Biomedical subjects
Publications and source records attributed to A Nicholls.
In a sample of 48 subjects, there was a significant inverse relation between item size and estimation of numerosity. This result was shown to be consistent with Gestalt theory. According to this approach, the components of good figures appear more numerous, and smaller items produce better figures.
Ehlers-Danlos syndrome (EDS) type I was diagnosed in an 18-year-old girl on the basis of marked skin hyperextensibility with generalized loose-jointedness, pigmented paper-tissue scars, and a pronounced tendency to bruising. Her father and one of her sisters showed a similar phenotype. Her mother was normal. Light microscopy of skin biopsies showed large, irregular collagen fibres in the father and daughter, with normal findings in the mother. Electron microscopy of the skin sections revealed a variation in diameter and shape of the collagen fibrils as well as slight dilatation of the rough endoplasmic reticulum of fibroblasts in father and daughter, but normal findings in the mother. Cultured fibroblasts did not show these changes. Measurements of collagen synthesis by fibroblast cultures showed that type III collagen levels were reduced to 50% of normal in the father and daughter, and were normal in the mother. The alpha I (III) proteins had a normal molecular weight, determined by SDS-PAGE electrophoresis. The phenotypes and biochemical results in the family members tested were compatible with autosomal dominant transmission. To our knowledge, this is the first report of a type III collagen deficiency in Ehlers-Danlos syndrome type I. The findings in this family, especially the pronounced bruising tendency, illustrate the heterogeneity within type I EDS.
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We have examined the collagenous proteins extracted from skin and produced by skin fibroblast cultures from the members of a family with mild dominant osteogenesis imperfecta (OI type I). The two affected patients, mother and son, produce two populations of alpha 1(I) chains of type I collagen, one chain being normal, the other containing a cysteine within the triple-helical domain. Both forms can be incorporated into triple-helical molecules with an alpha 2(I) chain. When two mutant alpha (I) chains are incorporated into the same molecule, a disulfide bonded dimer is produced. We have characterized these chains by sodium dodecyl sulfate-gel electrophoresis and CNBr-peptide mapping and by measuring a number of biosynthetic and physical variables. The cysteine was localized to the COOH-terminal peptide alpha (I) CB6. Molecules containing the mutant chains are stable, have a normal denaturation temperature, are secreted normally, and have normal levels of post-translational modification of lysyl residues and intracellular degradation. We have compared and contrasted these observations with those made in a patient with lethal osteogenesis imperfecta in which there was a cysteine substitution in alpha 1(I) CB6 (Steinmann, B., Rao, V. H., Vogel, A., Bruckner, P., Gitzelmann, R., and Byers, P. H. (1984) J. Biol. Chem 259, 11129-11138) and have concluded that the mutation in the present family occurs in the X or Y position of a Gly-X-Y repeating unit of collagen and not in the glycine position shown for the previous patient (Cohn, D. H., Byers, P. H., Steinmann, B, and Gelinas, R. E. (1986) Proc. Natl. Acad. Sci. U. S. A., in press.
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Sixty-two patients requiring regular treatment for osteoarthritis were entered into a 6-month open assessment of 1.5 g naproxen daily. Fourteen patients withdrew from the study because of side-effects, 9 because of poor efficacy and 2 for a combination of these reasons. Most side-effects related to the gastro-intestinal tract and were not of a serious nature, although 1 patient had a gastro-intestinal bleed at 24 weeks. A further patient developed neutropenia, but its relationship to naproxen therapy was considered unknown. Short-term studies of 1.5 g naproxen daily have shown an increased efficacy compared to lower doses with no increase in side-effects. It is concluded that the results of this study increase the confidence with which such a dose can be used.
Osteogenesis imperfecta (OI), a brittle-bone disorder, constitutes a major group of the inherited diseases of connective tissue. We have been studying an autosomal recessive form of OI in which the severely affected patient has inherited two abnormal pro-alpha 2(I) collagen alleles from consanguinous parents. Previously, nuclease S1 mapping was employed to localize a defect in the mRNA coding for the pro-alpha 2(I) collagen carboxyl-propeptide. The mutation prevents incorporation of pro-alpha 2(I) chains into the normal type I procollagen heterotrimer resulting in secretion of only pro-alpha 1(I) homotrimers. Here we report complete characterization of the corresponding region of the altered gene. Polyacrylamide gel electrophoresis and Southern blot hybridization showed a small homozygous deletion in the pro-alpha 2(I) collagen gene of the patient and a heterozygous pattern in both parents. Genomic cloning of the patient's DNA revealed a four nucleotide frameshift deletion in exon 1 near the end of translation which apparently instigates use of a new termination codon four nucleotides 3' to the original site. The mutation identified in this OI patient directly demonstrates the critical role of the carboxyl-propeptides in chain selection and assembly during the biosynthesis of procollagen.
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The molecular defect in a patient with a moderately severe form of osteogenesis imperfecta was characterized by nuclease S1 mapping. Single-stranded 5' and 3' end-labeled DNA probes coding for 80% of the carboxyl-propeptide of the pro alpha 2(I) collagen gene were hybridized to mRNA isolated from cultured fibroblasts of the patient and his parents. Nuclease S1 digestion revealed a homozygous mutation in the patient and a heterozygous pattern in the consanguineous parents. As a result of the defect in the gene, none of the pro alpha 2(I) chains synthesized by the patient's fibroblasts were incorporated into a type I procollagen heterotrimer consisting of two pro alpha 1(I) chains and one pro alpha 2(I) chain. Cultured skin fibroblasts from the patient have previously been shown to secrete only pro alpha 1(I) trimers. As shown here, fibroblasts from both parents, who do not have osteogenesis imperfecta, secrete both pro alpha 1(I) trimers and normal type I procollagen. A further observation was that synthesis of pro alpha 2(I) chains was decreased in fibroblasts from the patient and his parents. The decrease in the synthesis of pro alpha 2(I) chains is not caused by decreased transcription of the pro alpha 2(I) collagen alleles, since the pro alpha 1(I)/pro alpha 2(I) mRNA ratios were normal in the patient and his parents.
Cultured fibroblasts were examined from a patient with a nonlethal form of osteogenesis imperfecta. As reported previously (Nicholls, A. C., Pope, F. M., and Schloon, H. (1979) Lancet 1, 1193), the cells synthesized and secreted a type I procollagen which lacked pro-alpha 2(I) chains and consisted of a trimer of pro-alpha 1(I) chains. No pro-alpha 2(I) chains were recovered from the medium under conditions in which nonhelical pro-alpha 1(I) and pro-alpha 2(I) chains were readily detected in the medium of normal fibroblasts incubated with the hydroxylase inhibitor, alpha, alpha'-dipyridyl. Examination of cellular proteins demonstrated that the fibroblasts synthesized both pro-alpha 1(I) and pro-alpha 2(I) chains. The cellular pro-alpha 2(I) chains did not, however, become disulfide-linked into dimers or trimers of pro-alpha chains. Since the association of pro-alpha chains during the biosynthesis of type I procollagen is directed by the conformation of the COOH-terminal propeptides, the data suggest that the pro-alpha 2(I) chains synthesized by the fibroblasts have a mutated structure in the COOH-terminal propeptides which markedly reduces their affinity for pro-alpha 1(I) chains. A further observation was that the ratio of newly synthesized pro-alpha (I):pro-alpha 2(I) chains in the patient's fibroblasts was 7.18 +/- 0.58 S.E. instead of the value of 2.25 +/- 0.16 S.E. seen in control fibroblasts. One possible explanation for the high ratio is that the proband is homozygous for a mutation altering the structure of the pro-alpha 2(I) chain and that a secondary effect of the structural mutation is a decreased rate of synthesis of pro-alpha 2(I) chains.
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It is commonly believed that atherogenesis is accelerated in patients with chronic renal failure during treatment by long-term dialysis or renal transplantation. However, several recent studies have failed to confirm this concept, despite the fact that overall atherosclerotic deaths in these patients are much higher than in the normal population. The natural history of atherogenesis in renal failure becomes much clearer if one analyses autopsy series of the pre-dialysis era. It is apparent from such studies that atheroma is frequent in renal failure before the development of terminal uraemia and that hypertension emerges as the major risk factor. Subsequent atherosclerotic deaths during long-term dialysis or renal transplantation may reflect progression of previously acquired atheroma, but do not per se indicate that atherogenesis has been accelerated after the commencement of renal replacement therapy. A proper appreciation of the natural history of atheroma in renal failure may permit a more rational approach to therapeutic intervention.
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Twenty-six children suffering from juvenile chronic arthritis were entered into a 6-month open evaluation of naproxen suspension. Sixteen patients completed 6-months' treatment, 6 were lost to follow-up and 4 dropped out, 2 because of side-effects (rash, and burning on swallowing the formulation), 1 for lack of efficacy and 1 because of no further need of treatment. Pain severity scores were significantly reduced from admission levels at all monthly follow-up visits and significant overall improvement since the last visit was noted up to third month of treatment, as assessed by doctor and parent/patient. Transient indigestion was reported by 2 patients. No clinically significant trends were noted in any of the laboratory investigations carried out. The results add to the accumulation of data on the use of naproxen in children and underline its long-term efficacy and tolerance.
A double blind trial of folic acid against placebo was carried out on out-patients with epilepsy treated with Phenytoin. There was a minimum period on treatment of one year. While the group receiving folic acid in the treatment period showed a significant improvement in seizure frequency, the placebo group also showed some improvement. It is concluded that the improvement while on folic acid was not due to the folic acid treatment alone. The subjective well-being of patients was not influenced by folic acid therapy.
Eleven patients with recent kidney transplants have undergone serial pelvic imaging after autologous platelet labelling with indium-111. Rejection was accompanied by marked platelet deposition in the graft, whereas acute tubular necrosis was characterized by minimal platelet accumulation. The method has been quantified by comparing counts over the graft to counts from a similar area on the opposite site, and appears to distinguish between the two main causes of renal failure after transplantation. In addition, complications of transplant surgery may be demonstrated.
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Septicaemia is a common and potentially lethal hazard of haemodialysis and renal transplantation; it is usually caused by Staphylococcus pyogenes. In 6 patients with S. pyogenes septicaemia, fatal endocarditis and spinal osteomyelitis have each occurred once, and 3 patients have had recurrent episodes of septicaemia. The management of septicaemia in these patients must include a search for metastatic infection, and prolonged therapy with 2 antistaphylococcal agents is necessary to ensure eradication of infection. Access site infection in dialysis patients must be treated vigorously, and recognized as potentially hazardous by patients. The risk of sepsis in dialysis and transplant patients cannot be excluded, but devastating consequences may be avoided by simple measures.