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J Hardy

Publications and source records attributed to J Hardy.

At least 109 records · Page 6Linked to original sources
PubMed2000

The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease.

Although the varepsilon4 allele of the apolipoprotein E gene appears as an important biological marker for Alzheimer's disease (AD) susceptibility, other genetic determinants are clearly implicated in the AD process. Here, we propose that a genetic variation in the transcriptional factor LBP-1c/CP2/LSF gene, located close to the LRP locus, is a genetic susceptibility factor for AD. We report an association between a non-coding polymorphism (G-->A) in the 3'-untranslated region of this gene and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of these three independent populations provides evidence of a protective effect of the A allele (OR = 0.58, 95% CI 0.44-0.75). We describe a potential biologically relevant role for the A allele whereby it reduces binding to nuclear protein(s). The absence of the A allele was associated with a lower LBP-1c/CP2/LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP-1c/CP2/LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c/CP2/LSF interacts with proteins such as GSKbeta, Fe65 and certain factors involved in the inflammatory response.

3' Untranslated Regions↗
PubMed2000

The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity.

Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.

Benzothiazoles↗
PubMed2000

No association between TAU haplotype and Alzheimer's disease in population or clinic based series or in familial disease.

We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.

Age of Onset↗
PubMed2000

Variant Alzheimer's disease with spastic paraparesis: clinical characterization.

OBJECTIVE: To present the clinical, neuroimaging, and electrophysiologic characteristics of a variant AD phenotype. BACKGROUND: The authors have identified a large Finnish kindred with presenile dementia and spastic paraparesis due to deletion of exon 9 of presenilin 1. Neuropathologic analysis showed unusual cortical "cotton wool" plaques, immunoreactive for the beta-amyloid peptide but lacking congophilic cores. PATIENTS AND METHODS: Twenty-two affected individuals (16 men and 6 women) were identified in four successive generations. All surviving five patients were examined and subjected to molecular genetic analysis. In addition, the neurologic records of nine deceased patients were evaluated. Electrophysiologic investigations were available in eight cases. CT or MRI of the head had been performed on 11 patients and PET was performed on three patients. RESULT: The mean age at onset (+/-SD) was 50.9 +/- 5.2 years (range 40 to 61 years). Memory impairment was present in all patients. Memory impairment appeared simultaneously with or was preceded by walking difficulty due to spasticity of the lower extremities (10/14). Impaired fine coordination of hands (9/14) and dysarthria (6/14) in some patients suggested cerebellar involvement. EEG showed intermittent generalized delta-theta activity. Head MRI showed temporal and hippocampal atrophy; PET showed bilateral temporo-parietal hypometabolism. CONCLUSION: Spastic paraparesis or brisk stretch reflexes of lower extremities or clumsiness of hands combined with dementia suggests this variant of AD.

Age of Onset↗
PubMed2000

Linkage exclusion in French families with probable Parkinson' s disease.

We analyzed the segregation of genetic markers spanning chromosomal regions 2p13, 4p14-15, 4q21-23, 6q25-27, and 17q21 in nine French families affected by autosomal-dominant probable Parkinson's disease. These regions have been linked or associated with familial Parkinson's disease. Multipoint linkage and haplotype analyses excluded 2p13 and 4p14-15 loci in five of nine families. For three families, which were equivocal for two-point linkage at D4S405, the ubiquitin carboxy-terminal hydrolase gene (UCH-L1) was sequenced. In one family, a novel UCH-L1 M124L mutation that did not segregate with early-onset disease was identified. This suggests that rare variants in this gene may not be pathogenic. In seven of nine families, it could be inferred that affected individuals did not share 4q21-23 (alpha-synuclein) haplotypes. All families were unequivocally excluded by haplotype analysis from the parkin locus on 6q25-27. Finally, the 17q21 region was excluded in four of nine families, and no mutation in the tau gene was identified in the five remaining families. Findings from this study confirm genetic heterogeneity within familial parkinsonism.

Adult↗
PubMed2000

The future of genetic analysis of neurological disorders.

Molecular genetic analysis has allowed the elucidation of the etiology of many single-gene, neurodegenerative syndromes. However, as yet, it has had little direct impact on our understanding of the etiology in cases with more complex modes of inheritance. With the completion of the sequence of the human genome, it should be possible to start to attack these more complex problems. In this article, we review the genetic methods that may be used to dissect the etiologies of these diseases and outline what types of clinical samples will be needed for this quest.

Animals↗
PubMed2000

Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p.

The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight alpha-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dementia with psychosis.

Brain↗
PubMed2000

Fatigue in patients with prostate cancer receiving hormone therapy.

The aim of this study was to determine the prevalence, severity and correlates of fatigue in a convenience sample of outpatients with prostate cancer prior to and following 3-months treatment with first-line hormone therapy (cyproterone acetate and goserelin). 'Severe fatigue' in the patients (n=62) was defined as a score on the Fatigue Severity Scale (FSS) greater than the 95th percentile of a group of elderly volunteers without cancer. Subjects also completed other questionnaires about fatigue and about quality of life, anxiety/depression and personality. Subjects underwent a nutritional assessment, tests of voluntary muscle function and attention. The prevalence of 'severe fatigue' at baseline was 8/58 (14%). Median FSS scores increased significantly after 3 months treatment. On multivariate analysis psychological distress explained 28% of the variance in fatigue scores. Treatment was associated with a reduction in voluntary muscle function, loss of muscle bulk, a decline in virility and potency, an improvement in pain and a reduction in nausea/vomiting. Fatigue is an important but under-recognised side-effect of hormone therapy.

Aged↗
PubMed2000

What influences participation in clinical trials in palliative care in a cancer centre?

Like any other specialty, palliative care needs a scientific foundation on which to base its practice. Research in palliative care is particularly difficult because of the characteristics of the patient population under study (e.g. advanced disease, poor performance status and limited prognosis). The aim of this paper was to highlight the challenges of recruitment into clinical trials in palliative care. Information on all patients treated at a specialist cancer centre who were referred for consideration of entry into any one of 23 clinical trials in palliative care was collected prospectively over 4 years to determine factors that influence patients to accept or reject entry into a study. Of the 1206 patients referred, 558 (46%) met the entry criteria. Of these, 362 (30%) agreed to enter and 248 (21% of all those referred) completed the study. Thus, 65% of all eligible patients were entered into trials but only 44% of these completed the study. The relatively high percentage of patients entered probably reflects the site (a cancer centre with a high research profile) and is not typical of other palliative care centres or hospices. The most common reasons given for unwillingness to participate were a wish to defer to a later date, a deterioration in condition, distance from home to hospital, a lack of interest, transfer to another unit, inability to give consent and family objection. In order to maximise patient accrual into trials in palliative care, studies should be designed to suit the patient population under study (e.g. be of short duration with realistic entry criteria) and not necessarily mirror the trial methodology of therapeutic trials in oncology.

Adolescent↗
PubMed2000

[Agent liability: a law in flux].

This communication aims to show the impact of the recent reform of the French sanitary organization, and of the evolutions of the French law of liability. Contrary to what it seems, the important reform of the safety system has less immediate consequences than the change in laws on the way in which transfusion professionals perceive their juridical situation.

Blood Banks↗
PubMed2000

A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer.

BACKGROUND: Determining the prevalence of fatigue among cancer patients is complicated by the high prevalence of fatigue symptoms in the general population. The aim of this study was to determine the prevalence, severity and correlates of fatigue among both cancer patients and control subjects without cancer. PATIENTS AND METHODS: A total of 227 cancer patients and 98 control subjects were recruited to the study. They completed a number of questionnaires about fatigue, quality of life and psychological symptoms. The majority of subjects also underwent assessment of voluntary muscle function and nutritional status. Severe fatigue in the patients was defined as a score on the Fatigue Severity Scale in excess of the 95th percentile of the control group. RESULTS: The prevalence of severe fatigue was 15% among patients with recently diagnosed breast cancer, 16% among patients with recently diagnosed prostate cancer, 50% among patients with inoperable non small cell lung cancer and 78% among patients receiving specialist inpatient palliative care. In the patients a combination of dyspnoea, psychological distress, pain, and a measure of overall disease burden accounted for 56% of the variance in fatigue scores. CONCLUSIONS: Severe fatigue is a common problem among cancer patients, particularly those with advanced disease. Fatigue is significantly associated with the severity of psychological symptoms (anxiety and depression) and with the severity of pain and dyspnoea.

Adult↗
PubMed2000

Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases.

Endoproteolysis of beta-amyloid precursor protein (betaAPP) and Notch requires conserved aspartate residues in presenilins 1 and 2 (PS1 and PS2). Although PS1 and PS2 have therefore been proposed to be aspartyl proteases, no homology to other aspartyl proteases has been found. Here we identify homology between the presenilin active site and polytopic aspartyl proteases of bacterial origin, thus supporting the hypothesis that presenilins are novel aspartyl proteases.

Amyloid beta-Peptides↗
PubMed2000

Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

Amino Acid Substitution↗
PubMed2000

Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein.

Linkage of alpha-synuclein (alpha-SN) mutations to familial Parkinson's disease (PD) and presence of alpha-SN as a major constituent of Lewy body in both sporadic and familial PD implicate alpha-SN abnormality in PD pathogenesis. Here we demonstrate that overexpression of wild-type or mutant alpha-SN does not cause any deleterious effect on the growth or continued propagation of transfected human cells, but overproduction of mutant alpha-SN heightens their sensitivity to menadione-induced oxidative injury. Such enhanced vulnerability is more pronounced in neuronal transfectants than in their nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated alpha-SN, especially with an alanine-to-proline substitution at residue 30, sensitizes neuronal cells to oxidative damage.

Cell Line↗