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Biomedical subjects

M Lotz

Publications and source records attributed to M Lotz.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Quality assurance in clinical social work: how do social workers judge the success of their interventions?].

Therapy outcome is an important criterium for quality assurance. In this study, clinical social workers themselves estimated the outcome of their interventions in 2643 admissions of 2038 patients to a psychiatric hospital. These inpatients had been referred by a psychiatrist to the social worker and comprised 27 % of all patients admitted to the hospital within 11 years. The study purpose was to investigate how the outcome estimates relate to clinical and sociodemographic variables of the patients, to their specific problems, and to the applied interventions. The fewer areas of problems were perceived and the more interventions were performed, the more positive these interventions were evaluated. Administrative interventions were seen as more successful than counseling. Outcome estimates were particularly positive in long and intensive therapies.

Adult↗
PubMed1996

[Social work in inpatient psychiatric management. An empirical study of indications and success].

The participation of social work in inpatient psychiatric care is generally considered necessary, but there is a lack of empirical studies in this field. The analyses presented of a systematic documentation of social work interventions in 2038 cases during an 11-year period demonstrate that social workers are mostly involved in the treatment of chronic and previously treated patients. Interventions in younger patients, most of whom are suffering from psychoses, aim at rehabilitation through activity; in elderly patients with organic or depressive disorders, the major concern is to improve posthospital care; patients with neurotic or personality disorders comprise another group with a chronic course and a relatively poor outcome. As far as their goals are comparable, social workers and doctors agree on their objectives. Social workers usually see their own interventions as successful, but patient groups who benefit greatly can be differentiated from groups with poor outcome.

Adult↗
PubMed1995

A mRNA variant encoding a soluble form of 4-1BB, a member of the murine NGF/TNF receptor family.

The murine 4-1BB gene, encoding a member of the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor family, is thought to be selectively expressed in T cells and is involved in the regulation of lymphocyte proliferation. We detected two forms of the 4-1BB mRNA by RT-PCR which were expressed in an activation-dependent pattern in splenocytes and thymocytes. cDNA sequencing showed that the smaller form was a mRNA splice variant lacking the transmembrane region (4-1BB delta TM), because of the deletion of exon 8. The two forms of mRNA are differentially expressed in murine T cells, macrophages, 3T3 fibroblasts and epitheloid cells. Northern blotting also identifies two forms of mRNA of 1.5 and 2.4 kb, and the cell-type-specific pattern correlated with the PCR results. These results identify a novel form of 4-1BB. This and the previously known membrane-associated form have a broad tissue distribution, suggesting a more diverse role in host defense.

3T3 Cells↗
PubMed1995

Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes.

Articular cartilage chondrocytes have the unique ability to elaborate large amounts of extracellular pyrophosphate (PPi), and transforming growth factor beta (TGF beta) appears singular among cartilage regulatory factors in stimulating PPi production. TGF beta caused a time and dose-dependent increase in intracellular and extracellular PPi in human articular chondrocyte cultures. TGF beta and interleukin 1 beta (IL-1 beta) antagonistically regulate certain chondrocyte functions. IL-1 beta profoundly inhibited basal and TGF beta-induced PPi elaboration. To address mechanisms involved with the regulation of PPi synthesis by IL-1 beta and TGF beta, we analyzed the activity of the PPi-generating enzyme NTP pyrophosphohydrolase (NTPPPH) and the PPi-hydrolyzing enzyme alkaline phosphatase. Human chondrocyte NTPPPH activity was largely attributable to plasma cell membrane glycoprotein 1, PC-1. Furthermore, TGF beta induced comparable increases in the activity of extracellular PPi, intracellular PPi, and cellular NTPPPH and in the levels of PC-1 protein and mRNA in chondrocytes as well as a decrease in alkaline phosphatase. All of these TGF beta-induced responses were completely blocked by IL-1 beta. Thus, IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression.

Adult↗
PubMed1995

Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes.

This study analyzes cyclooxygenase II (COX-2) gene expression, protein synthesis, and PGE2 release in normal human articular chondrocytes. Stimulation of chondrocytes in primary culture resulted in a dose-dependent induction of COX-2 mRNA in response to IL-1 with an ED50 between 0.1 and 1 ng/ml. COX-2 mRNA was detectable after 2 h, reached high levels at 6 h, and showed a remarkably long duration of expression for at least 72 h. Analysis of other extracellular stimuli showed that COX-2 mRNA was inducible by other cytokines including TNF-alpha, IL-6, and LIF and by bacterial LPS. Dexamethasone completely inhibited IL-1-induced COX-2 mRNA expression. Analysis of signaling pathways showed that PMA and calcium ionophore A23187, but not dibutyryl cAMP, induced COX-2 mRNA. The combination of IL-1 and A23187 resulted in synergistic increases. IL-1 effects were not reduced by the protein kinase C inhibitor staurosporine or by the protein kinase A inhibitor H89 but blocked by the protein tyrosine kinase inhibitor herbimycin A. COX-2 protein was detected at 71 kDa by Western blotting in IL-1-stimulated, and to almost similar levels in A23187-treated, cells. Flow cytometric analysis showed that after IL-1 stimulation 78% of the chondrocytes expressed COX-2 protein. The patterns of COX-2 protein expression and the levels of PGE2 release correlated with the effects of the different stimuli and inhibitors on mRNA expression.

Cartilage, Articular↗
PubMed1995

Differentiation-dependent effects of IL-1 and TGF-beta on human articular chondrocyte proliferation are related to inducible nitric oxide synthase expression.

This study analyzed the effect of chondrocyte differentiation on iNOS expression and responses to IL-1 and TGF-beta. During subculturing of chondrocytes, the growth-stimulatory effects of TGF-beta decreased, and cells in later passages even were growth inhibited by TGF-beta. IL-1 beta responses showed an inverse pattern. The antiproliferative effects of IL-1 beta decreased, and, after passage 6, IL-1 beta became a growth stimulator for chondrocytes. This change in growth factor response pattern was associated with a decrease in type II collagen expression. To determine whether these changes in the growth regulatory effects of IL-1 beta and TGF-beta were related to nitric oxide (NO), inducible nitric oxide synthase (iNOS) expression and NO release were analyzed. In primary chondrocytes, TGF-beta did not stimulate iNOS mRNA expression or NO release, and, during co-incubation, it did not detectably alter the IL-1 beta effect. Preincubation with TGF-beta resulted in a time-dependent increase in IL-1-induced NO. With increasing passage number, the IL-1 beta effects decreased, and, after passage 6, IL-1 beta no longer detectably stimulated iNOS expression or NO release. However, TGF-beta increased NO production synergistically with IL-1 beta during the same culture period when it lost its growth-stimulatory effects. The antiproliferative effects of TGF-beta in late passage chondrocytes were reversed by the NO synthase inhibitor NG-monomethylarginine. These results suggest a novel pattern of iNOS regulation by IL-1 and TGF-beta and show that the factors that modulate iNOS expression and proliferation are dependent on the differentiation status of the cells.

Adult↗
PubMed1995

ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages.

We recently identified a gene that is induced by lymphocyte activation (ILA). The sequence of the full-length 1.4-kb cDNA characterized ILA as a new member of the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor family and the human homologue of the murine T-cell-specific receptor 4-1BB. The present study demonstrates ILA mRNA isoforms at 4.4, 4.0, and 1.8 kb in poly-A+ RNA from activated, but not from resting human peripheral blood T lymphocytes. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay was used to study tissue distribution and regulation of ILA expression. The gene was induced in T lymphocytes by phytohemagglutinin (PHA), phorbol myristate acetate (PMA), and antibody to CD3, in B lymphocytes by PMA and antibodies to cell surface Ig, and in blood monocytes by interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS), and PMA. In T lymphocytes, ILA mRNA was detectable 1.5 hours after stimulation, reached maximal levels at 8 hours, and declined to background levels by 48 hours. Induction of ILA mRNA required protein synthesis and was primarily due to increased transcription. Actinomycin D reduced ILA mRNA levels in activated lymphocytes 50% within 30 minutes, demonstrating a relatively short half-life of this mRNA. Analysis of nonlymphoid cells showed that ILA mRNA was not detectable in resting cells. However, in contrast to the lymphoid-specific expression of the murine 4-1BB gene, ILA was detected in nonlymphoid cells, including epithelial and hepatoma cells after stimulation with IL-1 beta. ILA was not detectable in several brain derived cell lines. The ILA cDNA encodes a 30-kD protein as demonstrated by in vitro translation, and this protein is immunoprecipitated by antisera that were raised against ILA peptides or a glutathione-S-transferase fusion protein. Flow cytometry showed expression of ILA protein on a subset of activated T or B lymphocytes. In conclusion, activation-dependent expression of ILA is found not only in T lymphocytes, but also in B lymphocytes, monocytes, and diverse nonlymphoid cell types.

Amino Acid Sequence↗
PubMed1995

Growth factor responsiveness of human articular chondrocytes in aging and development.

OBJECTIVE: To examine growth factor responses of human articular chondrocytes in aging and development. We have previously established a growth factor response profile for adult human articular chondrocytes and shown that transforming growth factor beta (TGF beta) is the most potent mitogen among a variety of factors tested. METHODS: Chondrocytes were isolated from human articular cartilage obtained from donors ages 11-83 years and tested in primary culture for proliferative responses to serum and recombinant preparations of the major chondrocyte growth factors. Proliferation was measured by 3H-thymidine incorporation and cell counting. Skeletal maturity of the young donors was determined by radiographic assessment of Risser's index. RESULTS: Chondrocytes showed a continuous age-related decline in the proliferative response to serum. Analysis of recombinant growth factors showed that with increasing donor age, there was a decrease in the levels of DNA synthesis in response to all factors tested. In chondrocytes from adult donors, there was no change in the relative potencies of the different growth factors. The decrease in the levels of DNA synthesis as measured by 3H-thymidine incorporation corresponded to a reduced rate of in vitro cell replication with increasing donor age. In addition to the quantitative changes in the proliferative responses of chondrocytes with increasing age, there was a qualitative change in the pattern of growth factor responses during development. Cells from young donors (ages 10-20) responded better to platelet-derived growth factor, AA chain homodimer (PDGF-AA) than to TGF beta 1, while the inverse pattern was seen in cells from adult donors. This decrease in the response to PDGF-AA was significantly correlated with increasing skeletal maturity. CONCLUSION: Chondrocyte growth factor responsiveness shows qualitative changes during development, and after skeletal maturity, there is a profound decline in the levels of DNA synthesis and cell replication in response to the known chondrocyte growth factors.

Adolescent↗
PubMed1995

Tyrosine kinases are involved with the expression of inducible nitric oxide synthase in human articular chondrocytes.

The present study characterizes mechanisms involved with the induction of nitric oxide (NO) production, nitric oxide synthase (NOS) enzymatic activity and mRNA expression in human articular chondrocytes. Activation of chondrocytes with lipopolysaccharide (LPS) or IL-1 resulted in time- and dose-dependent increases in iNOS mRNA followed by increased NOS enzymatic activity and NO release. The protein tyrosine kinase (PTK) inhibitors herbimycin A or genistein reduced IL-1 or LPS-induced NO release and NOS enzymatic activity. This was associated with inhibition of iNOS mRNA expression as determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. In contrast, inhibitors of protein kinase C (PKC) or protein kinase A (PKA) did not affect these responses. These results were confirmed in experiments with second messenger agonists where neither activation of PKC, nor increases in cyclic adenosine monophosphate (cAMP) or increased intracellular calcium levels were associated with the induction of iNOS mRNA or NO release. These results suggest that PKC, PKA and calcium-dependent signals are not required or sufficient for the stimulation of NO production. However, NO production is dependent on tyrosine kinases due to their role in the expression of iNOS mRNA.

Amino Acid Oxidoreductases↗
PubMed1995

IL-1-induced nitric oxide inhibits chondrocyte proliferation via PGE2.

IL-1 inhibits chondrocyte proliferation induced by TGF beta or serum. This study analyzed the role of nitric oxide (NO), which is induced at high levels by IL-1 in chondrocytes. NO, when administered through sodium nitroprusside (SNP), inhibited TGF beta or serum-induced chondrocyte proliferation. To determine whether IL-1-induced NO is responsible for growth inhibition by IL-1, chondrocytes were cultured in the presence of the nitric oxide synthase inhibitor N-monomethyl-L-arginine (NMA), which dose-dependently reduced the antiproliferative effects of IL-1. Analysis of interactions between PGE2, a known chondrocyte growth inhibitor, and NO showed that PGE2 does not induce NO and is not required for NO induction by IL-1. However, SNP induced high levels of PGE2, and NMA reduced IL-1-induced PGE2. This raised the possibility that PGE2 is a downstream mediator of the antiproliferative effects of NO. This was confirmed in experiments where the growth inhibitory effects of SNP were reduced by indomethacin. These results suggest that the chondrocyte growth inhibition by IL-1 in chondrocytes is due to the induction of NO, which stimulates the production of PGE2 as a mediator of its antiproliferative effects.

Amino Acid Oxidoreductases↗
PubMed1995

Increased intracellular Ca2+ selectively suppresses IL-1-induced NO production by reducing iNOS mRNA stability.

This study addresses the role of intracellular calcium (Ca2+) in the expression of iNOS, an IL-1 inducible gene in human articular chondrocytes. The calcium ionophore A23187 and ionomycin did not induce NO release or iNOS expression but inhibited dose dependently IL-1-induced NO release with IC50 of 200 nM and 100 nM, respectively. Increased intracellular Ca2+ induced by thapsigargin or cyclopiazonic acid, inhibitors of the endoplasmic reticulum Ca2+ ATPase, had similar inhibitory effects with IC50 of 1 nM and 3 microM, respectively. LPS and TNF alpha induced NO production were also suppressed by these Ca2+ elevating drugs. Levels of IL-1-induced iNOS protein were reduced by A23187, thapsigargin, and cyclopiazonic acid. These drugs as well as Bay K 8644 and KCl inhibited IL-1-induced iNOS mRNA expression. To analyze the role of Ca2+ in the expression of other IL-1 responsive genes in chondrocytes, these Ca2+ modulating drugs were tested for effects on COXII. In contrast to the inhibitory effects on iNOS mRNA, these drugs induced COXII mRNA expression and in combination with IL-1, enhanced COXII mRNA levels. Ca2+ mediated increases in COXII mRNA expression were associated with an increase in COXII protein. The kinetics of Ca2+ effects on IL-1-induced iNOS mRNA levels suggested a posttranscriptional mechanism. Analysis of iNOS mRNA half life showed that it was 6-7 h in IL-1-stimulated cells and decreased by A23187 to 2-3 h. In conclusion, these results show that Ca2+ inhibits IL-1-induced NO release, iNOS protein, and mRNA expression in human articular chondrocytes by reducing iNOS mRNA stability. Under identical conditions increased Ca2+ enhances IL-1-induced COXII gene and protein expression.

Amino Acid Oxidoreductases↗
PubMed1995

Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery.

Somatic gene therapy is a novel approach with the potential to achieve prolonged increases in circulating levels of peptide hormones and cytokines. The present study evaluates the effects of monthly, intramuscular injections of cDNA expression vectors encoding for transforming growth factor beta (TGF beta) or interleukin 2 (IL-2) on disease activity in the MRL/lpr/lpr murine model of systemic lupus erythematosus (SLE). Monthly injections of plasmids cDNA between 6 and 26 weeks significantly elevated the serum levels of TGF beta (P < 0.005) and IL-2 (P < 0.05) compared with a control plasmid without insert. TGF beta encoding plasmid had beneficial effects in murine SLE with a prolonged survival of 70% at 26 weeks compared with 40% in the control group, decreased anti-chromatin and rheumatoid factor antibodies and a 50% decrease in total IgG production. Renal function was improved with reduced BUN levels and kidney inflammation as estimated by an histologic score. Those beneficial effects occurred in the apparent absence of local or systemic side-effects. In contrast, IL-2 cDNA injections appeared harmful with a decreased survival to 20% at 26 weeks, enhanced total IgG synthesis and autoantibodies production with a 4.5-fold increase in antichromatin antibodies. These results indicate that somatic gene therapy may provide a simple, inexpensive and effective mechanism for the long-term control of autoimmune diseases.

Animals↗
PubMed1995

Cytokine regulation of chondrocyte functions.

Regulation of chondrocyte secretory functions and proliferation by cytokines and growth factors is central to cartilage development and maintenance of homeostasis in the mature organism. Depending on the type of extracellular stimulus, chondrocytes can be induced to enter a catabolic matrix degrading or anabolic matrix forming functional program. Interleukin I and transforming growth factor beta are the prototypic stimuli for the catabolic and anabolic program, respectively. Insight into the regulation of chondrocytes by cytokines and growth factors provides the basis for improved concepts of osteoarthritis pathogenesis and new perspectives for therapeutic interventions.

Cartilage↗
PubMed1995

Chondrocyte apoptosis induced by nitric oxide.

Chondrocytes stimulated with IL-1 produce high levels of nitric oxide (NO), which inhibits proliferation induced by transforming growth factor-beta or serum. This study analyzes the role of NO and IL-1 in the induction of chondrocyte cell death. NO generated from sodium nitroprusside induced apoptosis in cultured chondrocytes as demonstrated by electron microscopy, 4',6-dianidino-2-phenylindole dihydrochloride staining, FACS analysis, and histochemical detection of DNA fragmentation. Similar results were obtained with two other NO donors, 3-morpholinosynonimide-hydrochloride and s-nitroso-N-acetyl-D-L-penicillamine. In contrast, oxygen radicals generated by hypoxanthine/xanthine oxidase caused necrosis but did not induce chondrocyte apoptosis. To analyze whether endogenously generated NO induces apoptosis, chondrocytes were stimulated with IL-1, but there was no evidence for apoptotic changes. Combinations of NO inducers such as IL-1, lipopolysaccharide, tumor necrosis factor, and interferon-gamma also failed to trigger apoptosis. IL-1-stimulated chondrocytes are known to produce oxygen radicals that react with NO to form products that can induce cell death in other systems. We thus tested IL-1 in combination with the oxygen radical scavengers N-acetyl cysteine, dimethyl sulfoxide, or 5,5'-dimetylpyrroline 1-oxide. Under these conditions IL-1 was able to induce apoptosis, which was inhibited in a dose-dependent manner by the NO synthase inhibitor N-monomethyl L-arginine. Conversely, endogenous oxygen radicals induced by inflammatory mediators caused necrosis under conditions in which the simultaneous production of NO was reduced. These results suggest that NO, but not oxygen radicals, is the primary inducer of apoptosis in human articular chondrocytes.

Adult↗
PubMed1994

Inducible nitric oxide synthase from human articular chondrocytes: cDNA cloning and analysis of mRNA expression.

Human articular chondrocytes can be induced by IL-1 beta, TNF-alpha or LPS to release high levels of nitric oxide. Using degenerate PCR primers based on homologous regions from previously cloned NOS enzymes, a 1.9 kb cDNA fragment was amplified from IL-1 beta stimulated but not from resting chondrocytes. Screening of a lambda gt11 cDNA library, which was prepared from RNA of IL-1 beta activated chondrocytes, resulted in the isolation of the complete cDNA, encoding a protein of 1153 amino acids. Comparison of the cDNA sequence identified human chondrocyte iNOS to be almost identical to the sequence recently reported for the hepatocyte enzyme, differing in 12 amino acids. Northern blot analysis revealed, that stimulated chondrocytes express a single 4.5 kb iNOS mRNA species. IL-1 beta induction of iNOS mRNA was detectable by 6 h and continued to be elevated throughout a 72 h culture period. Screening of a human bone cDNA library identified this inducible NOS to be also expressed by bone cells.

Amino Acid Oxidoreductases↗
PubMed1994

Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway.

Activation of monocytes by bacterial lipopolysaccharides (LPSs) is a central component in the pathogenesis of septic shock syndrome. Interleukin 10 (IL-10) is a potent monocyte-deactivating factor and transcriptionally inhibits LPS-induced expression of proinflammatory mediators. The intracellular signaling pathways of LPS have been only partially characterized and mechanisms of IL-10 signaling remain unknown. We show that LPS activates the protein tyrosine kinase (PTK) p56lyn and that this is associated with tyrosine phosphorylation of the protooncogene product Vav. These events are completely blocked by the tyrosine kinase inhibitor herbimycin A. LPS also increases Ras activation in monocytes. LPS-triggered phosphorylation of mitogen-activated protein kinase is a downstream activation event that is also reduced by herbimycin A. Analysis of the IL-10 effects shows that it completely inhibits the p56lyn tyrosine kinase activation and all other subsequent events in this pathway including Ras activation. The IL-10 effects are selective since it reduced PTK-dependent cytokine mRNA expression but not the PTK independent induction of c-jun and c-fos mRNA in LPS-activated monocytes. These results identify the Ras signaling pathway as a component of intracellular signaling in LPS-stimulated monocytes and define early events in this response as targets of monocyte deactivation by IL-10.

Base Sequence↗
PubMed1994

Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells.

Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refractory to mitogens and growth factors in vitro. This study examined whether transforming growth factor beta (TGF-beta), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-beta 1 mRNA. In vitro release of TGF-beta by unstimulated cultures, or cultures stimulated by antibody to cell surface immunoglobulin (anti-mu) plus phorbol 12-myristate 13-acetate (PMA) was higher in CLL than in normal B cells. High levels of TGF-beta activity were also detected in plasma samples of CLL patients. The role of TGF-beta in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients proliferated in response to anti-mu, or the combination of anti-mu plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when presented on Fc gamma RII (CDw32)-expressing L cells. Neutralizing antibodies to TGF-beta increased CLL B cell proliferation in the absence or presence of additional stimuli. These effects were dose dependent and specific. Exogenous TGF-beta completely inhibited CLL B cell proliferation induced by anti-mu, PMA, and anti-TGF-beta. CLL B cell proliferation induced by anti-CD40 was reduced by exogenous TGF-beta. However, even at high doses, TGF-beta did not completely inhibit the anti-CD40 effect. In summary, TGF-beta is overexpressed in CLL. CLL B cells are sensitive to TGF-beta and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative responses of these leukemic cells and for the slow progression of the malignant process in vivo.

Aged↗