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Biomedical subjects

R J Young

Publications and source records attributed to R J Young.

At least 73 records · Page 4Linked to original sources
PubMed1996

Ranitidine therapy for esophagitis in children with developmental disabilities.

Esophagitis is common in children with cerebral palsy. Because histamine2-receptor antagonists such as ranitidine have not been uniformly effective, we treated disabled children with esophagitis with greater than usual doses. Endoscopy and pH monitoring were used to monitor dose and response to treatment. A dose of 9.3 +/- 0.9 mg/kg/day did not improve visual or microscopic esophagitis after 3 months. A dose of 14.8 +/- 3.9 mg/kg/day resulted in only slight microscopic improvement, but symptoms were improved. There was no correlation between esophageal reflux index at enrollment and either severity of esophagitis or response to treatment. Elevation of gastric pH by ranitidine was infrequent. These results affirm that pH monitoring does not reliably identify disabled children with reflux esophagitis nor does ranitidine reliably heal this disorder.

Adolescent↗
PubMed1996

Fatal acute hepatorenal failure following potassium permanganate ingestion.

Potassium permanganate (KMnO4), a powerful oxidizing agent, is readily available without prescription. Tissue contact produces coagulation necrosis and the lethal consequences of oral ingestion are well described, with most deaths because of airway oedema and obstruction or circulatory collapse. Whilst systemic toxicity is reported, its mechanism is unclear. We describe a case of suicidal ingestion of KMnO4 followed by acute hepatorenal toxicity resulting in the death of the patient. The clinical course bore close resemblance to that of severe paracetamol overdose. We discuss the pathogenesis of the systemic toxicity of KMnO4 and postulate that it is due to oxidative injury from free radicals generated by the absorbed permanganate ion. We recommend that N-acetyl cysteine be given within the first few hours to all patients with potassium permanganate poisoning.

Accidents, Home↗
PubMed1996

Reduced insulin-like growth factor binding protein-1 (IGFBP-1) levels correlate with increased cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM).

IGF-I and -II levels are altered in patients with atherogenic lipid profiles and may contribute to the development of macrovascular disease in NIDDM. We examined cardiovascular risk factors, IGF-I, IGF-II and IGFBP-1 in 74 NIDDM patients analysed as a whole group and according to treatment type. IGF-I was not significantly associated with cardiovascular risk factors but IGF-II levels correlated positively with total and LDL cholesterol most markedly in the diet treated group (0.72, p < 0.01 and 0.76, p < 0.01 respectively). In the whole group reduced IGFBP-1 levels were significantly associated with factors known to increase cardiovascular risk: i.e. low HDL cholesterol (0.31, p < 0.01) and elevated blood pressure (-0.35, p < 0.01), BMI (-0.37, p < 0.01), insulin (-0.29, p < 0.01) and proinsulin (-0.24, p < 0.01). In the treatment groups IGFBP-1 was lower in patients on diet alone (n = 11, 42.6 +/- 11.6 mu g/l) and sulphonylurea +/- insulin (n = 39, 53.2 +/- 7.6 mu g/l) relative to insulin treatment (n = 24, 103.0 +/- 19, 7 mu g/l, p < 0.05). The lower levels of IGFBP-1 were not due to a significant change in phosphorylation status from the highly phosphorylated circulating form since lesser and non-phosphorylated variants were undetectable in 53/74 patients. Multiple regression analysis revealed the best predictors of IGFBP-1 were BMI and MAP (R2 = 0.2. p < 0.001) and for blood pressure, IGFBP-1 and age (R2 = 0.47, p < 0.001). These findings indicate that in NIDDM patients low IGFBP-1 levels are associated with multiple factors predisposing to atherogenesis.

Blood Pressure↗
PubMed1995

Bent domain structure of recombinant human IgE-Fc in solution by X-ray and neutron scattering in conjunction with an automated curve fitting procedure.

Human immunoglobulin E (IgE) consists of 14 domains, each with the characteristic immunoglobulin fold structure. Compared with the 12-domain structure of immunoglobulin G (IgG), IgE has an additional pair of domains (C epsilon 2) in the Fc region in place of the hinge of IgG. The crystal structure of the 4-domain Fc fragment of IgG is known, but not that of the 6-domain Fc fragment of IgE (IgE-Fc). In order to elucidate the position of the C epsilon 2 domains in the domain structure of IgE-Fc, IgE-Fc was studied by synchrotron X-ray and pulsed neutron scattering. The upper limit on the X-ray radius of gyration RG which determines macromolecular elongation was determined to be 3.52 +/- 0.14 nm. That for the neutron RG (measured in 100% 2H2O buffers) was 3.53 +/- 0.05 nm. The X-ray and neutron cross-sectional radii of gyration were 1.89 +/- 0.05 and 1.56 +/- 0.09 nm, respectively. The scattering curves were modeled on the basis of a previously-predicted model for IgE-Fc (Helm, B. A., Ling, Y., Teale, C., Padlan, E. A., & Brüggemann, M. (1991) Eur. J. Immunol. 21, 1543-1548). The extended arrangement of domains in that model resulted in poor agreement with experimental data. Interactive and automated procedures for the fitting of crystallographically-derived domain models to scattering data were developed. Each pair of C epsilon 2, C epsilon 3, and C epsilon 4 domains was translated and rotated relative to the remaining structure in a comprehensive five-parameter search of more than 37,000 models. Substantially improved agreement between the experimental and calculated scattering curves was obtained. Bent models for IgE-Fc in which the C epsilon 2 domain pair is rotated by at least 40-50 degrees from its position in the previously predicted linear IgE model consistently gave the best agreement with the X-ray and neutron scattering curves. Such a structure for the Fc fragment accounts in part for the bent structure previously proposed for intact human IgE, which is important for understanding the interaction between IgE and its receptors.

Computer Simulation↗
PubMed1995

Hydrodynamic studies of a complex between the Fc fragment of human IgE and a soluble fragment of the Fc epsilon RI alpha chain.

The interaction between immunoglobulin E (IgE) and its high-affinity receptor Fc epsilon RI is central to allergic disease. The binding site for Fc epsilon RI lies in the third constant region domain of the epsilon heavy chain of IgE (C epsilon 3). Identical epitopes on the two C epsilon 3 domains in the IgE-Fc are predicted to be on opposite sides of the structure, and therefore each could bind independently to a receptor molecule. Titrations, however, reveal that the IgE-Fc forms an equimolar complex with a soluble fragment of the Fc epsilon RI alpha chain (sFc epsilon RI alpha), and the molecular weight of the complex, as determined by sedimentation equilibrium, confirms this stoichiometry. The measured sedimentation coefficients of the two ligands are in good agreement with computed values for a compact IgE-Fc and an elongated sFc epsilon RI alpha structure. The calculated sedimentation coefficients for possible models of a 1:1 complex lead to exclusion of all highly extended geometries for the complex. Possible explanations for the paradoxical stoichiometry of the IgE-Fc/sFc epsilon RI alpha complex, in terms of the curved shape of IgE, a conformational change in IgE when the receptor binds, and steric interference between two molecules of Fc epsilon RI binding to identical sites, are discussed.

Carbohydrate Sequence↗
PubMed1995

Action of metallic ions on the precocious development by rabbit sperm of motion patterns that are characteristic of hyperactivated motility.

An earlier study demonstrated that rabbit sperm incubated for 16 hr under capacitation conditions acquire motility patterns identical to those seen in rabbit sperm capacitated in vivo. We now show that similar motion patterns develop after 0.5 hr incubation in a Tris-buffered medium, medium M. Development and decline of the motion patterns occurred in three phases each recognized by the character of the biphasic motion patterns. Hyperactivated sperm were objectively identified and quantified by a previously developed computer-directed model. The percentage of motile sperm that acquired hyperactivated motility and the period they remained in this state varied among sperm from different rabbits. The decline in hyperactivated motility was paralleled by a decrease in the average sperm curvilinear velocity (VCL) and average amplitude of lateral head displacement (AALH), but was not accompanied by a concomitant decrease in percentage of motile sperm. Pb2+ and Cd2+, at concentrations that did not inhibit motility, prevented development of hyperactivated motility. Inhibition of hyperactivated motility by Pb2+ was time- and concentration-dependent; the average percentage of hyperactivated sperm decreased from approximately 30% to < 5% (n = 5) in 1 hr at a Pb2+ concentration of 25 microM. Cd2+ inhibition of hyperactivation was dependent only on concentration of the cation. At a concentration of 100 microM, the decrease in the percent of hyperactivated sperm was approximately 50% (n = 3). Hg2+, Zn2+, and Cr6+ at sublethal concentrations had no effect on hyperactivated motility development. These results suggest that Pb2+ and Cd2+, by virtue of their ability to prevent the wide curvature flagella beating that is characteristic of hyperactivation, can compromise fertilization at concentrations that do not inhibit sperm motility and act as a reproductive toxicant at a level other than spermatogenesis.

Animals↗
PubMed1995

Myelinated nerve fibre regeneration in diabetic sensory polyneuropathy: correlation with type of diabetes.

Observations were made on myelinated fibre regeneration in diabetic sensory polyneuropathy assessed in sural nerve biopsy specimens. These confirmed that regenerative clusters initially develop within abnormally persistent Schwann cell basal laminal tubes. The number of regenerating fibres, identified by light microscopy, was found to decline in proportion to the reduction in total myelinated fibre density. The relative number of regenerating fibres was significantly greater in patients with insulin-dependent as compared with those with non-insulin-dependent diabetes after correction for age. There was a slight negative correlation between the relative proportion of regenerating fibres and age, but this was not statistically significant. The progressive reduction in the number of regenerating fibres with declining total fibre density indicates that axonal regeneration fails with advancing neuropathy. The production of nerve growth factor (NGF) and NGF receptors by denervated Schwann cells is likely to be important for axonal regeneration. To investigate whether the failure of axonal regeneration could be related to a lack of NGF receptor production by Schwann cells, we examined the expression of p75 NGF receptors by Büngner bands immunocytochemically. In comparison with other types of peripheral neuropathy, p75 NGF receptor expression appeared to take place normally. It is concluded that failure of axonal regeneration constitutes an important component in diabetic neuropathy. Its explanation requires further investigation.

Adult↗
PubMed1995

Secretion of recombinant human IgE-Fc by mammalian cells and biological activity of glycosylation site mutants.

We have constructed an expression vector that leads to secretion of the whole Fc of human immunoglobulin E (hIgE-Fc) from mammalian cells at levels up to 100 mg/l of culture. Two surface glycosylation sites at Asn265 and Asn371 have been changed to glutamine, to obtain a more homogeneous preparation of hIgE-Fc for structural studies. Comparison of wild-type and mutant products revealed that Asn371 is rarely glycosylated in Chinese hamster ovary cells. Both the double mutant and wild-type hIgE-Fc bind to the high-affinity IgE receptor, Fc epsilon RI, with about the same affinity as myeloma IgE (Ka in the range 10(10)-10(11) M-1), and were able to sensitize isolated human basophils for anti-IgE triggering of histamine release. However, only the double mutant hIgE-Fc approached the affinity of myeloma IgE for the low-affinity receptor, Fc epsilon RII (Ka = 7.3 x 10(7) M-1), whereas the wild-type hIgE-Fc bound with a 10-fold lower affinity (Ka = 4.1 x 10(6) M-1).

Amino Acid Sequence↗
PubMed1995

Choice of treatment affects plasma levels of insulin-like growth factor-binding protein-1 in noninsulin-dependent diabetes mellitus.

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic effects of IGFs. Although IGFBP-1 levels are abnormally high in insulin-dependent diabetes (IDDM), relatively little is known in NIDDM; conflicting data have suggested both high and low levels. We investigated whether treatment modifies IGFBP-1 levels in two groups of NIDDM patients. Study 1 examined fasting concentrations in groups of patients with NIDDM, comparable except for treatment type (sulfonylurea, n = 23; once daily insulin, n = 15; sulfonylurea plus once daily insulin, n = 14; multiple insulin injections, n = 9) and 25 nondiabetic subjects. In sulfonylurea-treated patients there were markedly reduced plasma IGFBP-1 concentrations (median, interquartile range in parentheses): control, 61.0 (36-96) micrograms/L; sulfonylureas alone, 31.5 (21-61) micrograms/L (P < 0.01); and sulfonylureas plus insulin, 31.5 (9-53) micrograms/L (P < 0.01). Once daily insulin was associated with values similar to those in the control group [62.0 (27-103) micrograms/L; P = NS], whereas IGFBP-1 levels were higher with multiple insulin injection therapy [156.0 (71-184) micrograms/L; P < 0.05]. Proinsulin levels were higher in sulfonylurea-treated patients, but there was no significant correlation between IGFBP-1 and proinsulin within any individual group. Study 2 examined the effects of treatment on the dynamics of IGFBP-1 levels between 0800-1900 h. In control subjects (n = 8), levels fell from 0800 h (mean +/- SEM, 22.4 +/- 5.2 micrograms/L) to 1000 h (14 +/- 5.2 micrograms/L), followed by a rise, more rapid after food, to a peak at 1240 h (20.6 +/- 3.7 micrograms/L). Levels then declined until 1500 h (10.7 +/- 2.9 micrograms/L), with a further postprandial peak at 1840 h (23.1 +/- 3.2 micrograms/L). Sulfonylurea therapy (n = 6) resulted in a complete loss of this pattern, with a marked fall in IGFBP-1 from 0800 h (22 +/- 2.7 micrograms/L) to less than 7 micrograms/L for the remainder of the study (area under the curve, 1150-1400 h, P < 0.001 vs. control). By contrast, in metformin-treated patients (n = 7), neither IGFBP-1 levels nor postprandial peaks were significantly different from those in the control group. Our findings suggest that in patients with NIDDM, the regulation of IGFBP-1 is markedly influenced by the choice of treatment.

Carrier Proteins↗
PubMed1995

Teaching self-administration of nasogastric tube insertion to an adolescent with Crohn disease.

We examined the effectiveness of simulation training to teach an adolescent male with Crohn disease to self-administer nasogastric tube insertion. Nasogastric tube insertion was taught using simulation training, after which self-insertion skills were assessed. Results across skill components indicated that this subject was able to self-administer insertion of the nasogastric tube.

Adolescent↗
PubMed1994

The genetic engineering of monoclonal antibodies.

A number of recent technological developments have greatly facilitated the genetic engineering of immunoglobulins. The use of PCR has permitted the variable regions to be rapidly cloned either from a specific hybridoma source or as a gene library from non-immunised cells. The conversion of the rodent antibody into a humanized version is now well established. To develop these antibodies for clinical use has required the development of high level expression systems. For the expression of large multimeric glycoproteins, mammalian cell systems generally provide the highest levels of secreted product and therefore are the methods of choice for producing whole recombinant antibodies. Novel antigen-binding units have been developed by joining the two variable domains of an antibody into single-chain polypeptides. Such fragments can be produced in high yield by secretion from E. coli raising the prospect of bulk preparation of these antibody fragments for the development of low-cost immunopurification and assay reagents. Finally, the ability to screen for antigen binding by displaying immunoglobulin variable regions on the surface of filamentous bacteriaphages has opened up the possibility of bypassing the immune system to generate novel antibody specificities in vitro.

Amino Acid Sequence↗
PubMed1994

A dispersed family of repetitive DNA sequences exhibits characteristics of a transposable element in the genus Lycopersicon.

A segment of DNA 5' to the transcribed region of an auxin-regulated gene, ARPI, from Lycopersicon esculentum Mill. cv. VFN8 contains a sequence with the structural characteristics of a transposable element. The putative element (Lyt1) is 1340 bp long, has terminal inverted repeats of approximately 235 bp and is flanked by 9-bp direct repeats. Lyt1 has a structure similar to the Robertson's Mutator (Mu) family from maize. The terminal inverted repeats are 80% AT-rich, are 96.6% identical, and define a larger family of repetitive elements. Southern analysis and genomic dot-blot reconstructions detected at least 41 copies of Lyt1-hybridizing sequences in red-fruited Lycopersicon spp. (L. esculentum, L. pimpinellifolium and L. cheesmanii), and 2-8 copies in the green-fruited species (L. hirsutum, L. pennellii, L. peruvianum, L. chilense and L. chmielewskii). There were two to four copies in the Solanum spp. closely allied with the genus Lycopersicon (S. lycopersicoides, S. ochranthum and S. juglandifolium), while the more distantly related Solanum spp. showed little (one to two copies in S. tuberosum) to no (S. quitoense) detectable hybridization under stringent conditions. Linkage analysis in the F2 progeny of a cross between L. esculentum and L. cheesmanii indicated that at least six loci that hybridize to the Lyt1 sequence are dispersed in the genome. Polymerase chain reaction and Southern analyses revealed that some red-fruited accessions and L. chmielewskii lacked Lyt1 5' to the transcribed region of ARPI. Subsequent sequence analysis indicated that only one copy of the 9-bp direct repeat (target site) was present, suggesting that transposition of the element into the ARPI gene occurred after the divergence of the red-fruited and green-fruited Lycopersicon species.

Base Sequence↗