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J Orth

Publications and source records attributed to J Orth.

At least 19 recordsLinked to original sources
PubMed2004

Dose escalation study for defining the maximum tolerated dose of continuous oral trofosfamide in pretreated patients with metastatic lung cancer.

BACKGROUND: Trofosfamide is increasingly used in the treatment of patients with several types of malignancies. However, the optimal dose of trofosfamide for patients with advanced cancer has not been systematically investigated yet. The aim of this study was to define the maximum tolerated dose (MTD) of continuous oral trofosfamide. PATIENTS AND METHODS: 16 patients with advanced lung cancer (14 nonsmall cell lung cancer, 2 small cell lung cancer; 10 male, 6 female; median age 64 years (range 46-82); median Karnofsky status 70%; median number of organs involved 3 (range 1-6)) were enrolled. All patients were previously treated with chemotherapy (median 2x, range 1-6) and 8/16 (50%) with radiotherapy. Patients received trofosfamide p.o. administered in 3 doses per day for 3 weeks (1 cycle) using a 3-patient-cohort dose-escalation strategy. Toxicities were graded according to the WHO Criteria. RESULTS: Patients received a median of 2 cycles of trofosfamide (range 1-4) at 3 dose levels (90, 125, and 175 mg/m2). Grade 3 and 4 neutropenia, anemia, and thrombocytopenia were observed in 20, 13.3, and 6.6%, respectively. Dose-limiting toxicities during the first cycle were grade 3 muscle weakness and anorexia observed in 1/6 patients in cohort 1 (trofosfamide 90 mg/m2), grade 3 neutropenia in 1/6, and encephalopathy in 1/6 patients in cohort 3 (trofosfamide 175 mg/m2). Therefore, the dose level of 125 mg/m2 was defined as the MTD. CONCLUSION: Trofosfamide at 125 mg/m2 administered in 3 doses per day was well tolerated. This dose level is recommended for further clinical studies.

Administration, Oral↗
PubMed2001

Biological activity of a C-terminal fragment of Pasteurella multocida toxin.

The protein toxin of Pasteurella multocida PMT is a potent mitogen and activator of phospholipase Cbeta. In this study different toxin fragments were investigated. A C-terminal fragment encompassing amino acids 581 through 1285 (PMT581C) was constructed, which was inactive toward intact embryonic bovine lung (EBL) cells after addition to culture medium but caused reorganization of the actin cytoskeleton and rounding up of cells when introduced into the cells by electroporation. As the holotoxin, the toxin fragment PMT581C induced an increase in total inositol phosphate levels after introduction into the cell by electroporation. A C-terminal fragment shorter than PMT581C as well as N-terminal fragments were inactive. Exchange of cysteine-1165 for serine in the holotoxin resulted in a complete loss of the ability to increase inositol phosphate levels. Correspondingly, the mutated toxin fragment PMT581C.C1165S was inactive after cell introduction by electroporation, suggesting an essential role of Cys-1165 in the biological activity of the toxin.

Actins↗
PubMed2000

Clonal expansion of Melan A-specific cytotoxic T lymphocytes in a melanoma patient responding to continued immunization with melanoma-associated peptides.

Peptides derived from human tumor antigens have been used in a number of clinical trials to induce specific immune responses against autologous tumors in cancer patients. Although favorable clinical results were observed in single patients, immune responses correlating with tumor regression were either not detected or in case of responses, the T-cell specificity was difficult to demonstrate. In this study, we analyzed antigen-specific T-cell responses induced in the skin and in peripheral blood lymphocytes (PBL) in an HLA-A2-positive melanoma patient. The patient showed major regression of metastatic melanoma under continued immunization with peptides derived from the melanocyte differentiation antigens Melan A/MART-1, tyrosinase and gp100/Pmel17. Based on the identification of different T-cell receptor (TCR) families reactive with Melan A/MART-1, we have demonstrated that i.d. immunization with peptides alone leads to oligoclonal expansion of Melan A/MART-1-specific cytotoxic T lymphocytes (CTL), detectable in local delayed-type hypersensitivity (DTH) reactions and PBL. A monoclonal expansion of a Melan A/MART-1-specific TCR VB 16 CTL was reproducibly observed after in vitro stimulation with Melan A/MART-1 peptides. The same TCR VB 16 CTL clone was detected in skin biopsies taken from vitiligo areas. Our findings provide strong evidence for the effective induction of specific T-cell responses to Melan A/MART-1 by i.d. immunization with peptide alone, which accounts for dermal depigmentation, specific cytotoxicity against Melan A/MART-1-expressing melanoma cells and clinical tumor regression.

Antigens, Neoplasm↗
PubMed1998

Biocompatibility analysis of different biomaterials in human bone marrow cell cultures.

A cell culture system for biocompatibility testing of hip implant materials is described. Human bone marrow cells have been chosen because these cells are in direct contact with the biomaterial after implantation in situ. The sensitivity of this method is evaluated for materials which are already being used as implants in humans and animal, e.g., hydroxyapatite (HA) ceramic, pure titanium, and ultra-high-molecular-weight polyethylene (UHMWPE). As indicative parameters of biocompatibility primary cell adherence, cell number, cell proliferation, production of extracellular matrix, cell vitality, and cell differentiation are described. After 2 weeks in culture, obvious differences between the biomaterials with respect to the indicative parameters could be observed. Cell numbers were greatest on the HA specimens. In the case of titanium alloys, we observed a decreased number of cells. The production of extracellular matrix was high for the HA ceramics but reduced for titanium specimens. The polymers allowed only a few adherent cells and showed no signs of extracellular matrix production. The results can be correlated astonishingly well to animal experiments and clinical experiences. Therefore, we suggest that this cell culture system seems to be a useful tool for biocompatibility testing of bone implantation materials. It also helps reduce animal experiments. With the help of flow cytophotometry, we analyzed the influence of biomaterials on large numbers of cells with respect to differentiation. There were similar populations of T cells and monocytes on all specimens tested. Extended B-cell and granulocyte populations, however, were observed with titanium and UHMWPE. Most osteocalcin-containing cells adhered to the HA ceramics.

Aged↗
PubMed1997

Arrest of spermatogenesis and defective breast development in mice lacking A-myb.

The Myb gene family currently consists of three members, named A-, B- and c-myb. These genes encode nuclear proteins that bind DNA in a sequence-specific manner and function as regulators of transcription. In adult male mice, A-myb is expressed predominantly in male germ cells. In female mice, A-myb is expressed in breast ductal epithelium, mainly during pregnancy-induced ductal branching and alveolar development. We report here that mice homozygous for a germline mutation in A-myb develop to term but show defects in growth after birth and male infertility due to a block in spermatogenesis. Morphological examination of the testes of A-myb-/- males revealed that the germ cells enter meiotic prophase and arrest at pachytene. In adult homozygous null A-myb female mice, the breast epithelial compartment showed underdevelopment of breast tissue following pregnancy and the female mice were unable to nurse their newborn pups. These results demonstrate that A-myb plays a critical role in spermatogenesis and mammary gland development.

Animals↗
PubMed1994

Degeneration model of the porcine lumbar motion segment: effects of various intradiscal procedures.

In an experimental study with 18 minipigs, we have tried to establish a model for the standardized evaluation of mechanical, histological and radiological phenomena of degenerative and reparative processes within the lumbar motion segment. Comparing different operative techniques revealed that the intradiscal application of hyaluronic acid into the nuclear defect is likely to enhance the regeneration process. Using the measurement of disc compliance, a semiautomatic picture analyzer and a new semiquantitative disc score could make future studies more comparable. From this basis, the intradiscal application of hyaluronic acid deserves further evaluation.

Animals↗
PubMed1993

Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells.

Spermatogenesis is a unique system of differentiation involving cellular remodeling and the biogenesis of sperm-specific organelles. To study the biogenesis of one such organelle, the acrosome, we have been examining the gene expression, biosynthesis, and targeting of specific acrosomal proteins during mammalian spermatogenesis. An acrosomal marker that we recently purified and began characterizing is acrogranin, a 67,000-molecular-weight glycoprotein originally isolated from guinea pig testes. This glycoprotein is detected in pachytene spermatocytes and is found later in the acrosomes of developing spermatids and sperm. Immunoblotting of several tissues and immunofluorescent localization in frozen sections of guinea pig testes suggested that acrogranin was a germ cell-specific glycoprotein that was expressed meiotically and post-meiotically. However, Northern blot analysis demonstrated that the mRNA for acrogranin was ubiquitously expressed in all guinea pig and mouse tissues examined. Furthermore, the primary structures of guinea pig and mouse acrogranins, deduced from the cDNA sequences, reveal that this glycoprotein is a cysteine-rich molecule with a motif that is tandemly repeated seven times, very similar to that of the human epithelin/granulin precursor. We conclude that guinea pig and mouse acrogranins are homologues of the precursor of the human and rat epithelin/granulin peptides previously demonstrated to have growth-modulating properties.

Acrosome↗
PubMed1993

[Evaluation of the biocompatibility of implant materials with human bone marrow cell cultures].

A cell culture biocompatibility test for implant materials is described. For the first time, the human bone marrow cells that actually come into direct contact with the implanted biomaterial can be employed. The usefulness of this method is shown for materials which have long been used in the clinical situation (hydroxyapatite, commercially pure titanium and ultra-high molecular weight polyethylene). After two weeks in culture, light- and fluorescence-microscopic and SEM studies revealed significant differences in cell growth. Maximum compatibility was shown by the hydroxyapatite specimen. In the case of commercially pure titanium we found somewhat decreased biocompatibility. Polyethylene was associated with distinct signs of cytotoxicity. These results are compatible with those of animal experiments and clinical experience. Our system would thus appear to be a useful screening test for some implantation materials, and may help reduce the need for animal tests.

Biocompatible Materials↗
PubMed1991

[2- to 5-year follow-up of cementless implantable knee joint prosthesis of the Miller-Galante type].

Based on a prospective study protocol, the two- to five-year results of the Miller-Galante cementless total knee arthroplasty are presented. Sixty-four implants were placed in 59 patients: 60 implantations were cementless and 4 cemented. Clinically, the scores for pain, range of motion, walking and stair climbing improved significantly. Radiographically, the uncemented components displayed no signs of definite or possible loosening, whereas one of the cemented components was found to be definitely loose. On histological evaluation of the retrieved implants, all components had bone ingrowth.

Aged↗
PubMedDate not supplied

[Semiquantitative analysis of bone regeneration on porous metallic wire-mesh specimens with or without HA-coating in comparison to pure titanium in animal experiments].

INTRODUCTION: The aim of this study was to analyse the bone regeneration on porous metallic wire-mesh specimens of pure titanium, uncoated CoCrMb and HA-coated CoCrMb in a comparative animal experiment. MATERIAL AND METHODS: Uncoated and hydroxyapatite-coated CoCrMb (one-sided) specimens were tested in an animal experiment. The statistical interpretation was done macroscopically as well as microscopically. RESULTS: With regard to the histological and quantitative evaluation, it has been shown that the proximal coated CrCoMb implants were superior to the other specimen. The bone regeneration with the most distinctive extent of osseointegration has been seen by the HA-coated CrCoMb specimen. The uncoated distal CoCrMb specimen demonstrated the worst results. DISCUSSION: This study shows that specimens of titanium and uncoated CrCoMb implanted at the proximal metaphysis deliver comparable effects on the bone regeneration and osseointegration. The best results with regard to the bone regeneration and osseointegration were seen with the implanted hydroxyadaptite-coated CrCoMb specimen. In addition, it has been observed that the bone regeneration and osseointegration of the specimen depends on the place of implantation.

Animals↗
PubMedDate not supplied

[Human bone marrow cell culture--a sensitive method for the evaluation of the biocompatibility of materials used in orthopedics].

The objective of the study was to develop a test system to determine the cytotoxicity and biocompatibility of different biomaterials used in orthopedic surgery. This system was based on the use of a human bone marrow cell culture and the purpose was to find a screening method as a alternative to early animal experimental methods. The established human bone marrow cell culture has certain advantages when compared with other cell culture models. The result demonstrated a high conformity with animal experimental results.

Biocompatible Materials↗
PubMedDate not supplied

[A new plate for dorsal occipito-cervical fusion. Design, surgical technique, initial clinical results].

A survey of actually practiced methods for cranio-cervical fusion is presented, followed by the description of a new osteosynthesis-plate to solidly fuse this region. The new plate offers a number of advantages when compared with competing procedures. It is rigidly fixed to the occipital bone by five screws, sublaminar wireloops bond the vertebrae to be fused to both branches of the U-shaped plate where the individual loops are positioned into obliquely ascending slots. This safely prevents migration and disengagement resulting in a high initial horizontal and vertical stability allowing for a postoperative care without external support. During the procedure tightening of the wire loops may succeed on reposition of the deformity. The plate exists in two lengths allowing fusion of C0-C2 or more segments of the cervical spine. The typical indication is instability of C0-C2 in rheumatoid arthritis or tumoral lesions of the area. Clinical experience in 7 patients suffering from rheumatoid arthritis (follow-up: 6-31 months) is very positive, fusion has occurred in all cases.

Aged↗
PubMedDate not supplied

[Standardized infection model for the study of bony ingrowth dynamics of hydroxyapatite-coated and uncoated pure titanium mesh in swine femur].

The authors studied the ingrowth dynamics of bone tissue into the pores of Hydroxyapatite-coated (plasma-spraying technique) and uncoated wiremeshs of pure titanium in an infected implantation site. Samples of the tested materials were implanted into the femora of 15 adult Göttingen minipigs. Just before implantation they were contaminated with Staphylococcus aureus. The animals were sacrificed after 4, 8, 12 and 24 weeks. Undecalcified ground-sections of bone tissue were prepared (app. 100 microns) and stained with toluidine blue for comparative histological evaluation. The HA-coated implants demonstrated advanced new bone formation already after 4 weeks and nearly complete osseointegration after 12 weeks although all samples showed gross and histological signs of persisting infection. Comparable reactions of the uncoated implants could only be observed after 24 weeks. Signs of degradation of the Hydroxyapatite-coating could be seen in contact to soft tissue and were more extensive compared to the behaviour in an uninfected site. The results and possible clinical consequences are discussed.

Animals↗
PubMedDate not supplied

[Established aspects and current knowledge in biomaterials research].

A review of the currently clinically established biomaterials UHMWPE, Al2O3-ceramic, CoCr- and Ti-based alloys and HA-coatings is given on the basis of recognized and new insights. Advantages and disadvantages as well as prospectives (PE-disease, Ti wear, HA-resorption in vivo etc.) are discussed and documented with results from experimental and clinical experience. New surface hardening techniques for Ti-based alloys are mentioned. Experimental results and singular experience from clinical retrieval study of new plastics (PAEK, Triazin-resin) are presented. Composite materials as a basis for a new generation of isoelastic hip prosthesis stems are described at the end of this paper.

Absorption↗