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Biomedical subjects

R Gruber

Publications and source records attributed to R Gruber.

At least 55 records · Page 3Linked to original sources
PubMed1999

Regulatory effects of 1alpha,25-dihydroxyvitamin D3 on the cytokine production of human peripheral blood lymphocytes.

We studied the possible regulatory effects of 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3] on cytokine production and differentiation of subsets of CD4+ [T helper 1 (Th1) and Th2] and CD8+ [T cytotoxic 1 (Tc1) and Tc2] lymphocytes at the single cell level. PBMC from healthy donors were cultured with or without 1alpha,25-(OH)2D3 for up to 21 days. On days 0, 7, 14, and 21, the percentage of cytokine-producing T lymphocytes was analyzed by intracellular cytokine detection with mAb and flow cytometry. Simultaneous staining for cell surface markers allowed discrimination of CD4+ and CD8+ T cell subsets. After culture with 1alpha,25-(OH)2D3 (10(-8) mol/L), no significant effects on the proportion of interferon-gamma (IFNgamma)- or interleukin-4 (IL-4)-producing cells were detected, whereas reduced frequencies of IL-2-producing cells in the CD4+ as well as in the CD8+ population were found. An increase in the low percentage of CD4+ and CD8+ T cells producing the Th2 cytokine IL-13 was noticed. Most interestingly, IL-6-producing CD4+ and CD8+ T cells could only be detected in cultures with 1alpha,25-(OH)2D3, reaching a plateau after 14 days. The percentage of IL-6-producing T cells induced by 1alpha,25-(OH)2D3 after a given time period remained stable for at least 7 weeks. Studies of cytokine coexpression revealed that about 70% of IL-6-producing CD4+ and CD8+ cells were also positive for IL-2, but more than 90% were negative for IFNgamma, IL-4, or IL-13, respectively. This suggests that the IL-6-producing population does not match the Th1/Tc1-like (IFNgamma+) or Th2/Tc2-like (IL-4+ or IL-13+) subset. The influence of 1alpha,25-(OH)2D3 on cytokine production by lymphocytes is probably an important point of intersection between the endocrine and the immune system.

Adult↗
PubMed1999

Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia.

OBJECTIVE: The authors estimated the expression of adhesion molecule receptors (VLA-4 and LFA-1) on T helper (CD4+) and T suppressor/cytotoxic (CD8+) lymphocytes in schizophrenic patients before and during antipsychotic treatment and studied the relationship of these subpopulations to CSF measures and blood-brain barrier permeability. METHOD: Blood was drawn from hospitalized patients with schizophrenia before (N = 45) and after (N = 22) neuroleptic treatment and from an age-matched comparison group (N = 41). Lumbar punctures were performed on 32 of the schizophrenic patients. RESULTS: During antipsychotic treatment there were significant increases in the percentage of VLA-4+/CD4+ and VLA-4+/CD8+ cells. VLA-4+/CD4+ and LFA-1+/CD4+ cells were both closely related to disturbance of the blood-brain barrier. Higher values for VLA-4+/CD4+ and LFA-1+/CD4+ cells were found in patients with a disturbed blood-brain barrier. CONCLUSIONS: The findings suggest that adhesion molecules are involved in immunoregulation between the central nervous system and the peripheral immune system in schizophrenia.

Adult↗
PubMed1998

Delayed appearance of bilateral morgagni herniae in a child with Down's syndrome.

This case report describes the delayed presentation of bilateral Morgagni herniae in a 4 1/2-year-old boy with Down's syndrome. The authors emphasize the difficulties in establishing the diagnosis, although ultrasonography appears to be valuable. A review of the literature suggests an association between Morgagni hernias and trisomy 21.

Child, Preschool↗
PubMed1998

Autoantibodies against 60-kDa heat shock protein in schizophrenia.

Immunological abnormalities in schizophrenic patients have been reported for many years. However, the question of whether these parameters are involved in the pathophysiology of the disorder or represent treatment effects is still not answered. We investigated a combination of humoral and soluble immune parameters in 30 unmedicated schizophrenic patients before and during antipsychotic treatment and in 31 healthy controls. The aim of our study was to unravel an underlying immune process, to elucidate the influence of neuroleptic treatment and to identify a subgroup of schizophrenics. Antibodies against human 60-kDa heat-shock protein (HSP60), serum levels of soluble ICAM-1 and IL-2R were determined and correlated with parameters of blood-brain barrier and of psychopathology. In 10% of the drug-free but in 20% of the medicated schizophrenics, especially in females, we observed immunoreactivity against HSP60, high levels of IgG in CSF and a blood-brain barrier impairment. The high HSP antibody titres correlated with high levels of sIL-2R and sICAM-1. Only one of the controls showed antibodies against HSP60. Our results suggest that the observed immunological alterations are more pronounced during neuroleptic treatment than in the drug-free state. Whether or not this differential response to treatment with altered antibody production represents a subgroup of patients has yet to be determined.

Adolescent↗
PubMed1998

Lack of protection from HIV infection by the mutant HIV coreceptor CCR5 in intravenously HIV infected hemophilia patients.

The CCR5 chemokine receptor is an important coreceptor for macrophage-tropic HIV strains. Homozygous carriers of the mutated CCR5 receptor with a 32 bp deletion (delta 32-CCR5) are highly protected against HIV infection. A protective effect has also been described for heterozygous individuals carrying both mutated and wildtype CCR5 receptors. We compared the frequency of the mutated delta 32-CCR5 HIV coreceptor in HIV positive patients infected by sexual contact (N = 160) with intravenously HIV infected hemophilic patients (N = 84) and HIV negative individuals (N = 421). We found no protective effect of delta 32-CCR5 HIV coreceptor in hemophilic patients (p = 0.0134). If proteins of plasma concentrates would be responsible for facilitating the entry of HIV macrophages by upregulation of the CCR5 wildtype receptor it would be of therapeutical interest to identify the responsible plasma proteins.

Female↗
PubMed1998

Interaction of triiodothyronine with 1alpha,25-dihydroxyvitamin D3 on interleukin-6-dependent osteoclast-like cell formation in mouse bone marrow cell cultures.

In mouse bone marrow cultures, the formation of osteoclast-like, that is, tartrate-resistant acid phosphatase-positive (TRAP+) and calcitonin (CT) receptor-positive multinucleated cells (MNCs), induced by 10(-10) to 10(-8) mol/L 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], could be augmented by triiodothyronine (T3), which alone had no effect on osteoclast-like cell formation. The permissive effect of T3 increased the response to 1alpha,25(OH)2D3 by approximately one order of magnitude. Linear concentration dependence was observed between 10(-11) and 10(-8) mol/L T3. Importantly, inhibition of prostaglandin synthesis by indomethacin significantly impeded osteoclast-like cell formation by 1alpha,25(OH)2D3 and abrogated the effect of T3 thereon. Basal interleukin-6 (IL-6) production by cultured marrow cells was significantly stimulated by 1alpha,25(OH)2D3. However, even at an exceedingly high concentration of 20 ng/mL, IL-6 was ineffective in inducing osteoclast-like cell formation. Therefore, any hormonally induced rise in IL-6 release from bone marrow cells could not account for the observed changes in TRAP+ MNC numbers. Nevertheless, the stimulatory effect of 1alpha,25(OH)2D3 on osteoclastogenesis was partially dependent on IL-6 because it could be significantly blocked by a neutralizing monoclonal anti-IL-6 antibody, and to the same extent by a monoclonal anti-IL-6 receptor antibody. Unimpaired signaling through the IL-6/IL-6R system is also a prerequisite for the auxiliary effect of T3 on induction of osteoclast-like cells by 1alpha,25(OH)2D3. Our data provide evidence that 1alpha,25(OH)2D3 induces osteoclast-like cell formation, at least in part, in an IL-6-dependent mode of action, which is also subject to modulation by T3. The mechanism of interaction of the two hormones apparently involves joint stimulation of prostaglandin synthesis.

Acid Phosphatase↗
PubMed1998

Closed septal osteotomy.

A technique is described that permits realignment of the bony septum (perpendicular plate of the ethmoid, vomer, and vomerine ridge). It involves a closed fracture of the bones by means of a large, long nasal speculum. Mere spreading of the septum fractures the bony septum, permitting reasonable, midline realignment in most patients. Spreading with the speculum also infractures the turbinates in many instances and thereby helps open up the airway even further. Of the 32 patients reviewed, it was found that the perpendicular plate and vomer could be fractured in 100% of patients. The vomerine ridge (premaxilla area), on the other hand, could only be fractured in 69%. Of the patients in whom fracture was possible, the bony septum was straightened dramatically in 82% of patients and improved greatly in 18% of patients.

Humans↗
PubMed1998

Monoclonal antibody therapy for resected Dukes' C colorectal cancer: seven-year outcome of a multicenter randomized trial.

PURPOSE: As previously shown, antibody treatment increased survival of patients with resected colorectal cancer of stage Dukes' C. Since the 5-year analysis was criticized because of the wide range (2.7 to 7.5 years) of follow-up time, we performed a 7-year analysis with only four of 189 patients monitored for less than 5 years. PATIENTS AND METHODS: A total of 189 patients with resected Dukes' C colorectal cancer were randomly allocated to infusions of a total of 900 mg 17-1A antibody, 500 mg postoperatively followed by 4 monthly doses of 100 mg (n=99), or to observation only (n=90). Primary end points were overall survival and disease-free interval. Patients were stratified by a dynamic randomization according to center, sex, location of tumor, number of affected lymph nodes, and preoperative carcinoembryonic antigen concentration. RESULTS: Randomization produced balanced distribution of risk factors. After 7 years of follow-up evaluation, treatment had reduced overall mortality by 32% (Cox's proportional hazard, P < .01; log-rank, P=.01) and decreased the recurrence rate by 23% (Cox's proportional hazard, P < .04; log-rank, P=.07). The intention-to-treat analysis gave a significant effect for overall survival (Cox's proportional hazard, P < .01; log-rank, P=.02) and disease-free survival (Cox's proportional hazard, P=.02; log-rank, P=.11 ). While distant metastases were significantly reduced (Cox's proportional hazard, P=.004; log-rank, P=.004), local relapses were not (Cox's proportional hazard, P=.65; log-rank, P=.52). This differential effect of 17-1A antibody on disseminated isolated tumor cells versus occult local satellites may explain the increased significance seen in the overall survival. CONCLUSION: The now-matured study shows that 17-1A antibody administered after surgery prevents the development of distant metastasis in approximately one third of patients. The therapeutic effect is maintained after 7 years of follow-up evaluation.

Adenocarcinoma↗
PubMed1998

[Comparison of pharmacokinetic and pharmacodynamic data of interferon-beta 1a preparations after intramuscular and subcutaneous administration].

Today interferon-beta (IFN-beta) generally is accepted as a therapeutic approach in multiple sclerosis (MS). All human IFN-beta preparations contain interferon in a monomeric, biologically active and inactive polymeric form. Therefore, both the specification of the mass of IFN-beta (microgram) and the biological activity (IU) are used for the characterisation of any particular drug. Nevertheless, not all publications present data on both measurements, apparently resulting in inconsistent statements in some cases. To directly compare pharmacological data from studies distinguishing in methodology or time; only the specification of mass is valid. In Europe, basic pharmacokinetic and pharmacodynamic studies are available from three different IFN-beta 1a preparations. The standard drug, with the brandname Rebif, is clinically tested and approved for treatment in MS. This overview compares results from the three preparations: Rebif, second the so called reference drug, which is the very first IFN-beta 1a clinically tested in MS but unfortunately not approved up to now, and another preparation, which is approved by means of bioequivalence studies only, and therefore called comparison drug here. According to the data available now, it can be stated that the IFN-beta 1a drugs probably show identical results in bioavailability, when given subcutaneously (s.c.) or intramuscularly (i.m.). The data further indicate that all drugs reach the same level of activity in vivo, and will cause identical efficacy, if the same masses are given either s.c. or i.m.

Biological Availability↗
PubMed1997

Depletion of CD8+ T lymphocytes by murine monoclonal CD8 antibodies and restored specific T cell proliferation in vivo in a patient with chronic hepatitis C.

Cellular immune mechanisms, especially those mediated by CD8+ T cells, are important in the pathogenesis and control of viral infections. On the other hand, as shown for chronic lymphocytic choriomeningitis virus infection in the mouse, CD8+ T cells may not only hinder the elimination of a virus, but make the host unresponsive to a second viral infection. In hepatitis C virus (HCV) infections, at least 50% of the patients become chronically infected, despite the detection of HCV-specific CTL and a specific proliferative response to HCV Ags in PBL and in lymphocytes isolated from the liver. To better understand the immunopathologic mechanisms of CD8+ cells in vivo and to search for a potential treatment, we applied murine CD8 mAbs to a patient with therapy-resistant chronic HCV. A drastic reduction of CD8+ circulating lymphocytes, a reduction of CD8 molecule density, and complement fixation on CD8+ cells were observed. The reduction of CD8+ cells was compensated partially by an elevation of CD4+ cells. High concentrations of neutralizing human anti-mouse Abs were induced. After the Ab infusions, the CD4/CD8 ratio in peripheral blood increased from 1.6 to values of about 3 during therapy, and gradually decreased to 2.3 1 yr after the last mAb infusion. A continuing decrease of serum aminotransferases and clinical improvement was observed. Interestingly, after initiation of treatment, a significant proliferative response to HCV-specific Ags became measurable.

Adult↗
PubMed1997

Biologic properties of a bispecific single-chain antibody directed against 17-1A (EpCAM) and CD3: tumor cell-dependent T cell stimulation and cytotoxic activity.

Anti-CD3 x anti-tumor-bispecific Abs have been used to redirect cytotoxic T cells to tumor cells in an MHC-unrestricted fashion and to induce their rejection in vivo. We have recently described a recombinant bispecific single-chain Ab that combines four different V regions of two Abs, anti-17-1A and anti-CD3, on one polypeptide chain. It folds correctly to a 60-kDa globular protein and is secreted in fully functional form by a high producer Chinese hamster ovary cell line. In this work, we report that its remarkable cytotoxicity against 17-1A+ tumor cells is exerted via T cells without an apparent engagement of a detectable costimulatory pathway. T cells are activated only by the bispecific Ab when coincubated with 17-1A+ target cells. In a chromium release assay, CD8+ T cells reach maximal tumor cell cytotoxicity within 4 h, while CD4+ T cells need about 20 h to reach similar levels of cytotoxicity. Addition of costimulatory CD28 Abs did not lead to a further increase in cytotoxicity. Its remarkable stability at 37 degrees in serum, the ease of production, and purification by affinity chromatography via polyhistidine tail make this smaller version of a bispecific Ab a promising candidate for a therapeutic trial in patients with solid tumor. Because adjuvant therapy with an intact, much less cytotoxic IgG2a Ab against the 17-1A target had already increased the 7-yr survival of colorectal cancer patients by 30%, the presented small bispecific construct lacking the immunogenic murine Fc region as well as autochthonous T lymphocyte stimulatory activity warrants a therapeutic trial in patients with minimal residual 17-1A+ cancer.

Animals↗
PubMed1997

Occult epithelial tumor cells detected in bone marrow by an enzyme immunoassay specific for cytokeratin 19.

The presence of isolated carcinoma cells detected immunocytochemically in bone marrow has been shown to be of prognostic relevance for cancer patients. Unfortunately, the immunocytochemical method (ICC) is laborious and depends on the subjective interpretation of the individual investigator. Therefore, an immunoassay was designed for detection of cytokeratin 19 (CK19). By analyzing blood samples from 52 healthy volunteers and 40 bone-marrow aspirates from control patients, a cut-off point of 250 pg/ml CK19 was determined. Application of this cut-off point enabled a specificity of 95% to be shown for bone marrow and of nearly 100% for venous blood. The assay detected 10 HT-29 colon-carcinoma cells among 5 x 10(6) peripheral-blood leukocytes. In comparison with controls, bone-marrow samples of cancer patients were found to have significantly elevated levels of CK19 (p < 0.05). In the analysis of 386 marrow aspirates of cancer patients, a significant concordance of ELISA and ICC was observed (chi 2 = 18.3; p < 0.001). Both procedures, nevertheless, differed in 147 (38%) samples, of which more than two thirds (101) were only ELISA-positive. The CK status detected by ELISA did not correlate with the TNM stage and the histological grading. The established immunoassay allowed sensitive and specific detection of disseminated epithelial tumor cells and appeared to be faster, less laborious and more objective than ICC. Follow-up studies are required to assess the prognostic relevance of this ELISA before it can be applied as a routine method for monitoring of minimal residual epithelial cancer.

Biomarkers, Tumor↗
PubMed1997

[Lumbar fusion in adults--dorsal or combined ventral/dorsal approach?].

A retrospective study was conducted to compare the results of posterior with combined anterior/posterior lumbar fusion in adults. Seventy-six consecutive posterior cases fused with pedicle screws and 46 combined cases were included and followed for at least 2 years. Subjective assessment was based on the Visual Analogue Scales, Waddel Disability and Impairment Score and the GBB for objective quantification of complaints. Furthermore, a thorough clinical examination was done and X-rays including flexion/ extension radiographs, were taken. Questions were asked about the occupational status as well. Pain decreased significantly more in the combined cases than in the posterior fusion cases. In one case a lesion of the common iliac vein occurred during a retroperitoneal approach. Only about half the patients working preoperatively returned to work again. In conclusion, the benefit of better pain relief after combined fusion must be regarded in relation to a higher complication rate due to a second approach.

Adult↗
PubMed1997

17Beta-estradiol antagonizes effects of 1alpha,25-dihydroxyvitamin D3 on interleukin-6 production and osteoclast-like cell formation in mouse bone marrow primary cultures.

In mouse bone marrow primary cultures, the formation of osteoclast-like, i.e. tartrate-resistant acid phosphatase (TRAP)- and calcitonin receptor-positive multinucleated cells (MNC), when induced by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), can be suppressed by 17beta-estradiol (17beta-E2), whereas 17alpha-E2 is without any effect. 17beta-E2, above 10(-11) M, significantly reduced 1alpha,25(OH)2D3-mediated TRAP+ MNC formation in cultured bone marrow cells from both female and male mice. The estrogen at 10(-8) M suppressed the peak response to the vitamin D sterol by 50%. 17beta-E2 significantly suppressed basal and 1alpha,25(OH)2D3-stimulated cellular production of interleukin (IL)-6. IL-6 alone, although bone marrow cells in hormone-free culture produced appreciable amounts of the cytokine, did not induce any TRAP+ MNC. Therefore, the changes in IL-6 production induced by the hormones could not be the sole determinant for the extent of TRAP+ MNC formation. However, the stimulatory effect of 1alpha,25(OH)2D3 on osteoclastogenesis nevertheless can be significantly reduced by a neutralizing monoclonal anti-IL-6 antibody. In the presence of 10(-8) M 17beta-E2, the anti-IL-6 monoclonal antibody does not achieve any further suppression of 1alpha,25(OH)2D3-related osteoclast-like cell formation. Our data suggest that induction of osteoclastogenesis by 1alpha,25(OH)2D3 is partially dependent on IL-6 signaling and can be modulated by 17beta-E2 through interference with IL-6 receptor activation, in addition to inhibition of IL-6 production by marrow stromal cells.

Acid Phosphatase↗