CPB was analysed pre-, intra-, and postoperatively using flow cytometry. A significant increase in leukocyte counts was detected during CPB, resulting in a marked leukocytosis postoperatively. The total number of lymphocytes peaked in the early phase of CPB, followed by a significant decrease, mainly due to a loss in B and cytotoxic T lymphocytes. In contrast, the lymphocytopenia observed 8 h after protamin administration was mainly caused by a drop in the population of helper T lymphocytes. Activation of distinct cell populations could be detected during and following CPB. The results indicate an influence of CPB on the cellular immune system, however an immuno-suppression was detectable only transiently.

Aged↗
PubMed1997

A comparative evaluation of the effect of pump type and heparin-coated surfaces on platelets during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is associated with hemostatic disorders, mainly due to platelet function defects. In the present prospective study, platelet count and GMP-140 expression on platelets were investigated to comparatively evaluate the impact of different CPB-circuit systems on platelets. The study included 61 patients undergoing coronary artery bypass grafting, randomly assigned to 3 groups. In group A a roller pump, in group B a centrifugal pump, and in group C a centrifugal pump with a Carmeda heparin-coated CPB circuit was applied. Platelet count and GMP-140 expression were analysed pre, during, and following CPB. None of the tested CPB systems did affect platelet count. The percentage of GMP-140-positive platelets increased slightly early during CPB, whereas it decreased significantly postoperatively; group differences were observed between B and C after protamin administration. An advantage of the use of centrifugal pumps and heparin-coated circuits could not be proven with the present set-up. The results suggest that the benefit of the tested systems might depend on the operative procedure and management.

Anticoagulants↗
PubMed1997

Selective screening for the Factor V Leiden mutation: is it advisable prior to the prescription of oral contraceptives?

The cumulative thrombotic risk of Factor V (FV) Leiden and oral contraceptives (OC) recommends screening for the mutation. Assuming that a family history of thrombosis increases the patient's likelihood of bearing FV Leiden, a selective rather than universal screening would be performed. We studied the utility of a family history of thrombosis for screening of FV Leiden before prescription of OC and, furthermore, the utility of screening even if oral contraception is favoured. 101 patients who had their first and single thromboembolic event while using OC were interviewed. 609 women without any history of thromboembolism recruited by gynecologists completed a standard questionnaire. 101 of these women, age-matched and currently using OC, were selected for a case-control study. Regarding patients with previous thromboembolism, a family history in a first-degree relative had a positive predictive value (PPV) of only 14% for FV Leiden. A PPV of 12% was calculated by investigating the 609 thrombosis-free women. Inherited FV Leiden (odds ratio = 4.9) and acquired risk factors (odds ratio = 10.1) were both found to be the most prominent, but independent additional risks. Nevertheless, FV Leiden carriers, both heterozygotes and homozygotes, did not suffer earlier from thromboembolism than patients without the mutation. In conclusion, family history is an unreliable criterion to detect FV Leiden carriers. Screening for factor V Leiden can be worthwhile even if the advantages of oral contraception are higher assessed than the thrombotic risk. Affected women knowing about their additional risk could contribute to the prevention of thrombosis in risk situations.

Adolescent↗
PubMed1996

[The diagnosis and therapy of acquired factor-VIII inhibitors in combination with lupus anticoagulants].

HISTORY AND CLINICAL FINDINGS: A 63-year-old woman, known to have a primary factor VIII inhibitor (FFI) in combination with lupus anticoagulants (LA) was hospitalised because of life-threatening bleeding from mouth and neck. INVESTIGATIONS: The activity of coagulation factor VIII was 9% under substitution, while the factor VIII inhibitor titre was 123 U/ml. A lupus anticoagulant test was positive. Antibodies against varicella-zoster virus and Epstein-Barr virus were demonstrated. The right adrenal was found to be enlarged on computed tomography. TREATMENT AND COURSE: Coagulation became normal on administration of porcine factor VIII concentrate. Three cycles of a combination of three protein A immunoadsorptions, cyclophosphamide (twice 1.0 g intravenously), IgG (30 g daily for 5 days) as well as long-term oral cyclophosphamide administration (150 mg daily) during the interval were undertaken to reduce the inhibitor and produce immuno-tolerance. The factor VIII inhibitor titre was stabilised at a low level, but factor VIII activity could not be normalised without substitution. CONCLUSIONS: The simultaneous presence of specific and non-specific inhibitors makes laboratory diagnosis and treatment more difficult. Porcine factor VIII and a combination of immunoadsorption and suppression are important components in the treatment of bleeding episodes and the production of immunotolerance.

Autoimmune Diseases↗
PubMed1996

Changes in coagulation and fibrinolytic parameters caused by extracorporeal circulation.

During cardiopulmonary bypass (CPB) mechanical stress and the contact of blood with artificial surfaces lead to the activation of pro- and anticoagulant systems and the complement cascade, and to changes in cellular components. This phenomenon causes the "postperfusion-syndrome", with leukocytosis, increased capillary permeability, accumulation of interstitial fluid, and organ dysfunction. In this study, we focused on the influence of the extracorporeal circulation, sternotomy, and heparin administration on the activation of coagulation and fibrinolysis. In 15 patients we investigated coagulation parameters before, during and post CPB, i.e., fibrinogen, antithrombin (AT) III, thrombin-antithrombin complex (TAT), prothrombin fragments F1 + 2 (F1 + 2), factor (F) XIIa, tissue factor (TF), and parameters of the fibrinolytic system, i.e., plasmin-antiplasmin-complex (PAP), D-dimer, tissue-plasminogen-activator (tPA), urokinase-type plasminogen activator (uPA), and plasminogen-activator inhibitor type 1 (PAI 1). The results demonstrate distinct alterations in the above mentioned parameters. Despite administration of a high dose of heparin (activated clotting time [ACT] > 450s) combined with a low dose of aprotinin, activation of the coagulation and fibrinolytic pathways was observed. We found this activation was mainly caused by CPB and not by sternotomy. The activation of coagulation was due to foreign surface contact (F XII => F XIIa) as well as to an effect of tissue factor release in the late phase of CPB. The enhanced fibrinolytic activity during CPB was, at least in part, caused by tPA and was followed by PAI 1 release.

Anticoagulants↗
PubMed1995

Murine leukemia virus-induced neurodegeneration of rats: enhancement of neuropathogenicity correlates with enhanced viral tropism for macrophages, microglia, and brain vascular cells.

A highly neuropathogenic retrovirus, NT40, was generated by serially passaging an infectious molecular clone of Friend murine leukemia virus, FB29, through F344 Fisher rats. NT40 induced severe neurological signs such as reflex abnormalities and ataxia within 4-6 weeks following neonatal inoculation. FB29 led to only very mild neurological dysfunctions with longer incubation periods. Pathological alterations were characterized by mild (FB29) to extensive (NT40) noninflammatory spongiform degeneration, mainly of brain-stem areas. Infectious center assays revealed that viral titers in brain tissues of NT40-infected rats were 100-fold higher than those of FB29-infected animals. Employing immunohistochemistry, in situ hybridization, and flow cytometry, NT40 was found to infect many endothelial cells of brain blood vessels and microglia, whereas FB29 infected only microglia and those to a lower extent. However, when isolated from adult diseased rats, microglial cells turned out in both cases to be nonproductively infected with either FB29 or NT40. Of peripheral organs, we found enhanced levels of NT40 in peritoneal macrophages but not in spleen, thymus, or serum when compared to FB29. Altogether these data suggest that an expanded cellular tropism within the CNS and elevated viral titers in macrophages and microglia correlated with enhancement of neuropathogenicity.

3T3 Cells↗
PubMed1995

Effects of adoptive immune transfers on murine leukemia virus-infection of rats.

In a rat model, we have investigated the effects of adoptively transferred virus-specific immune cells on an established retroviral infection of various organs. The experimental design required inoculation of neonatal Fisher rats with a molecular clone of Friend murine leukemia virus (F-MuLV; FB29) which resulted in virus-specific immunotolerance, while infection of adult rats lead to a virus-specific humoral and cellular immune response. Adoptive transfer of virus-specific immune cells from immunized to immunotolerant (i.e., neonatally inoculated) rats was performed at around 15 days postpartum, a time when retroviral titers had already reached high levels in serum, spleen, thymus, and central nervous system (CNS). Seven days post-transfer (dpt), virus titers began to decline by 3-5 logs first in sera and at around 11-15 dpt, in spleens and thymi. Approximately 19 days post-transfer viral titers increased again. In the CNS, viral titers appeared not to change after adoptive transfer, although we observed an influx of activated T-cells and natural killer cells (NK-cells), but not of B-cells, into the CNS as well as an upregulation of major histocompatibility complex class I and II molecules between 8 and 21 dpt on both microglia and other brain cells. From these data we conclude that MuLV-infected cells of lymphoid organs can be eliminated by an antiviral immune response. In the CNS, however, most virus-infected cells escaped an immunological attack in spite of the presence of T- and NK-cells and may thus function as a reservoir for MuLVs.

Animals↗
PubMed1995

Phenotypic and functional characterization of CD8+ T lymphocytes from the central nervous system of rats with coronavirus JHM induced demyelinating encephalomyelitis.

Intracerebral infection of Lewis (LEW) inbred rats with the neurotropic strain of the murine coronavirus JHM (JHMV) frequently results in a monophasic paralytic disease. In contrast, infection of Brown Norway (BN) inbred rats does not lead to clinical disease. Previous findings indicated that in both rat strains brain-infiltrating leukocytes consisted mainly of CD8+ T lymphocytes. Here, we phenotypically as well as functionally characterised this T cell subset after isolation from the central nervous system (CNS). Using JHMV-infected target cells, MHC class I restricted, cytotoxic T lymphocytes were demonstrated to be present in the leukocyte fraction from the CNS of both, susceptible LEW and disease-resistant BN rats. However, compared to infected, but healthy BN rats, diseased LEW rats generated an enhanced cytotoxic immune response which became most prominent at the maximum of neurological disease. Recently published observations from our laboratory demonstrated a strong virus-specific antibody response in the CNS of BN rats. In LEW rats, however, the response was delayed and of low magnitude. This suggests, that consequences of cytotoxic T lymphocyte action in JHMV-infected CNS tissue largely depend on the efficacy of an accompanying virus-specific humoral immune response.

Animals↗
PubMed1994

Cervical lymphoid tissue but not the central nervous system supports proliferation of virus-specific T lymphocytes during coronavirus-induced encephalitis in rats.

The CD4+ T lymphocyte response in the central nervous system (CNS) and cervical lymph nodes (CLNs) of rats with different susceptibility to coronavirus-induced encephalitis was investigated. The majority of CD4+ T lymphocytes entering the virus-infected CNS in the course of the infection are primed cells that neither proliferate ex vivo nor can be stimulated to proliferation by viral antigens or mitogen in vitro. In contrast, T lymphocytes taken from CLNs of the same animals revealed a strong proliferative response. Restimulation of CLN lymphocytes by viral antigens disclosed a striking difference between the disease-resistant rat strain Brown Norway (BN) and the susceptible Lewis (LEW) strain. Whereas BN lymphocytes responded as early as 5 days post infection, it took more than 11 days until a comparable proliferation was detectable in LEW lymphocytes. From these data we postulate that the majority of T lymphocytes entering the virus-infected brain after sensitisation and expansion in cervical lymph nodes is unresponsive to further proliferation signals and that the kinetics and magnitude of T lymphocyte stimulation in CLNs play an important role in the clinical course of the infection.

Animals↗