[4th Ministerial Conference about the Environment and Health from 23-25 June 2004 in Budapest. The future of our children].
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Child↗
Biomedical subjects
H Schreiber
Publications and source records attributed to H Schreiber.
Nutrient emissions from diffuse and point sources into the River Danube and its main tributaries for the period of 1998-2000--results and problems.
Nutrient emissions by point and diffuse sources were estimated for 388 sub-catchments of the Danube river basin for the period 1998-2000 by means of the Model MONERIS. For nitrogen total emissions of 684 kt/a N were estimated for the Danube basin. 80% of these emissions were caused by diffuse sources (mainly groundwater, urban areas and tile drainage). For phosphorus the emission was 57 kt/a P, with a contribution of diffuse sources to this sum of 58%. The comparison of calculated and observed loads shows that the mean deviation for the investigated sub-catchments of the Danube river basin is 20% for dissolved inorganic nitrogen and 34% for phosphorus. The spatial resolution of the emission calculations allows the identification of regional hot spots and the derivation of specific regional measures to reduce the emissions into the Danube and consequently into the Western Black Sea.
Conservation of Natural Resources↗
Lessons learned from investigations on case study level for modelling of nutrient emissions in the Danube basin.
In the framework of the project daNUbs (Nutrient Management in the Danube Basin and its Impact on the Black Sea) the MONERIS emission model is used for the basin wide calculation of nutrient (nitrogen and phosphorus) emissions in the Danube Basin. The MONERIS model was developed and successfully applied for German river catchments. Based on investigations in selected test regions (case studies) the daNUbs approach is to check the applicability of the MONERIS emission model for the specific conditions of the Danube Basin in more detail than is possible with a basin wide application. Six case studies with areas of 400-3,500 km2 and several subcatchments have been selected in order to represent different conditions along the Danube Basin. In this study region intensive data collection and enhanced monitoring has been performed in order to raise the database significantly above the generally available data. Water balance as well as nutrient balance calculations have been performed with the MONERIS model as well as with other approaches. Results are compared to each other and to data from monitoring. Results up till now showed the applicability and sensitivity of the MONERIS approach in different conditions of the Danube Basin (e.g. emissions via groundwater). They indicated that the nitrogen retention in the catchments is well described with the MONERIS model.
Environmental Monitoring↗
Long-term MRI and clinical follow-up of symptomatic and presymptomatic carriers of dysferlin gene mutations.
We report the results of a longitudinal study involving MRI and clinical follow-up in nine siblings from four families with Miyoshi myopathy (MM). All individuals carried pathogenic dysferlin gene (DYSF) mutations with six of them suffering from symptomatic disease and three being presymptomatic. In presymptomatic subjects, MRI was sensitive to detect alterations in muscle tissue years before disease onset. The first MRI alteration to disclose was evidence for myoedema in dorsal compartment muscles of the legs followed by fatty degeneration. Moreover, MRI changes anticipated the topography of subsequent clinical muscle involvement and progressed from distal to proximal dorsal leg muscles. In symptomatic subjects, MRI changes reflected the pattern and severity of clinical muscle involvement. MRI evidence, however, suggests that muscle involvement is much more prominent in early disease stages than clinically seen. Clinical follow-up up to 8 years made evident that MM onset occurs at a mean age of 18.4 years. The most prominent initial deficit was impaired tiptoe gait due to muscle plantarflexor dysfunction followed by impaired dorsiflexor function. Dorsal compartments were predominantly affected not only in distal but also in proximal leg muscles, and a more rapid progression was noticed during the early phase of the disease. Our data suggest that MRI is a helpful diagnostic tool for an early diagnosis of MM and other distal myopathies since it provides sensitive and topographic information about initial and even preclinical muscle involvement. This is of particular relevance in Miyoshi myopathy because distinct CK elevation is present long before its clinical onset and often misdiagnosed as "idiopathic".
Adolescent↗
FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients.
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Adolescent↗
Immunodominance and tumor escape.
Cancers in mouse and man express multiple tumor-specific as well as tumor-associated antigens. Immunodominance in the host response to these antigens can result in successive selection of heritable antigen loss variants. Immunodominance may also prevent the development of responses to new tumor-specific antigens that may arise during tumor progression. Some tumor-specific antigens are retained during tumor progression possibly because they are essential for survival of the malignant phenotype. Immunodominance may allow cancer cells to escape even after loss of a single MHC Class I allele because cross-presentation of the retained antigen by this allele that must be expressed on the surrounding antigen presenting cells sustains the immunodominant response. This prevents effective responses to secondary antigens that may remain as potential targets. Immunization with in vitro selected cancer cell variants that lack the immunodominant antigen can break the immunodominance and prevent escape of cancers from host immunity.
Alleles↗
CSF filtration is an effective treatment of Guillain-Barré syndrome: a randomized clinical trial.
OBJECTIVE: To compare CSF filtration (CSFF) and plasma exchange (PE) in the treatment of patients with Guillain-Barré syndrome (GBS). METHODS: In a prospective controlled clinical trial, 37 patients with acute GBS were randomized to receive either CSFF or PE. Inclusion criteria were fulfillment of National Institute of Neurological and Communicative Disorders and Stroke criteria and disability to walk >5 m unassisted. RESULTS: With similar baseline features in both groups (initial disability grades on the six-point grading scale of the GBS Study Group) the primary outcome variable (improvement within 28 days after randomization) was almost identical (test for equivalence p = 0.0014), the mean grade values being 0.82 in the CSFF group and 0.80 in the PE group. After 56 days, 56% (9 of 16 patients) of the CSFF group and 37% (7 of 19 patients) of the PE group had reached grade 2 (i.e., ability of unassisted walking >5 m). After 6 months, the probability to reach grade 2 was about 80% in both groups. In the CSFF group, transient pleocytosis occurred without apparent clinical complications. Clinically relevant complications were higher in the PE-treated group. CONCLUSIONS: Although the number of patients was small, the authors found that the treatment of GBS with CSFF is at least as effective as with PE. CSFF might work by removing from the CSF inflammatory mediators, autoantibodies, or other factors.
Adult↗
Point mutation in essential genes with loss or mutation of the second allele: relevance to the retention of tumor-specific antigens.
Antigens that are tumor specific yet retained by tumor cells despite tumor progression offer stable and specific targets for immunologic and possibly other therapeutic interventions. Therefore, we have studied two CD4(+) T cell-recognized tumor-specific antigens that were retained during evolution of two ultraviolet-light-induced murine cancers to more aggressive growth. The antigens are ribosomal proteins altered by somatic tumor-specific point mutations, and the progressor (PRO) variants lack the corresponding normal alleles. In the first tumor, 6132A-PRO, the antigen is encoded by a point-mutated L9 ribosomal protein gene. The tumor lacks the normal L9 allele because of an interstitial deletion from chromosome 5. In the second tumor, 6139B-PRO, both alleles of the L26 gene have point mutations, and each encodes a different tumor-specific CD4(+) T cell-recognized antigen. Thus, for both L9 and L26 genes, we observe "two hit" kinetics commonly observed in genes suppressing tumor growth. Indeed, reintroduction of the lost wild-type L9 allele into the 6132A-PRO variant suppressed the growth of the tumor cells in vivo. Since both L9 and L26 encode proteins essential for ribosomal biogenesis, complete loss of the tumor-specific target antigens in the absence of a normal allele would abrogate tumor growth.
Alleles↗
Pharmacokinetic differences between a T cell-tolerizing and a T cell-activating peptide.
Vaccination with a peptide representing a CTL epitope from the human papillomavirus (HPV)16 E7 protein induces a specific CTL response that prevents the outgrowth of HPV16 E7-expressing tumors. In contrast, vaccination with a peptide encoding an adenovirus type 5 (Ad5) E1A CTL epitope results in CTL tolerance and enhanced growth of an Ad5 E1A-expressing tumor. It is unclear why these peptides induce such opposite effects. To determine whether a difference in pharmacokinetics can explain the functional contrasts, tritiated Ad5 E1A and HPV16 E7 peptides were injected into mice. Results show that the tolerizing peptide spread through the body 16 times faster than the activating peptide and was cleared at least 2 times faster. The HPV16 E7 peptide kinetics correlated with the kinetics of HPV16 E7-specific CTL induction. In contrast, Ad5 E1A peptide injection resulted in physical deletion of preexisting Ad5 E1A-specific CTLs within 24 h after injection. This tolerization occurred at the time when the peptide reached its maximum peptide concentration in the organs. These data suggest that ubiquitous expression of the tolerizing Ad5 E1A peptide within a short period of time causes activation-induced cell death of Ad5 E1A-specific CTLs. Therefore, information on the pharmacokinetics of peptides is vital for the safety and efficacy of peptide-based vaccines.
Adenovirus E1A Proteins↗
Role of TGF-beta in immune-evasion of cancer.
One of the major obstacles in tumor-immunology is the outgrowth of malignant tumors despite their immunogenicity and recognition by the immune-system. Multiple mechanisms for this phenomenon have been proposed. We review the possible involvement of transforming growth factor beta (TGF-beta) in this context. TGF-beta is a cytokine with pleiotropic functions, involved in multiple physiologic processes including immunoregulation. Immune elimination of most cancers ultimately depends on cytolytic T cells (CTL). We propose a mechanism of specific suppression of cytolytic T cell (CTL)-responses mediated through immunoglobulin-bound TGF-beta (IgG-TGF-beta), secreted by activated B cells, and a cell of myeloid origin. This mononuclear "Veto" cell presumably binds IgG-TGF-beta through Fc-receptors and activates latent TGF-beta. The suggestion that B cell responses can inhibit tumor rejection is supported by observations in B cell-deficient mice. Ways for enhancing effective cancer immunity by interfering with the network of interactions involving IgG-TGF-beta are discussed.
Animals↗
Tracking the common ancestry of antigenically distinct cancer variants.
In the months and years after first diagnosis, cancers often show an increase in their malignancy such as faster growth, resistance to chemo- and/or hormonal therapy, and loss of antigens targeted by immunotherapy. Our objective was to develop a model in which one can track the changes occurring as a result of in vivo immune selection, such as the loss of antigen, the emergence of previously hidden antigens, or the acquisition of new tumor-specific antigens. In this study, we used the primary UV-induced murine tumor 8101, which consists predominantly of regressor tumor cells that express the immunodominant mutant p68 antigen, but this tumor also contains progressor variants that have lost this antigen. To search for tumor-specific antigens on the immune escape progressors, we raised CD8+ T cells specific for these variants. We found that one of the escape variants expressed a previously unrecognized, unique tumor-specific antigen. However, this unique antigen was not readily detectable on any of the other 8101 lines we tested. To prove that these antigenically distinct cancer variants had indeed been derived from the same tumor and neither represented new tumors nor contaminations by other cell lines, we used unique tumor-specific p53 mutations as a lineage-specific marker to demonstrate that these antigenically distinct progressor variants were derived from the 8101 tumor. Because p53 mutations occur very early during UV carcinogenesis and vary from tumor to tumor, they provide convenient reliable markers for tracking the origin of cancers arising after immune selection or immunotherapy.
Amino Acid Sequence↗
First observation of self-amplified spontaneous emission in a free-electron laser at 109 nm wavelength
We present the first observation of self-amplified spontaneous emission (SASE) in a free-electron laser (FEL) in the vacuum ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approximately 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width, and intensity fluctuations, are all consistent with the present models for SASE FELs.
Journal Article↗
Growth regulated oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism.
Growth Regulated Oncogene-alpha (GRO-alpha) is an autocrine growth factor in melanoma and is a member of the C-X-C family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC Receptor 2. We found previously that variants of murine squamous cell carcinoma PAM 212 which grow and metastasize more rapidly in vivo constitutively express increased levels of murine GRO-alpha, designated mGRO-alpha, or KC. We have examined the possible role of mGRO-alpha expression in malignant progression of squamous cell carcinoma PAM 212 in homologous BALB/c and BALB CXC Receptor-2 deficient mice. Transfection of the PAM 212 cell line which exhibits low expression of GRO-alpha and malignant potential with a pActin-KC vector encoding mGRO-alpha enabled isolation of PAM-KC expressing cell lines. These PAM-KC transfectants displayed an increased rate of growth and metastasis in BALB/c mice, similar to the highly malignant phenotype observed in spontaneously occurring metastatic variants. Furthermore, the PAM-KC tumors showed an increase in infiltration of host leukocytes and CD31+ blood vessels, consistent with increased CXC chemokine activity. The increased growth of PAM-KC cells was attenuated in CXCR-2 deficient mice, indicating that the increased growth was dependent in part upon host cells responsive to the CXC chemokine. Together, these results show that a CXC chemokine such as GRO-alpha can promote malignant growth of murine squamous cell carcinoma by a host CXCR-2 dependent pathway. Oncogene (2000) 19, 3477 - 3486
Animals↗
Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein.
One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC x C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with Arg(12) mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg(12) mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitivity to the peptide. Immunization with CFA alone or with a different Arg(12) mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg(12) mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4(+) T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg(12) mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene-expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.
Animals↗
Immunological enhancement of primary tumor development and its prevention.
While it has been known for decades that the growth of tumor transplants can be enhanced immunologically, the potential significance of these previous findings to the development of primary tumors and the mechanisms of tumor enhancement has remained obscure. This review will summarize recent experiments indicating that primary tumor development can be enhanced by active immunization. The evidence suggests that antibodies, B cells and CD4+ T cells can play a critical role in enhancing the development of primary, tumors, whereas endogenous interferon-gamma (IFNgamma) can counteract enhancement. Thus, we envision two possible functions of IFNgamma: (i) preventing B cell and antibody enhancement and (ii) counteracting tumor promotion independent of T and B cells.
Animals↗
An inherited 4q35-EcoRI-DNA-fragment of 35 kb in a family with a sporadic case of facioscapulohumeral muscular dystrophy (FSHD).
We present a case of an adult male patient showing clinical, neurophysiological and histological signs consistent with the phenotype of facioscapulohumeral muscular dystrophy. On molecular testing with a 4q35-DNA-probe p13E-11 (D4F104S1), the patient, his clinically unaffected mother and two sisters shared a 4q35-EcoRI-DNA-fragment of 35 kb on the transition between FSHD1A-associated and polymorphic fragments. Explanatory hypotheses, such as reduced penetrance in females or a phenotype unlinked to the 4q35-locus are considered. Alternatively, additional changes in the unidentified FSHD1A gene could have caused the phenotype. Thus, in such rare cases, the diagnostic evidence of 4q35-EcoRI-fragments is still limited.
Adult↗
Brain morphology in adolescents at genetic risk for schizophrenia assessed by qualitative and quantitative magnetic resonance imaging.
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Adolescent↗
CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma.
CD4(+) T cells can eliminate tumor cells in vivo in the absence of CD8(+) T cells. We have CD4(+) T cells specific for a MHC class II-restricted, tumor-specific peptide derived from a mutant ribosomal protein expressed by the UV light-induced tumor 6132A-PRO. By using neutralizing mAb specific for murine IFN-gamma and adoptive transfer of CD4(+) T cells into severe combined immunodeficient mice, we show that anti-IFN-gamma treatment abolishes the CD4(+) T cell-mediated rejection of the tumor cells in vivo. The tumor cells were MHC class II negative, and IFN-gamma did not induce MHC class II expression in vitro. Therefore, the tumor-specific antigenic peptide must be presented by host cells and not the tumor cells. Tumor cells transduced to secrete IFN-gamma had a markedly reduced growth rate in severe combined immunodeficient mice, but IFN-gamma did not inhibit the growth of the tumor cells in vitro. Furthermore, tumor cells stably expressing a dominant-negative truncated form of the murine IFN-gamma receptor alpha chain, and therefore insensitive to IFN-gamma, nevertheless were rejected by the adoptively transferred CD4(+) T cells. Thus, host cells, and not tumor cells, seem to be the target of IFN-gamma. Together, these results show that CD4(+) T cells can eliminate IFN-gamma-insensitive, MHC class II-negative cancer cells by an indirect mechanism that depends on IFN-gamma.
Amino Acid Sequence↗