Leishmania major MAPK4 intercepts and redirects CD40 signaling promoting infection.

The parasite Leishmania resides as amastigotes within the macrophage parasitophorous vacuoles inflicting the disease Leishmaniasis. Leishmania selectively modulates mitogen-activated protein kinase (MAPK) phosphorylation subverting CD40-triggered anti-leishmanial functions of macrophages. The mechanism of any pathogen-derived molecule induced host MAPK modulation remains poorly understood. Herein, we show that of the fifteen MAPKs, LmjMAPK4 expression is higher in virulent L. major. LmjMAPK4- detected in parasitophorous vacuoles and cytoplasm- binds MEK-1/2, but not MKK-3/6. Lentivirally-overexpressed LmjMAPK4 augments CD40-activated MEK-1/2-ERK-1/2-MKP-1, but inhibits MKK3/6-p38MAPK-MKP-3, phosphorylation. A rationally-identified LmjMAPK4 inhibitor reinstates CD40-activated host-protective anti-leishmanial functions in L. major-infected susceptible BALB/c mice. These results identify LmjMAPK4 as a MAPK modulator at the host-pathogen interface and establish a pathogen-intercepted host receptor signaling as a scientific rationale for identifying drug targets.

Myotubularin-related protein-6 silencing protects mice from Leishmania donovani infection.

The protozoan parasite Leishmania donovani resides within mammalian macrophages and alters its antigen-presenting functions to negatively regulate host-protective T cell responses. This negative regulation of human T cell responses in vitro is attributed to myotubularin-related protein-6 (MTMR6), an ion channel-associated phosphatase. As mouse and human MTMR6 share homology, we studied whether MTMR6 silencing by lentivirally expressed MTMR6shRNA (Lv-MTMR6shRNA) reduced Leishmania growth in macrophages and whether MTMR6 silencing in Leishmania-susceptible BALB/c mice reduced the infection and reinstated host-protective T cell functions. MTMR6 silencing reduced amastigote count and IL-10 production, increased IL-12 expression and, induced IFN-γ-secreting T cells with anti-leishmanial activity in macrophage-T cell co-cultures. Lv-MTMR6shRNA reduced the infection, accompanied by increased IFN-γ expression, in susceptible BALB/c mice. Delays in Lv-MTMR6shRNA treatment by 7 days post-infection significantly reduced the infection suggesting MTMR6 as a plausible therapeutic target. Priming of BALB/c mice with avirulent parasites and Lv-MTMR6shRNA reduced parasite burden in challenge infection. These results indicate that MTMR6 is the first receptor-regulated ion channel-associated phosphatase regulating anti-leishmanial immune responses.

Accura balloon dilatation catheter for percutaneous balloon pulmonary valvuloplasty among adult patients-its protean use.

BACKGROUND: Percutaneous balloon pulmonary valvuloplasty (PBPV) is the treatment of choice for hemodynamically significant pulmonary stenosis (PS). Currently, the Tyshak balloon is preferred but requires multiple dilatations because of its instability across the valve leading to a watermelon seeding effect. Accura balloon (Vascular Concept, UK) offers an advantage in its self-positioning configuration, variable diameter, and rapid inflation-deflation sequence which shortens the procedural time and valve injury. METHOD: 43 patients with severe pulmonary valve stenosis underwent PBPV using an Accura balloon at LPS Institute of Cardiology, GSVM Medical College, Kanpur, UP, India from March 2018 to February 2022. The procedure was carried out using the standard technique but the metallic straightener was removed when the catheter reached the right atrium to facilitate its delivery across the pulmonary valve. Patients were followed up by 2D echo at 24 hours and 6 months. RESULT: Successful BPV was done in all 43 patients [with mean age 21.9 (range 18-41); 31 males and 12 females] among which 5 patients had dysplastic valves. The mean diameter of the annulus was 18.5 (range 15-21) mm. Immediate hemodynamic improvement was observed in 38 patients (88%) as peak systolic gradient reduced from 84±13 to 22±12 mmHg (P<0.005) while 5 patients (12%) had <50% reduction of resting gradient, though it came down significantly at 6 months. Fluoroscopy and procedural time were 5.2±1.9 min and 22.6±3.4 min respectively. Major complications (death, cardiac perforation, tamponade, tricuspid regurgitation, requirement of blood transfusion) were none. Minor complications (transient hypotension, ventricular premature contraction, transient bradycardia) were reported in all patients. Accura balloon being bulky were delivered over left atrial and super stiff Amplatz wire in 36 and 7 patients respectively. CONCLUSION: PBPV using Accura balloon is safe and effective for both stenosed and dysplastic valves. In a few patients, maximal effect will be observed over a period of 6 months.

Advantage of neuroeducation in managing mass psychogenic illness among rural school children in Nepal.

Introduction: Mass psychogenic illness (MPI), also known as mass hysteria (MH), is a mental health disorder that frequently occurs in Nepal. It primarily affects female students in government high schools and occurs during the course of the school day over a few days without corresponding organic causes. Purpose of the study: This study set out to evaluate and give neuroeducation with the goal of preventing and/or managing MPI after documenting the existing state of knowledge regarding MPI. Materials and methods: A total of 234 female students in grades 6 through 10 who attended MH-affected schools (SMH, n = 119) and schools without a mass hysteria history (SNOMH, n = 114) participated in this mass hysteria awareness study. Participants received written pre- and posttests formatted as questionnaires before and after receiving neuroeducation by watching a drama, viewing a human brain-spinal cord model demonstration, and attending an instructive lecture on the human neurological system, stress, and mass hysteria. Results: Our neuroeducation awareness study on mass hysteria was found to be effective among all of the participants from both SMH and SNOMH. The results indicated that the aforementioned neuroeducation tools are more effective in improving knowledge about mental stress differently in different grades of SMH and SNOMH students. The basic understanding of the human neurological system was not improved by the neuroeducation tool, according to our findings. Conclusion: Our study suggests that using day-structured neuroeducational tools might be an efficient way to treat mass psychogenic illness in Nepal.

Twelve-month clinical outcomes of "nano-crush technique" for the treatment of bifurcation lesions using ultra-thin (60 µm) sirolimus-eluting coronary stents.

BACKGROUND: Provisional stenting is preferred for bifurcation lesion; however, certain anatomical substrate does require two stents as a part of dedicated stent technique. Here, the present study evaluated outcomes of ultra-thin (60 µm) Supra family sirolimus-eluting stent (SES) (Sahajanand Medical Technologies Limited, Surat, India) for dedicated bifurcation lesions using nano-crush technique at 12 months angiographic follow-up. METHODS: This was prospective, single-center observational study which enrolled patients with de novo bifurcation lesion and underwent angioplasty with Supra family SES using nano-crush technique at a tertiary care center in India, between March-2017 and February-2019. Primary endpoint at 12 months was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), and clinically driven target lesion revascularization (CD-TLR). Secondary endpoints included patient-oriented composite endpoint (POCE), all-cause death, any revascularization, clinically driven target vessel revascularization, stent thrombosis, periprocedural and spontaneous MI, and device failure. RESULTS: The study enrolled total 63 patients with a mean age of 62.5±4.9 years and had male dominance (89%). Left main (LM) bifurcation and non-LM bifurcation were observed in 21 (33%) and 42 (67%) patients, respectively. Total 50 (80%) patients had Medina class- 1,1,1. At 12 months, TLF occurred in 4 (6%) patients which included one cardiac death (1.5%), two (3.0%) TV-MI, and one CD-TLR (1.5%). POCE was observed in 6 (9.6%) patients. Stent failure was seen in 2 (3.1%) patient and one patient (1.5%) developed late stent thrombosis. Twelve months angiographic follow-up indicated intact stent patency in all other patients. On multivariate analysis, LM bifurcation, renal dysfunction, LM bifurcation with renal dysfunction, ejection fraction (<35%) and calcified lesion were found as predictors of TLF. CONCLUSIONS: Dedicated stenting with ultra-thin Supra family SES for complex bifurcation lesion using nano-crush technique reported acceptable clinical outcomes among real-world patients and can be performed safely with ease without any procedural complications.

Transcatheter closure of secundum atrial septal defect using Cocoon septal occluder: immediate and long-term results.

BACKGROUND: Atrial septal defect (ASD) is one of the common congenital heart defects. Its management has transformed dramatically in the last 4 decades with the transition from surgical to percutaneous transcatheter closure for most secundum-type ASDs. Various devices are available for transcatheter closure of ASD with Amplatzer atrial septal occluder being most commonly used worldwide. Cocoon septal occlude has a nanocoating of platinum using nano-fusion technology over nitinol framework that imparts better radiopacity and excellent biocompatibility and prevents leaching of nickel into circulation, and by smoothening nitinol wire makes this device very soft and smooth. The aim of this study was to evaluate feasibility, effectiveness, safety, and long-term outcome of transcatheter closure of ASD using Cocoon septal occluder (Vascular Innovation, Thailand). RESULTS: All patients undergoing transcatheter closure of hemodynamically significant ASD between September 2012 and July 2019 in our institute were included into this single-center, prospective study. Exclusion criteria were defect > 40 mm, unsuitable anatomy, Eisenmenger syndrome, and anomalous pulmonary venous return. Three hundred and twenty patients underwent device closure, of which 238 (74%) were female. The mean age was 14.6 years (range 6-29), and the median weight was 30.2 kg (range 10-53 kg). Procedure was performed under fluoroscopy using transthoracic and transesophageal echocardiography in 298 (93.1%) and 22(6.9%) patients, respectively. Balloon-assisted technique was used, when septal defect was ≥ 34 mm, in 9 (2.8%) patients. The mean diameter of defect and device was 21.4 mm (range 12-36 mm) and 26.9 mm (range 14-40 mm), respectively. Aortic rim was absent in 11 (3.4%) patients. Primary success was achieved in 312 (97.5%) patients. Early embolization to right ventricle was noted in 2 (0.6%) patients. In both cases, 40-mm device was attempted for defect of 36 mm with inadequate aortic rim using balloon-assisted technique. One (0.3%) patient developed perforation of right atrium. All were surgically repaired. Three (0.9%) patients developed complete heart block following device deployment requiring device retrieval. Two patients had had moderate residual shunt at 6 months of follow-up. After mean follow-up of 50.92 months (range 12.5-89 months), no erosion, allergic reactions to nickel, or other major complications were reported. CONCLUSIONS: Percutaneous transcatheter closure of ASD by Cocoon septal occluder (up to 36 mm) is safe and feasible with high success rate and without any significant device-related major complications over long-term follow-up. With unique device design and excellent long-term safety, it could be preferred dual-disk occluder for transcatheter closure of atrial septal defect. In most of the patients, ASD device can be safely deployed under transthoracic echocardiographic guidance.

Development of the Antileishmanial Vaccine.

Search for an efficacious antileishmanial vaccine has led to clinical trials of numerous vaccine candidates in the past few decades. As no promising candidate has emerged from these studies, novel vaccine modalities and vaccine assessment techniques are still emerging for antileishmanial vaccine development. Briefly, this chapter discusses: (a) history and timeline of antileishmanial vaccine development; (b) techniques utilized for developing whole-parasite and subunit-based antileishmanial vaccine formulations, and (c) immunogenicity and post-challenge protective efficacy assessment of vaccine candidates.

Perforated balloon technique mediated intracoronary delivery of nicorandil to treat coronary no-reflow phenomenon: a novel pharmacological solution to precarious situation.

BACKGROUND: Coronary no-reflow (NRF) following percutaneous coronary intervention (PCI) is infrequent but one of the most dreaded complication which results from impaired flow of microvascular bed. It is associated with adverse outcome if flow is not restored. Objective of this study was to find safety, effectiveness and outcome of intracoronary nikorandil (IC) administered using perforated balloon technique (PBT) to reverse NRF. METHOD: 2-4 mg of nicorandil was diluted with 5 ml of normal saline and administered using PBT over 5-minute. Its effectiveness was evaluated after 10 minute qualitatively using TIMI flow and quantitatively corrected TIMI frame count (cTFC) method. RESULT: Study comprised of 84 patients (out of 1789 patients undergoing PCI between January 2019 and February 2020). Their mean age was 57.8±17.9 years. Following PBT, TIMI III flow was successfully normalized in 71 subjects (84.5%), ten (12%) patients had TIMI II flow and it was not successful in three (3.5%) patients. TIMI flow grade got bettered from 1.03 to 2.58 and cTIMI frame count regressed from 52.9±11 to 16.5±5 (P < 0.001). PBT was well tolerated except short lived drop in blood pressure (n=10; 11.9%). CONCLUSION: This study, for the first time to the best our knowledge, demonstrated that PBT mediated intracoronary administration of nikorandil distally was rapid, safe, and efficacious method to deal with NRF.

Trans-esophageal Echocardiographic Assessment of Left Atrial and Left Atrial Appendage Function in Atrial Fibrillation and Rheumatic Heart Disease.

INTRODUCTION: Rheumatic heart disease (RHD) is one of the most typical causes of atrial fibrillation in developing countries like India. The left atrial and left atrial appendage structure and function are deranged in atrial fibrillation and are a major source of thromboembolism. The goal of this study was to assess the left atrial and left atrial appendage function by transesophageal echocardiography in patients with atrial fibrillation and their comparison in patients with or without RHD. METHODS: A total of 172 consecutive patients with atrial fibrillation with or without RHD were subjected to trans-esophageal echocardiography to assess and compare left atrial (LA) and left atrial appendage (LAA) function. RESULTS: Out of 172 patients with atrial fibrillation, 100 were female (58.1%) and 72 were male (48.9%). The mean age was 54.11±12.3 years, and rheumatic heart disease (RHD) was the commonest cause of atrial fibrillation found in 121 (70.3%) patients. The mean left atrium diameter was significantly higher in RHD patients than in Non-RHD patients (52.08±10.13 vs. 46.67±6.78 mm, p=0.001). Mean left atrial ejection fraction was significantly lower in RHD patients as compared to Non-RHD patients (33.53±5.06 vs. 35.49±5.40%, p=0.024). The mean LAA orifice area of RHD patients was significantly higher than the Non-RHD patients (7.52±1.22 vs 6.94±1.17 mm2, p=0.005). Mean LAA emptying velocity was significantly lower in RHD patients than Non-RHD (20.49±3.95 vs. 22.8±5.96 ml/s, p=0.002). CONCLUSION: Rheumatic heart disease is still a common cause of atrial fibrillation in developing countries. LA and LAA function is impaired in atrial fibrillation, more in patients with rheumatic heart disease.

Idiopathic Intracranial Hypertension: A Case Report.

Idiopathic Intracranial Hypertension is a rare occurrence in young, physically fit male and a diagnosis of exclusion among most patients presenting with signs and symptoms of raised intracranial pressure. Here we describe a case of a young male in the ideal weight range with no previous exposure to offending chemicals presented with a history of headache, obscuration of vision, and photopsia. On examination, there were no positive neurological findings. Increased opening pressure was found on the lumbar puncture. Ophthalmological examination revealed bilateral papilledema. Humphrey’s Visual field test showed peripheral field loss. Magnetic resonance imaging scan of the brain and orbits were normal. The patient was diagnosed and managed in primary care setting after neurosurgical consultation. Though rare, we should suspect idiopathic intracranial hypertension in ideal body weighted male if the headache is persistent after other causes of headache have been ruled out.

Mechanism of noncoding RNA-associated N6-methyladenosine recognition by an RNA processing complex during IgH DNA recombination.

Immunoglobulin heavy chain (IgH) locus-associated G-rich long noncoding RNA (SµGLT) is important for physiological and pathological B cell DNA recombination. We demonstrate that the METTL3 enzyme-catalyzed N6-methyladenosine (m6A) RNA modification drives recognition and 3' end processing of SµGLT by the RNA exosome, promoting class switch recombination (CSR) and suppressing chromosomal translocations. The recognition is driven by interaction of the MPP6 adaptor protein with nuclear m6A reader YTHDC1. MPP6 and YTHDC1 promote CSR by recruiting AID and the RNA exosome to actively transcribe SµGLT. Direct suppression of m6A modification of SµGLT or of m6A reader YTHDC1 reduces CSR. Moreover, METTL3, an essential gene for B cell development in the bone marrow and germinal center, suppresses IgH-associated aberrant DNA breaks and prevents genomic instability. Taken together, we propose coordinated and central roles for MPP6, m6A modification, and m6A reader proteins in controlling long noncoding RNA processing, DNA recombination, and development in B cells.

LmjF.36.3850, a novel hypothetical Leishmania major protein, contributes to the infection.

Leishmania is a protozoan parasite that resides in mammalian macrophages and inflicts the disease known as leishmaniasis. Although prevalent in 88 countries, an anti-leishmanial vaccine remains elusive. While comparing the virulent and avirulent L. major transcriptomes by microarray, PCR and functional analyses for identifying a novel virulence-associated gene, we identified LmjF.36.3850, a hypothetical protein significantly less expressed in the avirulent parasite and without any known function. Motif search revealed that LmjF.36.3850 protein shared phosphorylation sites and other structural features with sucrose non-fermenting protein (Snf7) that shuttles virulence factors. LmjF.36.3850 was predicted to bind diacylglycerol (DAG) with energy value similar to PKCα and PKCß, to which DAG is a cofactor. Indeed, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a DAG analogue, enhanced the phosphorylation of PKCα and PKCßI. We cloned LmjF.36.3850 gene in a mammalian expression vector and primed susceptible BALB/c mice followed by challenge infection. We observed a higher parasite load, comparable antibody response and higher anti-inflammatory cytokines such as IL-4 and IL-10, while expression of major anti-leishmanial cytokine, IFN-γ, remained unchanged in LmjF.36.3850-vaccinated mice. CSA restimulated LN cells from vaccinated mice after challenge infection secreted comparable IL-4 and IL-10 but reduced IFN-γ, as compared to controls. These observations suggest a skewed Th2 response, diminished IFN-γ secreting Th1-TEM cells and increased central and effector memory subtype of Th2, Th17 and Treg cells in the vaccinated mice. These data indicate that LmjF.36.3850 is a plausible virulence factor that enhances disease-promoting response, possibly by interfering with PKC activation and by eliciting disease-promoting T cells.

Clinical safety and efficacy of World's thinnest (50 µm), very long (>40 mm) Everolimus Eluting Stent (SES) among real world patients.

BACKGROUND: Safety and efficacy of newer-generation and World's thinnest everolimus eluting stent (Evermine 50) in patients with very long and multiple lesions. METHOD: Total of 711 patients received >40 mm long, World's thinnest (50 µm) Evermine 50 Everolimus eluting stent (Meril Life Sciences Pvt. Ltd., India) for various indications at LPS Institute of Cardiology, GSVM Medical College, Kanpur, UP, India between August 2017 and December 2018. Primary outcome as Device-oriented composite outcome (DOCO)- composite of cardiovascular death, target vessel myocardial infarction, and target lesion revascularization, secondary end points including peri-procedural device failure (failure of stent delivery, change of stent, edge dissection, stent fracture), target vessel failure (TVF), Global Cardiovascular End Points (GCEP)- composite of all-cause death, any MI, and any revascularization, and stent thrombosis (ST) were evaluated at 1-year follow-up. RESULT: Mean age was 52.7±15.9 years and majority (78.6%) were male. Indications for implantation were STEMI (n=284; 46.2%), NSTEMI (n=201; 32.8%), UA (n=78; 12.6%), and CCS (n=52; 8.4%). Total of 989 lesions were treated among 711 patients. Median length of stent per lesion was 54±14 mm. DOCO occurred in 47 (6.6%) which was contributed by target vessel MI and TLR in 23 (3.2%) and 15 (2.1%) patients respectively. GCEP was observed in 117 (16.4%) at 12-month follow-up mainly attributed by any revascularization 60 (8.4%). Stent failure was seen in 36 (5.1%) patients mainly as result of failure of assigned stent delivery (n=18; 2.5%), and edge dissection (n=15; 2.1%). Definite and probable ST were observed in 8 (1.1%) and 6 (0.8%) patients respectively. CONCLUSION: Evermine 50 Everolimus eluting stent is safe and effective to treat unduly long and multiple lesions.

Residue-Specific Message Encoding in CD40-Ligand.

CD40-Ligand (CD40L)-CD40 interaction regulates immune responses against pathogens, autoantigens, and tumor and transplantation antigens. Single amino acid mutations within the 115-155 amino acids stretch, which is responsible for CD40L functions, result in XIgM syndrome. We hypothesize that each of these amino acids of CD40L encodes specific message that, when decoded by CD40 signaling, induces a specific profile of functions. We observed that every single substitution in the XIgM-related amino acids in the 115-155 41-mer peptide in CD40L selectively altered CD40 signaling and effector functions-cytokine productions, HMGCoA reductase, ceramide synthase, inducible nitric oxide synthase and arginase expression, survival of B cells, and control of Leishmania infection and anti-leishmanial T cell response-suggesting residue-specific encoding of a distinct set of messages that collectively define CD40L pleiotropy, serve as a target for engineering the ligand to generate superagonists as immunotherapeutic, and implicate the evolutionary diversification of functions among the ligands in a protein superfamily.

Development and Characterization of an Avirulent Leishmania major Strain.

Leishmania major causes cutaneous leishmaniasis. An antileishmanial vaccine for humans is unavailable. In this study, we report development of two attenuated L. major strains-5ASKH-HP and LV39-HP-by continuous culture (high passage) of the corresponding virulent strains (low passage). Both avirulent strains showed similar changes in proteome profiles when analyzed by surface-enhanced laser desorption ionization mass spectrometry. Liquid chromatography-mass spectrometry and microarray characterization of 5ASKH strains revealed substantially altered gene and protein expression profiles, respectively. Both virulent and avirulent L. major strains grew comparably in culture, but the avirulent strain survived significantly less in BALB/c-derived peritoneal macrophages. Both attenuated strains failed to infect BALB/c mice and elicited IFN-γ, but not IL-4 and IL-10, responses. 5ASKH-HP parasites failed to induce significant infection even in severely immunocompromised- SCID or inducible NO synthase-, CD40-, or IL-12-deficient mice, indicating attenuation. The avirulent strain induced less IL-10, but higher IL-12, in macrophages. The avirulent strain failed to reduce CD40 relocation to the detergent-resistant membrane domain and to inhibit CD40-induced phosphorylation of the kinases Lyn and protein kinase C-ß and MAPKs MKK-3/6 and p38MAPK or to upregulate MEK-1/2 and ERK-1/2 in BALB/c-derived peritoneal macrophages. The virulent and the avirulent strains reciprocally modulated CD40-induced Ras-mediated signaling through PI-3K and Raf-1. Avirulent 5ASKH-primed BALB/c mice were protected against virulent L. major challenge infection. The loss of virulence accompanied by substantially altered proteome profiles and the elicitation of host-protective immune responses indicate plausibly irreversible attenuation of the L. major strain and its potential use as a vaccine strain.

Transcatheter Device Closure of Perimembranous Ventricular Septal Defect in Pediatric Patients: Long-Term Outcomes.

AIMS: The aim of this study is to evaluate the safety and efficacy of transcatheter device closure of perimembranous ventricular septal defects in pediatric patients at long-term follow-up. MATERIALS AND METHODS: We prospectively studied 376 patients with perimembranous VSDs between September 2008 and December 2015 who underwent percutaneous closure at our center. Transthoracic echocardiography (TTE) and electrocardiogram were done before and after the procedure in all the patients. All patients were subjected to follow-up evaluation at 1, 3, 6, 12 months, and annually thereafter with TTE and electrocardiogram. RESULTS: A total of 376 patients (210 males and 166 females) underwent transcatheter closure of perimembranous VSD. Mean age of patients was 8.67 ± 3.02 (range 3-18 years) and mean weight was 21.15 ± 8.31 (range 8-65 kg). The procedure was carried out successfully in 98.93% of patients with no reported mortality. Rhythm disturbances occurred in 8.5% of patients after the procedure which included three cases of complete atrioventricular block. CONCLUSION: This study shows that in experienced hands transcatheter closure of perimembrnous VSD is safe and effective at long-term follow-up. With minimal morbidity and no mortality, the transcatheter is an effective alternative to surgical closure in selected patients.

Non-pharmaco, non-invasive management of coronary no-reflow phenomenon.

INTRODUCTION: No-reflow is an infrequent but dreaded complication of percutaneous coronary intervention (PCI), where the culprit is obstruction of the downstream microvascular bed. The aim of this study was to evaluate the efficacy and safety of forceful injection of blood (autologous blood transfusion - ABT) in reversing no-reflow during PCI because data regarding its effectiveness is not available. MATERIAL AND METHODS: 100-120 ml of blood was withdrawn through guiding catheter over 3 to 5 min using a 10 ml syringe and re-infused by forceful injection over 3 min through it, and its efficacy was assessed at 10 min using TIMI flow grade and quantitative corrected TIMI frame count. RESULTS: In total 93 patients received ABT following no-reflow. Their clinical presentation was ST-elevation myocardial infarction (STEMI) (n = 61; 65.6%), non-ST-elevation myocardial infarction (NSTEMI) (n = 23; 24.7%), and unstable angina (n = 9; 9.6%). It was observed among patients undergoing primary PCI (n = 18; 19.3%), pharmaco-invasive PCI (n = 27; 29%), rescue PCI (n = 11; 11.8%), and PCI for cardiogenic shock (n = 5; 5.3%). A mean volume of 108 ±4 ml blood was transfused. Commonest culprit vessel was left anterior descending artery (n = 51; 54.8%) followed by right coronary (n = 29; 31.2%), left circumflex (n = 19; 10.8%), and saphenous vein grafts (n = 3; 3.2%). Following ABT, TIMI 3 flow was successfully restored in 77 (82.7%) patients. TIMI flow grade improved from 1.02 to 2.52 and cTIMI frame count decreased from 60.6 ±12 to 16.1 ±6 (p < 0.001). ABT was well tolerated except transient hypotension (n = 17; 18.3%). Overall mortality was reported in 10 (10.7%) patients at 1 year. CONCLUSIONS: In this largest and only study to date, ABT is a safe and highly effective approach to reverse no-reflow by raising driving pressure across the capillary bed.

A Leishmania donovani dominant-negative mutant for eIF2α kinase LdeK1 elicits host-protective immune response.

Dominant-negative mutation of LdeK1 gene, an eIF2α kinase from Leishmania donovani, revealed its role in translation regulation in response to nutrient starvation earlier. However, whether the kinase influences the infectivity of the parasites which naturally encounters nutrient deprivation during its life cycle was interesting to investigate. Both in vitro and in vivo experiments resulted in decrease of the parasite burden in peritoneal macrophages and in splenic/ hepatic load, respectively. An insight into the immune response of mice infected with mutant parasite showed enhanced pro-inflammatory cytokines and nitric oxide levels but reduced TH 2 and Treg population. The significantly reduced loss of infectivity of the parasites lacking a functional LdeK1 by modulating the immune response towards host protection makes it a potential vaccine candidate against Leishmaniasis.

Ras isoforms selectively regulate antigen-specific immune response.

H-/K-Ras and N-Ras isoforms were proposed to lack functional specificities due to similarity in 1-165 amino acids. As recent studies implied Ras isoform-specific developmental effects, we examined their functional specificity using Leishmania major infection, anti-hapten antibody response and carrier-specific T cell response. While N-Ras overexpression increased L. major infection in resistant C57BL/6 mice, H-Ras or K-Ras overexpression reduced the infection in susceptible BALB/c mice. These Ras isoforms differentially regulated anti-TNP antibody response in TNP-Ova-primed, but not in TNP-Ficoll- or TNP-LPS-primed, BALB/c mice. Ras isoform-specific silencing selectively modulated Ova-specific T cell response. The data indicate Ras isoform-specific regulation of antigen-specific immune response.

Permanent Pacemaker Implantation in Patients With Isolated Persistent Left Superior Vena Cava From a Right-Sided Approach: Technical Considerations and Follow-Up Outcome.

BACKGROUND: Positioning a permanent pacing wire in patients with persistent left superior vena cava (PLSVC) to right ventricle often comes as on-table surprise. It is technically demanding and therefore most of operators prefer left-sided approach. We assessed technical challenges during pacemaker implantation, and their short- and long-term outcomes among patients with isolated PLSVC from a right-sided approach. METHODS: Thirty-one consecutive patients with isolated PLSVC and 93 patients with right superior vena cava (RSVC) were enrolled with syncope with sinus node dysfunction (SND) and atrioventricular (AV) block. Study was designed on the basis of nested case-control method, and therefore 1:3 proportions was the enrolment criteria to detect any difference as statistically significant as incidence of isolated PLSVC is low. RESULTS: Mean age of patients was 64.8 ± 10.5 years. SND was the most common indication (n = 55; 44%) followed by AV block (n = 47; 37%). Nineteen (20%) patients received tined pacing lead, while 105 (85%) had screwing lead. There was no significant difference in mean procedural time (25 ± 11 min vs. 23 ± 12 min; P = 0.24), mean fluoroscopic time (3.1 ± 2.2 min vs. 2.7 ± 2.1 min; P = 0.54), pacing parameters for atrial and ventricular leads, dislodgement rate (3.2% vs. 4.8%; P = 0.32) and follow-up duration (6.9 ± 1.3 years vs. 7.2 ± 1.1 years; P = 0.18) between two groups. Compared to patients with RSVC, those with PLSVC had alpha loop configuration for ventricular lead which was statistically significant (31 vs. 00; P = 0.002). CONCLUSIONS: Patients with PLSVC had alpha loop configuration for ventricular lead because of circuitous course via left mediastinum. Although pacemaker implantation through coronary sinus via isolated PLSVC from right sided-approach is technically challenging, it obtains good long-term results but needs frequent follow-up during the initial period.