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Biomedical subjects

R Gruber

Publications and source records attributed to R Gruber.

At least 19 recordsLinked to original sources
PubMed2003

Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro.

OBJECTIVE: To elucidate the role of bone morphogenetic protein 6 (BMP-6) in human articular cartilage, we investigated whether BMP-6 is expressed in adult human articular chondrocytes and analyzed the potential stimulatory effects of BMP-6 on these cells. In addition, we investigated whether osteoarthritic (OA) and normal cartilage chondrocytes behave differently. METHODS: Endogenous expression of the BMP-6 gene was examined by reverse transcription-polymerase chain reaction. BMP-6 protein was detected by Western immunoblotting. Chondrocytes were grown as monolayer cultures for 7 days in a chemically defined serum-free medium, in the absence or presence of recombinant BMP-6. Proteoglycan (PG) synthesis was measured by (35)S-sulfate incorporation into newly synthesized macromolecules. Cell proliferation was assessed by (3)H-thymidine incorporation. RESULTS: BMP-6 was expressed in both healthy and OA chondrocytes at the messenger RNA and protein levels. Total PG synthesis was significantly increased after BMP-6 stimulation of healthy (mean +/- SEM 191 +/- 11%; P < 0.001) and OA (150 +/- 25%; P < 0.03) chondrocyte cultures. A direct comparison between healthy and OA samples revealed no significant difference. The proliferation rates of normal and OA chondrocytes were not affected by BMP-6 treatment. CONCLUSION: BMP-6 is endogenously expressed in chondrocytes obtained from OA and normal adult human articular cartilage. Furthermore, BMP-6 has the potential to stimulate total PG synthesis in human articular chondrocytes derived from normal as well as OA joints. We conclude that the presence of BMP-6 in adult human articular cartilage indicates a functional role for this growth factor in the maintenance of joint integrity.

Adult↗
PubMed2002

Velocity scaling of ion neutralization in low energy ion scattering.

The ion fraction P+ is measured for He+ ions scattered by 129 degrees from a Cu surface. Both the primary energy and the angles of incidence and of exit are varied. From our results we conclude the following: along the incoming and outgoing trajectories, neutralization is due to Auger processes and depends on the normal velocity component v( perpendicular ) only. At higher energies, additional charge exchange is due to collision induced neutralization and reionization, both depending on the total ion energy only. Also in this regime P+ depends on v( perpendicular ), but via a two-valued function of the scattering geometry at fixed energy.

Journal Article↗
PubMed2002

Cartilage-derived morphogenetic protein-1 and -2 are endogenously expressed in healthy and osteoarthritic human articular chondrocytes and stimulate matrix synthesis.

OBJECTIVE: We investigated whether chondrocytes derived from osteoarthritic cartilage may lose their responsiveness to cartilage-derived morphogenetic protein-1, -2 (CDMP-1, -2) and osteogenic protein-1 (OP-1) compared with healthy cells, thus leading to an impaired maintenance of matrix integrity. DESIGN: Chondrocytes were isolated from articular cartilage from patients with and without osteoarthritic lesions. Cells were grown as monolayer cultures for 7 days in a chemically defined serum-free basal medium (BM) in the presence of recombinant CDMP-1, -2, and OP-1. Glycosaminoglycan synthesis was measured by [35S]Sulfate incorporation into newly synthesized macromolecules. Cell proliferation was investigated by [3H]Thymidine incorporation. The endogenous gene expression of CDMPs/OP-1 and their respective type I and type II receptors was examined using RT-PCR. The presence of CDMP proteins in tissue and cultured cells was detected by Western immunoblots. RESULTS: mRNAs coding for CDMPs and their respective receptors are endogenously expressed not only in healthy, but also in osteoarthritic cartilage. CDMP proteins are present in both normal and osteoarthritic articular cartilage and cultured chondrocytes. CDMP-1, CDMP-2 and OP-1 markedly increased glycosaminoglycan synthesis in both healthy (P< 0.01) and osteoarthritic (P< 0.05) human articular chondrocytes. A comparison of the glycosaminoglycan biosynthetic activity between healthy and osteoarthritic samples revealed no detectable difference, neither in stimulated nor in unstimulated cultures. [(3)H]Thymidine incorporation showed that CDMPs/OP-1 did not affect cell proliferation in vitro. CONCLUSION: CDMPs and OP-1 exert their anabolic effects on both healthy and osteoarthritic chondrocytes indicating no loss in responsiveness to these growth factors in OA. The endogenous expression of CDMPs/OP-1 and their receptors suggest an important role in cartilage homeostasis.

Adult↗
PubMed2001

Bispecific single-chain antibodies as effective tools for eliminating epithelial cancer cells from human stem cell preparations by redirected cell cytotoxicity.

High-dose chemotherapy (HDC) with autologous bone marrow or peripheral stem cell transplantation is discussed as one option to treat the extensive stage of a variety of tumors. Effective methods to eliminate contaminating tumor cells from human bone marrow or stem cell grafts may improve the outcome of the patients. We investigated 3 recombinant bispecific single-chain antibodies (bscAbs) directed against 17-1A (EpCAM), c-erbB-2 (HER-2/neu) and LeY on the one and CD3 on the other binding site for their ability to induce lysis of epithelial tumor cells by retargeting autochthonous T lymphocytes present in bone marrow mononuclear cells (BMMC) and in peripheral stem cell mononuclear cells (PSMC). The bscAbs showed remarkable specific lysis of different epithelial tumor cell lines with BMMCs as well as with PSMCs as effector cells. Investigation of the alpha 17-1A-alpha CD3 bscAb revealed a significant correlation between the percentage of CD3(+) cells present in the BMMCs and the rate of lysis as well as the absence of detrimental effects on the viability of hematopoietic progenitor cells as determined by colony-forming unit assays (CFUs). Our results indicate that recombinant bispecific single-chain antibodies could be new tools for purging of human bone marrow and peripheral stem cell grafts from contaminating epithelial cancer cells for patients receiving autologous stem cell transplantation after HDC.

Antibodies, Bispecific↗
PubMed2001

Anti-self antibodies selected from a human IgD heavy chain repertoire: a novel approach to generate therapeutic human antibodies against tumor-associated differentiation antigens.

Human antibodies were isolated by phage display from a naturally expressed human antibody repertoire. Antibody selection was carried out against the epithelial cell adhesion molecule (EpCAM) or 17-1A antigen, that in a clinical trial had been successfully used as a target for antibody therapy of minimal residual colorectal cancer. VH chains were selected from the human IgD repertoire expressed on naive B2 and autoreactive B1 lymphocytes. By guiding the selection through a murine template antibody, two EpCAM-specific human antibodies, HD69 and HD70, were obtained that closely resembled the murine therapeutic 17-1A antibody in their binding properties when expressed as complete huIgG1 molecules in CHO cells. However, both human antibodies recruited human cytotoxic effector cells far more efficiently than the murine 17-1A antibody used for clinical trials. Therefore, and in view of the long in vivo half-life of human IgG1 antibodies, HD69 and HD70 are regarded as highly promising third generation versions of the murine therapeutic antibody. Because of their origin from an evolutionary conserved germline VH repertoire, they are expected to exhibit minimal immunogenicity in patients.

Amino Acid Sequence↗
PubMed2001

Lowering HIV risk among ethnic minority drug users: comparing culturally targeted intervention to a standard intervention.

To test the efficacy of culturally targeted acquired immunodeficiency syndrome (AIDS) prevention programs on ethnic minority street drug users, 669 African-American and Puerto Rican drug users were assigned to receive either the National Institute on Drug Abuse (NIDA) standard intervention or a culturally competent enhanced intervention in a quasi-experimental study. The standard intervention was a two-session educational program, while both the African-American and Puerto Rican enhanced interventions provided additional AIDS information in a culturally appropriate fashion. Although human immunodeficiency virus (HIV) risk behaviors, as measured by Bell's risk indices, decreased, there were no meaningful significant differences between interventions. However, participants who went into drug treatment programs showed greater reduction in HIV risk behavior. Cultural interventions may provide better outcome if they concentrate on getting participants into drug treatment.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Effects of cartilage-derived morphogenetic proteins and osteogenic protein-1 on osteochondrogenic differentiation of periosteum-derived cells.

Localization studies and genetic evidence have implicated cartilage-derived morphogenetic proteins-1, -2 (CDMP-1 and CDMP-2), and osteogenic protein-1 (OP-1) in the osteochondrogenic differentiation of mesenchymal progenitor cells during embryonic development and in postnatal life. Based on their expression pattern and the evidence that periosteum contains mesenchymal cells in the cambium layer that can undergo bone and cartilage formation, we hypothesized that CDMPs and OP-1 may be involved in long bone development and fracture healing. To test this hypothesis, periosteum-derived cells from young calves were cultured as monolayers under serum-free conditions with and without the addition of recombinant CDMP-1, CDMP-2 and OP-1. Phenotypic analysis indicate that periosteum-derived cell populations prepared, expanded, and cultured under the conditions described below, constitutively express messenger RNAs for the bone markers osteocalcin, osteopontin and collagen type I, and the chondrogenic markers collagen type II and aggrecan as determined by RT-PCR. Moreover, histologic examinations showed positive staining for alcian blue and alkaline phosphatase (AP). Treatment of periosteum-derived cells with CDMPs and OP-1 resulted in a dose-dependent increase of cell proliferation; CDMP-2 was less active in this regard. Furthermore, all growth factors enhanced osteogenic differentiation as assessed by a time- and dose-dependent stimulation of AP activity and OP-1 increased messenger RNA expression for osteocalcin and collagen type I. We further examined the effects of CDMPs and OP-1 on chondrogenic differentiation of periosteum-derived cells. Both CDMPs and OP-1 stimulated (35)S-sulfate incorporation into newly synthesized macromolecules with OP-1 having a more pronounced stimulatory effect when compared with CDMP-1 and CDMP-2. Our results indicate that distinct members of the BMP-family increase the mitotic and metabolic activity of periosteum-derived cells. The enhancement of both the chondrogenic and osteogenic differentiation suggests that these growth factors might contribute to the local regulation of bone formation and fracture repair.

Animals↗
PubMed2001

Children's gender-related inferences and judgments: a cross-cultural study.

This study compared the gender-related inferences and judgments of elementary school children (N = 542) of 2 different age groups (3rd graders and 5th graders) from 2 different cultures: Taiwan, a traditional collectivistic culture, and Israel, an individualistic and less traditional culture. The children were presented with 4 stories, 2 about a male target and 2 about a female target with either traditionally masculine or traditionally feminine interests, and were asked to make cognitive and emotional-motivational inferences and judgments about them. Culture played an important role in children's gender-related inferences and judgments. Specifically, Taiwanese children distinguished more than did Israeli children between male targets behaving stereotypically and counterstereotypically. The findings are analyzed within the framework of the differences between the 2 cultures.

Child↗
PubMed2000

Differential stimulation by PGE(2) and calcemic hormones of IL-6 in stromal/osteoblastic cells.

Formation of osteoclast-like cells in mouse bone marrow cultures induced by either 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), parathyroid hormone (PTH) or prostaglandin E(2) (PGE(2)), respectively, shows partial dependence on interleukin-6 receptor (IL-6R) activation. This suggests that locally produced IL-6 could be relevant for osteoclast formation. Therefore, we evaluated the effects of 1,25-(OH)(2)D(3), PTH, and PGE(2) on IL-6 production in stromal/osteoblastic cell lines. It appeared that these bone resorptive factors differed widely in their ability to modulate IL-6 mRNA expression and, consequently, protein synthesis in each of the cell lines studied. While 1,25-(OH)(2)D(3) was marginally effective only in ST2 cells, and PTH caused a 2- to 20-fold increase in IL-6 levels MC3T3-E1 and UMR-106 cells, PGE(2) enhanced IL-6 production in the ST2 and MC3T3-E1 cell line by two to three orders of magnitude, respectively, and also induced IL-6 in fibroblastic L929 cells. PGE(2)-stimulated IL-6 release from mesenchymal cells seems to be important for autocrine/paracrine control of osteoclast formation in health and disease.

3T3 Cells↗
PubMed2000

Expansion of CD60 helper lymphocytes detected in peripheral lymphocytes of HIV-1 infected individuals is not paralleled in lymph nodes.

BACKGROUND AND OBJECTIVE: A significant expansion of CD8 cells with capability of Th2 type helper function had been observed in hemophiliacs with HIV infection. These cells were characterised by the surface co-expression of CD8 and CD60 antigen. Our objective was to investigate this lymphocyte subset in relation to other subsets in homosexuals and drug users in two compartments: blood and lymph nodes. Blood and lymph nodes from not HIV-infected persons served as control. RESULTS: CD8+CD60+ cells were expanded in perpheral blood of HIV - infected patients as compared to age matched controls (10.0 versus 4.1%, p <0.05). This difference was not observed in lymph node cell suspensions (6.2 vs. 4.3% of all lymph node cells; p = n.s.). The CD 4/CD8 ratio was significantly less impaired in lymph nodes than in blood (2.27 vs. 0.83; p <0.05). Cytotoxic T cells were more abundant in the lymph nodes of patients with early stage HIV disease when compared two late stage patients (4.3 vs 2.1%; p <0.05). Immunohistochemistry on frozen lymph node cuts showed presence of CD60 cells mainly in the interfollicular and paracortical area. In 3 of 10 HIV infected patients these cells were also found in the germinal centers. In controls no CD60 cells were detected in the follicles. Numbers and percentages of CD60 cellls and CD8+CD60+ cells in blood and in lymph nodes did not correlate with HIV - stage, CD4 count or plasma viral load. No correlation with lymph node viral load was seen. CONCLUSIONS: Our data confirm that like in hemophiliacs expansion of CD8+CD60+ is also found in the blood of other HIV risk groups and seems not to be specific for hemophiliacs. However, the higher percentage in peripheral blood is not paralleled in lymph nodes. Redistribution phenomena seem to be the most plausible explanation. According to these data, a major impact of CD8+CD60+ cells in the immunopathogenesis of HIV infection does not seem likely.

Antigens, CD↗
PubMed2000

The human antimouse immunoglobulin response and the anti-idiotypic network have no influence on clinical outcome in patients with minimal residual colorectal cancer treated with monoclonal antibody CO17-1A.

Murine monoclonal antibodies (mAbs), when administered to patients, induce a human antimouse immunoglobulin immune response, especially when multiple infusions are required to obtain therapeutic efficacy. In a randomized Phase II clinical study, 83 patients with colorectal carcinoma of stage Dukes C were treated with the murine IgG2a mAb 17-1A (ab1) after curative surgery. The regimen consisted of a single infusion of 500mg of 17-1A within 2 weeks after surgery, followed by 100mg of mAbs four times every 4 weeks. Sera were taken every 2-3 weeks and screened for human antimouse antibodies (HAMA). HAMA were measured by a capture ELISA and an indirect antihuman immunoglobulin ELISA for the analysis of IgG and IgM isotypes. Anti-idiotypic antibodies (ab2) were detected by an inhibition ELISA, and anti-anti-idiotypic antibodies (ab3), recognizing the original antigen, were determined by flow cytometric analysis. About 20% of patients failed to develop HAMA; in the other patients, antibody titers were initially low after the first two infusions and reached their maximum only after a fifth infusion at 18-20 weeks after surgery. An analysis that differentiated between patients who developed recurrences and those who remained tumor-free did not show any difference in antibody titers between the two groups, neither for total HAMA nor for IgG, IgM, or ab2. The formation of ab3 was analyzed in eight patients and proved to be negative in all of them. HAMA remained detectable up to 2 years after the last treatment. In patients who experienced adverse events associated with therapy, HAMA titers tended to rise earlier; this difference, however, was not statistically significant. Thus, neither a beneficial nor a detrimental effect of HAMA formation could be determined for the clinical response to antibody therapy.

Anaphylaxis↗
PubMed2000

Stimulatory effects of cartilage-derived morphogenetic proteins 1 and 2 on osteogenic differentiation of bone marrow stromal cells.

Cartilage-derived morphogenetic proteins 1 and 2 (CDMP-1 and CDMP-2) are members of the bone morphogenetic protein (BMP) family which play an important role in embryonic skeletal development. Throughout adult life, bone marrow-derived precursor cells maintain their ability to differentiate into osteoblasts in response to local growth factors. This study examines the osteogenic potential of CDMP-1, CDMP-2, BMP-6 and osteogenic protein 1 (OP-1) in bone marrow stromal cells (BMSC) and investigates the endogenous expression of CDMPs/BMPs and their respective activin receptor-like kinase (ALK) receptors. A 4-day exposure of BMSC to CDMP-1, CDMP-2, BMP-6, and OP-1 under serum-free conditions stimulated the progression of the osteogenic lineage in a dose-dependent manner as evaluated by alkaline phosphatase activity and osteocalcin synthesis. In contrast to the BMPs, CDMP-1 and especially CDMP-2 were significantly less osteogenic, as confirmed by Northern blot analysis. Moreover, BMSC were shown to express endogenously CDMP-2, BMP-2 to -6 and ALK-1, -2, -3, -5 and -6. Phenotypic characterization of BMSC by RT-PCR showed transcripts of the fat marker adipsin and the prechondrocytic marker procollagen type IIA; however, we were unable to detect the mature cartilage markers, procollagen type IIB and aggrecan, even after growth factor treatment. Our data indicate that CDMP-1, CDMP-2, BMP-6 and OP-1 enhance the osteogenic phenotype in BMSC, with CDMPs being clearly less osteogenic than BMPs. The endogenous expression of a variety of CDMPs/BMPs and their respective ALK receptors, suggests a possible involvement of these growth factors in the osteogenic differentiation of bone marrow progenitor cells.

Activin Receptors↗
PubMed2000

Combined transvaginal B-mode and color Doppler sonography for differential diagnosis of ovarian tumors: results of a multivariate logistic regression analysis.

OBJECTIVE: Transvaginal sonography is limited in its ability to assess early stage cancers of the ovary as well as in distinguishing benign processes. As a method for characterization of tumor vascularization, color-coded Doppler sonography may be able to improve the diagnostic accuracy of B-mode sonography. METHODS: Preoperative transvaginal B-mode and Doppler sonography was performed in 63 patients with unclear adnexal lesions prior to operation. Using multiple logistic regression, the independent variables of each procedure were selected and combined to yield a diagnostic flow chart. The diagnostic accuracy of this decision matrix was tested on 257 patients with unclear adnexal tumors. RESULTS: In the 63 adnexal tumors investigated, the diagnostic impact of isolated sonomorphological assessment with evidence of a "solid area" was 78%. Using Doppler sonography, the best discrimination was achieved by displaying the vascular distribution ("central vascularization"). Combining these independent significant variables of the two procedures raised the diagnostic accuracy to 90% (sensitivity 86%, specificity 93%). The validity achieved by this combination was confirmed by the independent application of this method to the 257 adnexal tumors with unclear malignancy status (diagnostic accuracy 93%, sensitivity 92%, specificity 94%). CONCLUSIONS: The combination of sonography and Doppler sonography achieves high and reproducible diagnostic accuracy in preoperative malignancy status assessment of adnexal tumors. The additional use of Doppler sonography can thus provide significant aid both for differential diagnostics of adnexal lesions and for the choice of surgical route in the case of an existing indication for operative therapy.

Adnexal Diseases↗
PubMed2000

Sleep patterns and sleep disruptions in school-age children.

This study assessed the sleep patterns, sleep disruptions, and sleepiness of school-age children. Sleep patterns of 140 children (72 boys and 68 girls; 2nd-, 4th-, and 6th-grade students) were evaluated with activity monitors (actigraphs). In addition, the children and their parents completed complementary sleep questionnaires and daily reports. The findings reflected significant age differences, indicating that older children have more delayed sleep onset times and increased reported daytime sleepiness. Girls were found to spend more time in sleep and to have an increased percentage of motionless sleep. Fragmented sleep was found in 18% of the children. No age differences were found in any of the sleep quality measures. Scores on objective sleep measures were associated with subjective reports of sleepiness. Family stress, parental age, and parental education were related to the child's sleep-wake measures.

Age Factors↗
PubMed2000

Instability of sleep patterns in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To compare the stability of the sleep-wake system of children with attention-deficit/hyperactivity disorder (ADHD) and controls by objective and subjective measures. METHOD: Thirty-eight school-age boys with diagnosed ADHD and 64 control school-age boys were examined using actigraphic monitoring and sleep diaries, over 5 consecutive nights. RESULTS: Increased instability in sleep onset, sleep duration, and true sleep were found in the ADHD group compared with the control group. Discriminant analysis revealed that children's classification (ADHD versus control) could be significantly predicted on the basis of their sleep measures. CONCLUSIONS: The findings support the hypothesis that instability of the sleep-wake system is a characteristic of children with ADHD. Given the potential negative effects of disturbed or unstable sleep on daytime functioning, it is recommended that a thorough sleep assessment be conducted when a sleep disturbance is suspected or when symptoms associated with daytime sleepiness or decreased arousal level are present.

Adolescent↗
PubMed2000

The immune system and schizophrenia. An integrative view.

Immune alterations in schizophrenia have been described for decades. Modern immunological methods and new insights into the highly developed and functionally differentiated immune system allow an integrative view of both the older and the recent findings of immunological abnormalities in schizophrenia. Both the unspecific and the specific arms of the immune system seem to be involved in the dysfunction of the immune system in schizophrenia. The unspecific, "innate" immune system shows signs of overactivation in unmedicated schizophrenic patients, as indicated by increased monocytes and gamma delta-cells. Increased levels of interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might be the result of the activation of monocytes/macrophages, too. On the other hand, several parameters of the specific cellular immune system are blunted, such as, for example, the decreased T helper-1 (TH-1)-related immune parameters in schizophrenic patients both in vitro and in vivo. It seems that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated with schizophrenia. During antipsychotic therapy with neuroleptics, the specific TH-1-related immune answer becomes activated, but in addition the B cell system and antibody production increase.

Humans↗