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Biomedical subjects

C J Ross

Publications and source records attributed to C J Ross.

11 recordsLinked to original sources
PubMed2000

Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated recombinant cells.

Most lysosomal enzyme deficiencies are catastrophic illnesses with no generally available treatments. We have used the beta-glucuronidase-deficient mouse model of mucopolysaccharidosis type VII (MPS VII) to develop an alternative approach to therapy. A "universal" cell line engineered to secrete the missing enzyme is implanted in all recipients requiring the same enzyme replacement. The cells, although nonautologous, are rendered immunologically tolerant by encapsulation in microcapsules that provide protection from immune mediators. Using this strategy, we injected beta-glucuronidase-secreting fibroblasts enclosed in alginate microcapsules into mutant MPS VII mice. After 24 hr, beta-glucuronidase activity was detected in the plasma, reaching 66% of physiological levels by 2 weeks postimplantation. Significant beta-glucuronidase activity was detected in liver and spleen for the duration of the 8-week experiment. Concomitantly, the intralysosomal accumulation of undegraded glycosaminoglycans was dramatically reduced in liver and spleen tissue sections and urinary glycosaminoglycan content was reduced to normal levels. Elevated secondary lysosomal enzymes beta-hexosaminidase and alpha-galactosidase were also reduced. However, implanted mutant MPS VII mice developed antibodies against the murine beta-glucuronidase, demonstrating a potential obstacle in patients with a null mutation who react against the replaced enzyme as a foreign antigen. The antibody response was transiently circumvented with a single treatment of purified anti-CD4 antibody coadministered with the microcapsules. This resulted in increased levels and duration of beta-glucuronidase delivery. Similarly, treated heterozygous mice maintained elevated levels of beta-glucuronidase and did not develop antibodies. This novel cell-based therapy demonstrates a potentially cost-effective and nonviral treatment applicable to all lysosomal storage diseases.

Alleles↗
PubMed2000

Somatic gene therapy for a neurodegenerative disease using microencapsulated recombinant cells.

Neurodegenerative diseases caused by lysosomal enzyme deficiencies are catastrophic illnesses with both peripheral organ and central nervous system abnormalities. The mucopolysaccharidosis type VII mouse with beta-glucuronidase deficiency was used to develop an alternate approach to gene therapy, in which a "universal" cell line engineered to secrete the missing enzyme is implanted directly into all recipients requiring the same enzyme replacement. The cells, though nonautologous, were rendered immunologically tolerable by protection in immunoisolating microcapsules. Since the blood-brain barrier impedes the passage of large molecules such as beta-glucuronidase, encapsulated cells producing beta-glucuronidase were introduced directly into the lateral ventricles of the brain. Based on this strategy, beta-glucuronidase was delivered throughout most of the central nervous system, reversing the histological pathology and reducing the previously elevated levels of lysosomal enzymes beta-hexosaminidase and alpha-galactosidase. The effectiveness of this approach was further demonstrated with improvements in the mutant circadian rhythm behavioral abnormalities. Compared to wild-type and heterozygous mice, the mutant mice had an unstable periodicity, fragmented activity, and a sixfold reduction in wheel running activity. After treatment, the mutant behavioral abnormalities were significantly improved with a more stable periodicity and a less fragmented pattern of activity. While the overall total activity level did not increase in the treated mutants, it did not show the deterioration observed in the sham-treated as well as in the untreated mutant mice. Hence, this alternative cell-based gene therapy demonstrates biochemical, histological, and behavioral efficacy and provides a potentially cost-effective and nonviral treatment applicable to all lysosomal storage diseases with neurological deficits.

Alginates↗
PubMed1999

Delivery of recombinant gene products to the central nervous system with nonautologous cells in alginate microcapsules.

Somatic gene therapy using nonautologous recombinant cells immunologically protected with alginate microcapsules has been successfully used to treat rodent genetic diseases. We now report the delivery of recombinant gene products to the brain in rodents by implanting microencapsulated cells for the purpose of eventually treating neurodegenerative diseases with this technology. Alginate-poly-L-lysine-alginate microcapsules enclosing mouse C2C12 myoblasts expressing the marker gene human growth hormone (hGH) at 95+/-20 ng/million cells/hr were implanted into the right lateral ventricles of mice under stereotaxic guidance. Control mice were implanted similarly with nontransfected but encapsulated cells. Delivery of hGH to the different regions of the brain at various times postimplantation was examined. At 7, 28, 56, and 112 days postimplantation, hGH was detected at high levels around the implantation site and also at lower levels in the surrounding regions, while control mice showed no signal. Immunohistochemical staining of the implanted brains showed that on days 7, 56, and 112 postimplantation, hGH was localized in the tissues around the implantation site. Mice implanted with encapsulated but nontransfected cells showed no signal. Hence, the feasibility of using encapsulated nonautologous cells to deliver recombinant gene products to the brain for extended periods may allow the application of this technology to the treatment of neurodegenerative genetic disorders.

Alginates↗
PubMed1998

Encapsulation of various recombinant mammalian cell types in different alginate microcapsules.

Microencapsulation of recombinant "universal" cells with immunoprotective membranes is an alternate approach to somatic gene therapy. Therapeutic gene products secreted by these cells can be delivered to different patients without immunosuppression or genetic modification of the host's cells. The encapsulation of different mammalian cell types (epithelial cells, fibroblasts, and myoblasts) is compared among three alginate-based microcapsules: (1) calcium-linked alginate microcapsules with a solubilized core and a poly-L-lysine-alginate-laminated surface; (2) barium-linked alginate beads with a gelled core; and (3) a hybrid formulation of barium-linked alginate beads with a poly-L-lysine-alginate-laminated surface. The mechanical stability of the different microcapsule types, as measured with a cone-and-plate shearing apparatus, was superior in the two barium-linked alginate beads. All cell types maintained high viability (65-90%) in culture after encapsulation. The recombinant gene products secreted by these cells (human growth hormone MW = 22,000, human factor IX MW = 57,000, and murine beta-glucuronidase MW = 300,000) were able to traverse the three microcapsule types at similar rates. Cell numbers within the microcapsules increased twofold to > 20-fold over 4 weeks, depending on the cell type. Epithelial and myoblast cell numbers were not affected by microcapsule formulation; however, fibroblasts proliferated the most in the calcium-linked alginate spheres. These results show that for culturing fibroblasts in a mechanically stable environment the classical calcium-linked microcapsules are adequate. However, where mechanical stability is a more critical requirement, the solid barium-linked gelled beads are more appropriate choices.

Alginates↗
PubMed1997

A sequence-ready physical map of a region of 12q24.1.

We developed a sequence-ready map of a part of human chromosome 12q24.1. We utilized a number of sequence-tagged site (STS) markers from 12q24.1 to screen large insert bacterial chromosome libraries and a chromosome 12-specific cosmid library. The clones were assembled into contiguous sets (contigs) by STS-content analysis. Contigs were extended by obtaining end sequences of bacterial clones, generation of additional STSs, rescreening the libraries, and screening the additional clones for the presence of STSs. The resulting contig covers nearly 2 Mb of DNA and provides an average marker resolution of 16 kb. Based on the STS content, we developed fingerprints of a subset of clones. The STS content and fingerprint data allowed us to define a minimal tiling path of clones. These clones are being used to sequence this part of chromosome 12. This contig contains the Ataxin 2 gene, and it covers the interval harboring the gene responsible for Darier disease.

Ataxins↗
PubMed1995

Comparisons of pulmonary artery pressure measurements in supine and 30 degree lateral positions.

The purpose of this study was to compare the effects on pulmonary artery pressure (PAP) measurements of using different anatomical reference points for transducer placement. Supine and 30 degree right and left lateral PAP measurements were examined in a sample of 40 hemodynamically stable post-cardiovascular surgery patients. The anatomical references for transducer placement were (a) the supine phlebostatic axis, (b) the right lateral phlebostatic axis, and (c) the mid-sternum at the fourth intercostal space. The results of analysis of variance procedures for repeated measures showed lateral compared to supine PAP measurements differed significantly regardless of the anatomical reference used for the transducer placement (p = < .0001). Clinically insignificant differences in supine and lateral PAP measurements were shown when the transducer reference was the supine phlebostatic axis. Use of the right lateral phlebostatic axis and the mid-sternum did result in clinically significant changes in lateral compared to supine PAP measurements. Implications for research and for clinical practice are discussed.

Adult↗
PubMed1995

Informational coping styles: a validity study.

Informational coping style may be an important determinant of coping with threatening situations that has important implications in terms of matching nursing interventions to patients. Two studies were conducted to examine aspects of the construct validity of a pen-and-paper instrument designed to measure informational coping style, the Miller Behavioral Style Scale (MBSS). In Study I, the MBSS was administered to 271 university students to examine item response frequencies, item correlations and internal consistency of the subscales. In Study II the coping responses to a series of different hypothetically threatening situations were examined in a sample of 60 students drawn from the sample used in Study I. The results of Study I indicate a need for revision of the items in the MBSS. The results of Study II provide modest evidence of construct validity and underrepresentation of the MBSS in terms of coping strategies. Furthermore, there was evidence to suggest that the structural approach used in the MBSS fails to capture the precise context in which a coping strategy would be applied and the extent to which a strategy would be used.

Adaptation, Psychological↗
PubMed1989

Hawaii Asian-American response to the Staying Healthy After Fifty program.

A nationwide project conducted by the American Association of Retired Persons, the American Red Cross, and the Dartmouth Institute for Better Health to disseminate a health promotion program for older adults included a study to test its ability to serve different ethnic minorities. This article reports how the Staying Healthy After Fifty Program, designed for the general United States population, was introduced into the State of Hawaii, how it was adapted for use with two Asian-American groups, the Japanese and Filipinos, and on the benefits reported by participants. To determine the appropriateness and effectiveness of the adapted SHAF program, a quasi-experimental design, involving a test group and a comparison group whose members completed questionnaires at three points in time, was used. The results of the data collected from the Hawaiian population were consistent with the results of the general U.S. population skills, health activities, and health care cost skills areas. Participants were very pleased with the course and its quality, as noted in the high ratings of course satisfaction.

Aged↗
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Child↗