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Background: Limited data exist on strain changes after transcatheter aortic valve implantation (TAVI) in patients with aortic regurgitation (AR)., Case Summary: Three patients with AR undergoing TAVI showed an initial reduction in global longitudinal strain (GLS), followed by sustained GLS improvement within the first year., Discussion: Findings align with those of surgically treated patients with AR. There is a possible superiority of GLS to left ventricular end-diastolic diameter ratio in assessing patients with severe volume overload., Competing Interests: Conflict of interest: J.B. reports research grant from the Novartis Foundation. I.G. reports the following disclosures: consultant (honoraria)—Zimmer Biomet, Atricure, Neosurgery, Neptune Medical, Abbvie, Johnson & Johnson, Durvena, Boston Scientific, Edwards Lifesciences, Medtronic, Help-TheraX, 3ive, Encompass, Summus Medical, Abbott SJM, BCI, and Xeltis Advisory Boards: Edwards Surgical, Medtronic Surgical, Medtronic Structural Mitral and Tricuspid, Trisol Medical, Valcare Medical, Durvena, Abbvie, Johnson & Johnson, Foldax Medical, Zimmer Biomet, Neosurgery, Abbvie, Boston Scientific, Summus Medical, and BCI Equity: Valcare Medical, Durvena, CardioMech, Vdyne, MitreMedical, MITRx, and BCI institutional funding to Columbia University: Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve. S.K. reports institutional research grants from Edwards Lifesciences, Medtronic, and Abbott, consulting fees from Abbott, Admedus, and Meril Lifesciences, and equity options from Biotrace Medical and Thubrikar Aortic Valve Inc. T.P.V. reports institutional funding to the Columbia University Irving Medical Center from Boston Scientific, Edwards Lifesciences, JenaValve, and Medtronic, and he personally received consulting fees from Abbott Vascular, 4C Medical, and Philips. R.T.H. reports speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, Medtronic, and Philips Healthcare; she has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Edwards Lifesciences, Medtronic, and Novartis; she is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored tricuspid valve trials, for which she receives no direct industry compensation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: The Commando technique for reconstruction of the aortomitral intervalvular fibrous body is effective to facilitate double valve surgery in cases of endocarditis or infiltrative calcification. The length of patch utilized in reconstruction of the intervalvular fibrous body has an important relationship to the geometry of the mitral valve (MV) and aortic valve (AV) and may impact on potential future valve-in-valve (VIV) therapy. Here we report anatomic measurements after Commando reconstruction in a small group of patients and analyse the impact of reconstruction techniques on transcatheter VIV therapies., Methods: Seven patients from January 2018 to April 2022 who underwent double valve surgery with the Commando technique with postoperative computed tomography (CT) scans were identified. Computed tomographic reconstruction of the AV and MV was performed using 3mensio software and virtual transcatheter valve replacement was performed. Two of these patients who had preoperative imaging was analysed to assess the change in aortomitral geometry resulting from reconstruction., Results: Measurements for each patient post-reconstruction are given in the table. Aortomitral length was grossly inversely proportional to aortomitral angle (AMA). AMA and aortomitral curtain (AMC) length were significantly altered post-Commando in 2 analysed patients with pre- and postoperative computed tomography scan. Transcatheter AV and MV replacements were feasible in all patients post-Commando. The AMA was larger and more favorable for mitral VIV in patients in which the AMC was short., Conclusions: AMC length, as determined by location of AV annular sutures, may be an important consideration in surgical decision-making for VIV after the Commando procedure., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: del Nido cardioplegia is used to pharmacologically arrest the heart during cardiac surgery and decrease reperfusion- and ischaemia-related myocardial injury. Studies have demonstrated the physiological differences between male and female hearts, potentially related to cardiac size or myocyte calcium handling; we aimed to assess for between-sex differences in clinical outcomes after receipt of del Nido cardioplegia., Methods: Patients who underwent coronary artery bypass or coronary artery bypass graft/valve surgery at our institution using del Nido cardioplegia (January 2014 to December 2019) were included (n = 2118). Clinical data were collected retrospectively. After the creation of a propensity-matched cohort (n = 1252), multivariable logistic regression was used to analyse binary postoperative outcomes, and a Gamma model was used for a continuous postoperative outcome. Our primary end-point was a composite end-point comprised of 30-day mortality and/or need for a post-bypass mechanical support device., Results: The final cohort included 459 females and 793 males (matched up to 1:2, all standardized mean differences <0.1). Multivariable logistic regression showed that biological sex was not associated with the composite primary end-point (odds ratio = 0.898, P = 0.779). A Gamma model indicated that there were no sex-related differences in vasoactive-inotropic scores reflecting vasopressor and inotrope usage at the time of patient operating room exit (exp[est] = 1.394, P = 0.189)., Conclusions: Our findings showed no significant between-sex differences in clinical outcomes after receiving del Nido cardioplegia, suggesting adequate myocardial protection as currently administered. Further research is warranted to elicit if there are sex-based differences between cardioplegic solutions., Irb Approval Date (protocol Number): 26 May 2021 (AAAR8359)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The aim of this study was to investigate the impact of hemiarch replacement in patients undergoing an open repair of proximal thoracic aortic aneurysm without arch aneurysm., Methods: A retrospective review was performed on 1132 patients undergoing proximal aortic aneurysm repair at our Aortic Center between 2005 and 2019. Inclusion criteria were all patients undergoing root or ascending aortic aneurysm repair with or without hemiarch replacement. Exclusion criteria were age <18 years, aortic arch diameter ≥4.5 cm, type A aortic dissection, previous ascending aortic replacement, ruptured aneurysm and endocarditis. Propensity score matching in a 2:1 ratio (573 non-hemiarch: 288 hemiarch) on 19 baseline characteristics was performed. The median follow-up time was 46.8 months (range 0.1-170.4 months)., Results: Hemiarch patients had significantly lower 10-year survival in the matched cohort (hemiarch 73.8%; 66.9-81.4%; vs non-hemiarch 86.5%; 81.1-92.3%; P < 0.001), driven by higher in-hospital mortality rate (4% vs 1%; P < 0.001). Cumulative incidence of aortic arch reintervention rates at 10 years was similarly low (hemiarch 1.0%; 0-2.5% vs non-hemiarch 1.3%; 0-2.6%, P = 0.615). Multivariate analysis with hazard ratios of the overall cohort showed hemiarch as an independent factor associated with long-term mortality (2.16; 1.42-3.27; P < 0.001) but not with aortic arch reintervention (0.76; 0.14-4.07, P = 0.750)., Conclusions: Hemiarch repair may be associated with higher short-term mortality compared to non-hemiarch. Arch reintervention was rare after a repair of proximal thoracic aortic aneurysm without arch aneurysm. Our data call for larger and prospective studies to further delineate the utility of hemiarch repair in proximal aortic surgery., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Few data exist on the use of del Nido cardioplegia in adults, specifically during operations requiring prolonged aortic cross-clamp. In this pilot study, we evaluate outcomes of patients undergoing surgery with cross-clamp time >3 h based on re-dosing strategy, using either full dose (FD; 1:4 blood to crystalloid ratio) or dilute (4:1 blood to crystalloid ratio) solution., Methods: Consecutive adult patients (>18 years) undergoing cardiac surgery from 2012 to 2018 with cross-clamp time >3 h were reviewed. Patients were excluded if del Nido cardioplegia was not used. Patients were categorized into FD or dilute groups based on re-dosing solution. Propensity score matching was used to control for baseline differences between groups. The primary endpoint was in-hospital mortality. Other outcomes examined included: postoperative mechanical support, arrhythmia, stroke, dialysis and cardiac function., Results: Included for analysis were 173 patients (115 male) with median age of 63.8 (interquartile range 53.9-73.1). Major comorbidities included diabetes (45), cerebrovascular disease (34), hypertension (131), atrial fibrillation (52) and previous cardiac surgery (83). There were 108 patients (62%) who received FD re-dosing, while 65 (38%) received dilute. A greater proportion of patients in the dilute group received retrograde delivery, for both induction (32/108 vs 39/65, P < 0.001) and re-dose (50/108 vs 53/65, P < 0.001). After propensity score matching, in-hospital mortality was not different between groups (6/48 vs 1/48, P = 0.131). There were no differences in rates of postoperative mechanical circulatory support, stroke, left ventricular ejection fraction or right ventricle dysfunction., Conclusions: Del Nido cardioplegia has been used in complex cardiac surgery requiring prolonged cross-clamp. Re-dosing can be performed with either FD or dilute del Nido solution with no statistical difference in outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: Chronic kidney disease (CKD) is prevalent in patients undergoing cardiovascular surgery, and it negatively impacts procedural outcomes; however, its influence on the outcomes of aortic surgery has not been well studied. This study aims to elucidate the importance of CKD on the outcomes of aortic root replacement (ARR)., Methods: Patients who underwent ARR between 2005 and 2019 were retrospectively reviewed (n = 882). Patients were divided into 3 groups based on the Kidney Disease: Improving Global Outcomes criteria: Group 1 [estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2, n = 421); Group 2 (eGFR = 30-59 ml/min/1.73 m2, n = 424); and Group 3 (eGFR < 30 ml/min/1.73 m2, n = 37). To reduce potential confounding, a propensity score matching was also performed between Group 1 and the combined group of Group 2 and Group 3. The primary end point was 10-year survival. Secondary end points were in-hospital mortality and perioperative morbidity., Results: Severe CKD patients presented with more advanced overall chronic and acute illnesses. Kaplan-Meier analysis showed a significant correlation between CKD stage and 10-year survival (log-rank P < 0.001). The number of events for Group 1 was 15, Group 2 was 49 and Group 3 was 11 in 10 years. Group 3 had significantly higher in-hospital mortality (13.5% vs 3.5% in Group 2 vs 0.7% in Group 1, P < 0.001) and stroke (8.1% vs 7.1% vs 1.2%, P < 0.001) as well as introduction to new dialysis (27.0% vs 5.4% vs 1.7%, P < 0.001). eGFR was shown to be an independent predictor of mortality (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99). Comparison between propensity matched groups showed similar postoperative outcomes, and eGFR was still identified as a predictor of mortality (hazard ratio, 0.97; 95% confidence interval, 0.95-0.99)., Conclusions: Higher stage in CKD negatively impacts the long-term survival in patients who are undergoing ARR., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: We compared the long-term outcomes between aortic valve reimplantation [David V (DV)] and aortic valve and root replacement with biological valved conduit [Bentall-De Bono (BD)] for the patients with aortic root aneurysm with tricuspid valve., Methods: Among 876 patients who underwent aortic root replacement in our institution between 2005 and 2018, 371 patients who underwent DV (n = 199) or BD (n = 172) for aortic root aneurysm with tricuspid valve were retrospectively reviewed. Exclusion criteria included aortic stenosis, infective endocarditis, previous prosthetic aortic valve, bicuspid aortic valve, aortic dissection and mechanical Bentall procedure. Propensity score matching was performed based on the patient characteristics, matching 90 patients in each group. The primary end point was all-cause mortality. Secondary end points were reoperation for any cause and specifically for aortic valve-related cause., Results: After propensity score matching, DV and BD groups each had 1 in-hospital mortality (1.1%). Survival at 10 years was 95.3% [95% confidence interval (CI) 85.8-98.5] in DV and 98.6% (95% CI 90.8-99.8) in BD (P = 0.345). The cumulative incidences of reoperation at 10 years in DV versus BD were 3.9% (95% CI 0.7-11.8) vs 18.1% (95% CI 6.9-33.4) for any cause (P = 0.046) and 1.9% (95% CI 0.1-8.8) vs 15.9% (95% CI 5.5-31.4) for aortic valve-related causes (P = 0.032). The reasons for valve-related reoperation were aortic insufficiency (3/5 in DV vs 5/10 in BD), aortic stenosis (0/5 vs 2/10) and infective endocarditis (2/5 vs 3/10)., Conclusions: Both DV and BD procedures for patients with aortic root aneurysm with tricuspid valve resulted in excellent 10-year survival. All-cause and aortic valve-related reoperations were significantly less frequent with valve-sparing root replacement, suggesting an advantage of DV over biological BD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: This study examined whether mobile phone-based support improve the rates, duration of exclusive breastfeeding (EBF) as well as infant growth patterns in Nigeria., Methods: A 6-month prospective randomized controlled trial with 75 participants assigned to receive 'usual care' or 'mobile phone-based support in addition to usual care' EBF rates and duration as well as anthropometric measurements of infants before and after intervention were compared using proportions and mean differences., Results: Attrition rates of 10.7% and 14.7% were observed in the intervention and control groups, respectively. Treatment groups were identical in all baseline characteristics and participants in the intervention group showed a slower rate of decline in the practice of EBF. The mean difference of 0.6 months (95% confidence interval: -0.22, 1.42) in EBF duration between intervention and control groups was not statistically significant (t = 1.45; p = 0.149). Similarly, the difference in the EBF rates at the 6th month for the intervention (55.2%) and control (46.8%) groups was not statistically significant (χ2 = 0.623; p = 0.430). Although the intervention group had significantly higher mean weight (p = 0.030) and length (p = 0.044) at the 6th month, the difference in the gain in weight and length of these infants over the period was only significant for the weight (p = 0.044). Although the incidence of adverse clinical nutritional status was more in the control group, these differences were not statistically significant., Conclusion: Mobile phone-based intervention has positive effects on the rate and duration of EBF as well as the growth of young infants. Sustaining this simple and cheap technology will improve infant wellbeing especially in resource-constrained settings., (© The Author(s) [2020]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The onset of the coronavirus disease 2019 (COVID-19) pandemic has forced our cardiac surgery programme and hospital to enact drastic measures that has forced us to change how we care for cardiac surgery patients, assist with COVID-19 care and enable support for the hospital in terms of physical resources, providers and resident training., Methods: In this review, we review the cardiovascular manifestations of COVID-19 and describe our system-wide adaptations to the pandemic, including the use of telemedicine, how a severe reduction in operative volume affected our programme, the process of redeployment of staff, repurposing of residents into specific task teams, the creation of operation room intensive care units, and the challenges that we faced in this process., Results: We offer a revised set of definitions of surgical priority during this pandemic and how this was applied to our system, followed by specific considerations in coronary/valve, aortic, heart failure and transplant surgery. Finally, we outline a path forward for cardiac surgery for the near future., Conclusions: We recognize that individual programmes around the world will eventually face COVID-19 with varying levels of infection burden and different resources, and we hope this document can assist programmes to plan for the future., (This article was received at JTCVS on 14 April 2020, Received in revised form and accepted at JTCVS on 18 April 2020. This article has been copublished in the European Journal of Cardio-Thoracic Surgery, The Journal of Thoracic and Cardiovascular Surgery and The Annals of Thoracic Surgery Copyright © 2020 Jointly between the European Association for Cardio-Thoracic Surgery, The American Association for Thoracic Surgery and The Society of Thoracic Surgeons. Published by Oxford University Press.)

Aims: To investigate valve sizing and the haemodynamic relevance of the predicted left ventricular outflow tract (LVOT) in patients with mitral annular calcification (MAC) undergoing transatrial transcatheter valve implantation (THV)., Methods and Results: In total, 21 patients undergoing transatrial THV, multiplanar reconstruction (MPR), maximum intensity projection (MIP), and cubic spline interpolation (CSI) were compared for MA sizing during diastole. In addition, predicted neo-LVOT areas were measured in 18 patients and correlated with the post-procedural haemodynamic dimensions. The procedure was successful in all patients (100%). Concomitant aortic valve replacement was performed in eight patients (43%) (AVR group). Sizing using MPR and MIP yielded comparable results in terms of area, perimeter, and diameter, whereas the dimensions obtained with CSI were systematically smaller. The simulated mean systolic neo-LVOT area was 133.4 ± 64.2 mm2 with an anticipated relative LVOT area reduction (neo-LVOT area/LVOT area × 100) of 59.3 ± 14.7%. The systolic relative LVOT area reduction, but not the absolute neo-LVOT area, was found to predict the peak (r = 0.69; P = 0.002) and mean (r = 0.65; P = 0.004) post-operative aortic gradient in the overall population as well as separately in the AVR (peak: r = 0.91; P = 0.002/mean: r = 0.85; P = 0.002) and no-AVR (peak: r = 0.89; P = 0.003/mean: r = 0.72; P = 0.008) groups., Conclusion: In patients with severe MAC undergoing transatrial transcatheter valve implantation, MPR, and MIP yielded comparable annular dimensions, while values obtained with CSI tended to be systematically smaller. Mitral annular area and the average annular diameter appear to be reliable parameters for valve selection. Simulated relative LVOT reduction was found to predict the post-procedural aortic gradients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Transcatheter aortic valve replacement (TAVR) is now an established therapy for intermediate-risk surgical candidates with symptomatic, severe aortic stenosis. The clinical impact of new-onset left bundle branch block (LBBB) after TAVR remains controversial and has not been studied in intermediate-risk patients. We therefore sought to analyse outcomes associated with new LBBB in a large cohort of intermediate-risk patients treated with TAVR., Methods and Results: A total of 2043 patients underwent TAVR in the PARTNER II trial and S3 intermediate-risk registry and survived to hospital discharge. Patients were excluded from the current analysis due to baseline conduction disturbances, pre-existing permanent pacemaker (PPM), and new PPM during the index hospitalization. Clinical outcomes at 2 years were compared between patients with and without persistent, new-onset LBBB at hospital discharge, and multivariable analysis was performed to identify predictors of mortality. Among 1179 intermediate-risk patients, new-onset LBBB at discharge occurred in 179 patients (15.2%). Patients with new LBBB were similar to those without except for more frequent diabetes and more frequent treatment with SAPIEN 3 vs. SAPIEN XT. At 2 years, new LBBB was associated with increased rates of all-cause mortality (19.3% vs. 10.8%, P = 0.002), cardiovascular mortality (16.2% vs. 6.5%, P < 0.001), rehospitalization, and new PPM implantation. By multivariable analysis, new LBBB remained an independent predictor of 2-year all-cause [hazard ratio (HR) 1.98, 95% confidence interval (95% CI) 1.33, 2.96; P < 0.001] and cardiovascular (HR 2.66 95% CI 1.67, 4.24; P < 0.001) mortality. New LBBB was also associated with worse left ventricular systolic function at 1 and 2-year follow-up., Conclusions: In a large cohort of intermediate-risk patients from the PARTNER II trial and registry, persistent, new-onset LBBB occurred in 15.2% of patients without baseline conduction disturbances or pacemaker. New LBBB was associated with adverse clinical outcomes at 2 years, including all-cause and cardiovascular mortality, rehospitalization, new pacemaker implantation, and worsened left ventricular systolic function., Clinical Trial Registration: ClinicalTrials.gov #NCT01314313 and NCT03222128., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

A hyperglycemic and hyperinsulinemic environment characteristic of type 2 diabetes causes insulin resistance. In adipocytes, defects in both insulin sensitivity and maximum response of glucose transport have been demonstrated. To investigate the molecular mechanisms, freshly isolated rat adipocytes were incubated in control (5.6 mM glucose, no insulin) and high glucose (20 mM)/high insulin (100 nM) (HG/HI) for 18 hours to induce insulin resistance. Insulin-resistant adipocytes manifested decreased sensitivity of glucose uptake associated with defects in insulin receptor substrate (IRS)-1 Tyr phosphorylation, association of p85 subunit of phosphatidylinositol-3-kinase, Akt Ser473 and Thr308 phosphorylation, accompanied by impaired glucose transporter 4 translocation. In contrast, protein kinase C (PKC)-ζ activity was augmented by chronic HG/HI. Inhibition of PKC-ζ with a specific cell-permeable peptide reversed the signaling defects and insulin sensitivity of glucose uptake. Transfection of dominant-negative, kinase-inactive PKC-ζ blocked insulin resistance, whereas constitutively active PKC-ζ recapitulated the defects. The HG/HI incubation was associated with stimulation of IRS-1 Ser318 and Akt Thr34 phosphorylation, targets of PKC-ζ. Transfection of IRS-1 S318A and Akt T34A each partially corrected insulin signaling, whereas combined transfection of both completely normalized insulin signaling. In vivo hyperglycemia/hyperinsulinemia in rats for 48 hours similarly resulted in activation of PKC-ζ and increased phosphorylation of IRS-1 Ser318 and Akt Thr34. These data indicate that impairment of insulin signaling by chronic HG/HI is mediated by dual defects at IRS-1 and Akt mediated by PKC-ζ.

Aims: Transthyretin cardiac amyloidosis (ATTR-CA) has been reported in patients with aortic stenosis (AS) but its prevalence and phenotype are not known. We examine elderly patients with severe symptomatic AS undergoing transcatheter aortic valve replacement (TAVR) and determine the prevalence and phenotype of ATTR-CA non-invasively., Methods and Results: We performed technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy prospectively on patients who underwent TAVR, to screen for ATTR-CA. Transthoracic echocardiography and speckle-strain imaging were performed. We assessed the association of several parameters with ATTR-CA using multivariable logistic regression and constructed receiver operating curves to evaluate the best predictors of ATTR-CA. Among 151 patients (mean age 84 ± 6 years, 68% men), 16% (n = 24) screened positive for ATTR-CA with 99mTc-PYP scintigraphy. Compared with patients without ATTR-CA, ATTR-CA patients had a thicker interventricular septum (1.3 vs. 1.1 cm, P = 0.007), higher left ventricular (LV) mass index (130 vs. 98 g/m2, P = 0.002), and lower stroke volume index (30 vs. 36 mL/m2, P = 0.009). ATTR-CA patients had advanced diastolic dysfunction with higher E/A ratio (2.3 vs. 0.9, P = 0.001) and lower deceleration time (176 vs. 257 ms, P < 0.0001); impairment in systolic function with lower ejection fraction (48% vs. 56%, P = 0.011), myocardial contraction fraction (26 vs. 41, P < 0.0001), and average of lateral and septal mitral annular tissue Doppler S' (4.0 vs. 6.6 cm/s, P < 0.0001). While ATTR-CA patients had more impaired global longitudinal strain (-12 vs. -16%, P = 0.007), relative apical longitudinal strain was the same regardless of ATTR-CA diagnosis (0.98 vs. 0.98, P = 0.991). Average S' best predicted ATTR-CA in multivariable logistic regression (odds ratio 16.67 per 1 cm/s decrease with AUC 0.96, 95% confidence interval 0.90-0.99, P = 0.002) with a value ≤6 conferring 100% sensitivity for predicting a positive 99mTc-PYP amyloid scan., Conclusions: Transthyretin cardiac amyloidosis is prevalent in 16% of patients with severe calcific AS undergoing TAVR and is associated with a severe AS phenotype of low-flow low-gradient with mildly reduced ejection fraction. Average tissue Doppler mitral annular S' of < 6 cm/s may be a sensitive measure that should prompt a confirmatory 99mTc-PYP scan and subsequent testing for ATTR-CA. Prospective assessment of outcomes after TAVR is needed in patients with and without ATTR-CA., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Objectives: We aimed to assess the incidence and possible differences in postoperative conduction delay after aortic root replacement (ARR) in bicuspid aortic valve (BAV) patients compared with a tricuspid aortic valve (TAV)., Methods: A total of 380 patients undergoing ARR at our institution between 2005 and 2013 were included in the analysis. Patients were stratified by aortic valve anatomy: BAV, n = 191 vs TAV, n = 189. Electrocardiographic and echocardiographic data were retrospectively analysed at different time points (pre-, postoperatively and at follow-up). Primary outcome of interest was permanent pacemaker (PPM) implantation within 30 days, the composite of new PPM or new left fascicular or bundle branch block (PPM or LBBB) was the secondary outcome of interest. Age range was 24-89.5 years and incidence of preoperative moderate to severe aortic stenosis was 9.7%., Results: BAV patients had higher incidence of PPM implantation within 30 days (5.8 vs 1.6% in TAV, P = 0.053); moreover, the composite of PPM or LBBB was also more frequent in BAV (8.4 vs 2.1%, P = 0.010). BAV was independently associated with PPM insertion (OR 4.08, P = 0.047) and also an independent predictor of PPM or LBBB in multiple regression (OR 4.96, P = 0.006)., Conclusions: Significantly higher incidence of PPM implantation or LBBB may exist after ARR in bicuspid patients and BAV was confirmed to be an independent predictor for postoperative conduction disturbances by multivariable regression., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Safe, timely red blood cell transfusion saves lives and chronic transfusion therapy (CTT) prevents or limits morbidities such as stroke, therefore improving quality of life of patients with sickle cell disease (SCD)., Methods: This questionnaire-based study assessed the ability of sickle cell centers in Nigeria to provide safe blood to patients with SCD between March and August 2014., Results: Out of the 73 hospitals contacted, responses were obtained from 31. Twenty four (78%) hospitals were unable to transfuse patients regularly due to blood scarcity. Packed red blood cells were available in 14 (45%), while only one provided leukocyte-depletion. Most centers assessed donor risk and screened for HIV in 30 (97%), hepatitis B in 31(100%) and hepatitis C in 27 (87%) hospitals. Extended phenotyping and alloantibody screening were not available in any center. A quarter of the hospitals could monitor iron overload, but only using serum ferritin. Access to iron chelators was limited and expensive. Seventeen (55%) tertiary hospitals offered CTT by top-up or manual exchange transfusion; previous stroke was the most common indication., Conclusion: Current efforts of Nigerian public hospitals to provide safe blood and CTT fall short of best practice. Provision of apheresis machines, improvement of voluntary non-remunerated donor drive, screening for red cell antigens and antibodies, and availability of iron chelators would significantly improve SCD care in Nigeria., (© The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In a previous transcriptomic analysis, abscisic acid (ABA) was found to affect the abundance of a number of transcripts in leaves of Cabernet Sauvignon grapevines with roots that had been exposed to 10 μm ABA for 2 h. Other work has indicated that ABA affects protein abundance and protein phosphorylation as well. In this study we investigated changes in protein abundance and phosphorylation of Cabernet Sauvignon grapevine leaves. Protein abundance was assessed by both label-free and isobaric-label quantitive proteomic methods. Each identified common proteins, but also additional proteins not found with the other method. Overall, several thousand proteins were identified and several hundred were quantified. In addition, hundreds of phosphoproteins were identified. Tens of proteins were found to be affected in the leaf after the roots had been exposed to ABA for 2 h, more than half of them were phosphorylated proteins. Many phosphosites were confirmed and several new ones were identified. ABA increased the abundance of some proteins, but the majority of the proteins had their protein abundance decreased. Many of these proteins were involved in growth and plant organ development, including proteins involved in protein synthesis, photosynthesis, sugar and amino-acid metabolism. This study provides new insights into how ABA regulates plant responses and acclimation to water deficits.

Objectives: Chronic kidney disease (CKD) is prevalent in patients undergoing aortic valve replacement (AVR). We sought to evaluate the impact of AVR on estimated glomerular filtration rate (eGFR) levels and determine the impact of reversibility of CKD on postoperative outcomes., Methods: We retrospectively reviewed 2169 patients who underwent isolated AVR between 2000 and 2012. eGFR was calculated using the CKD-EPI formula. Based on preoperative eGFR, patients were divided into three groups: NoCKD (eGFR >60, n = 1417), ModCKD (eGFR = 30-60, n = 619) and SevCKD (eGFR = 15-30, n = 86). End-stage renal disease patients (eGFR <15 and/or dialysis, n = 47) were excluded from the study., Results: Before AVR, eGFR in the NoCKD, ModCKD and SevCKD groups was 81.3 ± 14.2, 48.9 ± 8.10 and 25.3 ± 4.12 ml/min/1.73 m(2), respectively. NoCKD patients showed a decline in eGFR during the first month postoperatively; thereafter, eGFR remained stable over 1 year. ModCKD and SevCKD patients demonstrated an initial improvement in eGFR, which peaked at 1 week postoperatively. In ModCKD, eGFR stabilized at a slightly lower level thereafter out to 1-year follow-up. In SevCKD, eGFR declined slightly out to 6 months postoperatively. Regardlessly, eGFR in ModCKD at 1 year and in SevCKD at 6 months postoperatively demonstrated sustained improvement over baseline eGFR. Reversibility of CKD was associated with a better long-term survival in the ModCKD group (P < 0.001) and short-term survival in the SevCKD group (P = 0.018)., Conclusions: AVR confers a marked initial improvement in eGFR, which is sustained in patients with ModCKD and SevCKD, and is associated with a better survival. The reversible nature of CKD in certain patients warrants careful consideration during preoperative risk scoring and stratification., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Lesions in DNA can block replication fork progression, leading to its collapse and gross chromosomal rearrangements. To circumvent such outcomes, the DNA damage tolerance (DDT) pathway becomes engaged, allowing the replisome to bypass a lesion and complete S phase. Chromatin remodeling complexes have been implicated in the DDT pathways, and here we identify the NuA4 remodeler, which is a histone acetyltransferase, to function on the translesion synthesis (TLS) branch of DDT. Genetic analyses in Saccharomyces cerevisiae showed synergistic sensitivity to MMS when NuA4 alleles, esa1-L254P and yng2Δ, were combined with the error-free bypass mutant ubc13Δ. The loss of viability was less pronounced when NuA4 complex mutants were disrupted in combination with error-prone/TLS factors, such as rev3Δ, suggesting an epistatic relationship between NuA4 and error-prone bypass. Consistent with cellular viability measurements, replication profiles after exposure to MMS indicated that small regions of unreplicated DNA or damage were present to a greater extent in esa1-L254P/ubc13Δ mutants, which persist beyond the completion of bulk replication compared to esa1-L254P/rev3Δ. The critical role of NuA4 in error-prone bypass is functional even after the bulk of replication is complete. Underscoring this observation, when Yng2 expression is restricted specifically to G2/M of the cell cycle, viability and TLS-dependent mutagenesis rates were restored. Lastly, disruption of HTZ1, which is a target of NuA4, also resulted in mutagenic rates of reversion on level with esa1-L254P and yng2Δ mutants, indicating that the histone variant H2A.Z functions in vivo on the TLS branch of DDT., (Copyright © 2015 by the Genetics Society of America.)

Aortic valve stenosis is the most common form of valvular heart disease in the elderly population and occurs frequently in conjunction with coronary artery disease. The standard treatment option for patients with these two conditions has been surgical aortic valve replacement and coronary artery bypass grafting. The arrival of transcatheter aortic valve replacement has considerably shifted the treatment paradigms. Nevertheless, a lot of questions remain unanswered regarding the management of coronary artery disease in the setting of the transcatheter options for severe aortic stenosis. This article includes a comprehensive review of the literature and seeks to describe the actual knowledge on the topic of aortic stenosis and concomitant coronary artery disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Enterococci are an important cause of healthcare-associated infections. We retrospectively analyzed risk factors and outcome of vancomycin-resistant enterococci (VRE) and vancomycin-sensitive enterococci (VSE) infections., Methods: Seven hundred fifty-two patients who received hematopoietic stem cell transplants from 2004 through 2008 at the University of Minnesota were included., Results: Ninety-three patients had enterococcal bloodstream infection (BSI) during the first year after transplant. Vancomycin resistance was observed in 66% and 31% of isolates in adults and children, respectively. Cumulative incidence of VRE and VSE bacteremia was 6.6% (95% confidence interval [CI], 4.8%-8.4%) and 5.7% (95% CI, 4.0%-7.4%), respectively. Colonization with VRE before or after transplant was a risk factor for VRE bacteremia (odds ratio [OR], 3.3 [95% CI, 1.3-8.3] and 7.0 [95% CI, 4.0-14.8], respectively). Delay in engraftment increased the incidence of VRE bacteremia from 4.5% (95% CI, 2.9-6.6) if engrafted before day 21 and to 15% (95% CI, 3.2%-38%) if engrafted between days 36 and 42. In adults, mortality 30 days after infection was 38% for both VRE (95% CI, 25%-54%) and VSE cases (95% CI, 21%-62%). The hazard ratio for all-cause mortality up to 1 year after transplant was 4.2 (95% CI, 3.1-6.9) and 2.7 (95% CI, 1.4-5.1) for patients with VRE and VSE BSIs, respectively, compared to patients without enterococcal BSI. In pediatric patients, mortality 30 days after VRE and VSE bacteremia was 20% (95% CI, 5.4%-59%) and 4.5% (95% CI, .6%-28%), respectively., Conclusion: High rates of vancomycin resistance and association of enterococcal infections with significant mortality warrant further efforts to optimize prevention and management of these infections.

Polyketides are structurally diverse secondary metabolites, many of which have antibiotic or anticancer activity. Type I modular polyketide synthase (PKS) genes are typically large and encode repeating enzymatic domains that elongate and modify the nascent polyketide chain. A fosmid metagenomic library constructed from an agricultural soil was arrayed and the macroarray was screened for the presence of conserved ketosynthase [β-ketoacyl synthase (KS)] domains, enzymatic domains present in PKSs. Thirty-four clones containing KS domains were identified by Southern hybridization. Many of the KS domains contained within metagenomic clones shared significant similarity to PKS or nonribosomal peptide synthesis genes from members of the Cyanobacteria or the Proteobacteria phyla. However, analysis of complete clone insert sequences indicated that the blast analysis for KS domains did not reflect the true phylogenetic origin of many of these metagenomic clones that had a %G+C content and significant sequence similarity to genes from members of the phylum Acidobacteria. This conclusion of an Acidobacteria origin for several clones was further supported by evidence that cultured soil Acidobacteria from different subdivisions have genetic loci closely related to PKS domains contained within metagenomic clones, suggesting that Acidobacteria may be a source of novel polyketides. This study also demonstrates the utility of combining data from culture-dependent and -independent investigations in expanding our collective knowledge of microbial genomic diversity., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

The proglucagon gene (glu) encodes the incretin hormone glucagon-like peptide-1 (GLP-1), produced in the intestinal endocrine L cells. We found previously that the bipartite transcription factor beta-catenin/T cell factor (cat/TCF), the major effector of the canonical Wnt signaling pathway, activates intestinal glu expression and GLP-1 production. We show here that 100 nm insulin stimulated glu expression and enhanced GLP-1 content in the intestinal GLUTag L cell line as well as in primary fetal rat intestinal cell cultures. Increased intestinal glu mRNA expression and GLP-1 content were also observed in vivo in hyperinsulinemic MKR mice. In the GLUTag cells, insulin-induced activation of glu expression occurred through the same TCF site that mediates cat/TCF activation. Phosphatidylinositol 3-kinase inhibition, but not protein kinase B inhibition, attenuated the stimulation by insulin. Furthermore, nuclear beta-catenin content in the intestinal L cells was increased by insulin. Finally, insulin enhanced the binding of TCF-4 and beta-catenin to the TCF site in the glu promoter G2 enhancer element, as determined by quantitative chromatin immunoprecipitation assay. Collectively, these findings indicate that enhancement of beta-catenin nuclear translocation and cat/TCF binding are among the mechanisms underlying cross talk between the insulin and Wnt signaling pathways in intestinal endocrine L cells.

To gain insight into the impact of 2,4,6-trinitrotoluene (TNT) on soil microbial communities, we characterized the bacterial community of several TNT-contaminated soils from two sites with different histories of contamination and concentrations of TNT. The amount of extracted DNA, the total cell counts and the number of CFU were lower in the TNT-contaminated soils. Analysis of soil bacterial diversity by DGGE showed a predominance of Pseudomonadaceae and Xanthomonadaceae in the TNT-contaminated soils, as well as the presence of Caulobacteraceae. CFU from TNT-contaminated soils were identified as Pseudomonadaceae, and, to a lesser extent, Caulobacteraceae. Finally, a pristine soil was spiked with different concentrations of TNT and the soil microcosms were incubated for 4 months. The amount of extracted DNA decreased in the microcosms with a high TNT concentration [1.4 and 28.5 g TNT/kg (dry wt) of soil] over the incubation period. After 7 days of incubation of these soil microcosms, there was already a clear shift of their original flora towards a community dominated by Pseudomonadaceae, Xanthomonadaceae, Comamonadaceae and Caulobacteraceae. These results indicate that TNT affects soil bacterial diversity by selecting a narrow range of bacterial species that belong mostly to Pseudomonadaceae and Xanthomonadaceae.

Background: Recent clinical studies have shown Chlamydophila pneumoniae seropositivity to be related to overweight status and inversely related to insulin sensitivity. The present study was performed to investigate the potential effects of C. pneumoniae infection of adipocytes., Methods: 3T3-L1 cells and primary epididymal preadipocytes were infected with C. pneumoniae either before or after induction of differentiation, and the effects on adipogenesis and insulin signaling were determined. Tumor necrosis factor (TNF)-alpha signaling was examined by assessing the effects of C. pneumoniae infection in preadipocytes isolated from epididymal adipose tissue of both wild-type and TNF-alpha(-/-) mice., Results: C. pneumoniae successfully infected both undifferentiated and differentiated 3T3-L1 cells in vitro. The bacteria were also detected in adipose tissue of infected low-density lipoprotein receptor-deficient mice. TNF-alpha protein levels were significantly increased in cells infected with either live or heat-killed C. pneumoniae or treated with lipopolysaccharide or heat-shock protein 65; this increase was associated with inhibition of adipocyte differentiation and down-regulation of insulin-stimulated tyrosine-phosphorylated insulin receptor and its substrate. In contrast, C. pneumoniae infection in TNF-alpha(-/-) adipocytes produced no apparent changes, but addition of recombinant TNF-alpha reversed this effect., Conclusions: We demonstrate for the first time that C. pneumoniae can infect murine pre- and postdifferentiated adipocytes and, through a TNF-alpha-mediated inflammatory mechanism, can impair differentiation and insulin signaling.

Objective: Passive restraint of the left ventricle (LV) has been shown to have beneficial effects on acute hemodynamics and reverse remodeling in both animal and human models. The goals of this study were to test whether a left ventricular support device (LVSD) improves LV synchrony and/or affects cardiac performance., Methods: Ten dogs were chronically instrumented to measure hemodynamics and LV volume (sonomicrometry). Congestive heart failure (CHF) was induced by repeated intracoronary microembolization via a chronically implanted coronary catheter. The LVSD was implanted after establishment of CHF in five animals, and five animals were observed as controls. All animals were then observed for 8 weeks. A mathematical model to measure LV synchrony was used to evaluate LV motion over time., Results: Mean arterial pressure and LV pressures was significantly increased after LVSD therapy, and LV pressure-volume relationships were shifted leftwards, although no change was seen in ejection fraction, end-systolic elastance, or LV dP/dt versus control. There was no significant change in diastolic function in LVSD animals compared with control animals. End-diastolic volumes were reduced by 15% after 8 weeks with LVSD treatment, versus an increase of 8% in control animals (p<0.05). Synchrony was significantly improved with LVSD therapy compared with control (9% vs 76% of baseline) in 1 of 11 ventricular dimension axes (Anterior-Apex)., Conclusions: LVSD therapy provided only minimal improvement in ventricular synchrony and partially improved hemodynamics. Further study into mechanisms of benefit are warranted.

Metabolic flux through the hexosamine biosynthetic pathway (HBP) is increased in the presence of high glucose (HG) and potentially stimulates the expression of genes associated with the development of diabetic nephropathy. A number of synthetic processes are coupled to the HBP, including enzymatic intracellular O-glycosylation (O-GlcNAcylation), the addition of single O-linked N-acetylglucosamine monosaccharides to serine or threonine residues. Despite much data linking flow through the HBP and gene expression, the exact contribution of O-GlcNAcylation to HG-stimulated gene expression remains unclear. In glomerular mesangial cells, HG-stimulated plasminogen activator inhibitor-1 (PAI-1) gene expression requires the HBP and the transcription factor, Sp1. In this study, the specific role of O-GlcNAcylation in HG-induced PAI-1 expression was tested by limiting this modification with a dominant-negative O-linked N-acetylglucosamine transferase, by overexpression of neutral beta-N-acetylglucosaminidase, and by knockdown of O-linked beta-N-acetylglucosamine transferase expression by RNA interference. Decreasing O-GlcNAcylation by these means inhibited the ability of HG to increase endogenous PAI-1 mRNA and protein levels, the activity of a PAI-1 promoter-luciferase reporter gene, and Sp1 transcriptional activation. Conversely, treatment with the beta-N-acetylglucosaminidase inhibitor, O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate, in the presence of normal glucose increased Sp1 O-GlcNAcylation and PAI-1 mRNA and protein levels. These findings demonstrate for the first time that among the pathways served by the HBP, O-GlcNAcylation, is obligatory for HG-induced PAI-1 gene expression and Sp1 transcriptional activation in mesangial cells.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and beta-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and [3H]leucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.

CVI is a primary immunodeficiency characterized by a failure of B cell differentiation associated with an array of T cell defects, such as enhanced T cell apoptosis. In this study we investigated the mechanisms underlying CVI enhanced T cell death. We analysed both the expression of Fas using flow cytometry techniques and the expression of FasL mRNA using RT-PCR in CVI T cells. We could not find any significant differences between CVI and normal subjects with regard to Fas expression, although there was a subgroup of CVI patients with very high Fas expression which was accompanied by an up-regulation of FasL mRNA. However, attempts to induce Fas-mediated apoptosis in these high Fas expressing cells, as evaluated by propidium iodide staining and APO2.7 staining, were unsuccessful. We also investigated intracellular levels of Bcl-2, bcl-xl and bax in CD4(+) and CD8(+) CVI T cells, as well as the bax/Bcl-2 ratio, using flow cytometry techniques but could not detect any differences between CVI and normal subjects. Finally we analysed TNF-RI and TNF-RII mRNA expression in CD4(+) and CD8(+) CVI T cells using semiquantitative RT-PCR and found a significant increase in expression of both TNF-Rs in CD4(+) T cells from CVI patients. Our data suggest that the increased expression of both TNF-Rs on T cells may be one of the mechanisms responsible for the accelerated T cell apoptosis in CVI.

CVID is a primary immune disorder in which hypogammaglobulinaemia may be associated with a number of T cell defects including lymphopenia, anergy, impaired lymphocyte proliferation and deficient cytokine secretion. In this study we show that T cells of CVID subjects, in comparison with control T cells, undergo spontaneous apoptosis in culture and markedly accelerated apoptosis after gamma-irradiation. Although costimulation of the CD28 receptor following engagement of the TCR/CD3 receptor normally provides a second signal necessary for IL-2 secretion, CD28 costimulation in CVID does not significantly increase IL-2 production, nor does this combination of activators enhance the survival of irradiated CVID T cells, as it does for cultured normal T cells. Addition of IL-2 enhances CVID T cell survival, suggesting that the IL-2 signalling pathways are normal. CVID T cells have similar expression of Bcl-2 to control T cells. CD3 stimulation up-regulates T cell expression of bcl-xL mRNA for normal T cells, but anti-CD28 does not augment bcl-xL expression for CVID subjects with accelerated apoptosis. Defects of the CD28 receptor pathway, leading to cytokine deprivation and dysregulation of bcl-xL, could lead to poor T cell viability and some of the cellular defects observed in CVID.

Rapid enumeration methods based on the enzymatic hydrolysis of 4-methylumbelliferyl-beta-D-galactoside and 4-methylumbelliferyl-beta-D-glucuronide were optimized for freshwaters. The enzymes beta-D-galactosidase (GALase) and beta-D-glucuronidase (GLUase) were shown to be already induced in freshwaters when tested, respectively, with the inducers isopropyl-beta-D-thiogalactopyranoside and methyl-beta-D-glucuronide. Both enzymatic activities were compared, respectively, with plate counts of total and faecal coliforms in freshwaters. Enzymatic methods and reference plate counts were significantly correlated in log-log plots. Moreover, the GLUase method allowed the detection of viable (presenting a detectable GLUase activity) but nonculturable Escherichia coli.

We have described a novel macrophage-derived mucin secretagogue (MMS-68) that mediates mucin secretion in colon cancer cell lines and explants of normal and inflammatory bowel disease (IBD) mucosa. We compared MMS-68 induced mucin release with other known intestinal mucin secretagogues in normal colon explants and in the HT-29 colon cancer cell line, and to study the effects of MMS-68 on mucin release from inflamed and uninflamed ulcerative colitis (UC) and Crohn's disease (CD) mucosa. In normal colonic explants and HT-29 cells, each of the secretagogues including, MMS-68-induced mucin release two- to fivefold more than culture medium alone. In HT-29 cells, MMS-68 plus leukotriene C4 (LTC4) induced a 50% increase in mucin release over either secretagogue alone, and MMS-68 plus platelet-activating factor (PAF) markedly enhanced mucin release by eightfold over either secretagogue. In colonic explants from patients with UC and CD, the mucin release in response to MMS-68 was similar to that of normal colonic explants. Likewise, in isolated epithelial cells from CD and UC (whether involved or uninvolved), MMS-68-induced release was similar to that of epithelial cells isolated from normal colonic mucosa. The number of MMS-68-producing macrophages was lower in uninflamed UC mucosa compared with inflamed UC mucosa and CD mucosa. The mucin secretagogue activity of MMS-68 is comparable to that of other known secretagogues, and PAF can have a synergistic effect on this activity. Whole tissue explants and isolated colonic epithelial cells from patients with IBD respond at least as well as their normal counterparts to MMS-68. MMS-68 may play a role in mucin secretion in normal and inflamed colonic tissue.