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J Wagner

Publications and source records attributed to J Wagner.

At least 199 records · Page 11Linked to original sources
PubMed1995

Transgenic animals as models for human disease.

Since its first description in 1981 (1), transgenic technology has greatly influenced the focus and direction pace of biomedical research. Introduction of foreign DNA into the genome of animals by microinjection into fertilized oocytes is now used in almost every field of research spanning from oncology, immunology and neurology to cardiovascular medicine. The ability to integrate genes in the germline and their successful expression in the host provides an opportunity to study the role of a certain gene in the initiation and propagation of disease. Transgenic methodology serves as the link between molecular biology, introducing in vitro a defined genetic modification and whole animal physiology, with the resulting in vivo alteration of body function. This potential has been exploited to study the pathophysiological role of human genes. Transgenic animals have been used to study aspects of tumor development, immune regulation, cardiovascular development and atherosclerosis. These studies have provided new insights into the genetic origin of certain diseases and have improved our understanding of pathological processes on the cellular level. As a future goal, these studies may also serve the development of new diagnostic tools or novel therapeutic strategies such as gene therapy.

Animals↗
PubMed1995

Phase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

Preliminary results of a phase I study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given by 3-hour infusion, followed by carboplatin in chemotherapy-naive patients with stage IV non-small cell lung cancer indicate that both agents can be combined at clinically relevant single-agent doses. The paclitaxel (mg/m2)/carboplatin area under the concentration-time curve (mg.min/mL) dose level of 225/7 is projected to be the maximally tolerated and recommended phase II dose level for future evaluations. Dose-limiting neutropenia, thrombocytopenia, and nausea and vomiting preclude treatment with carboplatin doses estimated to target an area under the concentration-time curve of 9 mg.min/mL when given with paclitaxel 225 mg/m2. The heterogeneous nature of the principal toxicities, as well as the ability to administer clinically relevant single-agent doses of both agents in combination, also indicate that further dose escalation of paclitaxel and carboplatin using hematopoietic growth factors would not be feasible. The preliminary antitumor activity noted to data, as well as the safety associated with the clinically relevant single-agent doses that can be given in combination, indicate that phase II/III evaluations of this regimen are warranted in patients with both advanced and early stage non-small cell lung cancer.

Adult↗
PubMed1995

Toward a medical linguistic knowledge base.

This paper presents the design of a Medical Linguistic Knowledge Base (MLKB). This MLKB is intended to be the multilingual recipient for all the declarative knowledge about languages. It includes words, their syntax and their conceptual representation, typology of concepts of the domain, rules for semantic analysis and conceptual schemata. For that purpose, Sowa's conceptual graphs are considered as an adequate knowledge representation. The MLKB will be an enormous body of information, and the difficulty to feed it and to validate it appears immediately. Therefore, it is necessary to start an international initiative to merge efforts from different groups.

Language↗
PubMed1995

Current trends with natural language processing.

Natural Language Processing in the medical domain becomes more and more powerful, efficient, and ready to be used in daily practice. The needs for such tools are enormous in the medical field, due to the vast amount of written texts for medical records. In the authors' point of view, the Electronic Patient Record (EPR) is achieved neither with Information Systems of all kinds nor with commercially available word processing systems. Natural Language Processing (NLP) is one dimension of the EPR, as well as Image Processing and Decision Support Systems. Analysis of medical texts to facilitate indexing and retrieval is well known. The need for a generation tool is to produce progress notes from menu driven systems. The computer systems of tomorrow cannot miss any single dimension. Since 1988, we've been developing an NLP system; it is supported by the European program AIM (Advanced Informatics in Medicine) within the GALEN and HELIOS consortium and the CERS (Commission d'Encouragement á la Recherche Scientifique) in Switzerland. The main directions of development are: a medical language analyzer, a language generator, a query processor, and dictionary building tools to support the Medical Linguistic Knowledge Base (MLKB). The knowledge representation schema is essentially based on Sowa's conceptual graphs, and the MLKB is multilingual from its design phase; it currently incorporates the English and the French languages; it will also continue using German. The goal of this demonstration is to provide evidence of what exists today, what will be soon available, and what is planned for the long term. Complete sentences will be processed in real time, and the browsing capabilities of the MLKB will be exercised. In particular, the following features will be presented: Analysis of complete sentences with verbs and relatives, as extracted from clinical narratives, with special attention to the method of "proximity processing" as developed in our group and the rule based approach to language description to resolve the specific surface language problems as well as the language independent semantic situations. Comparison of results for English, French, and German sentences, showing the commonalities between these languages and, therefore, the re-usable features and the language specific aspects. Generation of noun phrases in English and French, showing the opportunities for translation between these two languages. Application of the analyzer to build a knowledge representation of ICD under the form of conceptual graphs and presentation of the possibilities of a natural language encoding of diagnosis. Strategies for query processing through a sample of abdominal ultrasonography reports, which have been analyzed and stored under the form of conceptual graphs. Feeding in and browsing of the Medical Linguistic Knowledge Base and other Dictionary Building Tools, using the perspective of an international initiative to converge towards a multilingual universal solution, valid for the medical domain. The demonstration platform is Microsoft Windows 4 on a PC, with Microsoft Visual Basic as the GUI and Quintus Prolog as NLP tools language. The same programs were originally developed for Unix-based workstations and are available on multiple platforms under Motif and X11. .

European Union↗
PubMed1995

In vivo gene transfer: focus on the kidney.

Renal gene transfer techniques are being developed as a novel experimental approach to understand the pathogenesis of renal disease and to potentially develop new therapeutic tools. We review the currently available technology to introduce foreign genetic material into renal tissue, i.e., retroviral, adenoviral, and liposomal transfer systems with their respective advantages and caveats. Today, the transfer efficiency of these methods appears to be sufficiently high to study the effects of transduced genes on renal function and morphology in rat kidney. This will allow (i) the elucidation of the function of genes on the course of renal disease in experimental animal models and (ii) the modulation of local expression of endogenous genes which presumptively contribute to renal pathology in these models. One strategy to accomplish this aim is the use of recombinant DNA technology to design antisense DNA constructs or oligonucleotides, which interfere with the renal expression of target genes. We will also discuss some of the shortcomings of the currently used techniques with respect to potential therapeutic use of gene transfer systems and gene modulation.

Animals↗
PubMed1994

Molecular cloning and tissue-specific RNA processing of a murine receptor-type protein tyrosine phosphatase.

The molecular cloning of a murine receptor-type protein tyrosine phosphatase, termed PTP NU-3, with an extracellular cell-adhesion-molecule-like domain is reported. NU-3 was isolated from 11.5-day total mouse embryonic RNA by reverse-transcriptase PCR using degenerate oligonucleotides flanking the conserved protein tyrosine phosphatase catalytic domain. This produced a 280-bp DNA probe which was subsequently employed to screen a mouse embryonic kidney library. Several overlapping cDNA clones were isolated, collectively forming a cDNA of 6.0 kb that encodes a putative 211-kDa protein. Northern-blot analysis of total RNA from adult and embryonic mouse tissues indicates the existence of two major PTP NU-3 transcripts of approximately 6 kb and 7 kb. Both messages are expressed predominantly in brain tissues and neuronal-derived cell lines, although detectable levels of the 7-kb message were found in other non-neuronal tissues. We have identified a unique 132-bp exon segment that is present in the 7-kb message but is completely absent in the 6-kb transcript, suggesting tissue-specific levels of expression and RNA processing. Analysis of the amino acid sequence encoded by the 132-bp segment reveals that it completes a partial fibronectin type-III element resulting in a protein with a total of nine such elements. Bacterial expression of the two catalytic domains demonstrated that only the first domain possesses enzymic activity towards a tyrosine phosphorylated substrate.

Amino Acid Sequence↗
PubMed1994

High frequency of germline p53 mutations in childhood adrenocortical cancer.

BACKGROUND: Adrenocortical carcinoma (ADCC) is a rare childhood cancer, affecting three of 1 million children younger than 16 years old in the United States. ADCC may be found in association with the Li-Fraumeni and Beckwith-Wiedemann syndromes. Children with ADCC are also at substantially increased risk of second primary cancers. Because of these associations, it is believed that the genetic basis for ADCC is stronger than for most childhood malignancies. Germline mutations of the TP53 tumor suppressor gene are associated with cancer predisposition in families with the Li-Fraumeni syndrome as well as in individuals with sporadically occurring component tumors of the syndrome. PURPOSE: We investigated the possibility that germline TP53 gene alterations existed in children with ADCC. METHODS: Sixteen children with ADCC under the age of 18 were identified from searches of medial oncology records at three Canadian hospitals. Eleven of these 16 patients identified were alive. The mean age at diagnosis was 4.8 years (range, 1-17 years). Family histories were obtained for 11 unselected children with ADCC (six girls and five boys). Pathologic confirmation of tumor diagnosis was obtained from the medical records. Using single-strand conformational polymorphism analysis followed by single-strand DNA sequencing, genomic DNA extracted from whole blood was analyzed for the presence of TP53 mutations for six living ADCC patients. RESULTS: Three of six (50%) children were found to carry germline TP53 mutations in exons 5, 6, and 7, respectively. Both wild-type and mutant alleles were identified in all three TP53 sequences, indicating that the patients were heterozygous for germline TP53 mutations. None of these children was from a family with the Li-Fraumeni syndrome. The mutation in one child was shown to be inherited from the mother, who subsequently developed breast cancer. A striking excess of cancer was found in one family of a patient carrying wild-type TP53. CONCLUSIONS: Our observation of a high frequency of germline TP53 mutations in children with sporadic ADCC suggests that these children may represent probands with which to ascertain Li-Fraumeni syndrome families. It may be reasonable for children with adrenocortical carcinoma to be candidates for germline TP53 analysis. In light of the wealth of information in the Li-Fraumeni literature that associates germline TP53 mutations with a variety of malignancies, this testing may have important consequences for risk assessment for other close relatives, including early-onset breast cancer in the mothers.

Adolescent↗
PubMed1994

Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia.

We recently demonstrated that reactive astrocytes express NADPH diaphorase activity, a marker for Nitric Oxide Synthase, following transient global ischemia (Neuroscience Letters 154: 125-128). There has been little evidence that astrocytes express Nitric Oxide Synthase or produce NO (nitric oxide) in vivo; although in vitro experiments have shown that cultured astrocytes can produce NO. To determine whether reactive astrocytes express inducible form of NOS (iNOS) in vivo, we studied the pathological changes of rat hippocampus by immunohistochemistry after 10 minutes of transient global ischemia, which results in the selective delayed death of CA1 pyramidal cells and marked gliosis in the CA1 subfield. In the normal hippocampus, astrocytes express neither NADPH diaphorase activity nor iNOS. After ischemia, the temporal and spatial pattern of iNOS, NADPH diaphorase, and GFAP are very similar, indicating that reactive astrocytes express iNOS. Double staining for NADPH diaphorase and GFAP, or iNOS and GFAP confirmed that reactive astrocytes express both NADPH diaphorase activity and iNOS immunoreactivity. These changes were observed three day after ischemia and increased in prominence from one week to one month. The staining pattern of OX42, an antibody that recognizes both microglia and macrophages, is spatially and temporally distinct from the pattern of NADPH diaphorase and iNOS staining. Thus, we conclude that transient global ischemia induces iNOS primarily in reactive astrocytes. This increase in NOS expression and, presumably, NO production by reactive astrocytes may play a role in the process of delayed neuronal death or in the remodeling responses that occur after ischemic damage.

Amino Acid Oxidoreductases↗
PubMed1994

Determination of distribution coefficients for some 5-HT3 receptor antagonists by reversed-phase high-performance liquid chromatography.

It is of major interest to determine the physico-chemical properties, dissociation constants and lipophilicity of potential drugs owing to their implication in absorption mechanisms. The HPLC capacity factors appear to be attractive and readily accessible lipophilic parameters. An isocratic HPLC method was designed using a C8 column to determine the relative lipophilicity for two sets of 5-HT3 receptor antagonists, including tropine and quinolizine analogues. Dimethyloctylamine was added to the eluent to mask silanophilic interactions and lead to a predominant partitioning mechanism. The capacity factors determined by a monocratic procedure showed good correlations with the distribution coefficients obtained by the shake-flask method, showing the validity of capacity factors as lipophilicity descriptors for close analogues.

Chemical Phenomena↗
PubMed1994

Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.

The FLT3/FLK2 receptor tyrosine kinase is closely related to two receptors, c-Kit and c-Fms, which function with their respective ligands, Kit ligand and macrophage colony-stimulating factor to control differentiation of haematopoietic and non-haematopoietic cells. FLT3/FLK2 is thought to be present on haematopoietic stem cells and found in brain, placenta and testis. We have purified to homogeneity and partially sequenced a soluble form of the FLT3/FLK2 ligand produced by mouse thymic stromal cells. We isolated several mouse and human complementary DNAs that encode polypeptides with identical N termini and different C termini. Some variants contain hydrophobic transmembrane segments, suggesting that processing may be required to release soluble ligand. The purified ligand enhances the response of mouse stem cells and a primitive human progenitor cell population to other growth factors such as interleukins IL-3 and IL-6 and to granulocyte-macrophage colony-stimulating factor, and also stimulates fetal thymocytes.

Amino Acid Sequence↗
PubMed1994

Nitric oxide: a downstream mediator of calcium toxicity in the ischemic cascade.

Loss of cellular calcium homeostasis or the production of nitric oxide (NO) have been cited as possible mechanisms that may contribute to neuronal degeneration during ischemia. We therefore examined whether cellular calcium blockade, using the agent HA1077, was protective during anoxia in hippocampal neuronal cell cultures, and whether the in vitro effects of this drug were linked to the NO pathway. Administration of the agent during anoxia was neuroprotective in neuronal cell culture. In contrast, HA1077 did not protect hippocampal neurons during NO exposure. In addition, inhibition of NO synthesis in conjunction with HA1077 application during anoxia did not significantly increase survival beyond the maximum protection afforded by HA1077 alone. These results suggest that calcium may be an initial messenger in the ischemic cascade, but that subsequent neuronal degeneration is dependent upon the NO pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Potential and limitations of an optically active crown ether for chiral separation in capillary zone electrophoresis.

Capillary zone electrophoresis using optically active 18-crown-6 tetracarboxylic acid (18C6H4) as chiral selector was studied for the enantiomeric separation of primary amines. From the separation of a variety of pharmaceutical drug substances, amino alcohols and amino acids, conclusions could be made concerning the influence of the chemical structure of the analytes on the separation. In addition, the effects of experimental parameters such as pH, proportion of organic modifier and buffer composition on the separation are discussed. A synergistic effect obtained by the joint application of 18C6H4 and a cyclodextrin was exploited to resolve analytes which were separated neither by the crown ether nor by the cyclodextrin.

Amines↗
PubMed1994

Human angiotensinogen is highly expressed in astrocytes in human cortical grafts.

Human fetal parietal cortical tissue was transplanted to cortical cavities in immunosuppressed rats. Protoplasmic astrocytes in the human cortical grafts highly expressed human angiotensinogen mRNA as identified with 35S-labeled and digoxigenin-labeled riboprobes combined with immunohistochemistry for glial fibrillary acidic protein. Antibodies to human specific neurofilament protein 70 KD were used to characterize neurons in the graft and fiber outgrowth into the host brain. Immunohistochemistry revealed human angiotensinogen-like immunoreactivity in many small protoplasmic astrocytes and very few large neurons. These results demonstrate that human angiotensinogen mRNA and protein is synthesized in immature human glia. We assume that angiotensinogen is transformed into angiotensin peptides, which may participate in the regulation of growth processes. The results suggest that human angiotensinogen may play a role during human embryogenesis.

Angiotensinogen↗
PubMed1994

[Bone metastasis of a prostate tumor and osteosynthesis material. A case report].

The detection of metastatic deposits at the site of previous osteosynthesis is difficult. Bone imaging and scanning with technectium 99m are unhelpful in differentiating between osteomyelitis, Paget's disease and a bone metastasis. The authors present details of a patient who had undergone osteosynthesis for a fracture of the left tibia in 1983. In October 1989 signs of inflammatory change appeared at the site of the previous fracture. It was initially treated as if it were osteomyelitis, with curettage and insertion of gentamycin beads, although no organisms were grown. Eventually the patient was transferred to the author's hospital and further investigation revealed a carcinoma of the prostate. Histological examination of biopsy specimens from the left tibia confirmed the presence of a metastasis from this growth.

Adenocarcinoma↗