Biomedical subjects
Publications and source records attributed to S A Peters.
The rare inherited disorder hyperprolinaemia type II presents with fits in childhood, usually precipitated by infection. A diagnosis of hyperprolinaemia type II and vitamin B(6) deficiency was made in a well nourished child with fits. It is thought that pyridoxine deficiency was implicated in her fits and was the result of inactivation of the vitamin by the proline metabolite, pyrroline-5-carboxylate.
A cohort of 946 children who were screened for otitis media with effusion (OME) from the ages of 2 to 4 were studied for language, reading, and spelling at 7 years of age. The effects of OME in combination with single risk factors and with increasing numbers of risk factors were investigated. An interaction with an additional risk factor was found only for gender and OME, with boys' spelling influenced negatively by a history of OME. OME in combination with preterm birth and low birthweight also appears to put children at risk for later language and educational problems. Although a negative linear relation between the number of risk factors and later functioning was found, it is suggested that OME, even when combined with a number of other risk factors, produces only minor effects on later language, reading, and spelling.
Vitamin E is an antioxidant and may have a role in the protection of lung tissue against oxidative damage in cystic fibrosis. Previous studies of vitamin E status in cystic fibrosis have used plasma or serum concentrations, which vary with levels of carrier lipoproteins and hence may not reflect the concentration of vitamin E in tissues, where it is found in highest concentration in membranes. Erythrocyte vitamin E concentration has been shown to correlate well with tissue concentrations of the vitamin in animals, but it has not previously been studied in patients with cystic fibrosis. Current guidelines on vitamin supplementation in cystic fibrosis include vitamin E. It is not presently clear which level of supplementation is most appropriate. To address this question, we examined the effect on erythrocyte vitamin E levels of supplementation with either 15 mg or 100 mg per day of vitamin E. Analysis was performed by high performance liquid chromatography before and 1 year after initiation of supplementation in children with cystic fibrosis. Erythrocyte vitamin E concentrations were below the normal range in almost all unsupplemented patients and rose into the normal range with a supplement of 100 mg per day, but not 15 mg per day. This rise was not accounted for by changes in general dietary treatment. We conclude that tissue vitamin E levels are low in patients with cystic fibrosis who do not receive supplements but can be normalized in most children with 100 mg of vitamin E. per day.
Processing of the 112 kDa ('112K') protein encoded by cowpea mosaic virus RNA 1 was examined in cowpea mesophyll protoplasts using a transient expression system. Cleavage of the 112K protein occurred via two alternative pathways either into VPg and 110K (24K + 87K) or into 26K (VPg + 24K) and 87K proteins. The 26K protein can be further cleaved into VPg and 24K proteins. The results support a model in which the 112K protein functions as the precursor of VPg during initiation of replication.
We have assessed the functional importance of the NTP-binding motif (NTBM) in the cowpea mosaic virus (CPMV) B-RNA-encoded 58K domain by changing two conserved amino acids within the consensus A and B sites (GKSRTGK500S and MDD545, respectively). Both Lys-500 to Thr and Asp-545 to Pro substitutions are lethal as mutant B-RNAs were no longer replicated in cowpea protoplasts. Transiently produced mutant proteins were not able to support trans-replication of CPMV M-RNA in cowpea protoplasts in contrast to transiently produced wild-type B proteins. Therefore loss of viral RNA synthesis was a result of a protein defect rather than an RNA template defect. Mutant B polyproteins were correctly processed in vitro and in vivo and the regulatory function of the 32K protein on processing of B proteins was not affected by these mutations. Since regulation of processing by the 32K protein depends on interaction with the 58K domain, the mutations in the NTBM apparently do not interfere with this interaction. The Asp-545 to Pro substitution left intact the binding properties of the 84K precursor of the 58K protein, with respect to ATP-agarose, whereas the Lys-500 to Thr substitution decreased the binding capacity of the 84K protein, suggesting that the Lys-500 residue is directly involved in ATP binding. The Lys-500 to Thr substitution in the 58K domain resulted in an altered distribution of viral proteins, which failed to aggregate into large cytopathic structures as observed in protoplasts infected with wild-type B-RNA. However viral proteins containing the Asp-545 to Pro substitution showed a normal distribution in protoplasts.
The relationship between long-lasting, bilateral otitis media with effusion (OME) between the ages of 2 and 4 and educational attainment, in particular, reading and spelling ability at 7 years of age, was studied in a prospective cohort study of 946 children. After selection, three groups were distinguished: 151 children with long-lasting, bilateral OME at preschool age, 37 preschool children treated with ventilation tubes, and 82 children with no history of OME at that age. Early bilateral OME was found to affect spelling ability, but not reading ability, at 7 years. The effects of OME did not appear to increase with the number of observations of OME. Also, recurrent hearing loss did not have more detrimental effects than continuous hearing loss. Effects of treatment with ventilation tubes were not found. Only the teachers' ratings of writing ability indicated a slight advantage of treatment with ventilation tubes. In conclusion, the educational consequences of early OME appear to be very small.
The current study, which is a follow-up on the epidemiological Nijmegen Otitis Media study, examines the relationship between early otitis media with effusion (OME) and later language ability in a group of children with systematically documented bilateral OME. In the Nijmegen Otitis Media study, children were screened using tympanometry at regular intervals of 3 months, between their second and fourth birthdays. At age 7, three groups of children participated in language testing: 82 OME-free children, 151 children with early bilateral OME, and 37 children treated with ventilation tubes at preschool age. A history of OME, even up to nine instances, did not have negative consequences for language performance at age 7. Intermittent, as opposed to more continuous, OME was not found to affect language ability negatively. The suggested benefit of treatment with ventilation tubes was not found.
The long-term effects of early OME on language and educational attainment were studied in 47 children of 7-8 years of age who had participated in an earlier pre-school study on otitis media with effusion (OME) and language development. At pre-school age OME was diagnosed by quarterly tympanometric screens (maximum nine) and language was assessed by a standard Reynell test. At school age the ears of the children were assessed by otomicroscopy, tympanometry and audiometry, and the development status by several language, reading and spelling tests. The association between early OME and language development found at pre-school age was no longer present at school age.
Vitamin supplements are routinely prescribed in cystic fibrosis, but published recommendations vary widely and there is little consistency in clinical practice. A review of the literature confirms that, while supplementation of the water-soluble vitamins (including B12 and folate) is unnecessary in uncomplicated cystic fibrosis, deficiency of the fat-soluble vitamins can lead to clinical problems. Supplements of these vitamins should be ensured for all patients with cystic fibrosis, while sparing them the unnecessary inconvenience of taking other vitamin supplements except where these are specifically indicated.
We have studied the regulation of proteolytic processing of the polyproteins encoded by cowpea mosaic virus M-RNA and B-RNA. For that purpose mutations were introduced in full-length cDNA clones of these RNAs. RNA transcripts were translated in rabbit reticulocyte lysate and the effect of mutations on the processing was analysed. These studies revealed that the 32K protein is released from the 200K B-polyprotein by an intramolecular cleavage and remains associated with the 170K protein, probably by interaction with the 58K domain of the 170K protein. In this complex the conformation of the 170K protein is such that further cleavages are very slow. This complex carries out the processing of the Gln/Met site in the M-polyprotein. The 170K protein produced by a B-RNA mutant that lacks the 32K coding region was efficiently processed into 110K, 87K, 84K, 60K, 58K and 24K cleavage products. Thus, the 32K protein regulates the B-polyprotein processing by slowing it down and, on the other hand, enhances trans cleavage of M-polyproteins at a Gln/Met site.
To study the processing of putative VPg precursors the expression of specific mutant transcripts derived from a full-length cDNA clone of cowpea mosaic virus (CPMV) B-RNA was examined in a rabbit reticulocyte lysate system. This study revealed that the 170K protein produced by a B-RNA mutant that lacks the 32K coding region was efficiently processed by mainly intramolecular cleavages at three different sites into three sets of proteins of 60K + 110K, 84K + 87K, and 58K + 112K. Further cleavage of the 60K protein into 58K and VPg has not been observed in this in vitro system. The 84K protein can be further processed by an intramolecular cleavage reaction via two alternative pathways, either into 26K (VPg + 24K) and 58K proteins or into 24K and 60K proteins. VPg can be released from the 112K (VPg + 110K) precursor either directly or via the 26K intermediate. Immunoblot analysis showed that the 112K protein is present in CPMV-infected plant cells indicating that the in vitro observations may hold true in vivo.
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