Biomedical subjects

John O'Brien

Publications and source records attributed to John O'Brien.

53 records · Page 3Linked to original sources

PubMed2002

Is late onset depression a prodrome to dementia?

BACKGROUND: Recent research suggests there are clinical and biological differences between late onset depression (LOD) and early-onset depression (EOD). OBJECTIVES: In this paper we review clinical, epidemiological, structural neuroimaging and genetic investigations of late life depression that have been performed over the past two decades and offer evidence that LOD is often a prodromal disorder for dementia. RESULTS: LOD patients are more likely to have cognitive impairment and to have more deep white matter lesions (DWMLs). Evidence concerning cortical and temporal lobe atrophy is conflicting, while the ApoE 4 allele is not associated with LOD. CONCLUSIONS: It is likely that LOD is not a prodrome for a particular type of dementia, but the majority of patients who do develop dementia will acquire Alzheimer's disease (AD) or a vascular dementia, as these are by far the most common causes of dementia. This issue requires further clarification with follow-up of patients over the long term.

Age of Onset↗

PubMed2002

Can psychiatric liaison reduce neuroleptic use and reduce health service utilization for dementia patients residing in care facilities.

BACKGROUND: The quality of care and overuse of neuroleptic medication in care environments are major issues in the care of elderly people with dementia. METHOD: The quality of care (Dementia Care Mapping), the severity of Behavioural and Psychological Symptoms (BPSD--Neuropsychiatric Inventory), expressive language skills (Sheffield Acquired Language Disorder scale), service utilization and use of neuroleptic drugs was compared over 9 months between six care facilities receiving a psychiatric liaison service and three facilities receiving the usual clinical support, using a single blind design. RESULTS: There was a significant reduction in neuroleptic usage in the facilities receiving the liaison service (McNemar test p<0.0001), but not amongst those receiving standard clinical support (McNemar test p=0.07). There were also significantly less GP contacts (t=3.9 p=0.0001) for residents in the facilities receiving the liaison service, and a three fold reduction in psychiatric in-patient bed usage (Bed days per person 0.6 vs. 1.5). Residents in care facilities receiving the liaison service experienced significantly less deterioration in expressive language skills (t=2.2 p=0.03), but there were no significant differences in BPSD or wellbeing. CONCLUSION: A resource efficient psychiatric liaison service can reduce neuroleptic drug use and reduce some aspects of health service utilization; but a more extensive intervention is probably required to improve the overall quality of care.

Aged↗

PubMed2002

A positive association between 5HT re-uptake binding sites and depression in dementia with Lewy bodies.

BACKGROUND: Depression is a common and distressing problem in the context of dementia, and is significantly more common in Dementia with Lewy bodies (DLB) than in Alzheimer's disease. The neurochemical basis for depression in DLB has not been investigated. AIM: To investigate the association between depression and 5HT transporter re-uptake binding in DLB patients. METHOD: A representative cohort of dementia patients received annual assessments, which included a standardised evaluation of depression until death. At post-mortem, (3H) cyanoimipramine autoradiography was used to quantify 5HT transporter re-uptake sites in the hippocampus and adjacent temporal cortex (Brodmann Area-BA 36, and 20); and parietal neocortex (BA 7a). RESULTS: Twenty-one cases were evaluated neurochemically, of whom seven had experienced a major depressive disorder. Major depression was associated with a significant preservation of 5HT transporter re-uptake sites in the parietal neocortex compared with non-affected cases (BA 7a area 1 t = 3.3, P = 0.004; BA 7a area 3 t = 3.8, P = 0.001). CONCLUSION: This preliminary report is important in challenging some of the assumptions about cortical monoamine functioning in depressed dementia.

Aged↗

PubMed2002

Comparative distribution of binding of the muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain.

Quinuclidinyl benzilate (QNB) and its derivatives are being developed to investigate muscarinic receptor changes in vivo in Alzheimer's disease and dementia with Lewy bodies. This is the first study of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB binding in vitro in human brain. We have compared the in vitro binding of the muscarinic ligands [3H]pirenzepine and [3H]AF-DX 384, which have selectivity for the M1 and M2/M4 receptor subtypes, respectively, to the binding of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB. This will provide a guide to the interpretation of in vivo SPET images generated with [123I]-(R,R)-I-QNB and [123I]-(R,S)-I-QNB. Binding was investigated in striatum, globus pallidus, thalamus and cerebellum, and cingulate, insula, temporal and occipital cortical areas, which show different proportions of muscarinic receptor subtypes, in post-mortem brain from normal individuals. M1 receptors are of high density in cortex and striatum and are relatively low in the thalamus and cerebellum, while M4 receptors are mainly expressed in the striatum, and M2 receptors are most evident in the cerebellum and thalamus. [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB density distribution patterns were consistent with binding to both M1 and M4 receptors, with [125I]-(R,R)-I-QNB additionally binding to a non-cholinergic site not displaceable by atropine. This distribution can be exploited by in vivo imaging, developing ligands for both SPET and PET, to reveal muscarinic receptor changes in Alzheimer's disease and dementia with Lewy bodies during the disease process and following cholinergic therapy.

Aged↗

PubMed2002

Disturbances of consciousness in dementia with Lewy bodies associated with alteration in nicotinic receptor binding in the temporal cortex.

Disturbances of consciousness, including fluctuations in attention and awareness, are a common and clinically important symptom in dementia with Lewy bodies (DLB). In the present study we investigate potential mechanisms of such disturbances of consciousness (DOC) in a clinicopathological study evaluating specific components of the cholinergic system. [3H]Epibatidine binding to the high-affinity nicotinic receptor in the temporal cortex (Brodmann's areas 20 and 36) differentiated DLB cases with and without DOC, being 62-66% higher in those with DOC (F=4.5,p=.025). The were no differences between DLB patients with or without DOC in 125I-labeled alpha-bungaratoxin binding to the low-affinity nicotinic receptor, [3H]pirenzepine binding to the muscarinic M1 receptor, or in choline acetyltransferase activity. These findings provide support for the hypothesis that cholinergic activity is an important neural correlate if consciousness and suggest a mechanism of DOC in DLB involving alterations in the nicotinic receptor, composed of predominantly alpha4 and beta2 subunits.

Aged↗

PubMed2002

An improved method of preparing microcarriers for biolistic transfection.

The hand-held gene gun uses a pulse of helium to fire small gold particles coated with desiccated DNA (microcarriers) at target cells. This method of biolistic transfection is becoming increasingly popular as an effective means of rapid gene delivery into mammalian tissue. Current methods of microcarrier preparation, however, are slow (up to 2 days) and can result in variations in transfection efficiency due to a number of problems including shearing of DNA, agglomeration and adhesion of gold particles. Here we describe an improved, more rapid method of microcarrier preparation. To evaluate the new procedure we have used DNA encoding yellow fluorescent protein (EYFP), a modified version of the green fluorescent protein, which we have transfected into HEK293 cells. The data show that transfection by the new method results in high levels of transfection efficiency and low variability compared to an alternative method.

Bacterial Proteins↗

PubMed2002

Construction of a 'unigene' cDNA clone set by oligonucleotide fingerprinting allows access to 25 000 potential sugar beet genes.

Access to the complete gene inventory of an organism is crucial to understanding physiological processes like development, differentiation, pathogenesis, or adaptation to the environment. Transcripts from many active genes are present at low copy numbers. Therefore, procedures that rely on random EST sequencing or on normalisation and subtraction methods have to produce massively redundant data to get access to low-abundance genes. Here, we present an improved oligonucleotide fingerprinting (ofp) approach to the genome of sugar beet (Beta vulgaris), a plant for which practically no molecular information has been available. To identify distinct genes and to provide a representative 'unigene' cDNA set for sugar beet, 159 936 cDNA clones were processed utilizing large-scale, high-throughput data generation and analysis methods. Data analysis yielded 30 444 ofp clusters reflecting the number of different genes in the original cDNA sample. A sample of 10 961 cDNA clones, each representing a different cluster, were selected for sequencing. Standard sequence analysis confirmed that 89% of these EST sequences did represent different genes. These results indicate that the full set of 30 444 ofp clusters represent up to 25 000 genes. We conclude that the ofp analysis pipeline is an accurate and effective way to construct large representative 'unigene' sets for any plant of interest with no requirement for prior molecular sequence data.

Arabidopsis↗

PubMed2002

Cognitive decline in a prospectively studied group of stroke survivors, with a particular emphasis on the >75's.

BACKGROUND: Although cognitive decline is frequent after stroke, there has been very little work focussing upon older age groups, in whom the majority of strokes occur. OBJECTIVE: To determine whether cognitive decline is more common in older (>75) compared to younger (<75) stroke survivors. METHOD: A cohort of 360 stroke survivors of all ages from a stroke register in Newcastle, UK, were assessed prospectively at 3 time points over 1 year with a standardized battery. Dementia was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. RESULTS: The overall one year prevalence of dementia was 23%, but rose from 7% in the under 65's to 53% in over 85's. People over 75 were significantly more likely to have dementia (Odds Ratio 8.9, 95% Confidence Intervals 4.1-19.1). CONCLUSION: The striking age related increase in the prevalence of dementia has important implications for service planning and clinical management.

Aged↗

PubMed2002

Xdigitise: visualization of hybridization experiments.

UNLABELLED: Xdigitise is a software system for visualization of hybridization experiments giving the user facilities to analyze the corresponding images manually or automatically. Images of the high-density DNA arrays are displayed as well as the results of an external image analysis bundled with Xdigitise, e.g. the spot locations are marked and the duplicate correlations are shown by a color scale. AVAILABILITY: Xdigitise can be downloaded from http://www.molgen.mpg.de/~xdigitise.

Algorithms↗

PubMed2002

Neuropsychological deficits in older stroke patients.

This paper examines the frequency of CIND, the profile of early cognitive deficits in stroke patients, the differences in the profile of cognitive impairment in people with CIND and those with vascular dementia, and the MRI associations of CIND in older stroke patients.

Aged↗

PubMed2002

Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia in the elderly following Alzheimer's disease (AD). Whilst the presence of Lewy bodies is essential, DLB shares with AD the presence of senile plaques (SP), but neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E (APO E) epsilon4 allele is the most consistently associated genetic risk factor for AD and has also been shown to associate with DLB. We have therefore analysed the APO E epsilon4 allele in a large series of DLB cases coming to autopsy to: (1) determine if the epsilon4 allele describes a similar risk in DLB development as in AD and (2) determine how APO E epsilon4 allele status correlates with clinical and neuropathological findings in DLB, and in AD, as an indication of the role of APO E in underlying disease biology. Both DLB and AD share an increased epsilon4 allele frequency, though in DLB the epsilon2 allele frequency is not reduced and there is a relative lack of epsilon4 homozygotes. In contrast to previous studies, no association of the epsilon4 allele with age at onset or duration of disease was found in either disorders. In DLB cases, overall a significantly shorter duration of illness was observed when compared with AD cases, though no significant effect of the epsilon4 allele on disease onset or duration was seen. The survival rate was reduced by the presence of the epsilon4 allele in DLB, as with AD. No effect on SP or NFT counts was seen with the epsilon4 allele, though DLB cases showed a lower SP burden in addition to the expected lower NFT counts. This study demonstrates that DLB shares the APO epsilon4 allele with AD as a common risk factor, but that there are differences in the way the epsilon4 allele affects the phenotypic expression of disease.

Adult↗

PubMed2002

Vascular basis of late-onset depressive disorder.

BACKGROUND: Growing evidence suggests that there may be a subtype of depression arising in later life that is characterised by a distinct clinical presentation and an association with cerebrovascular disease. This has been termed 'vascular depression'. AIMS: To review the evidence for associations between cardiovascular disease and depression and between cerebrovascular disease and depression, and to examine implications for clinical practice and research. METHOD: The authors reviewed the medical literature covering the past 5 years. RESULTS: There is strong evidence for an association between cardiovascular disease and depression, but this is not confined to older people. The causal pathway may be bi-directional. There is also a convergence of evidence suggesting a causal link between cerebrovascular disease and depression, especially that occurring later in life. The major focus has been on neuroradiological findings thought to be due to vascular disease, although the pathology may be heterogeneous. CONCLUSIONS: Although there are gaps in the evidence there is strong support for the concept of vascular depression, characterised by reduced depression ideation, subcortical neurological dysfunction, apathy and psychomotor change. This has implications for both treatment and prevention.

Age of Onset↗

PubMed2002

Head and neck cancer: gene therapy approaches. Part 1: adenoviral vectors.

Treatment options for recurrent or refractory head and neck cancer are limited. The goal of gene therapy is to introduce new genetic material into cancer cells without affecting toxicity to surrounding malignant cells. The most common vehicles for delivery of genes are adenoviruses. Adenoviruses gain access to malignant and normal cell cytoplasm via viral ligand binding to a unique cell surface receptor (the coxsackie adenovirus receptor [CAR]). However, this receptor is not cancer specific. Genetic modification of adenoviral DNA can create cancer specific targeting. Adenoviruses can be modified to express cancer specific ligands thereby focusing binding to malignant tissue. Furthermore, adenoviral delivered genes can be put under cancer specific promoter control to further limit gene expression in malignant tissue. Increased antitumour activity from such modifications has been demonstrated preclinically and several clinical trials have been completed demonstrating safety and clinical activity of non-replicating and conditional replicating adenoviral vector thereby opening the door for gene delivery and cancer specific targeting.

Adenoviridae↗

PubMed2002

Head and neck cancer: gene therapy approaches. Part II: genes delivered.

In Part I, the review summarised the safety of adenoviral vectors and provided insight into approaches being undertaken to improve the specificity, durability and potency of adenoviral delivery vehicles. In Part II, brief discussions are held regarding results of preclinical and clinical trials with a variety of different genes, which have demonstrated antitumour activity in squamous cell carcinoma of the head and neck region (HNSCC). Studies have been performed with a variety of immune modulatory genes. Preliminary results demonstrate activity with several cytokine genes, tumour antigen genes and co-stimulatory molecule genes. Despite only preliminary results, thus far, a theoretical attractive feature for the use of gene therapy for the enhancement of immune modulation is that local injection of the gene product appears to be well tolerated. It is also successful in inducing systemic immune response, potentially providing effect to metastatic sites distal from the injected site. Animal studies have confirmed efficacy in the use of specific targeting of molecules regulating cancer growth (EGF receptor [EGFR], super oxide dismutase [SOD], cyclin D1, E1A and Bcl-2). These approaches are discussed. However, the most significant clinical advances for the use of gene therapy in advanced HNSCC involves two agents: Adp53 and ONYX-015. Preliminary Phase I and II results suggest evidence of efficacy and justify accrual Phase III trials, which are currently ongoing.

Adenoviridae↗

PubMed2002

Mission vs. morale.

Explore the source record for details and available documents.

Community-Institutional Relations↗

PubMedDate not supplied

Regulation of gap junction coupling through the neuronal connexin Cx35 by nitric oxide and cGMP.

Gap-junctional coupling among neurons is subject to regulation by a number of neurotransmitters including nitric oxide. We studied the mechanisms by which NO regulates coupling in cells expressing Cx35, a connexin expressed in neurons throughout the central nervous system. NO donors caused potent uncoupling of HeLa cells stably transfected with Cx35. This effect was mimicked by Bay 21-4272, an activator of guanylyl cyclase. A pharmacological analysis indicated that NO-induced uncoupling involved both PKG-dependent and PKG-independent pathways. PKA was involved in both pathways, suggesting that PKG-dependent uncoupling may be indirect. In vitro, PKG phosphorylated Cx35 at three sites: Ser110, Ser276, and Ser289. A mutational analysis indicated that phosphorylation on Ser110 and Ser276, sites previously shown also to be phosphorylated by PKA, had a significant influence on regulation. Ser289 phosphorylation had very limited effects. We conclude that NO can regulate coupling through Cx35 and that regulation is indirect in HeLa cells.

Cell Communication↗

PubMedDate not supplied

Multiple neuronal connexins in the mammalian retina.

Gap junctions are abundant in the mammalian retina and many neuronal types form neural networks. Several different neuronal connexins have now been identified in the mammalian retina. Cx36 supports coupling in the AII amacrine cell network and is essential for processing rod signals. Cx36 is probably also responsible for photoreceptor coupling. Horizontal cells appear to be extensively coupled by either Cx50 or Cx57. These results indicate that multiple neuronal connexins are expressed in the mammalian retina and that different cell types express different connexins.

Amacrine Cells↗