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Background Bioprosthesis has been increasingly implanted for the treatment of transvalvular disease across the world. A new Dafodil™ pericardial bioprosthesis (Meril Life Sciences Pvt. Ltd., India) recently approved by Conformité Européenne (CE) is a tri-leaflet, stented, bovine valve. The purpose of Dafodil-1 first-in-human trial was to evaluate clinical safety and performance (including hemodynamic parameters) of the Dafodil pericardial bioprosthesis in patients who underwent aortic or mitral valve replacement. Methods This prospective, multicenter clinical trial enrolled 60 patients (Aortic: 30 patients; Mitral: 30 patients) from seven sites across India. Safety endpoints were early (≤30 days) and late (> 30 days) mortality and valve-related morbidity. The performance endpoints were hemodynamic performance, improvement in NYHA functional class, and change in the quality of life using SF-12v1 health survey. Results From July 2017 to July 2018, 60 patients underwent implantation of the Dafodil pericardial bioprosthesis. Post-operatively, NYHA functional class significantly improved in all the patients (Aortic: 90% NYHA class-I and 10% NYHA class-II; Mitral: 96.55% NYHA class-I and 3.45% NYHA class-II; P 2 effective orifice area (EOA)] pre-operatively to 14.49 ± 6.58 mmHg (EOA: 1.85 ± 0.27 cm2) at 12-month. Overall, the mitral mean pressure gradient and EOA were 4.41 ± 1.69 mmHg and 2.67 ± 0.48 cm2, respectively, at 12-month. Significant improvement (P Conclusions The clinical safety and performance of the Dafodil pericardial bioprosthesis were favourable at 12-month. Moreover, a study with a larger patient population and longer follow-up is warranted to further assess the device. Trial registration Dafodil-1 trial has been prospectively registered on 10/07/2017 under Clinical Trial Registry-India (http://www.ctri.nic.in). (Registration number: CTRI/2017/07/009008).

Objective. HLA-B27 and ERAP1 are the two strongest predisposing genetic factors to Ankylosing Spondylitis (AS). A key aminopeptidase in MHC class I presentation, ERAP1 potentially contributes to AS pathogenesis through altering HLA-B27 peptide presentation. We studied the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to Cytotoxic T lymphocytes (CTLs). Methods. ERAP1-silenced and -competent HeLa.B27/C1R.B27 cells were isotope labeled, mixed, lysed and then immuno-precipitated using W6/32 or ME1. Peptides bound to HLA-B27 were eluted and analyzed by tandem Mass Spectrometry. Selected peptides were synthesized and tested for HLA-B27 binding ability. The effect of ERAP1 silencing/mutation on presentation of an immunodominant viral HLA-B27 epitope, KK10, to CTL was also studied. Results. In both HeLa.B27 and C1R.B27 cells, the proportion of 9mer HLA-B27-bound peptides was decreased by ERAP1 silencing, whereas the percentage of longer peptides (11-13mers) increased. Surprisingly, following ERAP1 silencing, C-terminally extended peptides were readily identified. These were better able to bind to HLA-B27 than N-terminally extended peptides lacking a P2 Arginine. In both HeLa.B27 and mouse fibroblasts expressing HLA-B27, the absence of ERAP1 reduced recognition by HLA-B27-restricted KK10-specific CTLs following recombinant vaccinia viral infection or transfection with minigenes expressing KK10 precursors. Lastly, an AS protective variant, K528R-ERAP1, reduced KK10 CTL recognition following extended-KK10 minigene transfection compared to WT-ERAP1. Conclusion. Our study shows that ERAP1 directly alters peptide binding and presentation by HLA-B27, supporting a pathogenic mechanism in AS. ERAP1 inhibition could potentially be used for treatment of AS and other ERAP1-associated diseases. © 2013 American College of Rheumatology.

OBJECTIVE: HLA-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are the two strongest genetic factors predisposing to ankylosing spondylitis (AS). A key aminopeptidase in class I major histocompatibility complex presentation, ERAP1 potentially contributes to the pathogenesis of AS by altering HLA-B27 peptide presentation. The aim of this study was to analyze the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to cytotoxic T lymphocytes (CTLs). METHODS: ERAP1-silenced and -competent HeLa.B27 and C1R.B27 cells were isotope-labeled, mixed, lysed, and then immunoprecipitated using W6/32 or ME1 antibodies. Peptides bound to HLA-B27 were eluted and analyzed by tandem mass spectrometry. Selected peptides were synthesized and tested for HLA-B27 binding ability. The effect of ERAP1 silencing/mutation on presentation of an immunodominant viral HLA-B27 epitope, KK10, to CTLs was also studied. RESULTS: In both HeLa.B27 and C1R.B27 cells, the proportion of 9-mer HLA-B27-bound peptides was decreased by ERAP1 silencing, whereas the percentages of longer peptides (11-13 mer) were increased. Surprisingly, following ERAP1 silencing, C-terminally extended peptides were readily identified. These were better able to bind to HLA-B27 than were N-terminally extended peptides lacking an arginine at position 2. In both HeLa.B27 cells and mouse fibroblasts expressing HLA-B27, the absence of ERAP1 reduced peptide recognition by HLA-B27-restricted KK10-specific CTLs following infection with recombinant vaccinia virus or transfection with minigenes expressing KK10 precursors. Presence of an AS-protective variant of ERAP1, K528R, as compared to wild-type ERAP1, reduced the peptide recognition by KK10 CTLs following transfection with extended KK10 minigenes. CONCLUSION: These results show that ERAP1 directly alters peptide binding and presentation by HLA-B27, thus demonstrating a potential pathogenic mechanism in AS. Inhibition of ERAP1 could potentially be used for treatment of AS and other ERAP1-associated diseases.

Available data on the efficiency of endoventricular circular patch plasty (EVCPP) especially from Asian Indians are limited. The objective of the present investigation was to evaluate the efficacy of endoventricular circular patch plasty along with coronary artery bypass grafting (CABG). Patients having ischemic left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF)≤25%] with left ventricular dyskinetic or akinetic apical segement [as depicted by two dimensional (2D) echocardiography] were enrolled in the study. They were evaluated for 2D echocardiography and color Doppler parameters as well as functional capacity before surgery and after one, three and six months of surgery. 39 patients (35 males; average age 59 years) were enrolled in the study. There was significant (P

Studies are scant on the effects of short-term carvedilol treatment as an adjuvant to angiotensin-converting enzyme (ACE) inhibitor in patients with left ventricular (LV) systolic dysfunction. The objective of this study was to find the effects of short-term treatment of carvedilol on patients with ischemic LV systolic dysfunction (defined as LV ejection fraction (LVEF) ≤30% on 2D echocardiography) undergoing coronary artery bypass surgery (CABG). There were 74 patients that received ACE inhibitor without any β-blocker (control) and 67 patients that received carvedilol in addition to ACE inhibitor following CABG (carvedilol group). After 1 month of drug administration following CABG, the control group was found to have significantly greater percent improvement in LVEF (29.1% ± 5.39%) as compared with the carvedilol group (15.3% ± 4.89%). However, after 3 and 6 months, LVEF levels were found to be significantly greater in the carvedilol group as compared with the control group. Further, at 6 months of drug administration, LV end systolic diameter was significantly less in the carvedilol group (39.11 ± 1.10 mm) as compared with the control group (43.49 ± 1.39 mm). Thus, carvedilol produces beneficial effect on short-term administration in terms of LV contractility when given along with ACE inhibtior as compared with ACE inhibitor therapy alone.

Minor histocompatibility (H) Ags elicit T cell responses and thereby cause chronic graft rejection and graft-vs-host disease among MHC identical individuals. Although numerous independent H loci exist in mice of a given MHC haplotype, certain H Ags dominate the immune response and are thus of considerable conceptual and therapeutic importance. To identify these H Ags and their genes, lacZ-inducible CD8+ T cell hybrids were generated by immunizing C57BL/6 (B6) mice with MHC identical BALB.B spleen cells. The cDNA clones encoding the precursor for the antigenic peptide/Kb MHC class I complex were isolated by expression cloning using the BCZ39.84 T cell as a probe. The cDNAs defined a new H locus (termed H60), located on mouse chromosome 10, and encoded a novel protein that contains the naturally processed octapeptide LTFNYRNL (LYL8) presented by the Kb MHC molecule. Southern blot analysis revealed that the H60 locus was polymorphic among the BALB and the B6 strains. However, none of the H60 transcripts expressed in the donor BALB spleen were detected in the host B6 strain. The expression and immunogenicity of the LYL8/Kb complex in BALB.B and CXB recombinant inbred strains strongly suggested that the H60 locus may account for one of the previously described antigenic activity among these strains. The results establish the source of an immunodominant autosomal minor H Ag that, by its differential transcription in the donor vs the host strains, provides a novel peptide/MHC target for host CD8+ T cells.