Results after Repair of Functional Tricuspid Regurgitation with a Three-Dimensional Annuloplasty Ring.

BACKGROUND: Tricuspid valve (TV) repair is the recommended treatment for severe functional tricuspid regurgitation (fTR) in patients undergoing left-sided surgery. For this purpose, a wide range of annuloplasty devices differing in form and flexibility are available. This study reports the results using a three-dimensional annuloplasty ring (Medtronic, Contour 3D Ring) for TV repair and analysis of risk factors. METHODS: A cohort of 468 patients who underwent TV repair (TVr) with a concomitant cardiac procedure from December 2010 to January 2017 was retrospectively analyzed. RESULTS: At follow-up, 96.1% of patients had no/trivial or mild TR. The 30-day mortality was 4.7%; it significantly differed between electively performed operations (2.7%) and urgent/emergent operations (11.7%). Risk factors for recurrent moderate and severe TR were LVEF < 50%, TAPSE < 16 mm, and moderate mitral valve (MV) regurgitation at follow-up. Preoperatively reduced renal function lead to a higher 30-day and overall mortality. Reoperation of the TV was required in six patients (1.6%). Risk factors for TV related reoperations were preoperative TV annulus over 50 mm and an implanted permanent pacemaker. CONCLUSIONS: TVr with the Contour 3D annuloplasty ring shows low TR recurrence and reoperation rates. Risk-factor analysis for the recurrence of TR revealed the importance of left- and right-ventricular function.

Expression of Surface-associated 82 kDa proMMP-9 in Lymphatic Leukemia Blast Cells Differentially Correlates With Prognosis.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) degrade extracellular matrix and process regulatory proteins. Recently, a membrane-bound 82kDa variant of proMMP-9 identified on myeloid blasts was shown to be associated with prognosis. PATIENTS AND METHODS: To investigate the role of 82kDa proMMP-9 with acute lymphoblastic leukemia (ALL) and chronic lymphoid leukemia (CLL), we performed flow-cytometry analysis of expression on ALL blasts (n=18) and CLL lymphocytes (n=21) from blood and correlated data with clinical parameters. RESULTS: In ALL, mature B-linear blasts expressed higher levels of 82kDa proMMP-9 compared to T-linear blasts. Elevated levels of 82kDa proMMP-9 were found in elderly patients and at patients with relapse. No correlation was observed on blood cells and extramedullary disease. In CLL, the 82kDa proMMP-9 expression did not correlate with any of the clinical parameters. CONCLUSION: Our findings suggest that higher levels of 82kDa proMMP-9 expression on blast cells may correlate with a more unfavorable ALL-subtype. Further studies are required to clarify the prognostic role of the 82kDa pro-MMP-9 expression.

Expression profiles of HMGB1 on B-CLL related leukocytes contribute to prediction of relapse.

BACKGROUND: The High Mobility Group Box 1 (HMGB1) is a nuclear protein that is frequently overexpressed in hematologic diseases and might be of relevance in immunogenic cancer control thus correlating with patients' (pts.) prognosis in diseases such as acute myeloid, acute lymphatic and chronic lymphocytic leukemia. MATERIALS AND METHODS: Expression profiles of blasts from AML (n = 21), ALL (n = 16) and of B-lymphocytes of CLL (n = 9) pts. were analyzed for surface expression of HMGB1 using flow cytometry. Expression was quantified and correlated with clinically and prognostically relevant markers. RESULTS: Expression profiling of HMGB1 in blasts of AML and ALL subtypes did not show differences between primary vs. secondary disease development and gender related differences. In ALL pts. however, age groups at initial diagnosis between ≥20 vs. <20 years were compared and showed significant differences (≥20 vs. <20 years; 89% vs. 49%, p  <0.05) with higher expression in higher age. In AML and CLL these differences were not visible. To evaluate the prognostic significance of HMGB1 expression, expression quantity was correlated with established and prognostic classification systems (in AML ELN, in ALL GMALL) and probability to relapse. No significant correlation was seen in these entities. However, when AML pts. were analyzed for remission rates after first anthracycline based induction therapy, in those who did not experience a complete remission significantly enhanced HMGB1 surface expression was seen (98 vs. 94%; p < 0.05; n = 20). Furthermore, for CLL it was shown that higher HMGB1 expression was found in pretreated patients with relapsed or/and refractory disease (1 vs. more relapses; 94 vs. 98%; p  <0.05; n = 9). CONCLUSION: HMGB1 is frequently expressed in hematologic malignancies. In this study it was shown that HMGB1 surface expression on AML blasts can be used as predictors for treatment response. In CLL it may be a marker for advanced disease. In order to implement this marker in FACS routine it could be a useful and practical tool for prognostic assessment and treatment planning.

Chk1 Promotes DNA Damage Response Bypass following Oxidative Stress in a Model of Hydrogen Peroxide-Associated Ulcerative Colitis through JNK Inactivation and Chromatin Binding.

Dysregulation of c-Jun N-terminal kinase (JNK) activation promoted DNA damage response bypass and tumorigenesis in our model of hydrogen peroxide-associated ulcerative colitis (UC) and in patients with quiescent UC (QUC), UC-related dysplasia, and UC-related carcinoma (UC-CRC), thereby adapting to oxidative stress. In the UC model, we have observed features of oncogenic transformation: increased proliferation, undetected DNA damage, and apoptosis resistance. Here, we show that Chk1 was downregulated but activated in the acute and quiescent chronic phases. In both phases, Chk1 was linked to DNA damage response bypass by suppressing JNK activation following oxidative stress, promoting cell cycle progression despite DNA damage. Simultaneously, activated Chk1 was bound to chromatin. This triggered histone acetylation and the binding of histone acetyltransferases and transcription factors to chromatin. Thus, chromatin-immobilized activated Chk1 executed a dual function by suppressing DNA damage response and simultaneously inducing chromatin modulation. This caused undetected DNA damage and increased cellular proliferation through failure to transmit the appropriate DNA damage signal. Findings in vitro were corroborated by chromatin accumulation of activated Chk1, Ac-H3, Ac-H4, and c-Jun in active UC (AUC) in vivo. Targeting chromatin-bound Chk1, GCN5, PCAF, and p300/CBP could be a novel therapeutic strategy to prevent UC-related tumor progression.

Significance of Frequencies, Compositions, and/or Antileukemic Activity of (DC-stimulated) Invariant NKT, NK and CIK Cells on the Outcome of Patients With AML, ALL and CLL.

Invariant natural killer T (iNKT)/natural killer (NK)/cytokine-induced killer (CIK) cells are important for immune surveillance. (I) Novel combinations of antibody 6B11 (targeting the Vα24-Jα18-invariant T-cell receptor) with CD4/CD8/CD1d/Vα24 for iNKT subset detection and "T/NK cell-like"-iNKT subsets were defined. Compared with healthy peripheral blood mononuclear cells (MNC) (significantly) lower proportions of iNKT cells (6B11/6B11CD3/6B11CD161), NK cells (CD3CD56/CD3CD161), and CIK cells (CD3CD56/CD3CD161) were found in peripheral blood MNC from acute myeloid (AML)/acute myeloid, lymphoid (ALL)/chronic lymphoid leukemia (CLL) patients in acute disease stages. Subtyping of iNKT cells revealed (significantly) higher proportions of CD3 T cells and CD161 NK cells in AML/ALL/CLL expressing 6B11 compared with healthy MNC. Prognostic evaluations showed higher proportions of iNKT/NK/CIK cells in favorable AML subgroups (younger age, primary, no extramedullary disease, achievement/maintenance of complete remission) or adult ALL and CLL patients. (II) iNKT/NK/CIK cell frequencies increased after (vs. before) mixed lymphocyte cultures of T-cell-enriched immune reactive cells stimulated with MNC/whole blood with or without pretreatment with "cocktails" (dendritic cells generating methods/kits inducing blasts' conversion to leukemia-derived dendritic cells from AML patients). Individual "cocktails" leading to "highest" iNKT cell frequencies could be defined. Antileukemic blast lytic activity correlated significantly with frequencies of iNKT/NK/CIK cells. In summary healthy MNC show significantly more iNKT/NK/CIK cells compared with AML/ALL/CLL MNC, a shift in the iNKT cell composition is seen in healthy versus leukemic samples and iNKT/NK/CIK cell-proportions in AML/ALL/CLL MNC samples correlate with prognosis. "Cocktail"-treated AML blasts lead to higher iNKT/NK/CIK cell frequencies and samples with antileukemic activity show significantly higher frequencies of iNKT/NK/CIK cells. Proportions of iNKT/NK/CIK cells should regularly be evaluated in AML/ALL/CLL diagnosis panels for quantitative/prognostic estimation of individual patients' antileukemic potential and their role in dendritic cells/leukemia-derived dendritic cells triggered immune surveillance.

Inactivation of JNK2 as carcinogenic factor in colitis-associated and sporadic colorectal carcinogenesis.

We recently reported that dysregulated c-Jun N-terminal kinases (JNK) activity causes defective cell cycle checkpoint control, inducing neoplastic transformation in a cellular ulcerative colitis (UC) model. In the quiescent chronic phase of UC, p-p54 JNK was down-regulated and p-p46 JNK was up-regulated. Both were up-regulated in the acute phase. Consequently, increased p21WAF1 and γ-H2AX, two JNK-regulated proteins, induced cell cycle arrest. Their down-regulation led to checkpoint override, causing increased proliferation and undetected DNA damage in quiescent chronic phase, all characteristics of tumorigenesis. We investigated expression of p-JNK2, p-JNK1-3, p21WAF1, γ-H2AX and Ki67 by immunohistochemistry in cases of quiescent UC (QUC), active UC (AUC), UC-dysplasia and UC-related colorectal carcinoma (UC-CRC). Comparison was made to normal healthy colorectal mucosa, sporadic adenoma and colorectal carcinoma (CRC), diverticulitis and Crohns disease (CD). We found p-JNK2 up-regulation in AUC and its early down-regulation in UC-CRC and CRC carcinogenesis. With down-regulated p-JNK2, p21WAF1 was also decreased. Ki67 was inversely expressed, showing increased proliferation early in UC-CRC and CRC carcinogenesis. p-JNK1-3 was increased in AUC and QUC. Less increased γ-H2AX in UC-CRC compared to CRC gave evidence that colitis-triggered inflammation masks DNA damage, thus contributing to neoplastic transformation. We hypothesize that JNK-dependent cell cycle arrest is important in AUC, while chronic inflammation causes dysregulated JNK activity in quiescent phase that may contribute to checkpoint override, promoting UC carcinogenesis. We suggest restoring p-JNK2 expression as a novel therapeutic strategy to early prevent the development of UC-related cancer.

Expression of surface-associated 82kDa-proMMP-9 in primary acute leukemia blast cells inversely correlates with patients' risk.

With its ability to degrade extracellular matrix proteins and activate growth factors and cytokines, matrix metalloproteinase (MMP)-9 is an important regulator of cell function. Previously, we reported that myeloid leukemic cells express a unique 82kDa-proMMP-9 variant on their cell surface that is not affected by its natural inhibitor. In this study, we generated monoclonal antibodies that specifically recognize 82kDa-proMMP-9. Flow cytometry analysis using these antibodies revealed significant surface expression of 82kDa-proMMP-9 in monocytes, but minimal amounts in T and B cells isolated from peripheral blood of nine healthy donors and 22 patients with acute myeloid leukemia (AML). In all AML patients, blasts expressed 82kDa-proMMP-9 at levels of 4%-46%, with significantly higher levels in patients with a better risk defined according to National Comprehensive Cancer Network (NCCN) guidelines (ρ = -0.748, p < 0.001) and favorable phenotype according to the French-American-British classification (p = 0.02) compared with patients with adverse prognoses. Receiver operating characteristic curve analysis confirmed the diagnostic accuracy of 82kDa-proMMP-9 measurement in AML blasts (area under the curve: 0.893 [0.739-1.000], p = 0.019). It led us to define a cutoff value of 11.5% for identifying patients with lower NCCN risk (p = 0.005) and with a tendency toward a higher probability of response to anthracycline-based therapy (p = 0.109) and increased event-free survival (p = 0.24). Thus, 82kDa-proMMP-9 expression on blasts may represent a novel independent marker of prognosis in patients with AML.

Is a Profiled Annuloplasty Ring Suitable for Repair of Degenerative Mitral Regurgitation? A Single-Center Experience Comprising 200 Patients.

Background Various devices have been proposed for ring annuloplasty in patients with degenerative mitral valve disease. This study reports for the first time midterm results with the rigid three-dimensional Medtronic Profile 3D (Medtronic, Minneapolis, Minnesota, United States) annuloplasty ring. Methods Between June 2009 and June 2011, 200 patients (mean age 61 ± 13 years, 70% male) with severe degenerative mitral regurgitation underwent mitral valve repair using the Medtronic Profile 3D annuloplasty ring. A total of 106 patients (53.0%) underwent isolated mitral valve repair and 94 patients (47.0%) underwent a concomitant procedure such as coronary artery bypass grafting (n = 21), tricuspid valve surgery (n = 49), AF ablation (n = 17), and aortic valve surgery (n = 13). The follow-up is 94.5% complete (mean 2.5 ± 0.5 years). Results Thirty-day mortality was 1.5%. Survival at 3 years was 97.1 ± 1.6% for isolated procedures and 92.4 ± 2.8% for combined procedures (p = 0.137). Freedom from mitral valve-related reoperation at 3 years was 97.1 ± 1.7% for isolated procedures and 95.5 ± 2.2% for combined procedures (p = 0.561). Seven patients (3.5%) required a mitral valve-related reoperation. Two of these reoperations were required for endocarditis, two for ring dehiscence, one for progression of the native disease (flail leaflet), one for leaflet suture dehiscence, and one for persistent systolic anterior motion. Conclusion The three-dimensional Medtronic Profile 3D annuloplasty ring is suitable for mitral valve repair for degenerative diseases. This saddle-shaped annuloplasty device provides excellent early results with a very good functional outcome at midterm either in isolated or combined procedures.

DNA methylation in an engineered heart tissue model of cardiac hypertrophy: common signatures and effects of DNA methylation inhibitors.

DNA methylation affects transcriptional regulation and constitutes a drug target in cancer biology. In cardiac hypertrophy, DNA methylation may control the fetal gene program. We therefore investigated DNA methylation signatures and their dynamics in an in vitro model of cardiac hypertrophy based on engineered heart tissue (EHT). We exposed EHTs from neonatal rat cardiomyocytes to a 12-fold increased afterload (AE) or to phenylephrine (PE 20 µM) and compared DNA methylation signatures to control EHT by pull-down assay and DNA methylation microarray. A 7-day intervention sufficed to induce contractile dysfunction and significantly decrease promoter methylation of hypertrophy-associated upregulated genes such as Nppa (encoding ANP) and Acta1 (α-skeletal actin) in both intervention groups. To evaluate whether pathological consequences of AE are affected by inhibiting de novo DNA methylation we applied AE in the absence and presence of DNA methyltransferase (DNMT) inhibitors: 5-aza-2'-deoxycytidine (aza, 100 µM, nucleosidic inhibitor), RG108 (60 µM, non-nucleosidic) or methylene disalicylic acid (MDSA, 25 µM, non-nucleosidic). Aza had no effect on EHT function, but RG108 and MDSA partially prevented the detrimental consequences of AE on force, contraction and relaxation velocity. RG108 reduced AE-induced Atp2a2 (SERCA2a) promoter methylation. The results provide evidence for dynamic DNA methylation in cardiac hypertrophy and warrant further investigation of the potential of DNA methylation in the treatment of cardiac hypertrophy.

Do transvalvular pacemaker leads influence functional outcome after tricuspid ring annuloplasty?

OBJECTIVES: The impact of permanent pacemaker (PPM) leads on functional outcome of tricuspid valve (TV) repair has not been clearly demonstrated. Therefore, controversy exists as to whether transvalvular PPM leads should be explanted and replaced by epicardial leads at the time of valve repair. This study evaluates the influence of PPM leads on functional outcome, TV-related reoperations and survival in patients undergoing TV repair for functional tricuspid regurgitation (TR). METHODS: We retrospectively reviewed 415 consecutive patients who underwent TV ring annuloplasty at our institution from July 2007 to February 2013. In 112 patients (27%), a PPM was implanted either pre- or postoperatively. The follow-up is 94% complete (mean: 24.4 months; cumulative total 845 patient-years). RESULTS: The mean age was 70.2 ± 9.8 years and the mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) was 12.4%. Of note, 76.6% of the patients were in New York Heart Association class III or IV. Echocardiography documented moderate or severe TR in 96.4% of the patients, with a mean annulus diameter of 44.8 ± 5.4 mm. 95.4% of the patients underwent a combined procedure and 16.4% an urgent or emergent operation. The 30-day mortality was 7.5%. The preoperative TR grade was reduced from 2.47 ± 0.52 to 0.70 ± 0.54 (P < 0.001). At hospital discharge, residual ≥II TR was present in 7.1% of the patients. Freedom from recurrent ≥II TR at 5 years was 86.7 ± 3.2%. Upon uni- and multivariate analyses, the presence of a transvalvular PPM was not a risk factor for recurrent ≥II TR and late mortality. Freedom from TV-reoperations was 98.1 ± 0.8% at 5 years without significant difference between groups. CONCLUSION: The presence of a transvalvular PPM lead is not a risk factor for recurrent TR, TV-related reoperations and late mortality in patients undergoing ring annuloplasty for functional TR.

Early experiences with a new three-dimensional annuloplasty ring for the treatment of functional tricuspid regurgitation.

BACKGROUND: Various techniques and devices have been proposed for tricuspid valve (TV) repair in patients with tricuspid regurgitation (TR). However, residual or recurrent TR is not uncommon occurring in 20% to 30% of patients. This study reports first experiences with a new three-dimensional annuloplasty ring. METHODS: We retrospectively reviewed 200 consecutive patients who underwent TV repair for functional TR with the Contour 3D annuloplasty ring (Medtronic, Minneapolis, MN) from December 2010 to February 2013 at our institution. The follow-up is 98% complete (mean 1.0 ± 0.7 years; cumulative total 189 patient-years). RESULTS: Mean age was 70.4 ± 9.1 years and the median logistic European system for cardiac operative risk was 7%. Sixty-nine percent of the patients were in New York Heart Association class III/IV. Echocardiography documented moderate or severe TR in 97.5% of the patients, with a mean annulus diameter of 45.1 ± 4.9 mm; 93.5% of the patients underwent a combined procedure, and 20.5% an urgent or emergent operation. The 30-day mortality was 6%. The preoperative TR grade was reduced from 2.45 ± 0.53 to 0.77 ± 0.54 (p < 0.001). At hospital discharge residual II TR or greater was present in 4.3% of the patients. Freedom from recurrent II TR or greater at 2 years was 90.9% ± 4.2% and freedom from TV-related reoperations at 2 years was 98.5% ± 1.0%. No case of ring dehiscence occurred. Fourteen patients (7%) required a permanent pacemaker implantation for atrioventricular block. CONCLUSIONS: Tricuspid valve repair with the Contour 3D annuloplasty ring can be performed with a low rate of residual TR at hospital discharge, a low reoperation rate, and with an excellent early functional outcome.

Three-dimensional valve repair-the better care? Midterm results of a saddle-shaped, rigid annuloplasty ring in patients with ischemic mitral regurgitation.

OBJECTIVES: Undersized ring annuloplasty is the treatment of choice for functional mitral regurgitation. However, recurrence of mitral regurgitation within the first years is frequent. The aim of this study was to analyze the functional and clinical outcome after mitral valve repair with the 3-dimensional saddle-shaped Edwards GeoForm (Edwards Lifesciences LLC, Irvine, Calif) annuloplasty ring in patients with ischemic mitral regurgitation. METHODS: Between November 2006 and November 2012, 70 patients (mean age, 68 ± 10 years; mean left ventricular ejection fraction, 40% ± 15%) with functional mitral regurgitation due to ischemic cardiomyopathy underwent mitral valve repair with the Edwards GeoForm annuloplasty ring. Concomitant procedures, such as coronary artery bypass grafting (75.7%), tricuspid valve repair (25.7%), aortic valve replacement (8.6%), and the Maze procedure (4.3%), were performed in 92.9% of patients. Follow-up is 97% complete (mean, 3.0 ± 1.7 years). Transthoracic echocardiography was obtained 2.4 ± 1.7 years postoperatively. RESULTS: Thirty-day mortality was 5.9%. Overall survival at 5 years was 71.3% ± 6.9%. At 4 years, overall freedom from recurrence of mitral regurgitation grade 3+ or greater was 92.5% ± 3.6%, and freedom from recurrence of mitral regurgitation grade 2+ or greater was 71.0% ± 8.7%. Three patients required a mitral valve-related reoperation for ring dehiscence. New York Heart Association functional class improved from 3.6 ± 0.6 to 1.6 ± 0.6 during follow-up (P < .05). Mean mitral valve pressure gradient was 3.3 ± 1.8 mm Hg across all ring sizes at the time of follow-up. CONCLUSIONS: Mitral valve repair with the 3-dimensional saddle-shaped Edwards GeoForm annuloplasty ring in case of ischemic mitral regurgitation shows a low rate of recurrent regurgitation at 4 years. Clinically relevant mitral stenosis was not detected. The importance of secure anchoring of the device in the mitral annulus has to be emphasized to prevent ring dehiscence.

Repeated H2 O2 exposure drives cell cycle progression in an in vitro model of ulcerative colitis.

The production of hydrogen peroxide (H2 O2 ) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H2 O2 activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c-Jun N-terminal Kinases (JNK) that induces p21(WAF1) . Moreover, caspases circumvented the G1/S and intra-S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H2 O2 exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H2 O2 -exposed HCEC cells (C-cell cultures) was associated with (i) increased phospho-p46 JNK, (ii) decreased total JNK and phospho-p54 JNK and (iii) p21(WAF1) down-regulation. Altered JNK activation and p21(WAF1) down-regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H2 O2 exposure. This may cause increased proliferation of C-cell cultures, a defining initiating feature in the inflammation-carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non-apoptotic function of caspases, causing checkpoint adaptation in C-cell cultures. Additionally, loss of cell-contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell-contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H2 O2 -induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21(WAF1) , c-Fos, c-Jun/phospho-c-Jun, ATF2/phospho-ATF2, ß-catenin/TCF4-signalling, c-Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression.

Non-apoptotic function of caspases in a cellular model of hydrogen peroxide-associated colitis.

Oxidative stress, caused by reactive oxygen species (ROS), is a major contributor to inflammatory bowel disease (IBD)-associated neoplasia. We mimicked ROS exposure of the epithelium in IBD using non-tumour human colonic epithelial cells (HCEC) and hydrogen peroxide (H2 O2 ). A population of HCEC survived H2 O2 -induced oxidative stress via JNK-dependent cell cycle arrests. Caspases, p21(WAF1) and γ-H2AX were identified as JNK-regulated proteins. Up-regulation of caspases was linked to cell survival and not, as expected, to apoptosis. Inhibition using the pan-caspase inhibitor Z-VAD-FMK caused up-regulation of γ-H2AX, a DNA-damage sensor, indicating its negative regulation via caspases. Cell cycle analysis revealed an accumulation of HCEC in the G1 -phase as first response to oxidative stress and increased S-phase population and then apoptosis as second response following caspase inhibition. Thus, caspases execute a non-apoptotic function by promoting cells through G1 - and S-phase by overriding the G1 /S- and intra-S checkpoints despite DNA-damage. This led to the accumulation of cells in the G2 /M-phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC via γ-H2AX suppression, although its direct proteolytic inactivation was excluded. Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of γ-H2AX. As a consequence, undetected DNA-damage and increased proliferation were found in repeatedly H2 O2 -exposed HCEC. Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases. Overexpression of upstream p-JNK in active ulcerative colitis also suggests a potential importance of this pathway in vivo.

Integrated electrode and high density feedthrough system for chip-scale implantable devices.

High density feedthroughs have been developed which allow for the integration of chip-scale features and electrode arrays with up to 1141 stimulating sites to be located on a single implantable package. This layered technology displays hermetic properties and can be produced from as little as two laminated 200 µm thick alumina sheets. It can also be expanded to a greater number of layers to allow flexible routing to integrated electronics. The microelectrodes, which are produced from sintered platinum (Pt) particulate, have high charge injection capacity as a result of a porous surface morphology. Despite their inherent porosity the electrodes are electrically stable following more than 1.8 billion stimulation pulses delivered at clinically relevant levels. The ceramic-Pt constructs are also shown to have acceptable biological properties, causing no cell growth inhibition using standard leachant assays and support neural cell survival and differentiation under both passive conditions and active electrical stimulation.

Tricuspid valve repair: is ring annuloplasty superior?

OBJECTIVES: Tricuspid regurgitation (TR) secondary to left heart disease is the most common aetiology of tricuspid valve (TV) insufficiency. Valve annuloplasty is the primary treatment for TV insufficiency. Several studies have shown the superiority of annuloplasty with a prosthetic ring over other repair techniques. We reviewed our experience with different surgical techniques for the treatment of acquired TV disease focusing on long-term survival and incidence of reoperation. METHODS: A retrospective analysis of 717 consecutive patients who underwent TV surgery between 1975 and 2009 with either a ring annuloplasty [Group R: N = 433 (60%)] or a De Vega suture annuloplasty [Group NR: no ring; N = 255 (36%)]. Twenty-nine (4%) patients underwent other types of TV repair. A ring annuloplasty was performed predominantly in the late study period of 2000-09. TV aetiology was functional in 67% (479/717) of the patients. Ninety-one percent of the patients (n = 649) underwent concomitant coronary artery bypass grafting and/or mitral/aortic valve surgery. RESULTS: Patients who received a ring annuloplasty were older (67 ± 13 vs 60 ± 13 years; P < 0.001). Overall 30-day mortality was 13.8% (n = 95) [Group R: n = 55 (12.7%) and Group NR: n = 40 (15.7%)]. Ten-year actuarial survival after TV repair with either the De Vega suture or ring annuloplasty was 39 ± 3 and 46 ± 7%, respectively (P = 0.01). Twenty-eight (4%) patients required a TV reoperation after 5.9 ± 5.1 years. Freedom from TV reoperation 10 years after repair with a De Vega annuloplasty was 87.9 ± 3% compared with 98.4 ± 1% after the ring annuloplasty (P = 0.034). CONCLUSIONS: Patients who require TV surgery either as an isolated or a combined procedure constitute a high-risk group. The long-term survival is poor. Tricuspid valve repair with a ring annuloplasty is associated with improved survival and a lower reoperation rate than that with a suture annuloplasty.

Narrow band imaging for detection of dysplasia in colitis: a randomized controlled trial.

OBJECTIVES: In ulcerative colitis surveillance, chromoendoscopy improves dysplasia detection 3 ­ 5-fold compared with white light endoscopy (WLE). The aim of this study was to investigate whether narrow band imaging (NBI) can improve dysplasia detection compared with WLE. METHODS: This was a randomized, parallel-group trial. A total of 220 patients were needed to be recruited to detect a threefold increase in dysplasia detection. In all, 112 patients with long-standing ulcerative colitis were randomized to colonoscopic extubation with NBI (56) or WLE (56) (1:1 ratio) at two tertiary endoscopy units in the United Kingdom. Targeted biopsies of suspicious areas and quadrantic random biopsies every 10 cm were taken in both groups. The primary outcome measure was the proportion of patients with at least one area of dysplasia detected. In a prespecified mid-point analysis, the criteria for trial discontinuation were met and the trial was stopped and analyzed at this point. RESULTS: There was no difference in the primary outcome between the two groups, with 5 patients having at least one dysplastic lesion in each group (odds ratio (OR) 1.00, 95 % confidence interval (95 % CI) 0.27 ­ 3.67, P = 1.00). This remained unchanged when adjusted for other variables (OR 0.69, 95 % CI 0.16 ­ 2.96, P = 0.62). Overall, dysplasia detection was 9 % in each arm. Yield of dysplasia from random nontargeted biopsies was 1 / 2,707 (0.04 % ). CONCLUSIONS: Overall, in this multicenter parallel-group trial, there was no difference in dysplasia detection when using NBI compared with high-definition WLE colonoscopy. Random background biopsies were ineffective in detecting dysplasia.

Dynamic patient position changes during colonoscope withdrawal increase adenoma detection: a randomized, crossover trial.

BACKGROUND: Colonoscopy has a miss rate for adenomas that may partly relate to poor visualization of the colonic surface. Dynamic position changes during colonoscope withdrawal can improve luminal distension. OBJECTIVE: To assess whether position changes also improve adenoma and polyp detection. DESIGN: Randomized crossover clinical trial. SETTING: Academic endoscopy unit. PATIENTS: This study involved 130 patients who presented for routine colonoscopy. INTERVENTION: Examination either entirely in the left lateral position followed by position changes (cecum to hepatic flexure, left lateral; transverse colon, supine; splenic flexure and descending colon, right lateral) or vice versa. After both examinations, polyps were removed for histopathology. MAIN OUTCOME MEASUREMENTS: Proportion of patients with ≥1 polyp or adenoma detected between the hepatic flexure and the sigmoid-descending colon junction. Luminal distension was measured on a scale of 1 to 5: 1, total collapse; 5, fully distended. RESULTS: At least 1 adenoma was detected in 34% of patients in colon areas in which the patient position differed from left lateral (transverse colon, splenic flexure, descending colon) compared with 23% examined with the patient in the left lateral position alone (P = .01). At least 1 polyp was detected in 52% of patients with position changes versus 34% of patients examined in the left lateral position alone (P < .001). Adenoma and polyp detection were positively correlated with an improved distension score (correlation coefficient, 0.12; P < .001). Adenomas were detected in 16% of colon areas with adequate distension scores (4 and 5) compared with 7% of those with borderline or nondiagnostic scores (1-3; P < .001). LIMITATIONS: Single-operator study. CONCLUSION: Dynamic position changes during colonoscope withdrawal significantly improved polyp and adenoma detection. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00234650).

Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma.

Death-associated protein kinase (DAPK) has pro-apoptotic functions and participates in various apoptotic systems. DAPK acts as a tumor suppressor, and its inactivation by promoter hypermethylation has been frequently observed in various human cancers. As alterations of pro-apoptotic genes might cause instability in the balance of cell-turnover during chronic inflammatory processes, epigenetic silencing of DAPK might be involved in the carcinogenesis of ulcerative colitis-associated carcinoma (UCC). To evaluate the role of DAPK in the inflammation-driven carcinogenesis of ulcerative colitis (UC), we analyzed promoter hypermethylation and protein expression of DAPK using methylation-specific PCR and immunohistochemistry in 43 UCCs and paired UC-background mucosa, as well as in UC-background mucosa of 50 patients without UCC. The frequency of methylation of DAPK in UCCs was low (27.6%) compared to overall non-neoplastic UC-background mucosa (48.3%; p=0.02) and sporadic colorectal carcinoma (57.4%, p=0.019). The difference in the methylation frequency in UC-background mucosa in patients without UCC (54.2%), compared to those with UCC (40.0%), was not significant (p=0.141). Promoter methylation correlated significantly with decreased DAPK protein expression (p<0.001) and severity of inflammatory activity (p=0.024). In unmethylated UC-background mucosa, DAPK protein expression increased with activity of UC-associated inflammation, suggesting a protective role of the pro-apoptotic DAPK during the chronic inflammatory process of UC. Thus, inactivation of DAPK by promoter hypermethylation might be crucial for accumulation of DNA damage in inflamed mucosa of UC, and might therefore contribute to the initiation of the neoplastic process and development of UC-associated carcinoma.