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Biomedical subjects

A Dalton

Publications and source records attributed to A Dalton.

At least 19 recordsLinked to original sources
PubMed2006

Clinical features of hereditary spastic paraplegia due to spastin mutation.

BACKGROUND: Mutations in the spastin gene are the commonest cause of hereditary spastic paraparesis (HSP), accounting for up to 40% of autosomal dominant cases. The phenotype associated with HSP due to mutation in the spastin gene (SPG4) tends to be pure HSP. OBJECTIVE: To characterize in more detail the genetic and phenotypic characteristics of SPG4 by examining a large cohort of patients with HSP. METHODS: The authors identified patients who tested positive for spastin mutation using a direct sequencing approach of all exons. RESULTS: The authors identified spastin mutations in 53 patients. Twenty-seven of the mutations identified were novel. The phenotype in the majority of patients was of pure HSP. In one individual, a complicated phenotype with progressive bulbar dysfunction and respiratory insufficiency was observed. Evidence of lower motor neuron dysfunction in a subgroup of SPG4 patients was identified. The missense changes S44L and P45Q were identified in patients with other spastin mutations and seemed to be exerting a phenotype-modifying effect. CONCLUSION: These findings add to the number of spastin mutations identified and demonstrate the importance of screening the whole gene, given the possibility of double mutations and intragenic modifiers. The identification of the complicated phenotypes has important implications for identifying the phenotype of patients in whom spastin screening should be considered. The presence of lower motor neuron dysfunction in a subgroup of SPG4 patients suggests that the cellular dysfunction in SPG4 extends beyond the axonal projections of upper motor neurons and ascending sensory pathways.

Adenosine Triphosphatases↗
PubMed2006

Pulmonary infection in mild variant cystic fibrosis: implications for care.

BACKGROUND: Disease phenotype in cystic fibrosis (CF) shows considerable heterogeneity. Atypical or mild mutations in the CFTR gene have been linked to late-onset pulmonary disease; however, few reports document the condition of the airway in infants and young children with apparent "mild" disease. Prognosis is uncertain in this group of patients and this, in turn, has led to inconsistency in management. Our initial experience of pulmonary infection in children with mild variant CF prompted a more detailed review of clinical outcome. METHODS: A retrospective cohort study was carried out comparing frequency of bacterial isolates and clinical outcomes in eleven compound heterozygotes for DeltaF508 and a second mild mutation, mainly R117H, with a matched group of DeltaF508 homozygotes. RESULTS: Staphylococcus aureus was isolated in 8 of the 11 patients with mild variant disease and Pseudomonas aeruginosa found in 7 (64%), although the frequency of positive cultures was significantly less (2.8/year) than the DeltaF508 homozygotes (6.1/year, p<0.05). Shwachman scores (median+range) were significantly higher in patients with mild mutations - 94, 74-92 vs. 88, 77-91; p<0.005); there was also a small but significant difference in chest radiograph (Chrispin-Norman) scores (median+range) (mild 5.1, 4-9, vs. severe 5.8, 3-10; p 0.04). There was little difference in lung function in terms of FEV1 (median+range) between the two groups (% predicted, mild 86.5, 68-87 vs. severe 76.0, 65-88; p 0.5). CONCLUSIONS: Most patients with mild variant CF will have bacterial isolates from airway cultures requiring antibiotic therapy three to four times a year. Infection with both S. aureus and P. aeruginosa is common. Anti-staphylococcal prophylaxis for the first two years should be considered.

Anti-Bacterial Agents↗
PubMed2004

Infantile hereditary spastic paraparesis due to codominant mutations in the spastin gene.

The authors describe an infant with a severe spastic paraparesis caused by two codominant mutations of the spastin gene. This highlights the multiple molecular mechanisms that are likely to be involved in the molecular pathology of SPG4 and illustrates the importance of complete screening of the spastin gene in affected individuals, particularly if the index case has an unusual phenotype.

Adenosine Triphosphatases↗
PubMed2003

Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency.

Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation, a wider range of CPT II activity (10-60%) but little evidence of genotype-phenotype correlation. Residual CPT II mutant protein from myopathic patients shows thermal instability at 41 degrees C. The common 'polymorphisms' V3681 and M647V are strikingly overrepresented in the myopathic patients, the implication being that they may significantly influence the manifestation of clinical disease and could therefore potentially be considered as a susceptibility variants. Among myopathic individuals, males comprised 88% of patients, suggesting increased susceptibility to clinical disease. A small number of symptomatic patients appear to have significant residual CPT II activity (42-60%) The synergistic interaction of partial deficiencies of CPT II, muscle adenosine monophosphate deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration.

AMP Deaminase↗
PubMed2000

Partial impairment of immune functions in peripheral blood leukocytes from aged men with Down's syndrome.

Down's syndrome (DS) has been considered a model of accelerated aging and of Alzheimer's disease. We investigated immunologic functions using peripheral blood leukocytes in order to correlate the production of cytokines and development of neuropathological changes of Alzheimer type in aged persons with DS. Cytokine production (IL-1beta, IL-2, IL-6, IL-8, and TNF-alpha), phytohemagglutinin (PHA)-stimulated proliferation of nonadherent monocytes, and superoxide anion production from polymorphonuclear leukocytes were measured. PHA-stimulated proliferation in aged individuals (>30 years old) with DS was significantly lower than that of age- and sex-matched controls (DS vs control, 55,707+/-5810 vs 88,310+/-6994 cpm, P < 0.001). PHA-stimulated IL-2 production was also significantly decreased in aged individuals with DS (DS vs control, 7.1+/-2.1 vs 10.7+/-1.3 ng/ml). Interestingly, the decrease of proliferation and IL-2 production in aged males with DS is significantly greater than in aged women with DS. PHA-stimulated proliferation and IL-2 production of nonadherent monocytes in females was not significantly reduced. IL-1beta production by LPS-activated adherent monocytes was significantly decreased in older adults with DS compared with non-DS controls. Other immune parameters measured in DS were not significantly different from that of age-matched controls. We conclude that there is partial impairment of T lymphocytes in aged persons with DS that is significantly greater in males than in females.

Adult↗
PubMed1999

Neutrophil infiltration into human gliomas.

Human gliomas were analysed for the infiltration of neutrophils using immunohistochemistry by staining sections for CD15-positive and myeloperoxidase-positive cells. Over 70% of all glioma samples analysed (n = 105) had significant neutrophil infiltration, but there was a marked and significant correlation between tumour grade and the extent of the neutrophil infiltration. In the low grade tumours only 40-50% had significant infiltration, while in glioblastoma multiforme over 85% of the samples analysed had significant infiltration. Numbers of neutrophils infiltrating glioblastoma multiforme tumours were also greater than in the other tumour groups. Circulating white blood cell counts were elevated above the normal range in all glioma patients, but this elevation was entirely due to increased numbers of circulating neutrophils. Again, the highest numbers of circulating neutrophils were seen in the glioblastoma multiforme patients. These experiments indicate that glioma-derived factors may directly or indirectly affect the number of circulating neutrophils and influence their infiltration into the tumours.

Bone Marrow↗
PubMed1999

Disinfection of contact lenses without tap water rinsing: is it effective?

PURPOSE: To establish the efficacy of the two most popular contact lens disinfecting systems--one-step hydrogen peroxide and multipurpose disinfecting solution--for 1 month's use in practice in the absence of tap water rinsing. METHODS: This was a descriptive, prospective microbiological study of contact lens contamination with ideal hygiene compliance and new lenses and storage cases. One hundred and fifty contact lens wearers were instructed to avoid risk factors identified for Acanthamoeba infection. They were randomly assigned to use one of three disinfecting systems and taught to follow manufacturers' instructions. In addition, they were taught to avoid all use of tap water for contact lens hygiene, except for hand washing. RESULTS: There was no isolation of Acanthamoeba from any lens storage case, precluding the chance of amoebic infection. The multi-purpose solution gave the lowest rate of bacterial contamination, with 78% sterility and 15% of cases with < 10(4) bacteria/ml. For both one-step peroxide and multi-purpose solutions, Gram-negative bacteria were reduced in frequency compared with values expected historically, while Bacillus sp. were found more frequently. Storage cases of both one-step peroxide systems leaked fluid. CONCLUSIONS: On the basis of contamination in previous studies, when hydrogen peroxide and other chemical disinfectants were used together with tap water washing, it was expected that approximately 40% of lens storage cases would yield bacteria, often with a high count, and that up to 8% would yield Acanthamoeba. Such contamination did not occur, however, in this study. The multipurpose solution, for 1 month's use, gave the lowest rate of bacterial contamination with only 7% of storage cases harbouring bacteria at > 10(4)/ml and with 78% sterility. One of the two one-step hydrogen peroxide systems performed equally well. Importantly, Acanthamoeba was not isolated from any of the 150 storage cases. Whether lens storage cases need to be sterile or contain < 10(3) bacteria/ml solution within them is debatable, but it is essential that Acanthamoeba be absent from them.

Acanthamoeba↗
PubMed1997

Diagnosis of dementia in individuals with intellectual disability.

The foremost impediment to progress in the understanding and treatment of dementia in adults with intellectual disability is the lack of standardized criteria and diagnostic procedures. Standardized criteria for the diagnosis of dementia in individuals with intellectual disability are proposed, and their application is discussed. In addition, procedures for determining whether or not criteria are met in individual cases are outlined. It is the intention of the authors, who were participants of an International Colloquium on Alzheimer Disease and Mental Retardation, that these criteria be appropriate for use by both clinicians and researchers. Their use will improve communication among clinicians and researchers, and will allow researchers to test hypotheses concerning discrepancies in findings among research groups (e.g. dementia prevalence ranges and age of onset).

Age of Onset↗
PubMed1997

Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich's ataxia genes in spinocerebellar ataxia patients in the UK.

Accurate clinical diagnosis of the spinocerebellar ataxias (SCAs) can be difficult because of overlap in phenotype with other disorders and variation in clinical manifestations. Six SCA loci have been mapped and four disease causing genes identified, in addition to the causative gene for Friedreich's ataxia (FA). All of the identified mutations are expansions of trinucleotide repeat tracts. The SCA2 and SCA6 genes were published recently. The extent of the normal CAG size ranges at these loci and the relative frequencies of the known causes of SCA in the UK are not known. This study first investigated the normal size ranges of the SCA2 and SCA6 loci by genotyping control populations of West African and South African subjects, since African populations generally show the greatest allelic diversity. We found one allele larger than the previously determined normal range for SCA2, and our results at the SCA6 locus agreed with the previously reported normal range. The second component of the study assessed the relative frequencies of the SCA1, 2, 3, and 6, DRPLA, and FA trinucleotide repeat mutations in 146 patients presenting with SCA-like symptoms referred to genetic diagnostic laboratories in the UK. We detected mutations in 14% of patients referred with a diagnosis of autosomal dominant SCA, and in 15% of patients referred with spinocerebellar ataxia where we did not have sufficient family history data available to allow categorisation as familial or sporadic cases. Friedreich's ataxia accounted for 3% of the latter category of cases in our sample, but the most common causes of SCA were SCA2 and SCA6.

Adolescent↗
PubMed1997

Neonatal screening for cystic fibrosis in the Trent region (UK): two-stage immunoreactive trypsin screening compared with a three-stage protocol with DNA analysis as an intermediate step.

OBJECTIVES: To assess neonatal screening for cystic fibrosis using immunoreactive trypsin, either alone or in conjunction with DNA analysis for the delta F508 mutation. A novel three-stage screening protocol was compared with the previously introduced two-stage immunoreactive trypsin-DNA protocol. DESIGN: (a) Collection of data from a 4 1/2 year period (phase 1) of two-stage immunoreactive trypsin screening. The initial dried blood samples were obtained at 6 days of age and repeat samples at 27 days of age from babies with results above the 99.5th centile. Babies with persistent hypertrypsinaemia were referred for a diagnostic sweat test. (b) Retrospective DNA analysis: patients with cystic fibrosis diagnosed in phase 1 were genotyped and most samples from babies with increased initial immunoreactive trypsin but normal results in the second sample were analysed for the delta F508 mutation. (c) Phase 2, a prospective study of a three-stage neonatal screening protocol, in which only babies heterozygous for the delta F508 cystic fibrosis mutation progressed to the second immunoreactive trypsin test. SETTING: The Trent neonatal screening programme. SUBJECTS: 437 859 babies born between August 1989 and March 1996. MAIN OUTCOME MEASURES: Proportions of unaffected babies requiring a second blood sample or a sweat test. Overall sensitivity for the detection of cystic fibrosis. RESULTS: The two-stage screen failed to identify six out of 94 cases of cystic fibrosis (without meconium ileus). The introduction of the DNA analysis step would have resulted in one additional case being missed. With the three-stage screen there was a 92% reduction in babies requiring a second blood sample and an 80% reduction in negative sweat tests, results close to the predictions of the retrospective study. CONCLUSIONS: The three-stage screening protocol is a marked improvement on the two-stage immunoreactive trypsin strategy and on the two-stage immunoreactive trypsin-DNA strategy recently introduced in some other screening programmes.

Cystic Fibrosis↗