• Early biomarkers of joint damage in rheumatoid and psoriatic arthritis.

      Mc Ardle, Angela; Flatley, Brian; Pennington, Stephen R; FitzGerald, Oliver (Springer, 2015)
      Joint destruction, as evidenced by radiographic findings, is a significant problem for patients suffering from rheumatoid arthritis and psoriatic arthritis. Inherently irreversible and frequently progressive, the process of joint damage begins at and even before the clinical onset of disease. However, rheumatoid and psoriatic arthropathies are heterogeneous in nature and not all patients progress to joint damage. It is therefore important to identify patients susceptible to joint destruction in order to initiate more aggressive treatment as soon as possible and thereby potentially prevent irreversible joint damage. At the same time, the high cost and potential side effects associated with aggressive treatment mean it is also important not to over treat patients and especially those who, even if left untreated, would not progress to joint destruction. It is therefore clear that a protein biomarker signature that could predict joint damage at an early stage would support more informed clinical decisions on the most appropriate treatment regimens for individual patients. Although many candidate biomarkers for rheumatoid and psoriatic arthritis have been reported in the literature, relatively few have reached clinical use and as a consequence the number of prognostic biomarkers used in rheumatology has remained relatively static for several years. It has become evident that a significant challenge in the transition of biomarker candidates to clinical diagnostic assays lies in the development of suitably robust biomarker assays, especially multiplexed assays, and their clinical validation in appropriate patient sample cohorts. Recent developments in mass spectrometry-based targeted quantitative protein measurements have transformed our ability to rapidly develop multiplexed protein biomarker assays. These advances are likely to have a significant impact on the validation of biomarkers in the future. In this review, we have comprehensively compiled a list of candidate biomarkers in rheumatoid and psoriatic arthritis, evaluated the evidence for their potential as biomarkers of bone (joint) damage, and outlined how mass spectrometry-based targeted and multiplexed measurement of candidate biomarker proteins is likely to accelerate their clinical validation and the development of clinical diagnostic tests.
    • Ectopic focus in an accessory left atrial appendage: radiofrequency ablation of refractory atrial fibrillation.

      Killeen, Ronan P; O'Connor, Stephen A; Keane, David; Dodd, Jonathan D; Department of Radiology, St Vincent's University Hospital, Dublin, Ireland. (2012-02-01)
    • Effect of chronic hepatitis C virus infection on bone disease in postmenopausal women.

      Nanda, Kavinderjit S; Ryan, Elizabeth J; Murray, Barbara F; Brady, Jennifer J; McKenna, Malachi J; Nolan, Niamh; O'Farrelly, Cliona; Hegarty, John E; National Liver Transplant Unit, St Vincent's University Hospital, Dublin,, Ireland. (2012-02-01)
      BACKGROUND & AIMS: Limited data are available on the contribution of chronic HCV infection to the development of bone disease in postmenopausal women. We studied whether women who acquired HCV infection through administration of HCV genotype 1b-contaminated anti-D immunoglobulin from a single source had decreased bone mineral density (BMD) or altered levels of bone turnover markers (BTMs), compared with women who spontaneously resolved infection or age-matched healthy controls. METHODS: From a cohort of postmenopausal Irish women, we compared BMD, determined by dual-energy x-ray absorptiometry, and a panel of BTMs in 20 women chronically infected with HCV (PCR(+)), 21 women who had spontaneously resolved infection (PCR(-)), and 23 age-matched healthy controls. RESULTS: Levels of BTMs and BMD were similar in PCR(+) and PCR(-) women and healthy age-matched controls. However, there was an increased frequency of fractures in PCR(+) (n = 6) compared with PCR(-) women (n = 0, P = .007). PCR(+) women with fractures were postmenopausal for a longer time (median, 15.5, range, 5-20 years vs 4.5, range, 1-20 years in PCR(+) women without fractures; P = .033), had lower BMD at the hip (0.79, range, 0.77-0.9 g/cm(2) vs 0.96, range, 0.81-1.10 g/cm(2); P = .007), and had a lower body mass index (23.7, range 21.2-28.5 kg/m(2) vs 25.6, range 22.1-36.6 kg/m(2); P = .035). There was no difference in liver disease severity or BTMs in PCR(+) women with or without fractures. CONCLUSIONS: Chronic HCV infection did not lead to discernable metabolic bone disease in postmenopausal women, but it might be a risk factor for bone fractures, so preventive measures should be introduced. To view this article's video abstract, go to the AGA's YouTube Channel.
    • Effectiveness and cost of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in obesity services (STRIVE study): study protocol of an open-label, real-world, randomised, controlled trial.

      Papamargaritis, Dimitris; Al-Najim, Werd; Lim, Jonathan; Crane, James; Lean, Mike; le Roux, Carel; McGowan, Barbara; O'Shea, Donal; Webb, David; Wilding, John; et al. (2020-02-13)
      In this 2-year, multicentre, open-label, real-world randomised controlled trial, 384 adults with severe and complex obesity (defined as body mass index ≥35 kg/m2 plus either prediabetes, type 2 diabetes, hypertension or sleep apnoea) will be randomised via a 2:1 ratio to receive either standard SWMS care (n=128) or standard SWMS care plus a targeted prescribing pathway for LIRA 3 mg with prespecified stopping rules at 16, 32 and 52 weeks (n=256).The primary outcome is to compare the proportion of participants achieving a weight loss of ≥15% at 52 weeks with a targeted prescribing pathway versus standard care. Secondary outcomes include a comparison of (1) the weight loss maintenance at 104 weeks and (2) the budget impact and cost effectiveness between the two groups in a real-world setting.
    • Effects of heated humidification and topical steroids on compliance, nasal symptoms, and quality of life in patients with obstructive sleep apnea syndrome using nasal continuous positive airway pressure.

      Ryan, Silke; Doherty, Liam S; Nolan, Geraldine M; McNicholas, Walter T; Sleep Research Laboratory, St. Vincent's University Hospital, Dublin, Ireland. (2012-02-01)
      BACKGROUND: Nasal side effects are common in patients with obstructive sleep apnea syndrome (OSAS) starting on nasal continuous positive airway pressure (CPAP) therapy. We tested the hypothesis that heated humidification or nasal topical steroids improve compliance, nasal side effects and quality of life in this patient group. METHODS: 125 patients with the established diagnosis of OSAS (apnea/hypopnea index > or = 10/h), who tolerated CPAP via a nasal mask, and who had a successful CPAP titration were randomized to 4 weeks of dry CPAP, humidified CPAP or CPAP with additional topical nasal steroid application (fluticasone, GlaxoWellcome). Groups were similar in all demographic variables and in frequency of nasal symptoms at baseline. Outcome measures were objective compliance, quality of life (short form 36), subjective sleepiness (Epworth Sleepiness Scale score) and nasal symptoms such as runny, dry or blocked nose, sneezing and headaches; all variables assessed using a validated questionnaire and by direct interview. RESULTS: There was no difference in compliance between groups after 4 weeks (dry: 5.21 +/- 1.66 h/night, fluticasone: 5.66 +/- 1.68, humidifier: 5.21 +/- 1.84; p = 0.444). Quality of life and subjective sleepiness improved in all groups, but there were no differences in the extent of improvement. Nasal Symptoms were less frequently reported in the humidifier group (28%) than in the remaining groups (dry: 70%, fluticasone: 53%, p = 0.002). However, the addition of fluticasone resulted in increased frequency of sneezing. CONCLUSION: The addition of a humidifier, but not nasal steroids decreases the frequency of nasal symptoms in unselected OSAS patients initiating CPAP therapy; however compliance and quality of life remain unaltered.
    • Effects of radiation on levels of DNA damage in normal non-adjacent mucosa from colorectal cancer cases.

      Sheridan, Juliette; Tosetto, Miriam; Gorman, Julie; O'Donoghue, Diarmuid; Sheahan, Kieran; Hyland, John; Mulcahy, Hugh; Gibbons, David; O'Sullivan, Jacintha; Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. (2013-03)
      Defects in DNA repair pathways have been linked with colorectal cancer (CRC). Adjuvant radiotherapy has become commonplace in the treatment of rectal cancer however it is associated with a higher rate of second cancer formation. It is known that radiation results in DNA damage directly or indirectly by radiation-induced bystander effect (RIBE) by causing double-strand breaks (DSBs). The majority of work in RIBE has been performed in cell lines and limited studies have been in or ex vivo.
    • Effects of salmeterol on sleeping oxygen saturation in chronic obstructive pulmonary disease.

      Ryan, Silke; Doherty, Liam S; Rock, Clare; Nolan, Geraldine M; McNicholas, Walter T; Sleep Research Laboratory, St. Vincent's University Hospital, Dublin, Ireland. (2012-02-01)
      BACKGROUND: Sleep is associated with important adverse effects in patients with chronic obstructive pulmonary disease (COPD), such as disturbed sleep quality and gas exchange, including hypoxemia and hypercapnia. The effects of inhaled long-acting beta(2)-agonist therapy (LABA) on these disturbances are unclear. OBJECTIVES: The aim of the study was to assess the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation (SaO(2)) and sleep quality. METHODS: In a randomized, double-blind, placebo-controlled, crossover study of moderate/severe stable COPD patients, we compared the effects of 4 weeks of treatment with salmeterol 50 microg b.d. and matching placebo on sleeping SaO(2) and sleep quality. Overnight polysomnography (PSG) was performed at baseline, and after 4 and 8 weeks in addition to detailed pulmonary function testing. Of 15 patients included, 12 completed the trial (median age 69 years, forced expiratory volume in 1 s, FEV(1): 39%). RESULTS: Both mean SaO(2) [salmeterol vs. placebo: 92.9% (91.2, 94.7) vs. 91.0% (88.9, 94.8); p = 0.016] and the percentage of sleep spent below 90% of SaO(2) [1.8% (0.0, 10.8) vs. 25.6% (0.5, 53.5); p = 0.005] improved significantly with salmeterol. Sleep quality was similar with both salmeterol and placebo on PSG. Static lung volumes, particularly trapped gas volume, tended to improve with salmeterol. CONCLUSION: We conclude that inhaled LABA therapy improves sleeping SaO(2) without significant change in sleep quality.
    • Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis.

      McDermott, Edel; Murphy, Seamus; Keegan, Denise; O'Donoghue, Diarmuid; Mulcahy, Hugh; Doherty, Glen; Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. edelmcdermott@physicians.ie (2013-03)
      Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term.
    • The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL.

      Hutchinson, Michael; Kappos, Ludwig; Calabresi, Peter A; Confavreux, Christian; Giovannoni, Gavin; Galetta, Steven L; Havrdova, Eva; Lublin, Fred D; Miller, David H; O'Connor, Paul W; et al. (2012-02-01)
      The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, > or = 3), Expanded Disability Status Scale score (< or = 3.5, > 3.5), number of T2 lesions (< 9, > or = 9), presence of gadolinium-enhancing (Gd+) lesions (0, > or = 1), age (< 40, > or = 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., > or = 2 relapses in the year before study entry and > or = 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: > or = 9 T2 lesions at baseline, > or = 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment. These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.
    • Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium.

      Bryant, Josephine M; Grogono, Dorothy M; Rodriguez-Rincon, Daniela; Everall, Isobel; Brown, Karen P; Moreno, Pablo; Verma, Deepshikha; Hill, Emily; Drijkoningen, Judith; Gilligan, Peter; et al. (2016-11-11)
      Lung infections with Mycobacterium abscessus, a species of multidrug resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF) where they accelerate inflammatory lung damage leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
    • Emerging evidence for Gleason grade migration and distance impact in prostate cancer? An analysis of the rapid access prostate clinic in a tertiary referral center: St. Vincent's University Hospital, Dublin (2009-2011).

      O'Kelly, F; Thomas, A Z; Murray, D; Lee, P; O'Carroll, R F; Nicholson, P; Forristal, H; Swan, N; Galvin, D; Mulvin, D; et al. (2013-09)
      Recent evidence has suggested that the introduction of rapid access prostate cancer programs has led to a more streamlined pathway for patients, and was designed to ultimately reduce referral delays.
    • Encephalopathy associated with autoimmune thyroid disease in patients with Graves' disease: clinical manifestations, follow-up, and outcomes.

      Tamagno, Gianluca; Celik, Yahya; Simo, Rafael; Dihne, Marcel; Kimura, Kazumi; Gelosa, Giorgio; Lee, Byung I; Hommet, Caroline; Murialdo, Giovanni; Department of Endocrinology and Diabetes Mellitus, St Vincent's University, Hospital, University College Dublin, Dublin, Ireland. gianluca.tamagno@ucd.ie (2012-02-01)
      BACKGROUND: The encephalopathy associated with autoimmune thyroid disease (EAATD) is characterized by neurological/psychiatric symptoms, high levels of anti-thyroid antibodies, increased cerebrospinal fluid protein concentration, non-specific electroencephalogram abnormalities, and responsiveness to the corticosteroid treatment in patients with an autoimmune thyroid disease. Almost all EAATD patients are affected by Hashimoto's thyroiditis (HT), although fourteen EAATD patients with Graves' disease (GD) have been also reported. METHODS: We have recorded and analyzed the clinical, biological, radiological, and electrophysiological findings and the data on the therapeutic management of all GD patients with EAATD reported so far as well as the clinical outcomes in those followed-up in the long term. RESULTS: Twelve of the fourteen patients with EAATD and GD were women. The majority of GD patients with EAATD presented with mild hyperthyroidism at EAATD onset or shortly before it. Active anti-thyroid autoimmunity was detected in all cases. Most of the patients dramatically responded to corticosteroids. The long term clinical outcome was benign but EAATD can relapse, especially at the time of corticosteroid dose tapering or withdrawal. GD and HT patients with EAATD present with a similar clinical, biological, radiological, and electrophysiological picture and require an unaffected EAATD management. CONCLUSIONS: GD and HT equally represent the possible background condition for the development of EAATD, which should be considered in the differential diagnosis of all patients with encephalopathy of unknown origin and an autoimmune thyroid disease, regardless of the nature of the underlying autoimmune thyroid disease.
    • Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.

      Burke, J P; Watson, R W G; Mulsow, J J; Docherty, N G; Coffey, J C; O'Connell, P R; Department of Surgery, St Vincent's University Hospital, Dublin, Ireland. (2012-02-01)
      BACKGROUND: Fibroblasts isolated from strictures in Crohn's disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn's stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.
    • Endoscopic resection of a large inflammatory fibroid polyp of the caecum.

      McCawley, N; Sheahan, K; Hanly, A M; Departments of Colorectal Surgery Histopathology, St Vincents University Hospital, Elm Park, Dublin, Ireland. (2013-02)
    • Epidural analgesia for labour: maternal knowledge, preferences and informed consent.

      Fröhlich, S; Tan, T; Walsh, A; Carey, M; Department of Anaesthesia and Intensive Care Medicine, St Vincent's University Hospital, Elm Park, Dublin 4. (2012-02-29)
      Epidural analgesia has become increasingly popular as a form of labour analgesia in Ireland. However obtaining true inform consent has always been difficult. Our study recruited 100 parturients who had undergone epidural analgesia for labour, aimed to determine the information they received prior to regional analgesia, and to ascertain their preferences regarding informed consent. Only 65 (65%) of patients planned to have an epidural. Knowledge of potential complications was variable and inaccurate, with less than 30 (30%) of women aware of the most common complications. Most women 79 (79%) believed that discomfort during labour affected their ability to provide informed consent, and believe consent should be taken prior to onset of labour (96, 96%). The results of this study helps define the standards of consent Irish patients expect for epidural analgesia during labour.
    • ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly.

      Ubags, Niki D; Baker, Jonathan; Boots, Agnes; Costa, Rita; El-Merhie, Natalia; Fabre, Aurélie; Faiz, Alen; Heijink, Irene H; Hiemstra, Pieter S; Lehmann, Mareike; et al. (2020-03-02)
      In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.
    • Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial.

      Nichol, Alistair; French, Craig; Little, Lorraine; Presneill, Jeffrey; Cooper, D James; Haddad, Samir; Duranteau, Jacques; Huet, Olivier; Skrifvars, Markus; Arabi, Yaseen; et al. (2015-02-08)
      Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.
    • ESGAR consensus statement on liver MR imaging and clinical use of liver-specific contrast agents.

      Neri, E; Bali, M A; Ba-Ssalamah, A; Boraschi, P; Brancatelli, G; Alves, F Caseiro; Grazioli, L; Helmberger, T; Lee, J M; Manfredi, R; et al. (Springer, 2016-04)
      To develop a consensus and provide updated recommendations on liver MR imaging and the clinical use of liver-specific contrast agents.
    • Estrogen and gastrointestinal malignancy.

      Hogan, A M; Collins, D; Baird, A W; Winter, D C; Institute for Clinical Outcomes Research and Education (iCORE), St. Vincent's, University Hospital, Elm Park, Dublin 4, Ireland. Aislinghogan@yahoo.com (2012-02-01)
      The concept that E2 exerts an effect on the gastrointestinal tract is not new and its actions on intestinal mucosa have been investigated for at least three decades. An attempt to consolidate results of these investigations generates more questions than answers, thus suggesting that many unexplored avenues remain and that the full capabilities of this steroid hormone are far from understood. Evidence of its role in esophageal, gastric and gallbladder cancers is confusing and often equivocal. The most compelling evidence regards the protective role conferred by estrogen (or perhaps ERbeta) against the development and proliferation of colon cancer. Not only has the effect been described but also many mechanisms of action have been explored. It is likely that, along with surgery, chemotherapy and radiotherapy, hormonal manipulation will play an integral role in colon cancer management in the very near future.
    • Estrogen and its role in gastrointestinal health and disease.

      Hogan, Aisling M; Collins, Danielle; Baird, Alan W; Winter, Des C; Institute for Clinical Outcomes Research and Education (iCORE), St. Vincent's, University Hospital, Dublin, 4, Ireland. Aislinghogan@yahoo.com (2012-02-01)
      INTRODUCTION: While the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes. METHODS: A literature search was conducted using the PubMed database and the search terms were "estrogen," "estrogen AND gastrointestinal tract," "estrogen AND colon," "estrogen AND esophagus," "estrogen AND small intestine," "estrogen AND stomach," "estrogen AND gallbladder," and "estrogen AND motility." Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis. CONCLUSIONS: Effects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.