• Headshop heartache: acute mephedrone 'meow' myocarditis.

      Nicholson, Patrick J; Quinn, Martin J; Dodd, Jonathan D; Department of Cardiology, St Vincent's University Hospital, Dublin, Ireland. (2012-02-01)
    • Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain.

      Rieckmann, Nina; Neumann, Konrad; Feger, Sarah; Ibes, Paolo; Napp, Adriane; Preuß, Daniel; Dreger, Henryk; Feuchtner, Gudrun; Plank, Fabian; Suchánek, Vojtěch; et al. (2020-05-14)
      Background: Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD. Methods: From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale. Results: Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p < 0.01), and highest anxiety levels (8.3 ± 4.1, 7.5 ± 4.1, 6.5 ± 4.0, 4.7 ± 4.5, respectively, all adjusted p < 0.01). On all other measures, patients with typical or atypical angina had lower HRQoL compared to the two other groups (all adjusted p < 0.05). HRQoL did not differ between patients with and without obstructive CAD while women had worse HRQoL compared with men, irrespective of age and angina type. Conclusions: Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women.
    • Hedgehog signaling and therapeutics in pancreatic cancer.

      Kelleher, Fergal C; Department of Medical Oncology, St Vincent's University Hospital, Dublin,, Ireland. fergalkelleher@hotmail.com (2012-02-01)
      OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.
    • Hedgehog signaling and therapeutics in pancreatic cancer.

      Kelleher, Fergal C; Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland. fergalkelleher@hotmail.com (2011-04)
      To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis.
    • Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.

      Dwyer, Jeremy P; Sarwar, Shahzad; Egan, Brian; Nolan, Niamh; Hegarty, John; Liver Unit, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. (2011-11)
      Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.
    • Hepatic transplantation outcomes for carefully selected cirrhotic patients with hepatocellular carcinoma: experience at a small- to medium-volume centre.

      Qasim, A; Zaman, M B; Maguire, D; Geoghegan, J; Gibney, R; Nolan, N; Traynor, O; Hegarty, J; McCormick, P A; St Vincent's University Hospital, Dublin, Ireland. asgharqasim@yahoo.co.uk (2012-02-01)
      BACKGROUND: Hepatic transplantation outcomes for cirrhotic patients with hepatocellular carcinoma (HCC) at a small- to medium-volume centre are not fully known due to relative novelty of patient selection criteria. AIM: To determine hepatic transplantation outcomes for HCC at a small- to medium-volume centre. Patients and methods Hepatocellular carcinoma patients were listed for transplantation according to the International Guideline and further categorized as those fulfilling or exceeding Milan or University of San Francisco (UCSF) criteria on explanted liver morphology. Outcomes including mortality, retransplantation, and tumour recurrence rate were analysed. RESULTS: Twenty-six patients had HCC and on explanted liver morphology, Milan and UCSF criteria met 15 and 18 patients, respectively. Patients and graft survival at 3 months, 1 and 5 years were 100, 96, 84, and 88, 84, 77%, respectively. Outcomes favoured Milan criteria but did not reach statistical significance. CONCLUSIONS: Hepatic transplantation for HCC at a small-to medium-volume transplant centre had comparable survival outcomes to high-volume centres.
    • Hepatocellular carcinoma complicating cystic fibrosis related liver disease.

      O'Donnell, D H; Ryan, R; Hayes, B; Fennelly, D; Gibney, R G; Department of Radiology, St Vincent's University Hospital, Dublin 4, Ireland., davidhodonnell@hotmail.com (2012-02-01)
      Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.
    • Hepatocellular carcinoma: illustrated guide to systematic radiologic diagnosis and staging according to guidelines of the American Association for the Study of Liver Diseases.

      McEvoy, Sinead H; McCarthy, Colin J; Lavelle, Lisa P; Moran, Deirdre E; Cantwell, Colin P; Skehan, Stephen J; Gibney, Robert G; Malone, Dermot E; Department of Radiology, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. (2013-10)
      Hepatocellular carcinoma is a malignancy that predominantly occurs in the setting of cirrhosis. Its incidence is rising worldwide. Hepatocellular carcinoma differs from most malignancies because it is commonly diagnosed on the basis of imaging features alone, without histologic confirmation. The guidelines from the American Association for the Study of Liver Diseases (AASLD) are a leading statement for the diagnosis and staging of hepatocellular carcinoma, and they have recently been updated, incorporating several important changes. AASLD advocates the use of the Barcelona Clinic Liver Cancer (BCLC) staging system, which combines validated imaging and clinical predictors of survival to determine stage and which links staging with treatment options. Each stage of the BCLC system is outlined clearly, with emphasis on case examples. Focal liver lesions identified at ultrasonographic surveillance in patients with cirrhosis require further investigation. Lesions larger than 1 cm should be assessed with multiphasic computed tomography or magnetic resonance imaging. Use of proper equipment and protocols is essential. Lesions larger than 1 cm can be diagnosed as hepatocellular carcinoma from a single study if the characteristic dynamic perfusion pattern of arterial hyperenhancement and venous or delayed phase washout is demonstrated. If the imaging characteristics of hepatocellular carcinoma are not met, the alternate modality should be performed. Biopsy should be used if neither modality is diagnostic of hepatocellular carcinoma. Once the diagnosis has been made, the cancer should be assigned a BCLC stage, which will help determine suitable treatment options. Radiologists require a systematic approach to diagnose and stage hepatocellular carcinoma with appropriate accuracy and precision.
    • Hereditary mixed polyposis syndrome due to a BMPR1A mutation.

      O'Riordan, J M; O'Donoghue, D; Green, A; Keegan, D; Hawkes, L A; Payne, S J; Sheahan, K; Winter, D C; The Centre for Colorectal Disease, St Vincents' University Hospital, Elm Park, Dublin, Ireland. jamoriordan@rcsi.ie (2010-06)
      The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)-beta signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF-beta pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.
    • The 'hidden work' of a hospital neurologist: 1000 consults later.

      Ali, E; Chaila, E; Hutchinson, M; Tubridy, N; Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin,, Ireland. (2012-02-01)
      BACKGROUND: A new Web-based, internal neurology referral service was introduced in our department to expedite inpatient review for other departments and to allow assessment of the impact of neurology consults on patient care throughout the hospital, especially in the emergency department (ED). The results of the analysis of the first 1000 referrals using the new system are presented. Methods: An intranet referral system was designed by the consultant neurologists. The previous method of referral was by handwritten letter. The electronic template included 'drop-down' menus and mandatory fields to help guide referring teams. An outcome section is completed by the neurology team. Results: An average of 17 referrals was seen weekly. Seventy-seven per cent were seen within 24 h of referral. A consultant neurologist saw 87% of the referrals directly; 13% were first seen by a registrar and later discussed with a consultant. Forty per cent were seen in the ED of which a one-third of the patients were discharged following assessment. The most common reason for referral was seizure(s) or an episode of collapse (28%). Patients presenting with stroke/transient ischaemic attack represented 13.5%, and 12.5% presented with headaches. The management of 79% of referred cases was deemed to have been significantly changed after neurology review. Discussion: The introduction of a neurology consultant-designed and consultant-led intranet referral service has greatly enhanced the delivery of the consult service to patients in our hospital. This referral system contributes significantly to hospital efficiency and to access for patients to specialist assessment.
    • High clusterin expression correlates with a poor outcome in stage II colorectal cancers.

      Kevans, David; Foley, Jane; Tenniswood, Martin; Sheahan, Kieran; Hyland, John; O'Donoghue, Diarmuid; Mulcahy, Hugh; O'Sullivan, Jacintha; Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park, Dublin, 4, Ireland. (2012-02-01)
      The role of clusterin in tumor growth and progression remains unclear. Overexpression of cytoplasmic clusterin has been studied in aggressive colon tumors; however, no correlation between clusterin expression and survival in colorectal cancer has been identified to date. We assessed levels of clusterin expression in a group of stage II colorectal cancer patients to assess its utility as a prognostic marker. The study included 251 patients with stage II colorectal cancer. Tissue microarrays were constructed and immunohistochemistry done and correlated with clinical features and long term outcome. Dual immunofluorescence and confocal microscopy were used with terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling probes and clusterin antibody to assess the degree of co localization. Percentage epithelial cytoplasmic staining was higher in tumor compared with nonadjacent normal mucosa (P < 0.001). Within the stromal compartment, percentage cytoplamic staining and intensity was lower in tumor tissue compared with normal nonadjacent mucosa (P < or = 0.001). Survival was significantly associated with percentage epithelial cytoplasmic staining (P < 0.001), epithelial cytoplasmic staining intensity (P < 0.001), percentage stromal cytoplasmic staining (P = 0.002), and stromal cytoplasmic staining intensity (P < 0.001). Clusterin levels are associated with poor survival in stage II colorectal cancer.
    • High prevalence of psoriatic arthritis in patients with severe psoriasis with suboptimal performance of screening questionnaires.

      Haroon, Muhammad; Kirby, Brian; FitzGerald, Oliver; Department of Rheumatology, St Vincent's University Hospital, Elm Park, Dublin, 4, Ireland. (2013-05)
      The objectives of this study were to: (1) assess the prevalence of psoriatic arthritis (PsA) among Psoriasis (Ps) patients attending dermatology clinics; (2) identify clinical predictors of the development of PsA; and (3) compare the performance of three PsA screening questionnaires: Psoriatic Arthritis Screening and Evaluation (PASE), Psoriasis Epidemiology Screening Tool (PEST) and Toronto Psoriatic Arthritis Screening (ToPAS).
    • A high-density ERP study reveals latency, amplitude, and topographical differences in multiple sclerosis patients versus controls.

      Whelan, R; Lonergan, R; Kiiski, H; Nolan, H; Kinsella, K; Bramham, J; O'Brien, M; Reilly, R B; Hutchinson, M; Tubridy, N; et al. (2012-02-01)
      OBJECTIVE: To quantify latency, amplitude and topographical differences in event-related potential (ERP) components between multiple sclerosis (MS) patients and controls and to compare ERP findings with results from the paced auditory serial addition test (PASAT). METHODS: Fifty-four subjects (17 relapsing remitting (RRMS) patients, 16 secondary progressive (SPMS) patients, and 21 controls) completed visual and auditory oddball tasks while data were recorded from 134 EEG channels. Latency and amplitude differences, calculated using composite mean amplitude measures, were tested using an ANOVA. Topographical differences were tested using statistical parametric mapping (SPM). RESULTS: In the visual modality, P2, P3 amplitudes and N2 latency were significantly different across groups. In the auditory modality, P2, N2, and P3 latencies and N1 amplitude were significantly different across groups. There were no significant differences between RRMS and SPMS patients on any ERP component. There were topographical differences between MS patients and controls for both early and late components for the visual modality, but only in the early components for the auditory modality. PASAT score correlated significantly with auditory P3 latency for MS patients. CONCLUSIONS: There were significant ERP differences between MS patients and controls. SIGNIFICANCE: The present study indicated that both early sensory and later cognitive ERP components are impaired in MS patients relative to controls.
    • High-grade histologic features of DCIS are associated with R5 rather than R3 calcifications in breast screening mammography.

      Hayes, Brian D; Brodie, Caroline; O'Doherty, Ann; Quinn, Cecily M; Department of Histopathology, St Vincent's University Hospital, Elm Park, Dublin, Ireland. dr.brian.hayes@gmail.com (2013)
      Mammographic calcification is an important radiologic feature of early breast carcinoma whose index of suspicion for malignancy may be reported by a five-tier R-category system. This study aims to describe the histologic diagnoses underlying screen-detected mammographic calcifications using both digital and screen-film mammography, and to correlate these findings with radiologic R-categories. Patients attending the Merrion Breast Screening Unit in Dublin between 2000 and 2011 were identified, who underwent needle-core biopsy for assessment of mammographic calcifications without associated mass or architectural distortion. Radiologic R-category was correlated with biopsy and excision histology reports. A total of 776 cases of calcification were identified, involving 769 individual patients. The radiologic R-categories were as follows: R3 513 (66.1%), R4 192 (24.7%), R5 71 (9.1%). The positive predictive values for malignancy were R3 32.6%, R4 69.8%, R5 95.8%. Several histologic features of DCIS were associated with R5 rather than R3 radiology: high nuclear grade, solid or cribriform architecture, necrosis, periductal inflammation or fibrosis, and associated microinvasive or invasive carcinoma. Mammographic lesions and histologic whole and invasive tumors increased in size from R3 to R5. Radiologic size of calcifications correlated with whole (but not invasive) tumor size, although it tended to underestimate it by several millimeters. Digital-detected calcifications were more likely than screen-film detected to be categorized as R3 and less likely R4 or R5, and there was no significant difference in positive predictive value between the two imaging techniques in any R-category. In conclusion, histologic features of DCIS, in particular those associated with high grade, are associated with R5 radiology. There is no significant difference in positive predictive value for malignancy in any R-category between digital and screen-film mammography.
    • How early should psoriatic arthritis be treated with a TNF-blocker?

      Harty, Leonard; Veale, Douglas James; Dublin Academic Medical Centre, Department of Rheumatology, St Vincent's, University Hospital, University College Dublin, Dublin, Ireland. (2012-02-01)
      PURPOSE OF REVIEW: Psoriatic arthritis (PsA) is the second most commonly identified inflammatory arthropathy in early arthritis clinics. It is a complex multisystem disease involving the skin and joints, but may also present with inflammation of the spine - spondylitis, digits - dactylitis, eyes - uveitis and ligamentous insertions - enthesitis. The skin manifestations may be mild or patchy and often precede the joint inflammation. Joint erosions, however, may occur within the first 2 years in up to half of PsA patients and an erosion rate of 11% per annum has been reported suggesting it is not a benign disease as it was once regarded. RECENT FINDINGS: Therapy with mild anti-inflammatories is only beneficial in very mild or localized disease. In cases of more widespread joint involvement systemic therapy with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate may be required and in the case of extra-articular or spinal disease, in which DMARDs have failed to show efficacy, biologic therapy may be highly effective. SUMMARY: The question of how early treatment should be instituted should be decided in a specialist rheumatology referral centre following appropriate assessment. Optimal therapy with combination DMARD and biologics may result in remission rates of up to 60%.
    • How I do it: the stapled ileal J pouch at restorative proctocolectomy.

      Martin, S T; Tevlin, R; Heeney, A; Peirce, C; Hyland, J M; Winter, D C; Institute for Clinical Outcomes Research and Education (iCORE), Department of Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. (2011-12)
      Ileal pouch-anal anastomosis (IPAA) following proctocolectomy is the preferred option for patients with medically refractory ulcerative colitis, indeterminate colitis, and familial adenomatous polyposis. However, it remains a procedure associated with morbidity and mortality. Pelvic sepsis, pouch fistulae, and anastomotic dehiscence predispose to pouch failure. We report our experience with an adaptation for the formation of the stapled ileal J pouch using the GIA™ 100 stapling device (Covidien, Mansfield, Massachusetts, USA). When creating the J pouch, we remove the bevelled plastic protector from the thin fork of the stapling device, allowing the staple line to be completed to the tip of the stapled efferent limb of the pouch, thereby minimizing potential blind ending in the efferent limb and injury to the transverse staple line.
    • Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.

      Moran, Ellen M; Mullan, Ronan; McCormick, Jennifer; Connolly, Mary; Sullivan, Owen; Fitzgerald, Oliver; Bresnihan, Barry; Veale, Douglas J; Fearon, Ursula; Department of Rheumatology, St, Vincent's University Hospital, Dublin Academic Healthcare and The Conway Institute of Biomolecular and Biomedical Research, Elm Park, Dublin 4, Ireland. el.moran@ucd.ie. (2009)
      INTRODUCTION: The aim of this study was to examine IL-17A in patients, following anti-TNF-alpha therapy and the effect of IL-17A on matrix turnover and cartilage degradation. METHODS: IL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +/- TNF-alpha and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP/TIMP were assessed in patients pre/post biologic therapy. RESULTS: IL-17A levels were higher in RA vs osteoarthritis (OA)/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-alpha and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-alpha or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1/TIMP4, MMP3/TIMP1 and MMP3/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients. CONCLUSIONS: IL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.
    • Hyaline Vascular Castleman disease involving the Biliary Tract

      SN Kalimuthu, SN; Traynor, O; Albores-Saavedra, J; Sheahan, K; Gibbons, D (Irish Medical Journal, 2013-03)
    • Hypoxemia in patients with COPD: cause, effects, and disease progression.

      Kent, Brian D; Mitchell, Patrick D; McNicholas, Walter T; Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin,, Ireland. brian.kent@ucd.ie (2012-02-01)
      Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.
    • Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.

      Biniecka, Monika; Fox, Edward; Gao, Wei; Ng, Chin Teck; Veale, Douglas J; Fearon, Ursula; O'Sullivan, Jacintha; Dublin Academic Medical Centre, St. Vincent's University Hospital, and The Conway, Institute of Biomolecular and Biomedical Research, University College Dublin,, Dublin, Ireland. (2012-02-01)
      OBJECTIVE: To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels. METHODS: Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO(2)) were measured at arthroscopy using a Licox probe. Synovial expression of lipid peroxidation (4-hydroxynonenal [4-HNE]) and mitochondrial cytochrome c oxidase subunit II (CytcO II) deficiency were assessed by immunohistochemistry. In vitro levels of mtDNA point mutations, reactive oxygen species (ROS), mitochondrial membrane potential, and markers of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine [8-oxodG]) and lipid peroxidation (4-HNE) were determined in human synoviocytes under normoxia and hypoxia (1%) in the presence or absence of superoxide dismutase (SOD) or N-acetylcysteine (NAC) or a hydroxylase inhibitor (dimethyloxalylglycine [DMOG]). Patients were categorized according to their in vivo tPO(2) level (<20 mm Hg or >20 mm Hg), and mtDNA point mutations, immunochemistry features, and stress markers were compared between groups. RESULTS: The median tPO(2) level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P = 0.05) and with higher synovial 4-HNE cytoplasmic expression (P = 0.04). Synovial expression of CytcO II correlated with in vivo tPO(2) levels (P = 0.03), and levels were lower in patients with tPO(2) <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC. CONCLUSION: These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.