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Biomedical subjects

C Walsh

Publications and source records attributed to C Walsh.

At least 109 records · Page 6Linked to original sources
PubMed1994

An examination of linkage of schizophrenia and schizoaffective disorder to the pseudoautosomal region (Xp22.3)

We investigated linkage between schizophrenia and the loci DXYS14, DXYS17, and MIC2 within the pseudoautosomal region in 85 families with two or more siblings suffering from schizophrenia or schizoaffective disorder. A maximum lod score of 2.44 was reached at MIC2, with a dominant model of inheritance at a recombination fraction of 0.367 in females and 0.046 in males (a F:M sex ratio > 1, i.e. opposite to that expected with a pseudoautosomal locus). Evidence consistent with linkage (P = 0.01) was also obtained with a sibling pair analysis at the MIC2 locus. These data do not support (although they do not definitively exclude) a locus within the pseudoautosomal region; they are consistent with the presence of a gene that predisposes to schizophrenia in the sex-specific regions of the X and Y chromosomes.

Adult↗
PubMed1994

Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression.

The spatial patterns of IGF2 and H19 gene expression are strikingly similar during parts of human embryonic/fetal and early postnatal development. Notable exceptions were found with the ciliary anlage of the embryonic retina and the choroid plexus/leptomeninges, where transcripts from the IGF2 but not the H19 locus could be detected. Moreover, in contrast to the other tissue samples examined, the choroid plexus/leptomeninges expressed both parental IGF2 alleles. Whilst RNase protection analysis revealed a weak activity of the P1 promoter in the choroid plexus/leptomeninges, the P2, P3 and P4 promoters were all active wherever IGF2 was expressed. We discuss these observations with respect to a hypothesized coordinated control of the reciprocally imprinted and closely linked IGF2 and H19 loci.

Alleles↗
PubMed1993

Clonal dispersion in proliferative layers of developing cerebral cortex.

In the adult cerebral cortex, many retrovirally labelled clones are widely dispersed, though the mechanisms of this dispersion are not well understood. Here we investigate the temporal sequence of clonal dispersion after labelling progenitors of rat cortical cells with replication-incompetent retroviruses at early stages of cortical neurogenesis, 14-15 days after conception (E14/15). The location of labelled daughter cells was determined 3, 6 or 10 days later. Labelled sibling cells were radially arrayed three days after infection (E18). In contrast, by six days after infection (E20/21), 43% of cortical clones were dispersed non-radially by at least 500 microns. Four of these widespread clones were dispersed longitudinally by > or = 2 mm, implying sustained rates of dispersion of > 15 microns per hour. Dispersed sibling cells occurred within proliferative zones of the forebrain in 35% of widely dispersed clones, suggesting that some dispersion reflects movement of dividing cells. Some clones dispersed beyond the neocortex into the olfactory bulb. Progenitor cell dispersion represents a previously unrecognized mode of migration by which sibling cells become widely dispersed in the developing forebrain.

Animals↗
PubMed1993

Phase II multicenter evaluation of prolonged murine monoclonal antibody 17-1A therapy in pancreatic carcinoma.

Twenty-eight patients with unresectable, measurable pancreatic carcinoma and Eastern Oncology Cooperative Group (ECOG) performance status of 0 or 1 were treated with the murine monoclonal antibody 17-1A, planning to administer 500 mg i.v. three times weekly for 8 weeks. Treatment was well tolerated, with an 18% incidence (five patients) of hypersensitivity reactions. All hypersensitivity episodes occurred in the first 3 weeks of therapy and required treatment discontinuation. Six patients required early discontinuation of therapy due to symptomatic progressive disease and one patient was removed from the study due to a protocol violation. Sixteen patients received the full course of 12 g of antibody. One patient has exhibited a durable partial response. Antibody pharmacokinetics were determined in five patients. In four patients peak 17-1A levels averaged 100 micrograms/ml with mean harmonic t1/2 of 16.8 h in a one-compartment model. Neither pretreatment nor posttreatment levels of circulating 17-1A changed significantly during the 8 weeks of treatment. This study demonstrates the feasibility and acceptable toxicity of repetitive dosing with an unconjugated murine monoclonal antibody. The lack of efficacy of treatment suggests that factors other than prolonged exposure of tumor and cytotoxic effector cells to murine antibody are required for successful antibody therapy of pancreatic cancer.

Aged↗
PubMed1993

Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma.

The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with granulocyte-macrophage colony stimulating factor (GMCSF) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of GMCSF. Eight patients received standard dose m-BACOD plus GMCSF without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus GMCSF, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals.

AIDS-Related Opportunistic Infections↗
PubMed1993

Cell lineage and regional specification in the mammalian neocortex.

The cerebral cortex is the largest structure in the mammalian brain and shows compartmentalization of distinct functions into cortical areas. How does this compartmentalization arise during development? In studies of cell lineage, dividing progenitor cells are labeled to produce clones of labeled adult cortical neurons, so that patterns of clones can be related to the functional architecture of the cortex. A library, consisting of many genetically distinct retroviruses, distinguishable with polymerase chain reaction amplification, allows the cells of a clone to be tagged and traced even when they disperse widely. Recent results indicate that progenitor cells frequently give rise to cortical neurons with heterogeneous cytoarchitectonic locations and functional roles. This suggests that cytoarchitectonic areas arise through mechanisms requiring intercellular communication, rather than inheriting signals about their functional roles from progenitor cells.

Animals↗
PubMed1992

Roles of FAD and 8-hydroxy-5-deazaflavin chromophores in photoreactivation by Anacystis nidulans DNA photolyase.

DNA photolyase from the cyanobacterium Anacystis nidulans contains two chromophores, flavin adenine dinucleotide (FADH2) and 8-hydroxy-5-deazaflavin (8-HDF) (Eker, A. P. M., Kooiman, P., Hessels, J. K. C., and Yasui, A. (1990) J. Biol. Chem. 265, 8009-8015). While evidence exists that the flavin chromophore (in FADH2 form) can catalyze photorepair directly and that the 8-HDF chromophore is the major photosensitizer in photoreactivation it was not known whether 8-HDF splits pyrimidine dimer directly or indirectly through energy transfer to FADH2 at the catalytic center. We constructed a plasmid which over-produces the A. nidulans photolyase in Escherichia coli and purified the enzyme from this organism. Apoenzyme was prepared and enzyme containing stoichiometric amounts of either or both chromophores was reconstituted. The substrate binding and catalytic activities of the apoenzyme (apoE), E-FADH2, E-8-HDF, E-FAD(ox)-8-HDF, and E-FADH2-8-HDF were investigated. We found that FAD is required for substrate binding and catalysis and that 8-HDF is not essential for binding DNA, and participates in catalysis only through energy transfer to FADH2. The quantum yields of energy transfer from 8-HDF to FADH2 and of electron transfer from FADH2 to thymine dimer are near unity.

Apoenzymes↗
PubMed1992

Widespread dispersion of neuronal clones across functional regions of the cerebral cortex.

The cerebral cortex of the mammalian brain has expanded rapidly during the course of evolution and acquired structurally distinguishable areas devoted to separate functions. In some brain regions, topographic restrictions to cell intermixing occur during embryonic development. As a means of examining experimentally whether such restrictions occur during formation of functional subdivisions in the rat neocortex, clonally related neocortical cells were marked by retroviral-mediated transfer of a histochemical marker gene. Clonal boundaries were determined by infection of the developing brain with a library of genetically distinct viruses and amplification of single viral genomes by the polymerase chain reaction. Many clonally related neurons in the cerebral cortex became widely dispersed across functional areas of the cortex. Specification of cortical areas therefore occurs after neurogenesis.

Animals↗
PubMed1992

Multipotent neural cell lines can engraft and participate in development of mouse cerebellum.

Multipotent neural cell lines were generated via retrovirus-mediated v-myc transfer into murine cerebellar progenitor cells. When transplanted back into the cerebellum of newborn mice, these cells integrated into the cerebellum in a nontumorigenic, cytoarchitecturally appropriate manner. Cells from the same clonal line differentiated into neurons or glia in a manner appropriate to their site of engraftment. Engrafted cells, identified by lacZ expression and PCR-mediated detection of a unique sequence arrangement, could be identified in animals up to 22 months postengraftment. Electron microscopic and immunohistochemical analysis demonstrated that some engrafted cells were similar to host neurons and glia. Some transplant-derived neurons received appropriate synapses and formed normal intercellular contacts. These data indicate that generating immortalized cell lines for repair of, or transport of genes into, the CNS may be feasible. Such lines may also provide a model for commitment and differentiation of cerebellar progenitor cells.

Aging↗
PubMed1992

A sensitive method for the detection of poly-A tails of mRNA using a biotin-labelled heteropolymer of dT:rA.

We have developed a highly sensitive non-radioactive in situ hybridization technique that enables us to study the production of mRNAs in tissues. As part of the validation procedure of our methods, we examined various methods of detecting poly-A RNA tails of mRNA. We have used three types of biotin-labelled probes complementary to poly-A sequences: a 25-mer poly-dT oligonucleotide, a polymer of dT, and a heteropolymer of dT:rA. All the probes had the same specificity of reactivity but the heteropolymer of dT:rA gave the strongest signals as visualized histochemically by the use of alkaline phosphatase as the detection enzyme. All the probes tested for poly-A detection showed reactivity. The poly-dT oligonucleotide showed a strength of signal comparable to published results. The biotinylated polymer of dT gave a stronger signal than that of the oligonucleotide, and the heteropolymer was the strongest of all. The strong signal seen with the heteropolymer probe is due to probe complexing during hybridization, in which additional binding between sense and antisense strands of the probe (i.e. poly-rA and poly-dT) amplifies the number of biotin molecules at the hybridization site; this strategy has been exploited by us as a means of visualizing low copy numbers of specific mRNAs.

Bone Marrow↗
PubMed1992

Purification of glutathionylspermidine and trypanothione synthetases from Crithidia fasciculata.

Two enzymes involved in the biosynthesis of the trypanosomatid-specific dithiol trypanothione-glutathionylspermidine (Gsp) synthetase and trypanothione (TSH) synthetase--have been identified and purified individually from Crithidia fasciculata. The Gsp synthetase has been purified 93-fold and the TSH synthetase 52-fold to apparent homogeneity from a single DEAE fraction that contained both activities. This constitutes the first indication that the enzymatic conversion of two glutathione molecules and one spermidine to the N1,N8-bis(glutathionyl)spermidine (TSH) occurs in two discrete enzymatic steps. Gsp synthetase, which has a kcat of 600/min, shows no detectable TSH synthetase activity, whereas TSH synthetase does not make any detectable Gsp and has a kcat of 75/min. The 90-kDa Gsp synthetase and 82-kDa TSH synthetase are separable on phenyl Superose and remain separated on gel filtration columns in high salt (0.8 M NaCl). Active complexes can be formed under low to moderate salt conditions (0.0-0.15 M NaCl), consistent with a functional complex in vivo.

Amide Synthases↗