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Biomedical subjects

D G Healy

Publications and source records attributed to D G Healy.

At least 19 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

Sleep-related problems of Parkinson's disease.

OBJECTIVE: To define the epidemiology, characteristics and aetiology of nocturnal symptoms and sleep disorders in patients with Parkinson's disease (PD) and evaluate the available methods for their diagnosis and management. METHODS: A review of the English-language literature pertaining to sleep disturbances associated with PD, using the Medline database and bibliographies in relevant articles. RESULTS: Sleep-related problems specific to PD may occur early and even predate the diagnosis of the disease but are generally more frequent and more severe in patients with advanced PD. These problems can seriously compromise patients' quality of life and lead to impaired functioning in daily activities. Scales designed specifically for the assessment of sleep problems in patients with PD have recently been developed. Evidence base for the treatment of sleep disturbances in PD is poor, and only nocturnal akinesia, excessive day-time sleepiness and rapid eye movement behaviour disorder have been partially addressed. CONCLUSIONS: Sleep disorders associated with PD are a common and under-recognised problem. The assessment of sleep should be part of the routine evaluation of patients with PD, and large-scale controlled therapeutic trials are necessary.

Humans↗
PubMed2006

The alpha-synuclein gene in multiple system atrophy.

BACKGROUND: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. METHOD: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. RESULTS AND CONCLUSION: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Gene Expression↗
PubMed2006

Successful perioperative utilisation of inhaled nitric oxide in mitral valve surgery.

Pulmonary hypertension associated with mitral valve disease can significantly complicate mitral valve replacement. Nitric oxide (NO) has an established role in congenital heart surgery and in cardiac transplantation. However the evidence to date suggests that iNO does not provide a clinical advantage in pulmonary hypertension associated with valvular heart disease. We discuss a 56-year-old male with acute mitral incompetence who underwent emergency surgery. Following mitral valve replacement he was weaned off cardiopulmonary bypass with an intra-aortic balloon pump and high doses of inotropic support but continued to be hypotensive. Inspection of the heart showed right-sided dysfunction and evidence of pulmonary hypertension. Following the introduction of iNO he rapidly improved. He was successfully separated from the cardiopulmonary bypass support and subsequently made a full recovery and was discharged. We believe that this case demonstrates the utility of iNO in the management of pulmonary hypertension secondary to valvular disease in the acute setting. This is in contrast to the evidence against its utility in established pulmonary hypertension in chronic valvular heart disease. Further confirmation of this observation may lead to the therapeutic use of NO in this subpopulation of cardiac surgery patients.

Administration, Inhalation↗
PubMed2005

Population genetic approaches to neurological disease: Parkinson's disease as an example.

Parkinson's disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility. The role that the "Mendelian" genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinson's disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinson's disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions.

Enzymes↗
PubMed2005

The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group.

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

Aged↗
PubMed2005

Traumatic rupture of the aorta in an 11-year-old patient: surgical considerations in the technique of repair.

We describe an 11-year-old child who presented with a traumatic aortic transection. This is an extremely rare occurrence in this age group. In managing the injury the future growth of the child must be considered. Primary repair is ideal when possible, but in choosing a graft, the choice of size and material should take cognisance of the risk of a coarctation-like syndrome in the future.

Anastomosis, Surgical↗
PubMed2004

PINK1 (PARK6) associated Parkinson disease in Ireland.

Mutations in the PINK1 gene have recently been shown to cause autosomal recessive Parkinson disease (PD). The authors assessed the prevalence of PINK1 gene mutations in 290 well-characterized early- and late-onset PD patients from Ireland. In a 51-year-old PD patient with a family history of PD, the authors identified a novel heterozygous mutation (R147H) in exon 2 of the PINK1 gene. Overall, these data indicate that PINK1 mutations are a rare cause of PD in Ireland.

Adolescent↗
PubMed2004

The -1021C->T DBH gene variant is not associated with epilepsy or antiepileptic drug response.

Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE). Animal studies show that genes in the NE pathway are candidates for susceptibility to epilepsy and antiepileptic drug (AED) response. The authors genotyped the -1021C-->T major functional polymorphism in the DBH gene in 675 patients with epilepsy and 1,087 controls. The authors found no association with epilepsy, several epilepsy subtypes, or AED response. The results suggest that the -1021C-->T variant does not contribute to epilepsy.

Anticonvulsants↗
PubMed2004

Genetic approaches to solving common diseases.

The pathway to solving simple Mendelian inherited neurological disease is now well established. Barely a month goes by without new linkage data or mutations in a novel gene being reported. These developments are giving insights into a range of neurological conditions from the cortex to the muscle. However, most of these diseases are individually rare, and one of the major challenges facing neuroscience is to devise methods to find the genetic variants that confer risk of common diseases and differential response to treatment. This latter area is an important emerging field known as pharmacogenomics. Unlike Mendelian genetics where effective strategies are well established, the strategies for detecting moderate genetic effects in populations have been problematic. It is likely that a combination of techniques will be used, involving both linkage analysis and linkage disequilibrium mapping. In this review we consider some of the approaches that can be taken to resolve the common genetic variation underlying common disease.

Chromosome Mapping↗
PubMed2004

Speed and spinal injuries.

Road traffic accidents (RTA) are a significant cause of spinal trauma. On the 31st of October 2002 a new penalty system for speed related driving offences was introduced in Ireland. Our intention was to assess the effects of the introduction of this system on the activity of the National Spinal Injuries Centre (NSIC) with a retrospective review of all admissions from November 1998 until October 2003. The number of new acute admissions to the spinal injury unit during the study period was 831. In the first 6 months of the new system the number of RTA related admissions fell significantly to 17 compared to an average of 33 in the preceding 4 years. However, this effect was not maintained in the second 6 months. The fall in spinal injuries following RTA in the first 6 months of the new system parallels the pattern of road death reduction in this period. This suggests that driving behaviour can be modified with direct benefits in reducing spinal injuries. However, this effect has not persisted in the second 6 months of the new system suggesting that to maintain this change the perception and familiarity of a penalty are important factors in its impact.

Accidental Falls↗
PubMed2004

Tau gene and Parkinson's disease: a case-control study and meta-analysis.

OBJECTIVE: To investigate whether the tau H1 haplotype is a genetic risk factor in Parkinson's disease and to report a meta-analysis on all previously published data METHODS: and results: In a sample of 580 patients with Parkinson's disease and 513 controls there was an increased risk of Parkinson's disease for both the tau H1 haplotype (p<or=0.0064; odds ratio (OR) 1.34 (95% confidence interval (CI), 1.04 to 1.72)) and the H1H1 genotype (p<or=0.0047; OR 1.42 (1.1 to 1.83)). Under a fixed effect model, the summary OR for this showed that individuals homozygous for the H1 allele were 1.57 times more likely to develop Parkinson's disease than individuals carrying the H2 allele (95% CI 1.33 to 1.85; p<0.00001). The population attributable risk for the tau variant, for the main comparison of H1H1 against H2 carriers, was 24.8% for all studies combined. CONCLUSIONS: Homozygosity for the tau H1 is associated with an increased risk of Parkinson's disease. This adds to the growing body of evidence that common genetic variation contributes to the pathogenesis of this disorder.

Alleles↗
PubMed2004

DJ-1 mutations in Parkinson's disease.

Mutations in the DJ-1 gene have recently been shown to cause autosomal recessive Parkinson's disease. To estimate the prevalence of this mutation, an analysis was undertaken of 39 index cases of Parkinson's disease in whom a family history suggested autosomal recessive inheritance. No DJ-1 mutations were found in these patients, indicating that this gene is unlikely to be of numerical significance in clinical practice. The hypothesis was also tested that young onset Parkinson's disease patients in whom, despite extensive analysis, only a single heterozygous parkin mutation was found, might harbour a second mutation in the DJ-1 gene--that is, digenic inheritance. No patient was found with a single mutation in both DJ-1 and parkin genes, making this mode of inheritance unlikely. Finally it was confirmed that PARK6 and PARK7 (DJ-1), despite being phenotypically similar and mapping to the same small chromosomal region of 1p36, are caused by mutations in separate genes.

Age of Onset↗
PubMed2001

Uterine relaxant effects of cyclooxygenase-2 inhibitors in vitro.

OBJECTIVE: To compare the effects of three cyclooxygenase-2 (COX-2) inhibitors: nimesulide, meloxicam, and celecoxib, which exhibit varying COX-2 selectivity, on contractile activity in pregnant (before and after labor) and nonpregnant human myometrial tissue in vitro. METHODS: Isometric tension recording was performed under physiologic conditions in isolated myometrial strips obtained from 33 women undergoing hysterectomy or either elective or emergency cesarean section. The effects of cumulative additions of nimesulide, meloxicam, and celecoxib (between 1 nmol/L and 100 micromol/L) on myometrial contractility were measured, and values for -log(10) EC(50) and mean maximal inhibition were compared. RESULTS: Nimesulide, meloxicam, and celecoxib exerted significant relaxant effects on contractility in nonpregnant, pregnant nonlabor, and pregnant labor myometrial strips. Values for -log(10) EC(50) values (+/- standard error of the mean) were as follows: nimesulide (nonpregnant) 5.14 +/- 0.93 (n = 6), (pregnant nonlabor) 4.91 +/- 0.75 (n = 6), and (pregnant labor) 5.84 +/- 0.35 (n = 6); meloxicam (nonpregnant) 6.53 +/- 0.57 (n = 6), (pregnant nonlabor) 4.80 +/- 0.71 (n = 6), and (pregnant labor) 5.62 +/- 0.21 (n = 6); celecoxib (nonpregnant) 6.15 +/- 0.99 (n = 6), (pregnant nonlabor) 7.08 +/- 0.98 (n = 6), and (pregnant labor) 7.25 +/- 0.99 (n = 3). Celecoxib exhibited greater potency than nimesulide or meloxicam (P < .01). The range of maximal relaxation values achieved in the three tissue types were as follows: nimesulide 68-70% (n = 18; P < .01), meloxicam 69-84% (n = 18; P < .01), and celecoxib 69-77% (n = 15; P < .01). CONCLUSION: COX-2 inhibitors exert significant relaxation in human myometrium with a similar potency in nonpregnant and pregnant (before and after labor onset) tissues. Celecoxib, a COX-2 specific inhibitor, was more potent than nimesulide or meloxicam, COX-2 preferential inhibitors.

Adult↗
PubMed1999

Metyrapone displays antidepressant-like properties in preclinical paradigms.

A possible involvement of glucocorticoids in the aetiology of depression is suggested by commonly reported hypothalamo-pituitary-adrenocortical (HPA) axis abnormalities in depressed patients, the modulation of the HPA axis by antidepressant drugs and clinical reports of antidepressant efficacy with antiglucocorticoid agents. The effects of treatment with metyrapone, a glucocorticoid synthesis inhibitor, and the tricyclic antidepressant, desipramine, in two rodent models of depression, namely the forced swim test and olfactory bulbectomized (OB) rat, were investigated. In addition, the effect of chronic metyrapone and desipramine treatments on the hypothermic response to a challenge with the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was assessed. There is experimental evidence to suggest that attenuation of the hypothermic response to this agonist occurs following chronic antidepressant treatment. In the forced swim test, metyrapone (50 mg/kg) and desipramine (10 mg/kg) significantly reduced the immobility time. In the olfactory bulbectomized rat model of depression, chronic administration (14 days) of metyrapone (50 mg/kg b.i.d.) and desipramine (5 mg/kg b.i.d.) attenuated the OB-related hyperactivity in a novel stressful environment. Chronic metyrapone treatment (50 mg/kg b.i.d.) attenuated the hypothermic response to an acute challenge with 8-OH-DPAT (0.05 mg/kg s.c.), indicating a change to the sensitivity of 5-HT1A receptors. These preclinical tests demonstrate an antidepressant-like profile for metyrapone. Further exploration of the therapeutic potential and possible mechanism of action of glucocorticoid antagonism in depression is warranted.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMedDate not supplied

Acute acalculous cholecystitis following coronary artery bypass surgery.

BACKGROUND: Significant gastrointestinal complications following cardiac surgery requiring cardiopulmonary bypass (CPB) are relatively infrequent but are associated with high morbidity and mortality rates. Acute acalculous cholecystitis (AAC) may be a devastating complication if the diagnosis is missed or management delayed. AIM: We present two cases of AAC that followed coronary artery bypass graft (CABG) surgery. RESULTS: In one case a cholecystectomy was performed whereas percutaneous drainage was utilised in the second case. The application of these two different individualised treatment options lead to successful outcomes in both cases. CONCLUSION: Awareness with vigilance enables early diagnosis and treatment. The clinical state of the patient at the time of diagnosis ultimately determines the management strategy in the post cardiac surgery patient.

Adult↗