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Biomedical subjects

B O'Neill

Publications and source records attributed to B O'Neill.

At least 37 records · Page 2Linked to original sources
PubMed2000

Head restraints--the neglected countermeasure.

In a rear-end crash, if an occupant's head is unsupported it lags behind as the torso is accelerated forward. This causes the neck to change shape, first taking an s-shape and then bending backward in a 'whiplash' motion. This sudden differential movement of the head and torso can cause 'whiplash' injuries to the neck. This paper reviews methods to minimize the differential head/torso movement and reduce the resulting injuries, focusing on the necessary first step for prevention, which is a head restraint that is behind and close to the back of an occupant's head during the crash. The history of head restraints since the 1950s is reviewed, with particular attention to advanced restraint designs that are proving effective in reducing whiplash injury risk in dynamic tests using a new crash test dummy neck and a new neck injury criterion.

Accidents, Traffic↗
PubMed2000

Sirolimus, a new potent immunosuppressant agent for refractory cardiac transplantation rejection: two case reports.

Rejection remains a major cause of both early and late morbidity and mortality following heart transplantation despite major advances in immunosuppressive therapy. A major hurdle in the successful management of patients who have undergone heart transplantation is preventing and treating graft rejection. Cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus (FK506) and OKT3 are well documented, effective immunosuppressive medications that prevent and treat acute or chronic rejection following heart transplantation. One of the macrolide antibiotics, sirolimus, is known to have immunosuppressant activity. In two patients with chronic rejection of cardiac grafts refractory to usual antirejection medications, sirolimus was successfully used to suppress graft rejection. Both patients continued to be rejection free after 10 months of sirolimus treatment despite significant decreases in doses of other immunosuppressants.

Administration, Oral↗
PubMed2000

Ribozyme-based therapeutic approaches for autosomal dominant retinitis pigmentosa.

PURPOSE: To design, generate, and compare in vitro a range of hammerhead ribozymes targeting retinal transcripts implicated in autosomal dominant retinitis pigmentosa (adRP) and thereby identify ribozymes that may be valuable as therapeutic agents for adRP. To address mutational heterogeneity in rhodopsin and peripherin-linked adRP using mutation-independent ribozyme-based therapeutic approaches. METHODS: Ribozyme and cDNAs constructs were cloned into pcDNA3 and expressed in vitro from the T7 promoter. Cleavage reactions were separated on polyacrylamide gels, visualized by autoradiography, and quantified using an instant imager. Ribozymes targeting rhodopsin and peripherin transcripts in a mutation-independent manner (Rz9, Rz10, and Rz40) and a multimeric ribozyme (RzMM) targeting rhodopsin transcripts were evaluated for in vitro activity. Parameters such as V:(max), K:(m), k(2) and k(-1) were established for each ribozyme. RESULTS: Four ribozymes targeting retinal transcripts were evaluated. Mutation-independent ribozymes targeting degenerate sites or untranslated regions in retinal transcripts resulted in cleavage products of predicted size, whereas transcripts from modified replacement genes remained intact. Detailed kinetic evaluation of ribozymes revealed substantial differences in cleavage rates between ribozymes. CONCLUSIONS: Mutation-independent hammerhead ribozymes targeting rhodopsin and peripherin have been screened in vitro, and a number of extremely efficient ribozymes identified subsequent to detailed kinetic analyses, suggesting that these ribozymes may provide mutation-independent methods of treating adRP. These are the first ribozymes reported that potentially will provide benefit for inherited retinopathies.

Autoradiography↗
PubMed1999

A mutation-independent therapeutic strategem for osteogenesis imperfecta.

Given the genetically heterogeneous nature of many dominantly inherited disorders, it will be imperative to design mutation-independent therapeutic strategies to circumvent such heterogeneity. Intragenic polymorphism represents a genomic resource that may be harnessed in the development of allele-specific mutation-independent therapeutics. A hammerhead ribozyme, Rzpol1a1, selectively cleaves a common single-nucleotide polymorphism (SNP) of the human COL1A1 transcript (heterozygosity frequency of 2 pq = 0.4032, from Hardy-Weinberg equilibrium). One SNP variant contains a hammerhead ribozyme cleavage site, and the other does not. Kinetic evaluation shows Rzpol1a1 to be both specific and extremely efficient in vitro. Thus, a single efficient ribozyme has been characterized that should be valuable in the development of a gene therapy suitable for up to 1 in 5 dominant-negative osteogenesis imperfecta (OI) patients, where over 150 different mutations have been identified to date. Given the increasing characterization of intragenic SNP, it is predicted that such a mutation-independent strategy, based on selective silencing of mutant alleles at SNP, may become increasingly important in future genomics-driven drug development for many heterogeneous dominant disorders and complex traits.

Alleles↗
PubMed1998

Characterization of a sodium-dependent transport system for butyrobetaine into rat liver plasma membrane vesicles.

Butyrobetaine transport into the liver was studied using isolated rat hepatocyte plasma membrane vesicles. In the presence of a sodium chloride gradient, an overshoot could be observed, indicating active sodium-dependent transport. A similar overshoot was recorded in the presence of lithium, but not of potassium, cesium, or choline chloride. Investigation of several sodium salts revealed that an overshoot could only be observed in the presence of chloride, but not of nitrate, thiocyanate, sulfate, or gluconate. An osmolarity plot in the presence of sodium chloride revealed a slope different from zero and a positive intercept, indicating active transport and nonspecific binding, respectively. In agreement with the osmolarity plot, the kinetic characterization of butyrobetaine transport revealed a binding and a saturable component. The saturable component could be described by Michaelis-Menten kinetics, with a Km of 4.88 +/- 0.70 mmol/L and a Vmax of 4.16 +/- 0.73 picomoles per milligram of protein per second. Butyrobetaine transport could be inhibited significantly (30%) by 250 micromol/L propionylcarnitine, but not by D- or L-carnitine, other acylcarnitines (acetylcarnitine, isovalerylcarnitine, palmitoylcarnitine), trimethyllysine, or quinine. Butyrobetaine transport activity was also expressed in Xenopus laevis oocytes by injecting mRNA isolated from rat liver or kidney. After 5 days of cultivation, the endogenous butyrobetaine transport activity was increased by 82% in oocytes injected with liver mRNA and by 99% in oocytes injected with kidney mRNA. The studies show that butyrobetaine is transported actively across the basolateral plasma membrane of hepatocytes and that this transport is driven by sodium and chloride gradients. This transport is quite specific for butyrobetaine and is not rate-limiting for carnitine biosynthesis.

Animals↗
PubMed1997

Effects of quinapril on coronary blood flow in coronary artery disease patients with endothelial dysfunction. TREND Investigators. Trial on Reversing Endothelial Dysfunction.

This pilot study evaluates the effects of quinapril, an angiotensin-converting enzyme inhibitor with high tissue-binding affinity, on microvascular endothelial function in patients with mild (<40% narrowing) coronary artery disease and epicardial endothelial dysfunction. Patients randomized to quinapril had a trend suggesting an increase in endothelium-dependent coronary blood flow response.

Acetylcholine↗
PubMed1997

The real enemy.

Explore the source record for details and available documents.

Attitude of Health Personnel↗
PubMed1997

Differential interaction of bile acids from patients with inborn errors of bile acid synthesis with hepatocellular bile acid transporters.

People with genetic or acquired defects in the biosynthesis of bile acids may suffer from cholestasis. Patients with a deficiency of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase from 3 beta, 7 alpha-dihydroxy- and 3 beta, 7 alpha, 12 alpha-trihydroxy-5-cholenoic acids, the sulfated and partially glycine-conjugated forms of which are found in their urine and bile. 3-Oxo-delta 4 bile acids are detected in the urine of patients with a deficiency of 5 beta-reductase. It has been postulated that these unusual bile acids might act as cholestatic agents in these patients. The aim of the present study was to test this hypothesis in an in vitro system, since the abnormal bile acids would be metabolized in in vivo experiments. Basolateral (sinusoidal) and canalicular plasma membrane vesicles were isolated from rat liver. A rapid filtration method was used to determine transport of cholyltaurine in the presence of model bile acids into the isolated vesicles. It was found that 3 beta, 7 alpha-dihydroxy-5-cholenoic acid and 7 alpha-hydroxy-3-oxo-4-cholenoic acid both inhibited the apical, ATP-dependent transport system for cholyltaurine in a competitive manner with K(m) values of 15 microM and 16 microM, respectively. Radioactively labeled 3 beta, 7 alpha-dihydroxy-5-cholenoyltaurine and 7 alpha-hydroxy-3-oxo-4-cholenoyltaurine were not transported by the same transport system. The same types of experiments were performed with basolateral plasma membrane vesicles. It was found that, in contrast to the canalicular ATP-dependent bile acid transport system, only 7 alpha-hydroxy-3-oxo-4-cholenoyltaurine was a competitive inhibitor of the sodium-dependent transport system for cholyltaurine with a K(m) of 16 microM. Studies with radioactively labeled 7 alpha-hydroxy-3-oxo-4-cholenoyltaurine and 3 beta, 7 alpha-dihydroxy-5-cholenoyltaurine revealed that 7 alpha-hydroxy-3-oxo-4-cholenoyltaurine was transported in a sodium-dependent manner into basolateral rat liver plasma membrane vesicles, whereas 3 beta, 7 alpha-dihydroxy-5-cholenoyltaurine was not transported in a sodium-dependent way. These results support the hypothesis that the unusual bile acids found in patients with defects in bile acid biosynthesis might act as cholestatic agents by inhibiting the canalicular ATP-dependent transport system for bile acids which constitutes the rate-limiting step in the overall process of bile acid transport across hepatocytes. Furthermore, the experiments demonstrated that, despite similar substrate specificities, the basolateral sodium-dependent and the apical ATP-dependent transport system for cholyltaurine might have different recognition sites for bile acids.

Animals↗
PubMed1997

Strategems in vitro for gene therapies directed to dominant mutations.

A major difficulty associated with the design of gene therapies for autosomal dominant diseases is the immense intragenic heterogeneity often encountered in such conditions. In order to overcome such difficulties we have designed, and evaluated in vitro, three strategies which avoid a requirement to target individual mutations for genetic suppression. In the first, normal and mutant alleles are suppressed by targeting sequences in transcribed but untranslated regions of transcript (UTRs), enabling introduction of a replacement gene with the correct coding sequencing but altered UTRs to prevent suppression. A second approach involves suppression in coding sequence and concurrent introduction of a replacement gene by exploiting the degeneracy of the genetic code. A third strategy utilises intragenic polymorphism to suppress the disease allele specifically, the advantage being that a proportion of patients with different disease mutations have the same polymorphism. These approaches provide a wider choice of target sequence than those directed to single disease mutations and are appropriate for many mutations within a given gene. General methods for suppression may be directed towards the primary defect or a secondary effect associated with the disease process, such as apoptosis. Three general methods targeting the primary defect which circumvent problems of allelic genetic heterogeneity are explored in vitro using hammerhead ribozymes designed to target transcripts from the rhodopsin, peripherin and collagen 1A1 and 1A2 genes, extensive genetic heterogeneity being a feature of associated disease pathologies.

Alleles↗
PubMed1996

Zik1, a transcriptional repressor that interacts with the heterogeneous nuclear ribonucleoprotein particle K protein.

The heterogeneous nuclear ribonucleoprotein particle (hnRNP) K protein is comprised of multiple modular domains that serve to engage a diverse group of molecular partners including DNA, RNA, the product of the proto-oncogene vav, and tyrosine and serine/threonine kinases. To identify additional K protein molecular partners and to further understand its function, we used a fragment of K protein as a bait in the yeast two-hybrid screen. The deduced primary structure of one of the positive clones revealed a novel zinc finger protein, hereby denoted as Zik1. In addition to the nine contiguous zinc fingers in the C terminus, Zik1 contains a KRAB-A domain thought to be involved in transcriptional repression. Zik1 and K protein bound in vitro and co-immunoprecipitated from cell extracts indicating that in vivo their interaction is direct. Expression of Gal4 DNA-binding domain-Zik1 fusion protein repressed a gene promoter bearing Gal4-binding elements, indicating that from cognate DNA elements Zik1 is a transcriptional repressor. The known diverse nature of K protein molecular interactions and now the identification of a K protein partner that is a transcriptional repressor lends support to the notion that K protein is a remarkably versatile molecule that may be acting as a docking platform to facilitate communication among molecules involved in signal transduction and gene expression.

Amino Acid Sequence↗
PubMed1996

Thymoma and agranulocytosis: two case reports and literature review.

Thymoma with agranulocytosis is a rare association. We describe two cases of agranulocytosis presenting with sepsis which were both found to have coincident benign spindle cell thymomas. One case, associated with promyelocyte arrest and hypogammaglobulinaemia, was treated successfully with granulocyte colony-stimulating factor (G-CSF). Thymectomy had no effect. The other case, associated with complete myeloid aplasia, proceeded to a fatal outcome after failure of treatment with granulocyte-macrophage colony stimulating factor (GM-CSF), plasmapheresis, thymectomy, intravenous immunoglobulin, cyclophosphamide and methylprednisolone. We also review the literature of thymoma in association with agranulocytosis.

Agranulocytosis↗