Byrne S.,Beaumont Hospital |
Byrne S.,Trinity Biomedical science Institute |
Heverin M.,Trinity Biomedical science Institute |
Elamin M.,Trinity Biomedical science Institute |
And 9 more authors.
Annals of Neurology | Year: 2013
Objective Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal dementia (FTD) in 14% of cases. Five percent report a family history of ALS, and other ALS patients report a family history of other neurodegenerative diseases. The objective of this study was to conduct a family aggregation study of ALS, and neurodegenerative and neuropsychiatric conditions in ALS kindreds and matched healthy controls. The aim was to determine the true rate of familial ALS and the recurrence risk of ALS in family members, and to identify kindreds with increased aggregation of neurodegenerative and neuropsychiatric disease in the context of the recently described expanded hexanucleotide repeat in C9orf72. Methods A prospective, population-based, case-control family aggregation study was conducted. Family history information was collected through questionnaires and interviews from ALS patients and matched controls. Cause of death was verified with death certification. The recurrence rate of ALS and the risk in family members of other neurodegenerative and neuropsychiatric disease was calculated using the relative risk (lambda) and cumulative risk using Kaplan-Meier analysis. Results Medical histories from 9,684 first- and second-degree relatives of 172 ALS probands and 192 controls were obtained. Cause of death was verified in 2,494 cases. Sixteen percent (n = 27) of ALS patients had a family history of ALS. The lifetime hazard ratio (HR) of developing ALS among first- and second-degree relatives was 34.3 (p < 0.0001) in relatives of ALS patients with the C9orf72 repeat expansion, and 2.3 (p = 0.019) in relatives of ALS patients without the expansion. The relatives of ALS patients also had an increased HR of developing a psychotic illness (HR = 4.7, p = 0.004, 95% confidence interval [CI] = 1.6-12.3) and of suicide (HR = 5.6, p < 0.0001, 95% CI = 2.4-12.9) Interpretation The true rate of familial ALS in Ireland is 16%. There is an overlap between ALS, FTD, and neuropsychiatric disease that is pronounced in kindreds with the C9orf72 repeat expansion, but is also present in kindreds of those without the C9orf72 expanded repeat. © 2013 American Neurological Association.
Rooney J.,Trinity Biomedical science Institute |
Vajda A.,Trinity Biomedical science Institute |
Heverin M.,Trinity Biomedical science Institute |
Elamin M.,Trinity Biomedical science Institute |
And 5 more authors.
Neurology | Year: 2015
Objective: Few spatial cluster analyses of amyotrophic lateral sclerosis (ALS) incidence have been conducted on prospective incident population-based cohorts; we report results of a formal cluster analysis of the Irish ALS cohort from January 1, 1995, to December 31, 2013. Methods: We identified 1,684 incident cases from the Irish ALS register. Population data from 4 census years were used to calculate age-and sex-standardized expected ALS cases for 3,355 areas. Spatial cluster analysis was performed to identify high-risk clusters using both SaTScan and FleXScan software. Poisson-based, time period-stratified statistics and time-stratified Bayesian smoothed risk mapping were used to audit completeness of case ascertainment of the register. Results: No significant high-risk clusters of incident ALS were identified. However, SaTScan revealed 2 significant areas of lower-than-average ALS risk-one centered on County Kilkenny (relative risk 0.53, p 0.012) and a smaller area in County Clare (relative risk 0.0, p 0.029). Audit of case ascertainment did not indicate any failure to detect cases in these areas. Conclusions: The absence of high-risk ALS clusters in Ireland contrasts with previous studies. Our study has several advantages, notably the use of a long-running prospective ALS register with nationwide case ascertainment. The presence of 2 low-risk areas was unexpected. No obvious ascertainment, demographic, or common environmental factors explain this finding. However, we postulate that historical factors may have led to altered genetic admixture in these regions, possibly contributing to lower rates. © 2015 American Academy of Neurology.
Pollock J.K.,Trinity Biomedical science Institute |
Verma N.K.,Nanyang Technological University |
O'Boyle N.M.,Trinity Biomedical science Institute |
Carr M.,Trinity Biomedical science Institute |
And 2 more authors.
Biochemical Pharmacology | Year: 2014
The capacity of T-lymphocytes to migrate and localise in tissues is important in their protective function against infectious agents, however, the ability of these cells to infiltrate the tumour microenvironment is a major contributing factor in the development of cancer. T-cell migration requires ligand (ICAM-1)/integrin (LFA-1) interaction, activating intracellular signalling pathways which result in a distinct polarised morphology, with an actin-rich lamellipodium and microtubule (MT)-rich uropod. Combretastatin (CA)-4 is a MT-destabilising agent that possesses potent anti-tumour properties. In this study, the effect of CA-4 and its novel analogue CA-432 on human T-cell migration was assessed. Cellular pretreatment with either of CA compounds inhibited the migration and chemotaxis of the T-cell line HuT-78 and primary peripheral blood lymphocyte (PBL) T-cells. This migration-inhibitory effect of CA compounds was due to the disruption of the MT network of T-cells through tubulin depolymerisation, reduced tubulin acetylation and decreased MT stability. In addition, both CA compounds induced the RhoA/RhoA associated kinase (ROCK) signalling pathway, leading to the phosphorylation of myosin light chain (MLC). Furthermore, the siRNA-mediated depletion of GEF-H1, a MT-associated nucleotide exchange factor that activates RhoA upon release from MTs, in T-cells prevented CA-induced phosphorylation of MLC and attenuated the formation of actin-rich membrane protrusions and cell contractility. These results suggest an important role for a GEF-H1/RhoA/ROCK/MLC signalling axis in mediating CA-induced contractility of T-cells. Therapeutic agents that target cytoskeletal proteins and are effective in inhibiting cell migration may open new avenues in the treatment of cancer and metastasis. © 2014 Elsevier Inc. All rights reserved.
Kenna K.P.,Trinity College Dublin |
Mclaughlin R.L.,Trinity College Dublin |
Hardiman O.,Trinity Biomedical science Institute |
Bradley D.G.,Trinity College Dublin
Human Mutation | Year: 2013
The potential pathogenicity of genetic variants identified in disease-based resequencing studies is often overlooked where variants have previously been reported in dbSNP, the 1000 genomes project, or the National Heart, Lung and Blood Institute Exome Sequencing Project (ESP). In this work, we estimate that collectively, these databases capture ∼52% of mutations (dbSNP 50.4%; 1000 genomes 4.8%; and ESP 10.2%) reported as disease causing within phenotype-based locus-specific databases (LSDBs). To investigate whether these mutations may simply represent benign population variants, we evaluated whether the carrier frequencies associated with mutations implicated in amyotrophic lateral sclerosis were higher than what could be accounted for by high-penetrance disease models. In doing so, we have questioned the veracity of 51 mutations, but also demonstrated that each of the three databases included credible disease variants. Our results demonstrate the benefits of using databases such as dbSNP, the 1000 genomes project, and the ESP to evaluate the pathogenicity of putative disease variants, and suggest that many disease mutations reported across LSDBs may not actually be pathogenic. However, they also demonstrate that even in the context of rare Mendelian disorders, the potential pathogenicity of variants reported by these databases should not be overlooked without proper evaluation. © 2013 Wiley Periodicals, Inc.
Higgs R.,Trinity Biomedical science Institute |
Higgins S.C.,Trinity Biomedical science Institute |
Ross P.J.,Trinity Biomedical science Institute |
Mills K.H.G.,Trinity Biomedical science Institute
Mucosal Immunology | Year: 2012
Bordetella pertussis causes whooping cough, a severe respiratory tract infection in infants and children, and also infects adults. Studies in murine models have shown that innate immune mechanisms involving dendritic cells, macrophages, neutrophils, natural killer cells, and antimicrobial peptides help to control the infection, while complete bacterial clearance requires cellular immunity mediated by T-helper type 1 (Th1) and Th17 cells. Whole cell pertussis vaccines (wP) are effective, but reactogenic, and have been replaced in most developed countries by acellular pertussis vaccines (aP). However, the incidence of pertussis is still high in many vaccinated populations; this may reflect sub-optimal, waning, or escape from immunity induced by current aP. Protective immunity generated by wP appears to be mediated largely by Th1 cells, whereas less efficacious alum-adjuvanted aP induce strong antibody Th2 and Th17 responses. New generation aP that induce Th1 rather than Th2 responses are required to improve vaccine efficacy and prevent further spread of B. pertussis. © 2012 Society for Mucosal Immunology.
Senge M.O.,Trinity Biomedical science Institute
Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences | Year: 2012
Galvinols are interesting, sterically hindered compounds that serve as precursors for the generation of stable galvinoxyl radicals. In order to elucidate their basic structural chemistry and the influence of steric effects on their conformation a comparative analysis of several galvinol derivatives was undertaken. The aryl and quinoid subunits could clearly be identified, and substituents at the connecting methine bridge were found to influence the conformation of the molecules. As a result of the sterically hindered residues the molecules pack mainly through weak van der Waals interactions without formation of hydrogen bonds. The observation of different crystal forms and packing for galvinols and their conformational flexibility will impact current solid-state applications and provides unambiguous structural data for theoretical calculations. © 2012 Verlag der Zeitschrift fur Naturforschung, Tubingen.
Quinn S.R.,Trinity Biomedical science Institute |
O'Neill L.A.,Trinity Biomedical science Institute
Current Topics in Microbiology and Immunology | Year: 2014
Recent studies have shown an important interplay between Interleukin 10 (IL-10) and microRNAs. IL-10 can be directly post-transcriptionally regulated by several microRNA, including miR-106a, miR-4661, miR-98, miR-27, let7 and miR-1423p/5p. miRNA targeting of IL-10 has been suggested to play a role in autoimmune and inflammatory diseases such as SLE, reperfusion injury and asthma. Another miRNA, miR-21, has been shown to indirectly regulate IL-10 via downregulation of the IL-10 inhibitor PDCD4. The targeting of IL-10 in this way has been linked to host defence modulation by Mycobacterium leprae. Viral miRNAs, such as miR-K12-3 from Kaposi's sarcoma-associated herpesvirus (KSHV), can also decrease IL-10 to promote tumour development. Finally this interplay can operate in a feedback loop, with IL-10 capable of regulating microRNAs, upregulating those that can contribute to exerting the anti-inflammatory response, such as miR-187, and downregulating those that are highly pro-inflammatory, such as miR-155. Understanding the two-way regulation between miRNA and IL-10 is giving rise to new insights into this important cytokine. © 2014 Springer-Verlag Berlin Heidelberg.
Maher B.M.,Trinity College Dublin |
Mulcahy M.E.,Trinity College Dublin |
Murphy A.G.,Trinity College Dublin |
Wilk M.,Trinity College Dublin |
And 4 more authors.
Infection and Immunity | Year: 2013
Recent work has identified T cells and the cytokines they produce as important correlates of immune protection during Staphylococcus aureus infections through the ability of these T cells to regulate local neutrophil responses. However, the specific T-cell subsets that are involved in coordinating protection at distinct sites of infection remains to be established. In this study, we identify for the first time an important role for γδT cells in controlling S. aureus surgical site infection (SSI). γδT cells are recruited to the wound site following S. aureus challenge, where they represent the primary source of interleukin 17 (IL-17), with a small contribution from other non-γδT cells. The IL-17 response is entirely dependent upon IL-1 receptor signaling. Using IL-17 receptor- deficient mice, we demonstrate that IL-17 is required to control bacterial clearance during S. aureus SSI. However, we demonstrate a strain-dependent requirement for γδT cells in this process due to the differential abilities of individual strains to activate IL-1ß production. IL-1ß processing relies upon activation of the Nlrp3 inflammasome complex, and we demonstrate that Nlrp3-deficient and IL-1 receptor-deficient mice have an impaired ability to control S. aureus SSI due to reduced production of IL-17 by γδT cells at the site of infection. Given that IL-17 has been identified as an important correlate of immune protection during S. aureus infection, it is vital that the unique cellular sources of this cytokine and mechanisms inducing its activation are identified at distinct sites of infection. Our study demonstrates that while IL-17 may be critically important for mediating immune protection during S. aureus SSI, the relative contribution of γδT cells to these protective effects may be strain dependent. © 2013, American Society for Microbiology.
Vinardell T.,Trinity Biomedical science Institute |
Vinardell T.,Trinity College Dublin |
Sheehy E.J.,Trinity Biomedical science Institute |
Sheehy E.J.,Trinity College Dublin |
And 4 more authors.
Tissue Engineering - Part A | Year: 2012
Joint-derived stem cells are a promising alternative cell source for cartilage repair therapies that may overcome many of the problems associated with the use of primary chondrocytes (CCs). The objective of this study was to compare the in vitro functionality and in vivo phenotypic stability of cartilaginous tissues engineered using bone marrow-derived stem cells (BMSCs) and joint tissue-derived stem cells following encapsulation in agarose hydrogels. Culture-expanded BMSCs, fat pad-derived stem cells (FPSCs), and synovial membrane-derived stem cells (SDSCs) were encapsulated in agarose and maintained in a chondrogenic medium supplemented with transforming growth factor-β3. After 21 days of culture, constructs were either implanted subcutaneously into the back of nude mice for an additional 28 days or maintained for a similar period in vitro in either chondrogenic or hypertrophic media formulations. After 49 days of in vitro culture in chondrogenic media, SDSC constructs accumulated the highest levels of sulfated glycosaminoglycan (sGAG) (∼2.8% w/w) and collagen (∼1.8% w/w) and were mechanically stiffer than constructs engineered using other cell types. After subcutaneous implantation in nude mice, sGAG content significantly decreased for all stem cell-seeded constructs, while no significant change was observed in the control constructs engineered using primary CCs, indicating that the in vitro chondrocyte-like phenotype generated in all stem cell-seeded agarose constructs was transient. FPSCs and SDSCs appeared to undergo fibrous dedifferentiation or resorption, as evident from increased collagen type I staining and a dramatic loss in sGAG content. BMSCs followed a more endochondral pathway with increased type X collagen expression and mineralization of the engineered tissue. In conclusion, while joint tissue-derived stem cells possess a strong intrinsic chondrogenic capacity, further studies are needed to identify the factors that will lead to the generation of a more stable chondrogenic phenotype. © 2012, Mary Ann Liebert, Inc.
Kearney C.J.,Trinity College Dublin |
Cullen S.P.,Trinity College Dublin |
Tynan G.A.,Trinity Biomedical science Institute |
Henry C.M.,Trinity College Dublin |
And 4 more authors.
Cell Death and Differentiation | Year: 2015
TNF promotes a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing RIPK3. Because necrosis is generally more pro-inflammatory than apoptosis, it is widely presumed that TNF-induced necroptosis may be detrimental in vivo due to excessive inflammation. However, because TNF is intrinsically highly pro-inflammatory, due to its ability to trigger the production of multiple cytokines and chemokines, rapid cell death via necroptosis may blunt rather than enhance TNF-induced inflammation. Here we show that TNF-induced necroptosis potently suppressed the production of multiple TNF-induced pro-inflammatory factors due to RIPK3-dependent cell death. Similarly, necroptosis also suppressed LPS-induced pro-inflammatory cytokine production. Consistent with these observations, supernatants from TNF-stimulated cells were more pro-inflammatory than those from TNF-induced necroptotic cells in vivo. Thus necroptosis attenuates TNF-and LPS-driven inflammation, which may benefit intracellular pathogens that evoke this mode of cell death by suppressing host immune responses. © 2015 Macmillan Publishers Limited.