Biomedical subjects

I Hargreaves

Publications and source records attributed to I Hargreaves.

14 recordsLinked to original sources

PubMed2006

PINK1 protein in normal human brain and Parkinson's disease.

Parkinson's disease is a common incurable neurodegenerative disease whose molecular aetiology remains unclear. The identification of Mendelian genes causing rare familial forms of Parkinson's disease has revealed novel proteins and pathways that are likely to be relevant in the pathogenesis of sporadic Parkinson's disease. Recently, mutations in a novel gene, PINK1, encoding a 581 amino acid protein with both mitochondrial targeting and serine/threonine kinase domains, were identified as a cause of autosomal recessive parkinsonism. This provided important evidence for the role of the mitochondrial dysfunction and kinase pathways in neurodegeneration. In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. The possible role of the PINK1 protein was also assessed in a number of neurodegenerative diseases characterized by proteinaceous inclusions. For these studies, rabbit polyclonal antibodies were raised against two peptide sequences within the N-terminal hydrophilic loops of PINK1 protein. Using immunohistochemistry and western blotting we were able to demonstrate that PINK1 is a ubiquitous protein expressed throughout the human brain and it is found in all cell types showing a punctate cytoplasmic staining pattern consistent with mitochondrial localization. Fractionation studies of human and rat brain confirm that PINK1 is localized to the mitochondrial membranes. In addition, we show that PINK1 is detected in a proportion of Lewy bodies in cases of sporadic Parkinson's disease and Parkinson's disease associated with heterozygous mutations in the PINK1 gene, which are clinically and pathologically indistinguishable from the sporadic cases. PINK1 was absent in cortical Lewy bodies, in neurofibrillary tangles in Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, and in the glial and neuronal alpha-synuclein positive inclusions in multiple system atrophy. These studies provide for the first time in vivo morphological and biochemical evidence to support a mitochondrial localization of PINK1 and underpin the significance of mitochondrial dysfunction in the pathogenesis of nigral cell degeneration in Parkinson's disease.

Alzheimer Disease↗

PubMed2006

The significance of reduced respiratory chain enzyme activities: clinical, biochemical and radiological associations.

BACKGROUND: Mitochondrial diseases are an important group of neurometabolic disorders in children with varied clinical presentations and diagnosis that can be difficult to confirm. AIM: To report the significance of reduced respiratory chain enzyme (RCE) activity in muscle biopsy samples from children. METHODS: Retrospective odds ratio was used to compare clinical and biochemical features, DNA studies, neuroimaging, and muscle biopsies in 18 children with and 48 without reduced RCE activity. RESULTS: Children with reduced RCE activity were significantly more likely to have consanguineous parents, to present with acute encephalopathy and lactic acidaemia and/or within the first year of life; to have an axonal neuropathy, CSF lactate >4 mmol/l; and/or to have signal change in the basal ganglia. There were positive associations with a maternal family history of possible mitochondrial cytopathy; a presentation with failure to thrive and lactic acidaemia, ragged red fibres, reduced fibroblast fatty acid oxidation and with an abnormal allopurinol loading test. There was no association with ophthalmic abnormalities, deafness, epilepsy or myopathy. CONCLUSION: The association of these clinical, biochemical and radiological features with reduced RCE activity suggests a possible causative link.

Adolescent↗

PubMed2005

Nonsense mutations in mitochondrial DNA associated with myalgia and exercise intolerance.

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Codon, Nonsense↗

PubMed2002

Cytochrome oxidase deficiency in Lowe syndrome.

We report on a patient with complex IV deficiency who in later clinical course was diagnosed as a Lowe syndrome. Mitochondrial abnormalities can be present in Lowe syndrome and might lead to misdiagnosis, additionally because clinical features can be overlapping.

Cytochrome-c Oxidase Deficiency↗

PubMed2001

Neonatal presentation of coenzyme Q10 deficiency.

We report a neonate with ubiquinone deficiency. Skeletal muscle analysis revealed markedly diminished mitochondrial complex II + III activity that could be restored by addition of a ubiquinone analogue. Ubiquinone deficiency was confirmed by high-performance liquid chromatography. Oral ubiquinone therapy was not associated with clinical improvement; the patient died at 2 years.

Chromatography, High Pressure Liquid↗

PubMed2001

A qualitative study of mindfulness-based cognitive therapy for depression.

Psychotherapeutic interventions containing training in mindfulness meditation have been shown to help participants with a variety of somatic and psychological conditions. Mindfulness-based cognitive therapy (MBCT) is a meditation-based psychotherapeutic intervention designed to help reduce the risk of relapse of recurrent depression. There is encouraging early evidence from multi-centre randomized controlled trials. However, little is known of the process by which MBCT may bring therapeutic benefits. This study set out to explore participants' accounts of MBCT in the mental-health context. Seven participants were interviewed in two phases. Interview data from four participants were obtained in the weeks following MBCT. Grounded theory techniques were used to identify several categories that combine to describe the ways in which mental-health difficulties arose as well as their experiences of MBCT. Three further participants who have continued to practise MBCT were interviewed so as to further validate, elucidate and extend these categories. The theory suggested that the preconceptions and expectations of therapy are important influences on later experiences of MBCT. Important areas of therapeutic change ('coming to terms') were identified, including the development of mindfulness skills, an attitude of acceptance and 'living in the moment'. The development of mindfulness skills was seen to hold a key role in the development of change. Generalization of these skills to everyday life was seen as important, and several ways in which this happened, including the use of breathing spaces, were discussed. The study emphasized the role of continued skills practice for participants' therapeutic gains. In addition, several of the concepts and categories offered support to cognitive accounts of mood disorder and the role of MBCT in reducing relapse.

Cognitive Behavioral Therapy↗

PubMed1999

A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy.

We report the first missense mutation in the mtDNA gene for subunit II of cytochrome c oxidase (COX). The mutation was identified in a 14-year-old boy with a proximal myopathy and lactic acidosis. Muscle histochemistry and mitochondrial respiratory-chain enzymology demonstrated a marked reduction in COX activity. Immunohistochemistry and immunoblot analyses with COX subunit-specific monoclonal antibodies showed a pattern suggestive of a primary mtDNA defect, most likely involving CO II, for COX subunit II (COX II). mtDNA-sequence analysis demonstrated a novel heteroplasmic T-->A transversion at nucleotide position 7,671 in CO II. This mutation changes a methionine to a lysine residue in the middle of the first N-terminal membrane-spanning region of COX II. The immunoblot studies demonstrated a severe reduction in cross-reactivity, not only for COX II but also for the mtDNA-encoded subunit COX III and for nuclear-encoded subunits Vb, VIa, VIb, and VIc. Steady-state levels of the mtDNA-encoded subunit COX I showed a mild reduction, but spectrophotometric analysis revealed a dramatic decrease in COX I-associated heme a3 levels. These observations suggest that, in the COX protein, a structural association of COX II with COX I is necessary to stabilize the binding of heme a3 to COX I.

Acidosis, Lactic↗

PubMed1997

Psychosocial adjustment in male-to-female transsexuals: an overview of the research evidence.

Transsexualism has been defined as an extreme gender dysphoria; it refers to unhappiness with one's biological sex and the desire to have the body of the opposite sex and to be regarded by others as a member of that other sex. Transsexualism is not a common condition, but its prevalence is not yet known. A large number of transsexuals receive hormonal treatment and sex reassignment surgery (SRS). In spite of years of poor quality research, due in part to methodological problems, recent research on surgical outcomes has provided important information. However, psychological research into transsexualism has ignored the cognitive style and psychological functioning of transsexuals, and very little effort has been made to incorporate research findings into the development of psychological treatments to improve the quality of life for transsexuals.

Adult↗

PubMed1990

Community health staff's prejudice and knowledge about AIDS.

Health service workers' attitudes to their patients carry significant health care consequences. In order to investigate the relationships between health workers' attitudes to groups at high risk of AIDS and their knowledge of the disease and views on procedures for care, community health care workers and students completed a social distance questionnaire concerning groups defined by ethnicity, sexual proclivity, or illness. There was strong negativity towards individuals of minority sexual proclivity and AIDS high risk groups. Fear of the disease and ignorance of its transmission and effective care procedures increase with prejudice towards these groups. Analysis of their relevant prior learning experiences demonstrates the need for an educational programme which addresses the identified sources of ignorance and which also necessarily concentrates on the prejudices which serve as a barrier to effective patient care.

Acquired Immunodeficiency Syndrome↗

PubMed1985