Biomedical subjects

R Schwab

Publications and source records attributed to R Schwab.

At least 37 records · Page 2Linked to original sources

PubMed1998

Bcr-Abl kinase promotes cell cycle entry of primary myeloid CML cells in the absence of growth factors.

Cell cycle control of both immature and differentiated primary myeloid normal and chronic-phase chronic myeloid leukaemia (CML) cells to growth factor deprivation was studied. CD34+ cells were cultured in liquid culture. After removal of growth factors for 48 h normal cells were very efficiently arrested with the fraction of cells in S phase reduced by 70.8 +/- 6.5% in CD34+ and 50.5 +/- 4.2% in CD34- cells. In contrast, a significantly higher proportion of leukaemic cells remained in S phase. The fraction of S-phase cells was reduced by only 29.3 +/- 5.7% in CD34+ CML cells and 21.2 +/- 3.8% in CD34- cells. This abnormal negative cell cycle control in leukaemic cells was specific for growth factor deprivation. Reaction to IFN-alpha and TNF-alpha treatment was identical both in normal and CML cells. Equal quantities of the cytokines TNF-alpha, IL-1alpha, IL-1RA and IL-6 were produced by CML and normal cells. However, production of GM-CSF, with a median of 11 +/- 5 pg/ml, was found only in the supernatants of CML cells. But antibodies to GM-CSF did not restore growth factor dependence of the leukaemic cells. The defect was completely corrected by the abl-specific tyrosine kinase inhibitor CGP 57148 without effecting cell cycle control of normal cells. Our results demonstrate a directly Bcr-Abl-dependent defective response of both immature and differentiated primary myeloid CML cells to growth factor deprivation.

Benzamides↗

PubMed1997

Expanded CD4+ and CD8+ T cell clones in elderly humans.

The diversity of the human TCR repertoire in aging has been studied by examining the profiles of complementarity-determining region 3 (CDR3) sizes expressed by the BV families. The TCRBV CDR3 profile, which shows size heterogeneity in young adult humans, is significantly restricted in aged humans. Clonal T cell expansions were identified using a PCR-based approach, in one or more BV families from all 14 healthy persons over the age of 65 that we studied. CD4+ T cell expansions were identified in 8 of 11 donors and CD8+ T cell expansions in 7 of 10 donors. These clonal expansions were stable during a 2-year period. Interestingly, more than half of the aged persons had clonal expansions within the BV3, -14, -16, and -23 families. Although there was no homology among the eight CDR3 sequences identified in clonal T cells from 8 aged persons, selective pressure on the expanded T cell clones was suggested by the fact that the BV families used by the T cell clones were not proportional to the number of genes in the different BV families.

Adult↗

PubMed1997

Effect of endotoxin administration on the severity of acute pancreatitis in two experimental models.

CONCLUSIONS: Endotoxemia can transform acute pancreatitis (AP) into a more severe form of the disease in models of AP provoked by common pancreatico-biliary duct ligation or L-arginine injection. BACKGROUND: It has been shown that systemic endotoxemia is a common feature in severe AP. The effect of endotoxemia on the course of experimental pancreatitis is unknown. METHODS: AP was induced by common pancreatico-biliary duct ligation (experiment 1) and i.p. injection of 250 mg/100 g body wt of L-arginine (experiment 2). Test animals of both experiments received i.p. injections of 0.5 and 1.0 mg/100 g body wt of endotoxin at the induction of AP. Saline-treated and only endotoxin-dosed animals served as controls for both experiments. Mortality rates and pancreatic histology were investigated at 48 h. RESULTS: The mortality rate was significantly elevated (60%, p < 0.05) in experiment 1 when 1.0 mg/100 g of endotoxin was given. In experiment 2, the mortality rate was also increased (30%) at this dose of endotoxin without reaching significance. Histologic changes were more severe in both groups of AP treated by the two doses of endotoxin than without it. Acinar necrosis and hemorrhage were highly elevated (p < 0.01) in both experiments when AP was combined with 1.0 mg/100 g body wt of endotoxin. The animals receiving only endotoxin showed only slight inflammatory and necrotic changes.

Acute Disease↗

PubMed1997

Peritoneal lavage reduces lipopolysaccharide-induced elevation of serum TNF-alpha and IL-6 mortality in mice.

The contribution of peritoneal cells to lipopolysaccharide (LPS)-induced elevation of serum TNF-alpha and IL-6 levels and mortality has been studied. Peritoneal lavage performed before LPS administration reduced serum cytokine levels by approximately 50% and mortality from 50 to 100%. The effect of peritoneal lavage is due to the removal of peritoneal cells as reinjection of peritoneal cells eliminated the protective effect of lavage on LPS-induced mortality. A special role of peritoneal macrophages in the systemic response to LPS was suggested by the finding that LPS-induced an increase in intracellular TNF-alpha and IL-6 peritoneal macrophages but in neither splenic nor bone marrow macrophages. Intraperitoneal injection of thioglycollate broth 4 days prior to lavage increased the number of peritoneal cells removed by lavage and increased protection from LPS mortality. Peritoneal lavage performed 30 to 120 minutes after the LPS administration completely protected all mice from LPS-induced mortality, suggesting the possibility that such treatment may offer a novel therapeutic approach to septic shock.

Animals↗

PubMed1997

Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans.

Elevated plasma homocysteine concentration is an independent risk factor for vascular disease in humans. In addition to nutritional and genetic factors, an interruption of the coordinate regulatory function of S-adenosylmethionine has been proposed to be involved in the occurrence of hyperhomocysteinemia. The effect of oral S-adenosylmethionine on homocysteine metabolism in humans is unknown. We investigated the effect of oral S-adenosylmethionine (400 mg) on plasma levels of 5-methyltetrahydrofolate, which is the active form of folate in the remethylation of homocysteine to methionine, S-adenosylhomocysteine, the demethylated product of S-adenosylmethionine, homocysteine and methionine over 24 hr in 14 healthy subjects. After oral administration, S-adenosylmethionine increased from 38.0 +/- 13.4 to 361.8 +/- 66.4 nmol/liter (mean +/- S.E., P < .001) and returned to base-line values with a half-life of 1.7 +/- 0.3 hr. Both S-adenosylhomocysteine and 5-methyltetrahydrofolate showed a significant transient increase (from 29.9 +/- 3.7 to 51.7 +/- 7.1 nmol/liter, and from 25.1 +/- 2.5 to 36.2 +/- 3.5 nmol/liter, respectively, P < .001), although homocysteine and methionine did not change over the time of measurement. These changes were not found in subjects without previous S-adenosylmethionine administration. The observed metabolic changes suggest that S-adenosylmethionine, at least in concentrations obtained in this study, does not inhibit 5,10-methylenetetrahydrofolate reductase, the 5-methyltetrahydrofolate forming enzyme. Rather they indicate a positive effect on 5-methyltetrahydrofolate, a key cofactor in homocysteine metabolism, which should be considered in homocysteine lowering strategies for the prevention of vascular disease.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗

PubMed1996

Cationic lipid mediated transfer of c-abl and bcr antisense oligonucleotides to immature normal myeloid cells: uptake, biological effects and modulation of gene expression.

Uptake and biochemical and biological effects of antisense oligodeoxynucleotides (ODN) specific for c-abl and bcr genes were studied in normal immature myeloid cells. CD34-positive cells were purified by positive and negative selection and cultured in liquid culture for 7 days. These cells were then incubated with ODNs, either alone or in combination with cationic lipids. The uptake of ODNs was enhanced by the use of cationic lipids. In addition, very low concentrations of ODNs in combination with cationic lipids were capable of specifically inhibiting the expression of the c-abl gene. In contrast, no effects were seen on the expression of bcr. However, despite the effective blocking of c-abl expression, no changes in cellular growth patterns were observed in liquid culture or in a colony-forming assay. We conclude tht the use of cationic lipids might enhance the gene-regulatory effects of ODNs by increasing their uptake into normal hematopoietic cells.

Antigens, CD34↗

PubMed1996

Primary proliferating immature myeloid cells from CML patients are not resistant to induction of apoptosis by DNA damage and growth factor withdrawal.

Induction of apoptosis by growth factor deprivation or gamma-irradiation-induced DNA damage was directly studied in proliferating primary haemopoietic cells derived from CD34-positive cells of 13 CML patients and 12 normal controls. CD34-positive cells were cultured in the presence of appropriate concentrations of SCF and G-CSF for 5-7 d. After gamma irradiation with 500 rad or growth factor deprivation, the fraction of apoptotic cells was assessed by two independent methods applying either measurement of cells incorporating FITC-labelled dUTP by terminal transferase or assessment of the fraction of cells with a less than 2N DNA content in flow cytometry. Proliferating CML cells were not resistant to the induction of apoptosis either after gamma irradiation or subsequent to growth factor deprivation. A similar fraction of normal and CML cells underwent apoptosis 48 h after withdrawal of growth factors. CML cells displayed an increased susceptibility to induction of apoptosis after DNA damage. A significantly higher proportion of apoptotic cells were detected in samples derived from CML patients after irradiation with 0.5 Gy. These results, in conjunction with conflicting observations by other investigators, on the induction of apoptosis by gamma irradiation in various bcr-abl positive cells, suggest that bcr-abl-dependent effects on apoptosis strongly depend on the cells used. Our observations in CML cells derived exclusively from newly diagnosed CML patients demonstrate that bcr-abl expression per se is not sufficient to induce resistance to apoptosis.

Apoptosis↗

PubMed1996

[Latissimus dorsi for autologous volume substitution in defects after breast saving therapy].

The present paper is based on the prospective data on breast conserving therapy recorded since 1977 in the "Basel protocol". Here both surgical and radio-oncological procedures are standardized, and a form sheet is provided for registering the pathological findings. Since our data showed that local recurrence free survival of patients treated by tumor resection only just in sano or questionably in sano was statistically significantly worse, it was decided to fill the volume defect occurring during breast conserving therapy with autologous tissue, in selected cases. Also an adjuvant radiation therapy was performed. Since January. 1st, 1992 we performed volume substitution by a latissimus dorsi flap in 27 patients treated by a surgically "enlarged" breast conserving concept. A classical skin muscle island, a deepithelized skin muscle island or a mere muscle island flap were performed. Aim of this pilot study was to further optimize early and late cosmetic results, to enlarge indication for breast conserving therapy and improve loco-regional tumor control.

Adult↗

PubMed1995

[Radiographically demonstrable spinal changes in asymptomatic young men].

PURPOSE: To find reliable data of the incidence of different variations of the spine. MATERIAL AND METHODS: Standardised radiographic examinations of 10,922 young, healthy pilot aspirants of the German air force were made. Radiographic examination included the whole spine in a.p. and lateral projection, the cervical spine in oblique projection and in a subunit of 5781 men the lumbar spine in oblique projection. RESULTS: The following incidences were found: mild habit scoliosis: 80.4%, structural scoliosis: 9%, severe thoracal kyphosis without severe lumbar lordosis: 5.1% and together with severe lumbar lordosis: 30.8%, mild forms of kyphosis of adolescence: 23.3%, severe forms: 2.1% and cuneiform deformation of vertebral body: 4.9%, sacralization: 7.8%, lumbarization: 5.9%, spondylolysis: 6.2%, spondylolisthesis: 4.3% and lumbar chondrosis: 2.1%. Chondrosis of the thoracal and cervical spine, osteochondrosis and coalescent vertebral bodies were found in less than 0.8% each. CONCLUSION: In only 2.6% were there no pathological findings. This shows importance of radiological spine examinations especially for industrial and preventive medicine.

Adolescent↗

PubMed1995

Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia.

Cell cycle control subsequent to gamma irradiation or growth factor starvation has been studied in immative hematopoietic cells of 19 previously untreated chronic myeloid leukemia (CML) patients in chronic phase compared with 18 normal controls. CD34-positive cells were cultured for seven days in the presence of optimal concentrations of appropriate growth factors. At day 7 of culture both S-phase fraction and differentiation were identical in normal and leukemic cells. In normal cells the proportion of S-phase cells was reduced by irradiation with 500 rad from 40 +/- 3% to 16 +/- 2%. In contrast, in CML cells a reduction of S-phase cells from 35 +/- 2% to 25 +/- 3% was observed. Moreover, irradiated CML cells arrested at a smaller number of cells in G2. Similarly, a significantly higher proportion of CML cells remained in S phase after withdrawal of growth factors. Semiquantitative PCR of p21 (waf1/cip1) induction by gamma irradiation provided no evidence for a major functional deficiency of p53 response to irradiation in these cells. Our results demonstrate an abnormal cell cycle arrest in chronic-phase CML cells both after gamma irradiation and after growth factor removal. This observation might have important implications for understanding the pathogenesis of both hyperplasia of chronic phase and the development of blast crisis in CML. The molecular mechanisms underlying these abnormalities in bcr-abl-positive cells remain to be clarified.

Actins↗

PubMed1994

Effect of aging on murine macrophages. Diminished response to IFN-gamma for enhanced oxidative metabolism.

The ability of macrophages to secrete reactive oxygen intermediates, as well as reactive nitrogen intermediates, correlates closely with their capacity to perform two critical effector functions: intracellular killing of microorganisms and lysis of tumor cells. In this study, age-associated changes in the ability of caseinate-elicited peritoneal macrophages to release hydrogen peroxide were determined. Macrophages from aged BALB/c mice produced 50% less hydrogen peroxide than those from young mice in response to PMA or opsonized zymosan. In contrast, the production of macrophage-activating cytokines including IFN-gamma was not diminished in splenocyte supernatants from the aged group. Furthermore, no difference was detected in surface expression of IFN-gamma receptor in old and young mice. Macrophage responses to IFN-gamma, however, declined with aging. In vitro, IFN-gamma-induced release of hydrogen peroxide and nitric oxide was 50% lower in old mice than in young mice. IFN-gamma-induced tyrosine phosphorylation of MAPK, an early activation event, was undetectable in macrophages from the aged mice. These data demonstrate that diminished responses of macrophages to activating signals are one aspect of the impaired immune response in aged mice.

Aging↗

PubMed1994

Soluble beta 2-microglobulin-free class I heavy chains are released from the surface of activated and leukemia cells by a metalloprotease.

Regulation of the expression of major histocompatibility complex (MHC) class I heavy chains not associated with beta 2-microglobulin (beta 2m) on freshly isolated and in vitro cultured human B and T leukemia cells was analyzed. These beta 2m-free class I heavy chains originate from surface beta 2m-associated MHC class I molecules and are expressed as integral membrane glycoproteins on activated, but not resting, cells. We found that the levels of beta 2m-free class I heavy chains can be regulated by proteolytic cleavage and release into the medium of soluble molecules containing the extracellular domains. The release is mediated by a Zn(2+)-dependent, membrane-bound metalloprotease that does not cleave HLA-DR, CD4, and CD71 surface receptors and can be activated by phorbol myristate acetate. Specific cleavage by the metalloprotease occurs at a site close to the papain cleavage site in the alpha 3 domain of class I heavy chains. This site is not accessible to the metalloprotease in beta 2m-associated MHC class I molecules. The dissociation of beta 2m-associated MHC class I molecules and subsequent cleavage of beta 2m-free class I heavy chains may be partially responsible for controlling the levels of MHC class I molecules on the surface of activated cells.

Antigens, CD↗

PubMed1994

How to improve the uterotomy healing. I. Effects of fibrin and tumor necrosis factor-alpha in the rat uterotomy model.

Suboptimal uterotomy healing following cesarean delivery or metroplastic operations may lead to considerable complications. New insights in the biology of wound healing and the availability of a variety of biologic response modifiers open the possibility to modulate the process of wound healing in order to gain clinical benefits. Can uterotomy healing be improved by local application of biosubstances? We developed an uterotomy model in the rat and measured the bursting pressure at defined times postwounding as a functional parameter of wound healing. In addition, the healing process was assessed by serial light microscopic histology. Uterotomy healing was investigated in the presence of fibrin alone or with fibrin containing tumor necrosis factor-alpha (TNF-alpha-fibrin) compared to controls. The fibrin matrix incorporated into rat uterotomies reduced wound hemorrhage and led to a 45% increase of early (Day 3) bursting pressure (not significant). With 20 micrograms TNF-alpha in the fibrin matrix, Day 3 bursting pressure was elevated by more than 100% (P < 0.05). Histologically, inflammation and granulation tissue formation was markedly enhanced. Two micrograms of TNF-alpha/wound did not show any effect and 200 micrograms TNF-alpha even led to a decrease in early bursting strength. After 1 week, no differences in bursting pressure or wound histology could be detected between uterotomies treated with fibrin or TNF-alpha-fibrin compared to controls. The rat uterotomy model appears to be suitable for investigating new biological means to improve uterine wound healing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Acute and long-term effects of adrenocorticotropin and dexamethasone on the auditory brainstem response in multiple sclerosis patients.

Auditory brain-stem responses (ABRs) were compared in two groups of multiple sclerosis (MS) patients receiving standard treatment with adrenocorticotropin (ACTH) and with dexamethasone (DEX). ABRs were recorded prior to treatment, on the 1st and 8th day of therapy, and 21 days after the hormonal treatment had been discontinued. ABRs in MS patients were within the normal range of variability. Latencies of ABR components increased with increasing rate of presentation, and with decreasing intensity of the click stimuli. Changes in ABRs displayed a consistent pattern in patients treated with ACTH, but showed less coherence after DEX. In ACTH treated patients' latencies of the late ABR waves V and Vn were prolonged after clicks of high intensity, and reduced following clicks of low intensity resulting in a decreased slope of the latency-intensity function of these ABR waves. This pattern became most prominent in the recordings after the treatment had been discontinued, and could reflect an improved transmission across both afferent excitatory and recurrent inhibitory synapses in the auditory pathways. The findings indicate that--besides a common anti-inflammatory action--therapies with ACTH and DEX differ with regard to their influence on central nervous functioning.

Adolescent↗

PubMed1993

Effect of age on the expressed B cell repertoire: role of B cell subsets.

Aged humans and experimental animals are impaired in their responses to most foreign antigens although they produce greater amounts of autoantibodies. We have examined the effect of age on the production of antibodies to a prototypic foreign antigen, sheep erythrocytes (SRBC), and to a prototypic autoantigen, bromelain-treated mouse erythrocytes (BrMRBC), in young and old mice before and after immunization with SRBC. Old mice express more anti-BrMRBC plaque-forming cell (PFC) antibodies before and an even greater number after immunization with SRBC than young mice. Conversely, old mice produce far fewer anti-SRBC PFC than young mice following immunization with SRBC. We hypothesized that the differences in the responses of old mice to BrMRBC and SRBC reflects differences in the activity of CD5+ and CD5- B cells. To test this hypothesis we immunized young and old mice with foreign antigens reported (and confirmed in our studies) to stimulate CD5+ B cells [TNP-ficoll and phosphorylcholine-keyhole limpet hemocyanin (KLH)] or CD5- B cells (SRBC and TNP-KLH). We found that the PFC response of old mice to antigens mediated by CD5+ B cells was equal to or greater than that of young mice. In contrast the PFC response of old mice induced by antigens mediated by CD5- B cells was only 10% that of young mice. Thus it appears that the immune response of old mice is well maintained for antigens which elicit a CD5+ B cell response but not for those which elicit a CD5- B cell response.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1993

Acute effects of different intensities of weight lifting on serum testosterone.

The purpose of this investigation was to determine the effect of moderate weight lifting (MWL) and light weight lifting (LWL) on concentrations of serum testosterone in males. Baseline testosterone concentrations were determined via an indwelling catheter in the median cubital vein. An initial sample of blood was followed 7 min later by five samples taken at 4-min intervals. A final sample was taken 10 min after the last 4-min blood draw. Blood samples were obtained at similar times and intervals on the weight lifting days. The MWL consisted of four sets of six squats at 90-95% of a six-repetition maximum (RM), while the LWL consisted of four sets of 9 or 10 repetitions at 60-65% of the weight used for the sets during MWL. There was a significant increase in serum testosterone concentrations following the fourth set for both MWL and LWL when compared with baseline concentrations and both MWL and LWL testosterone concentrations returned to baseline levels at 10 min postexercise. These results indicate that MWL and LWL caused increases in serum testosterone that were greater than those associated with baseline levels. Postexercise responses for the MWL and LWL were similar.

Adult↗

PubMed1992

Altered major histocompatibility complex-restricted antigen recognition by T cells from elderly humans.

Positive selection of T cells within the thymus gland leads to major histocompatibility complex (MHC)-restricted recognition of antigen by T lymphocytes. As the thymus gland involutes with age, altered MHC-restricted antigen recognition by T cells from elderly humans would be expected. We have tested this hypothesis by comparing the proliferative response of T cells and T cell clones from aged and young subjects to influenza determinants presented by autologous or allogeneic antigen-presenting cells (APC). Under conditions in which the allogeneic mixed lymphocyte reaction was minimal, T cells from six of seven aged donors but only one of seven young donors were stimulated by influenza vaccine presented by allogeneic APC. More importantly, one-half of the influenza-specific T cell clones derived from aged donors, but none of the clones derived from young donors, were activated by influenza vaccine presented by allogeneic APC. While 80% of the MHC-nonrestricted influenza-specific T cell clones expressed the gamma/delta T cell receptor, 20% of these clones expressed the alpha/beta T cell receptor. Thus, changes in MHC-restricted antigen recognition by T cells and in altered distribution of alpha/beta versus the gamma/delta T cell receptor bearing antigen-specific T cell clones occur with aging.

Adult↗

PubMed1992

The origin and fate of beta 2m-free MHC class I molecules induced on activated T cells.

We report here that the expression of major histocompatibility complex (MHC) class I heavy chains not associated with beta 2-microglobulin is induced on resting human T cells by a variety of stimuli. These beta 2m-free class I heavy chains are not transported as such from the endoplasmic reticulum but originate from surface beta 2m-associated MHC class I molecules. beta 2m-free class I heavy chains are spontaneously released from the surface of activated cells. Cross-linking of beta 2m-free class I heavy chains with specific monoclonal antibodies results in the rapid down-regulation and internalization of these molecules. In contrast, beta 2m-associated MHC class I molecules display a different pattern of modulation. Previously, we reported that beta 2m-free class I heavy chains interact with CD8 molecules expressed on the same activated T cells. We propose that interactions between these molecules are involved in a mechanism regulating the function of activated T cells.

Brefeldin A↗