Biomedical subjects

E Storey

Publications and source records attributed to E Storey.

At least 37 records · Page 2Linked to original sources

PubMed1999

Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene.

Mutations in the presenilin 1 (PS1) gene are responsible for approximately 50% of early onset autosomal-dominant Alzheimer's disease cases. A PCR based mutation detection method, chemical cleavage of mismatch, was used to detect a novel PS1 mutation in the coding sequence of the PS1 gene. Sequencing confirmed a T to C transition altering a leucine to proline at codon 219 of the PS1 gene. This is a novel mutation in exon 7 of the PS1 gene occurring outside the transmembrane regions of IV and V.

Age of Onset↗

PubMed1999

Spinocerebellar ataxia type 2: clinical features of a pedigree displaying prominent frontal-executive dysfunction.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a recently delineated cause of autosomal dominant cerebellar ataxia type I. The basic clinical neurologic features of SCA2 have been described in the literature, but neuropsychological features have not, despite statements that some patients became demented. OBJECTIVE: To describe the clinical and neuropsychological features of patients from a pedigree with SCA2. PATIENTS AND METHODS: We studied 8 affected members of an Australian pedigree of northern Italian origin with autosomal dominant cerebellar ataxia type I caused by SCA2. Patients underwent clinical neurologic examination and abbreviated neuropsychological testing, while some also underwent magnetic resonance imaging. The results were compared with pooled results from previously published studies of patients with SCA2. RESULTS: The pedigree displayed anticipation, with earlier onset in later generations, and there was an inverse correlation between repeat number and age at onset. The principal difference from other clinical reports of SCA2 was our finding of unequivocal frontal-executive dysfunction in 5 of 6 individuals who could be tested quantitatively, despite Mini-Mental State Examination scores in the nondemented range. This feature did not appear to correlate with either repeat size or duration of illness. CONCLUSIONS: In light of a recent report of frontal-executive dysfunction in spinocerebellar ataxia type III, we postulate that this pattern may be common to the autosomal dominant cerebellar ataxias and frequently may be overlooked because of the insensitivity of routine screening tests such as the Mini-Mental State Examination.

Adult↗

PubMed1999

The amyloid precursor protein of Alzheimer's disease and the Abeta peptide.

Alzheimer's disease is characterized by the accumulation of beta amyloid peptides in plaques and vessel walls and by the intraneuronal accumulation of paired helical filaments composed of hyperphosphorylated tau. In this review, we concentrate on the biology of amyloid precursor protein, and on the central role of amyloid in the pathogenesis of Alzheimer's disease. Amyloid precursor protein (APP) is part of a super-family of transmembrane and secreted proteins. It appears to have a number of roles, including regulation of haemostasis and mediation of neuroprotection. APP also has potentially important metal and heparin-binding properties, and the current challenge is to synthesize all these varied activities into a coherent view of its function. Cleavage of amyloid precursor protein by beta-and gamma-secretases results in the generation of the Abeta (betaA4) peptide, whereas alpha-secretase cleaves within the Abeta sequence and prevents formation from APP. Recent findings indicate that the site of gamma-secretase cleavage is critical to the development of amyloid deposits; Abeta1-42 is much more amyloidogenic than Abeta1-40. Abeta1-42 formation is favoured by mutations in the two presenilin genes (PS1 and PS2), and by the commonest amyloid precursor protein mutations. Transgenic mouse models of Alzheimer's disease incorporating various mutations in the presenilin gene now exist, and have shown amyloid accumulation and cognitive impairment. Neurofibrillary tangles have not been reproduced in these models, however. While aggregated Abeta is neurotoxic, perhaps via an oxidative mechanism, the relationship between such toxicity and neurofibrillary tangle formation remains a subject of ongoing research.

Alzheimer Disease↗

PubMed1999

Amyloid precursor protein of Alzheimer's disease: evidence for a stable, full-length, trans-membrane pool in primary neuronal cultures.

We and colleagues have shown that the amyloid protein precursor of Alzheimer's disease (APP) is distributed along the surface of neurites of fixed but nonpermeabilized neurons in primary culture in a segmental pattern, which shows colocalization with some markers of adhesion patches. This is in contrast to the diffuse pattern of immunoreactivity seen after permeabilization. We have also recently demonstrated that the APP in these surface patches is likely to be integral to the membrane rather than secreted and re-adsorbed, based on alkali stripping experiments and on soluble APP adsorption experiments. Total cellular APP has previously been shown to have a short half-life of approximately 30-60 min. We confirm this in neurons in primary culture in pulse-chase experiments using short labelling times. Additionally, we provide evidence that a separate, stable pool of neuronal APP can be demonstrated in pulse-chase experiments using long labelling times. Experiments involving inhibition of protein synthesis suggest that this corresponds with the surface, segmental pool. Metabolic labelling followed by surface biotinylation and two-stage precipitation demonstrates that the surface APP is trans-membrane and full-length (not carboxyl-terminal truncated), and confirms that the surface APP belongs to the stable pool. This two-stage procedure is necessary as the surface APP appears to be present in low copy number, and is difficult to detect by direct labelling. This information is consistent with a role for APP in stable cell-matrix or cell-cell interactions.

Alzheimer Disease↗

PubMed1999

Industrial hygiene recommendations as interventions: a collaborative model within occupational medicine.

The authors conducted a cross-sectional telephone survey of patients and employers to evaluate the effectiveness of conducting industrial hygiene work site visits as part of the medical management of clinic patients with suspected occupational disease. Industrial hygiene interventions were intended to keep the index patient from ongoing exposure while simultaneously protecting co-workers from future disease. The demographics of the 76 work sites and patients are summarized. According to the employers, 78 percent had implemented at least one recommended intervention, and 52 percent of the employers had implemented the priority intervention. The factors associated with the employers' implementation of the recommended industrial hygiene controls are presented. Employers were 3.7 times more likely to implement the priority intervention (p = .04) if they believed a worker's illness was work-related. Employers with joint labor-management health and safety committees were 3.8 times as likely to implement the priority intervention (p = 0.04). The factors associated with changes in the patients' self-reported disease status are explored and the social and economic implications of this model, are discussed. Patients who reported an improvement in disease status were 5.5 times more likely to have maintained or increased their salary (p = 0.03). Patients were 10.4 times more likely to be working if the employer had implemented any intervention (p = 0.02) and 13.3 times more likely if the priority intervention (p = 0.01) had been adopted. Those patients who left their original employer suffered a median decrease in salary of 35 percent if they found work with a different employer and a 90 percent decrease when they failed to find a new job.

Connecticut↗

PubMed1999

Fatalities from occupational diseases in Connecticut.

Occupational diseases in Connecticut were identified using reports to the Workers' Compensation Commission, Connecticut OSHA, Vital Statistics, and the Tumor Registry. There were 93 identified fatalities from occupational disease in 1995, and 90 in 1994, approximately three times the number of traumatic occupational fatalities. Identified fatalities were predominantly from asbestos-related diseases, including mesothelioma and asbestosis. Most occupational diseases are not readily identifiable with current reporting mechanisms. Based on national estimates, these figures are considered to be an underestimate of the true burden of occupational disease. Increased awareness and reporting of occupational diseases is needed to properly identify and prevent these common conditions.

Asbestosis↗

PubMed1998

Hypersensitivity pneumonitis: a sentinel event investigation in a wet building.

Hypersensitivity pneumonitis (HP) as a sentinel event implies a remediable exposure and an exposed cohort that require evaluation. A patient with HP convincingly related to her building led to a questionnaire survey in follow-up. Building coworkers demonstrated substantially higher symptom rates than did controls in five other buildings, although no further cases of disease were identified. It is likely that moisture sources in the building included an oversized cooling system and below-grade moisture, but the building met all applicable regulations and standards. Screening investigations for disease are not mandated by law and are often not conducted, in part because cost coverage is unclear. The absence of regulatory or professional standards that adequately address moisture in the built environment forces occupational health professionals to rely on disease documentation strategies to justify intervention.

Alveolitis, Extrinsic Allergic↗

PubMed1998

Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission.

The gene for spinocerebellar ataxia 7 (SCA7) includes a transcribed, translated CAG tract that is expanded in SCA7 patients. We have determined expansions in 73 individuals from 17 SCA7 kindreds and compared them with repeat lengths of 180 unaffected individuals. Subjects with abnormal expansions comprise 59 clinically affected individuals and 14 at-risk currently unaffected individuals predicted to carry the mutation by haplotype analysis. For expanded alleles, CAG repeat length correlates with disease progression and severity and correlates inversely with age of onset. Increased repeat lengths are seen in generational transmission of the disease allele, consistent with the pattern of clinical anticipation seen in these kindreds. Repeat lengths in expanded alleles show somatic mosaicism in leukocyte DNA, suggesting that these alleles are unstable within individuals as well as between generations. Although dynamic repeat expansions from paternal transmissions are greater than those from maternal transmissions, maternal transmission of disease is more common, suggesting germline or embryonic effects of the repeat expansion.

Adolescent↗

PubMed1998

Building-associated pulmonary disease from exposure to Stachybotrys chartarum and Aspergillus versicolor.

The authors present an outbreak of disease associated with exposure to Stachybotrys chartarum and Aspergillus species. A courthouse and two associated office buildings had generated discomfort among employees for two years since initial occupancy. Multiple interventions had been unsuccessful An initial evaluation of 14 individuals identified three with potential asthma and three with symptoms consistent with interstitial lung disease. A clinical screening protocol to identify individuals who should be removed from work identified three likely and seven possible cases of building-related asthma. Detailed environmental and engineering assessments of the building identified major problems in mechanical system design, building construction, and operational strategies leading to excess moisture and elevated relative humidities. Moisture-damaged interior surfaces in both buildings were contaminated with S. chartarum, A. versicolor, and Penicillium species. Aspergillus species, especially A. versicolor, at concentrations of 10(1) to 10(4)/m3 dominated the indoor air under normal operating conditions. Bulk samples also revealed large quantities of Stachybotrys. A questionnaire survey of the three case and two control buildings documented between three- and 15-fold increases in symptoms. A nested case-control study suggested emphysematous-like disease in individuals meeting questionnaire definitions for cases. Replication of analysis strategies used in similar previous investigations suggested an association between worsening symptoms and decreased diffusing capacity of the lung. Performance on neuropsychological measures was similar for both cases and controls, although workers with symptoms reported increased levels of current but not past psychiatric symptomatology. Chemical analyses demonstrated the presence of satratoxins G and H. Cytotoxic laboratory analyses demonstrated the presence of agents with biological effectiveness in bulk materials. No association was seen between IgE or IgG antibodies and the presence of disease. This outbreak represents a likely human response to inhaled fungal toxins in indoor environments. Moisture indoors represents a public health issue currently inadequately addressed by building, health, or housing codes.

Adult↗

PubMed1997

Down-regulation of the amyloid protein precursor of Alzheimer's disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata.

The hallmark of Alzheimer's disease is the cerebral deposition of amyloid which is derived from the amyloid precursor protein (APP). The function of APP is unknown but there is increasing evidence for the role of APP in cell-cell and/or cell-matrix interactions. Primary cultures of murine neurons were treated with antisense oligonucleotides to down-regulate APP. This paper presents evidence that APP mediates a substrate-specific interaction between neurons and extracellular matrix components collagen type I, laminin and heparan sulphate proteoglycan but not fibronectin or poly-L-lysine. It remains to be determined whether this effect is the direct result of APP-matrix interactions, or whether an intermediatry pathway is involved.

Alzheimer Disease↗

PubMed1997

Tardive tremor.

Explore the source record for details and available documents.

Anti-Dyskinesia Agents↗

PubMed1997

The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathologic phenotypes in an Australian kindred.

Fatal familial insomnia (FFI) is an inherited prion disease characterized by progressive insomnia and dysautonomia with only modest cognitive impairment early in the disease, associated with atrophy and gliosis in the medial thalamus, but without spongiform change. FFI is associated with an aspartic acid to asparagine mutation at codon 178 of the PrP gene (D178N) in conjunction with methionine at the codon 129 polymorphic site on the mutant allele (cis-129M). We report a pedigree with this genotype in which marked clinicopathologic phenotypic heterogeneity occurred including typical Creutzfeldt-Jakob disease, FFI, and what was thought to be an autosomal dominant cerebellar ataxia (ADCA)-like-illness, suggesting that the genotype-phenotype correlation is not as tight for this mutation as is frequently supposed.

Adult↗

PubMed1996

Alzheimer's disease amyloid precursor protein on the surface of cortical neurons in primary culture co-localizes with adhesion patch components.

Immunofluorescence on primary dissociated rat neuronal cultures (cortical, hippocampal, and cerebellar) and organotypic hippocampal cultures was used to investigate the pattern of distribution of cell-surface amyloid protein (APP). Antibodies directed against the extracellular (N-terminal) portion of APP or against the entire molecule, but not against the C-terminal portion, revealed a striking segmental pattern of immunoreactivity along both axons and dendrites of all neuronal types tested. The pattern first developed between 24 and 48 h in culture. The segments showed co-localization with beta 1-integrin and talin immunoreactivities, but not with GAP-43 or clathrin, indicating that they may mark adhesion patches. Confocal laser microscopy supported a surface location for the APP responsible for the segmented pattern on neurites, as did the reduction of segmental immunoreactivity after exposure to mu-calpain or trypsin. It is conjectured that APP may have a role in cell-substratum interactions in the medium term, during such events as synaptic plasticity and neurite stability during extension.

Alzheimer Disease↗

PubMed1996

The amyloid precursor protein of Alzheimer's disease is found on the surface of static but not activity motile portions of neurites.

We have previously found that the amyloid precursor protein (APP) of Alzheimer's disease is present on the surface of rat cortical neurons in culture, in a segmental pattern which first becomes evident after 24 hours and is fully developed by five days. As APP has previously been reported to have a short half-life in neuronal cell lines, and has been shown to contain binding sites for various extracellular matrix components within its extracellular domain, we hypothesized that APP would be associated with portions of neurites undergoing rapid structural change, such as growth cones. To test this hypothesis, we observed selected neurons by video time-lapse differential interference microscopy on 24-hour-old primary rat neuronal cultures for up to 45 minutes, followed by fixation and immunocytochemistry to ascertain surface APP distribution on those same neurons. In contrast to our predictions, surface APP was not found on active portions of neurites, even if the activity produced no net translational movement. This result indicates that surface APP is actually associated with stable portions of neurites, a conclusion that tallies with other recent results showing that neuronal surface APP has a longer half-life than general cellular APP, and is associated with markers of adhesion patches, which themselves are relatively stable structures.

Amyloid beta-Protein Precursor↗

PubMed1996

Non-invasive neurochemical analysis of focal excitotoxic lesions in models of neurodegenerative illness using spectroscopic imaging.

Water-suppressed chemical shift magnetic resonance imaging was used to detect neurochemical alterations in vivo in neurotoxin-induced rat models of Huntington's and Parkinson's disease. The toxins were: N-methyl-4-phenylpyridinium (MPP+), aminooxyacetic acid (AOAA), 3-nitropropionic acid (3-NP), malonate, and azide. Local or systemic injection of these compounds caused secondary excitotoxic lesions by selective inhibition of mitochondrial respiration that gave rise to elevated lactate concentrations in the striatum. In addition, decreased N-acetylaspartate (NAA) concentrations were noted at the lesion site over time. Measurements of lactate washout kinetics demonstrated that t1/2 followed the order: 3-NP approximately MPP+ >> AOAA approximately malonate, which parallels the expected lifetimes of the neurotoxins based on their mechanisms of action. Further increases in lactate were also caused by intravenous infusion of glucose. At least part of the excitotoxicity is mediated through indirect glutamate pathways because lactate production and lesion size were diminished using unilateral decortectomies (blockade of glutamatergic input) or glutamate antagonists (MK-801). Lesion size and lactate were also diminished by energy repletion with ubiquinone and nicotinamide. Lactate measurements determined by magnetic resonance agreed with biochemical measurements made using freeze clamp techniques. Lesion size as measured with MR, although larger by 30%, agreed well with lesion size determined histologically. These experiments provide evidence for impairment of intracellular energy metabolism leading to indirect excitotoxicity for all the compounds mentioned before and demonstrate the feasibility of small-volume metabolite imaging for in vivo neurochemical analysis.

Aging↗

PubMed1995

Amyloid, aluminium and the aetiology of Alzheimer's disease.

Several lines of evidence suggest that neurotoxic beta A4 amyloid deposits are of prime importance in the pathogenesis of Alzheimer's disease. Epidemiologically determined risk factors such as Down's syndrome, head injury and apoE allelic status can be explained on the basis of this hypothesis. However, there are difficulties with the hypothesis--amyloid accumulation may be necessary, but is not sufficient to produce the neuronal damage seen in Alzheimer's disease. The association between aluminum exposure and Alzheimer's disease remains unproven and is considered to be increasingly peripheral to recent developments in our understanding of the disease.

Aluminum↗

PubMed1995

Intracellular production of beta A4 amyloid of Alzheimer's disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein.

The amyloid precursor protein (APP) undergoes abnormal metabolism in Alzheimer's disease, resulting in the accumulation of beta A4 amyloid in the brain. Normal APP metabolism includes the release of a truncated form (sAPP) which has been cleaved at the alpha-secretase site within the beta A4 amyloidogenic domain. However, intact forms of beta A4 protein may also be generated by the beta- and gamma-secretases. Soluble forms of beta A4 have been detected in various cell lines and in cerebrospinal fluid. Previous studies of protein kinase C activation have suggested a reciprocal relationship between sAPP secretion and beta A4 production and release. We find that phorbol ester activation of protein kinase C in untransfected SH-SY5Y neuroblastoma cells increases the release of sAPP without affecting beta A4 secretion. We provide further evidence for intracellular beta A4 production. Treatment of SY5Y cells with the protease inhibitor phosphoramidon results in a 2-fold increase in beta A4 secretion and an increase in the amount of beta A4 recovered from cell lysates, yet it does not affect sAPP secretion. The protease inhibitors thiorphan and N-[(RS)-2-carboxy-3-phenylpropanoyl]-L-leucine had no effect on beta A4 or sAPP secretion. The lysosomotropic agents chloroquine and NH4Cl decreased beta A4 secretion, providing additional evidence for the involvement of intracellular acidic compartments in the production of beta A4. Our results therefore demonstrate a double dissociation between the secretion of sAPP and beta A4 in the SH-SY5Y cell line. The effect of phosphoramidon supports previous studies which show that metalloproteases are involved in the biogenesis of beta A4.

Alzheimer Disease↗

PubMed1994

Movement disorder following excitotoxin lesions in primates.

We previously reported on the histologic and neurochemical features of quinolinic acid lesions in primates which produce many of the characteristic features of Huntington's disease (HD). We now report on the effects of apomorphine in generating a movement disorder in four of these animals. Animals were tested with saline or apomorphine both before and after the lesions. All animals showed few spontaneous abnormal movements after lesioning, but showed marked dyskinetic movements following apomorphine administration. These results show that excitotoxin lesions in primates can produce an apomorphine-inducible movement disorder which closely resembles that of HD.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗