• X inactivation in females with X-linked Charcot-Marie-Tooth disease.

      Murphy, Sinéad M; Ovens, Richard; Polke, James; Siskind, Carly E; Laurà, Matilde; Bull, Karen; Ramdharry, Gita; Houlden, Henry; Murphy, Raymond P J; Shy, Michael E; et al. (Neuromuscular disorders : NMD, 2012-07)
      X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X.
    • An X11alpha/FSBP complex represses transcription of the GSK3beta gene promoter.

      Lau, Kwok-Fai; Perkinton, Michael S; Rodriguez, Lilia; McLoughlin, Declan M; Miller, Christopher C J; Department of Biochemistry Science, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR. kflau@cuhk.edu.hk (2010-08-04)
      X11alpha is a neuronal adaptor protein that interacts with the amyloid precursor protein (APP) through a centrally located phosphotyrosine binding domain to inhibit the production of Abeta peptide that is deposited in Alzheimer's disease brains. X11alpha also contains two C-terminal postsynaptic density-95, large discs, zona occludens 1 (PDZ) domains, and we show here that through its PDZ domains, X11alpha interacts with a novel transcription factor, fibrinogen silencer binding protein. Moreover, we show that an X11alpha/fibrinogen silencer binding protein complex signals to the nucleus to repress glycogen synthase kinase-3beta promoter activity. Glycogen synthase kinase-3beta is a favoured candidate kinase for phosphorylating tau in Alzheimer's disease. Our findings show a new function for X11alpha that may impact on Alzheimer's disease pathogenesis.
    • X11beta rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice.

      Mitchell, Jacqueline C; Ariff, Belall B; Yates, Darran M; Lau, Kwok-Fai; Perkinton, Michael S; Rogelj, Boris; Stephenson, John D; Miller, Christopher C J; McLoughlin, Declan M; MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London SE5 8AF, UK. (2009-12-01)
      Increased production and deposition of amyloid beta-protein (Abeta) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral Abeta levels represent potential therapeutic targets for Alzheimer's disease. X11beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11beta inhibits Abeta production in a number of experimental systems. However, whether these changes to APP processing and Abeta production induced by X11beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11beta-mediated reduction in cerebral Abeta is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer's disease. Overexpression of X11beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11beta function represents a therapeutic target for Abeta-mediated neuronal dysfunction in Alzheimer's disease.
    • Young patients with chronic lymphocytic leukaemia.

      Kelly, Mary; Dowling, Maura; Meenaghan, Teresa; Tullamore General Hospital, Offaly, Ireland. (2012-01-31)
    • Young, Male and Feeling Suicidal in Ireland: Is Help or Harm Just One Click Away?

      Gilhooley, J; Bolger, M; Charles, A; Cleary, E; Lane, A; Malone, K (Irish Medical Journal, 2015-12)
      Reports suggest an association between internet use and the elevated risk of suicide and self harm. 1 This study examined the resources a suicidal person might find when searching the internet ’front page’ for help. Voluntary suicide help websites accounted for 7/12 front page hits. The National Suicide Research Foundation (NSRF) and the National Office for Suicide Prevention (NOSP), a blog and a newspaper article made up the remainder. Sites were difficult to navigate and highly variable in content. Phone credit was required in many cases in order to contact helplines; opening hours and locations were limited. Most statutory websites referred help-seekers to the voluntary sector, mainly the Samaritans. Information on fundraising and volunteering competed with other sources of help. Of concern, the front page also included links to methods to complete suicide. Irish professional medical bodies offered very limited advice. Our findings suggest that online information is variable and potentially harmful. There is an opportunity for all agencies and providers to generate a co-ordinated internet front page tailored for at-risk groups
    • 'YouTube': a useful tool for reminiscence therapy in dementia?

      O'Rourke, Julia; Tobin, Fiona; O'Callaghan, Susan; Sowman, Rebecca; Collins, D R; Department of Speech & Language Therapy, Adelaide & Meath Hospital Tallaght, Dublin, Ireland. orourke.julia@gmail.com (2011-11)
    • YouTube: A useful tool for the older generation?

      Collins, DR; Sowman, R; Tobin, F; O'Rourke, J; Liston, R (Geriatric Medicine: Midlife & Beyond, 2010)
    • Z α-1 antitrypsin deficiency and the endoplasmic reticulum stress response.

      Greene, Catherine M; McElvaney, Noel G; Catherine M Greene, Noel G McElvaney, Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. (2010-10-06)
      The serine proteinase inhibitor α-1 antitrypsin (AAT) is produced principally by the liver at the rate of 2 g/d. It is secreted into the circulation and provides an antiprotease protective screen throughout the body but most importantly in the lung, where it can neutralise the activity of the serine protease neutrophil elastase. Mutations leading to deficiency in AAT are associated with liver and lung disease. The most notable is the Z AAT mutation, which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine. More than 95% of all individuals with AAT deficiency carry at least one Z allele. ZAAT protein is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum (ER) of hepatocytes and other AAT-producing cells. This results in a loss of function associated with decreased circulating and intrapulmonary levels of AAT. However, the misfolded protein acquires a toxic gain of function that impacts on the ER. A major function of the ER is to ensure correct protein folding. ZAAT interferes with this function and promotes ER stress responses and inflammation. Here the signalling pathways activated during ER stress in response to accumulation of ZAAT are described and therapeutic strategies that can potentially relieve ER stress are discussed.
    • Zebrafish: an exciting model for investigating the spatio-temporal pattern of enteric nervous system development.

      Doodnath, Reshma; Dervan, Adrian; Wride, Michael A; Puri, Prem; National Children's Research Centre, Our Lady's Children's Hospital, Crumlin,, Dublin 12, Ireland. rdoodnath@gmail.com (2012-02-01)
      AIM: Recently, the zebrafish (Danio rerio) has been shown to be an excellent model for human paediatric research. Advantages over other models include its small size, externally visually accessible development and ease of experimental manipulation. The enteric nervous system (ENS) consists of neurons and enteric glia. Glial cells permit cell bodies and processes of neurons to be arranged and maintained in a proper spatial arrangement, and are essential in the maintenance of basic physiological functions of neurons. Glial fibrillary acidic protein (GFAP) is expressed in astrocytes, but also expressed outside of the central nervous system. The aim of this study was to investigate the spatio-temporal pattern of GFAP expression in developing zebrafish ENS from 24 h post-fertilization (hpf), using transgenic fish that express green fluorescent protein (GFP). METHODS: Zebrafish embryos were collected from transgenic GFP Tg(GFAP:GFP)(mi2001) adult zebrafish from 24 to 120 hpf, fixed and processed for whole mount immunohistochemistry. Antibodies to Phox2b were used to identify enteric neurons. Specimens were mounted on slides and imaging was performed using a fluorescent laser confocal microscope. RESULTS: GFAP:GFP labelling outside the spinal cord was identified in embryos from 48 hpf. The patterning was intracellular and consisted of elongated profiles that appeared to migrate away from the spinal cord into the periphery. At 72 and 96 hpf, GFAP:GFP was expressed dorsally and ventrally to the intestinal tract. At 120 hpf, GFAP:GFP was expressed throughout the intestinal wall, and clusters of enteric neurons were identified using Phox2b immunofluorescence along the pathway of GFAP:GFP positive processes, indicative of a migratory pathway of ENS precursors from the spinal cord into the intestine. CONCLUSION: The pattern of migration of GFAP:GFP expressing cells outside the spinal cord suggests an organized, early developing migratory pathway to the ENS. This shows for the first time that Tg(GFAP:GFP)(mi2001) zebrafish model is an ideal one to study spatio-temporal patterning of early ENS development.
    • Zero ischemia laparoscopic partial thulium laser nephrectomy.

      Thomas, Arun Z; Smyth, Lisa; Hennessey, Derek; O'Kelly, Fardod; Moran, Diarmaid; Lynch, Thomas H; Department of Urology, St James Hospital , Dublin, Ireland . (2013-11)
      Laser technology presents a promising alternative to achieve tumor excision and renal hemostasis with or without hilar occlusion, yet its use in partial nephrectomy has not been significantly evaluated. We prospectively evaluated the thulium:yttrium-aluminum-garnet laser in laparoscopic partial nephrectomy (LPN) in our institution over a 1-year period.
    • Zinc status in children with CF

      Roddy, M (2009)
      9th National Cystic Fibrosis Conference, Kilarney
    • ZNF804A and social cognition in patients with schizophrenia and healthy controls.

      Hargreaves, A; Morris, D W; Rose, E; Fahey, C; Moore, S; Cummings, E; Tropea, D; Gill, M; Corvin, A; Donohoe, G (2012-02)
    • ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia.

      Donohoe, Gary; Rose, Emma; Frodl, Thomas; Morris, Derek; Spoletini, Ilaria; Adriano, Fulvia; Bernardini, Sergio; Caltagirone, Carlo; Bossù, Paola; Gill, Michael; et al. (2011-02-01)
      ZNF804A rs1344706 is the first genetic risk variant to achieve genome wide significance for psychosis. Following earlier evidence that patients carrying the ZNF804A risk allele had relatively spared memory function compared to patient non-carriers, we investigated whether ZNF804A was also associated with variation in brain volume. In a sample of 70 patients and 38 healthy participants we used voxel based morphometry to compare homozygous (AA) carriers of the ZNF804A risk allele to heterozygous and homozygous (AC/CC) non-carriers for both whole brain volume and specific regions implicated in earlier ZNF804A studies-the dorsolateral pre-frontal cortex, the hippocampus, and the amygdala. For patients, but not for controls, we found that homozygous 'AA' risk carriers had relatively larger gray matter volumes than heterozygous/homozygous non-carriers (AC/CC), particularly for hippocampal volumes. These data are consistent with our earlier behavioral data and suggest that ZNF804A is delineating a schizophrenia subtype characterized by relatively intact brain volume. Establishing if this represents a discrete molecular pathogenesis with consequences for nosology and treatment will be an important next step in understanding ZNF084A's role in illness risk.