Impaired Cardiac AMPK (5'-Adenosine Monophosphate-Activated Protein Kinase) and Ca2+-Handling, and Action Potential Duration Heterogeneity in Ibrutinib-Induced Ventricular Arrhythmia Vulnerability.

BACKGROUND: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS: The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.

Methicillin-Resistant Staphylococcus aureus Infection and its Health Perspective: A Review.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a potential threat globally since it is associated with high morbidity and mortality. In addition, the ability of MRSA to develop resistance and adapt to various environments makes it exceptional from other bacterial strains. Effective management is best determined by the site of infection. OBJECTIVES: This study aims to summarize and assess the epidemiology of MRSA, resistance, detection of MRSA in humans, animals, and food products, treatment employed, and combination therapy. METHODS: For the present review, we collected data from PubMed, Embase, Web of Science, BioMed Central, Medline, Encyclopedia of Life Sciences, Scopus, Cochrane Library, and ScienceDirect that report the epidemiology of MRSA, drug resistance in MRSA, spread of MRSA infection, diagnosis of infection, existing and emerging remedies of MRSA infections. Collected data were analyzed and represented in this article with the help of Figures and Tables. RESULTS: S. aureus resistance to vancomycin is because of genetic adaptation and also due to the widespread and indiscriminate use of antibiotics in the treatment of MRSA infection. Specifically, infections related to vancomycin-resistant S. aureus are life-threatening and difficult to treat. MRSA epidemiology with the recognition of community-acquired-MRSA transmission between livestock and humans is also reported and is alarming. Multiple studies suggested that early detection of MRSA colonization and elimination of carriage can help reduce the risk of subsequent infection. Specifically, PCR-based screening from different body sites offers the highest overall sensitivity for the detection of MRSA carriage. CONCLUSION: Screening novel mutants and methods of transmission in each environment will assist in managing MRSA. Further, effective MRSA control in all clinical setups is required with the avoidance of uncontrolled antibiotic usage.

Seaweed and Seaweed-Based Functional Metabolites as Potential Modulators of Growth, Immune and Antioxidant Responses, and Gut Microbiota in Fish.

Seaweed, also known as macroalgae, represents a vast resource that can be categorized into three taxonomic groups: Rhodophyta (red), Chlorophyta (green), and Phaeophyceae (brown). They are a good source of essential nutrients such as proteins, minerals, vitamins, and omega-3 fatty acids. Seaweed also contains a wide range of functional metabolites, including polyphenols, polysaccharides, and pigments. This study comprehensively discusses seaweed and seaweed-derived metabolites and their potential as a functional feed ingredient in aquafeed for aquaculture production. Past research has discussed the nutritional role of seaweed in promoting the growth performance of fish, but their effects on immune response and gut health in fish have received considerably less attention in the published literature. Existing research, however, has demonstrated that dietary seaweed and seaweed-based metabolite supplementation positively impact the antioxidant status, disease resistance, and stress response in fish. Additionally, seaweed supplementation can promote the growth of beneficial bacteria and inhibit the proliferation of harmful bacteria, thereby improving gut health and nutrient absorption in fish. Nevertheless, an important balance remains between dietary seaweed inclusion level and the resultant metabolic alteration in fish. This review highlights the current state of knowledge and the associated importance of continued research endeavors regarding seaweed and seaweed-based functional metabolites as potential modulators of growth, immune and antioxidant response, and gut microbiota composition in fish.

Uncoupling cytosolic calcium from membrane voltage by transient receptor potential melastatin 4 channel (TRPM4) modulation: A novel strategy to treat ventricular arrhythmias.

The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca2+) signaling, which plays an important role in driving membrane voltage, has not been targeted for therapeutic purposes in arrhythmogenesis. There is clear evidence for bidirectional coupling between membrane voltage and intracellular Ca2+. Cytosolic Ca2+ regulates membrane voltage through Ca2+-sensitive membrane currents. As a component of Ca2+-sensitive currents, Ca2+-activated nonspecific cationic current through the TRPM4 (transient receptor potential melastatin 4) channel plays a significant role in Ca2+-driven changes in membrane electrophysiology. In myopathic and ischemic ventricles, upregulation and/or enhanced activity of this current is associated with the generation of afterdepolarization (both early and delayed), reduction of repolarization reserve, and increased propensity to ventricular arrhythmias. In this review, we describe a novel concept for the management of ventricular arrhythmias in the remodeled ventricle based on mechanistic concepts from experimental studies, by uncoupling the Ca2+-induced changes in membrane voltage by inhibition of this TRPM4-mediated current.

Reducing Maternal Mortality Rates in Alabama Through Patient Education: A Scoping Review.

Maternal mortality continues to rise in the United States and disproportionately affects those in Alabama. Lack of patient education on warning signs is a preventable cause of maternal mortality. This article aims to systematically quantify existing research investigating the effect of patient education on maternal outcomes. The inclusion criteria required an article to be (a) original research, (b) conducted within the United States, (c) in English, and (d) published between January 2012 and September 2022. PubMed® and Embase® databases were searched using key words and filters. Rayyan®, a systematic review research tool, was utilized to assess articles in a blinded two-person review process. A blinded third researcher resolved conflicts. A total of 3,139 articles were compiled; 3,115 articles did not meet inclusion criteria, and 24 articles were retrieved after an abstract review. Ultimately, 11 articles were included after a full-text review. None of these articles were specific to Alabama. However, they did contain evidence for patient education improving maternal mortality. More research is required in Alabama to demonstrate the effect of educating patients on maternal mortality. These articles contain evidence for education as a tool to improve maternal outcomes.

Orientation of conduction velocity vectors on cardiac mapping surfaces.

AIMS: Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. METHODS AND RESULTS: Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LATs) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 µm and 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased. Three-dimensional and 2D left ventricle CV at 500 µm resolution increased from 429.2 ± 189.3 to 527.7 ± 253.8 mm/s (P < 0.01), respectively, with modest correlation (R = 0.64). Decreasing the resolution to 4 mm significantly increased 2D CV and weakened the correlation (R = 0.46). The majority of CV vectors were not parallel (<30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. CONCLUSION: Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and significantly compounded by mapping resolution. Three-dimensional electric field-based approaches are needed in mapping true CV on mapping surfaces.

Revisiting the South Indian Traditional Plants against Several Targets of SARS-CoV-2 - An in silico Approach.

BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

GlmU Inhibitors as Promising Antibacterial Agents: A Review.

Bacterial infections are a major cause of mortality and morbidity in humans throughout the world. Infections due to resistant bacterial strains such as methicillin-resistant Staphyloccocusaureus vancomycin, resistant Enterococci, Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium are alarming. Hence the development of new antibacterial agents, which act via a novel mechanism of action, became a priority in antibacterial research. One such approach to overcome bacterial resistance is to target novel protein and develop antibacterial agents that act via different mechanisms of action. Bacterial GlmU is one such bifunctional enzyme that catalyzes the two consecutive reactions during the biosynthesis of uridine 5'-diphospho-Nacetylglucosamine, an essential precursor for the biosynthesis of bacterial cell wall peptidoglycan. This enzyme comprises two distinct active sites; acetyltransferase and uridyltransferase and both these active sites act independently during catalytic reactions. GlmU is considered an attractive target for the design and development of newer antibacterial agents due to its important role in bacterial cell wall synthesis and the absence of comparable enzymes in humans. Availability of three dimensions X-crystallographic structures of GlmU and their known catalytic mechanism from different bacterial strains have instigated research efforts for the development of novel antibacterial agents. Several GlmU inhibitors belonging to different chemical classes like 2- phenylbenzofuran derivative, quinazolines, aminoquinazolines, sulfonamides, arylsulfonamide, D-glucopyranoside 6-phosphates, terreic acid, iodoacetamide, N-ethyl maleimide, and Nethylmaleimide etc., have been reported in the literature. In the present review, we present an update on GlmU inhibitors and their associated antibacterial activities. This review may be useful for the design and development of novel GlmU inhibitors with potent antibacterial activity.

Statins Protect Against Early Stages of Doxorubicin-induced Cardiotoxicity Through the Regulation of Akt Signaling and SERCA2.

Background: Doxorubicin-induced cardiomyopathy (DICM) is one of the complications that can limit treatment for a significant number of cancer patients. In animal models, the administration of statins can prevent the development of DICM. Therefore, the use of statins with anthracyclines potentially could enable cancer patients to complete their chemotherapy without added cardiotoxicity. The precise mechanism mediating the cardioprotection is not well understood. The purpose of this study is to determine the molecular mechanism by which rosuvastatin confers cardioprotection in a mouse model of DICM. Methods: Rosuvastatin was intraperitoneally administered into adult male mice at 100 µg/kg daily for 7 days, followed by a single intraperitoneal doxorubicin injection at 10 mg/kg. Animals continued to receive rosuvastatin daily for an additional 14 days. Cardiac function was assessed by echocardiography. Optical calcium mapping was performed on retrograde Langendorff perfused isolated hearts. Ventricular tissue samples were analyzed by immunofluorescence microscopy, Western blotting, and quantitative polymerase chain reaction. Results: Exposure to doxorubicin resulted in significantly reduced fractional shortening (27.4% ± 1.11% vs 40% ± 5.8% in controls; P < 0.001) and re-expression of the fetal gene program. However, we found no evidence of maladaptive cardiac hypertrophy or adverse ventricular remodeling in mice exposed to this dose of doxorubicin. In contrast, rosuvastatin-doxorubicin-treated mice maintained their cardiac function (39% ± 1.26%; P < 0.001). Mechanistically, the effect of rosuvastatin was associated with activation of Akt and phosphorylation of phospholamban with preserved sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (SERCA2)-mediated Ca2+ reuptake. These effects occurred independently of perturbations in ryanodine receptor 2 function. Conclusions: Rosuvastatin counteracts the cardiotoxic effects of doxorubicin by directly targeting sarcoplasmic calcium cycling.

Contexte: La cardiomyopathie induite par la doxorubicine (CMID) est l'une des complications pouvant limiter le traitement d'un nombre considérable de patients atteints de cancer. Dans des modèles animaux, l'administration de statines peut prévenir l'apparition d'une CMID. Ainsi, l'utilisation de statines avec les anthracyclines pourrait vraisemblablement permettre aux patients de compléter leur chimiothérapie en évitant une cardiotoxicité supplémentaire. Le mécanisme précis qui sous-tend cet effet cardioprotecteur n'est pas entièrement élucidé. Cette étude a pour objectif de déterminer dans un modèle murin de CMID le mécanisme moléculaire par lequel la rosuvastatine confère une cardioprotection. Méthodologie: La rosuvastatine a été administrée par voie intrapéritonéale à des souris adultes mâles à une dose de 100 µg/kg par jour pendant sept jours, suivie d'une dose unique de doxorubicine de 10 mg/kg administrée par injection intrapéritonéale. Les animaux poursuivaient ensuite le traitement par la rosuvastatine une fois par jour pendant 14 jours supplémentaires. La fonction cardiaque a été mesurée par échocardiographie. Une cartographie optique du calcium a été réalisée sur des cœurs isolés soumis à une perfusion rétrograde selon la méthode de Langendorff. Des échantillons de tissu ventriculaire ont été analysés par microscopie en immunofluorescence, par buvardage de western et par mesure quantitative de l'amplification en chaîne par polymérase. Résultats: L'exposition à la doxorubicine a entraîné une diminution significative de la fraction de raccourcissement (27,4 % ± 1,11 % vs 40 % ± 5,8 % dans le groupe témoin; p < 0,001) et la réexpression du programme génique fœtal. Toutefois, aucune hypertrophie cardiaque inadaptée ni aucun remodelage ventriculaire indésirable n'ont été observés chez les souris ayant été exposées à la dose de doxorubicine étudiée. En revanche, la fonction cardiaque a été préservée chez les souris traitées par l'association rosuvastatine-doxorubicine (39 % ± 1,26 %; p < 0,001). Sur le plan du mode d'action, l'effet de la rosuvastatine a été associé à une activation de l'Akt et à une phosphorylation du phospholambane, avec préservation du recaptage de Ca2+ médié par la pompe SERCA2 (sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2). Ces effets sont survenus indépendamment des perturbations de la fonction du récepteur RyR2 (ryanodine receptor 2). Conclusions: La rosuvastatine neutralise les effets cardiotoxiques de la doxorubicine en ciblant directement la circulation sarcoplasmique du calcium.

Synchronizing systolic calcium release with azumolene in an experimental model.

Background: Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca2+) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). Objective: In the present study, we explored the effects of RyR2 stabilization by azumolene on systolic Ca2+ release synchrony and myocardial contractility. Methods: After completion of baseline optical mapping, Langendorff-perfused rabbit hearts were subjected to global ischemia followed by reperfusion with azumolene or deionized distilled water (vehicle). Following reperfusion, LDVF was induced with burst pacing. In the first series of experiments (n = 16), epicardial Ca2+ transient was analyzed for Ca2+ transient amplitude alternans and dispersion of Ca2+ transient amplitude alternans index (CAAI). In the second series of experiments following the same protocol (n = 12), ventricular contractility was assessed by measuring the left ventricular pressure. Results: Ischemic LDVF led to greater CAAI (0.06 ± 0.02 at baseline vs 0.12 ± 0.02 post-LDVF, P < .01) and magnitude of dispersion of CAAI (0.04 ± 0.01 vs 0.09 ± 0.01, P < .01) in control hearts. In azumolene-treated hearts, no significant changes in CAAI (0.05 ± 0.01 vs 0.05 ± 0.01, P = .84) and dispersion of CAAI (0.04 ± 0.01 vs 0.04 ± 0.01, P = .99) were noted following ischemic LDVF. Ischemic LDVF was associated with reduction in left ventricular developed pressure (100% vs 36.8% ± 6.1%, P = .002) and dP/dtmax (100% vs 45.3% ± 6.5%, P = .003) in control hearts, but these reductions were mitigated (left ventricular developed pressure: 100% vs 74.0% ± 8.1%, P = .052, dP/dtmax: 100% vs 80.8% ± 7.9%, P = .09) in azumolene-treated hearts. Conclusion: Treatment with azumolene is associated with improvement of systolic Ca2+ release synchrony and myocardial contractility following ischemic LDVF.

Exploring the role and lived experiences of people with disabilities working in the agricultural sector in northern Nigeria.

Background: It is estimated that over 75.0% of households in sub-Saharan Africa are involved in agriculture, and the majority of the poor in rural areas rely on agriculture for their livelihoods. One billion people living with disabilities in low- and middle-income countries are argued to make up the poorest of the poor, yet to our knowledge, no literature has captured the livelihood of people living with disabilities in the context of farming in Nigeria, specifically northern Nigeria where most of the households are involved in agriculture and related activities. Objectives: This article reports on findings from a study that sought to understand disability in the context of northern Nigerian farming, with a particular focus on the role and lived experiences of people living with disabilities working in the agricultural sector. Method: A survey questionnaire was developed and captured the experiences of 1067 people living with disabilities working in the agricultural sector across five states (Adamawa, Bauchi, Jigawa, Kaduna and Yobe) in northern Nigeria. Results: Findings indicate that people with disabilities are actively participating in agricultural activities for several reasons, which specifically included 'forced to and for survival'. When participants reported needing care, this was predominantly provided by family members. Findings also showed that participants with disabilities experienced several economic and sociocultural challenges because of their impairments. Conclusion: This study adds to the very limited literature on farmers living with disabilities in sub-Saharan Africa and so highlights the need for more research to be conducted with farmers living with disabilities in Nigeria, particularly female farmers living with disabilities. These will provide more evidence pertaining to the experiences of farmers living with disabilities in order to provide effective disability- and gender-inclusive agricultural and entrepreneurship programmes in Nigeria. Contribution: The results of this research reveal important insights relating to the experiences of farmers living with disabilities in northern Nigeria, which can contribute to informing future developmental projects to achieve effective inclusion and actively benefit people living with disabilities.

Metabolic risk factors in first acute coronary syndrome (MERIFACS) Study.

OBJECTIVES: In acute coronary syndrome (ACS) patients the focus is on major conventional risk factors - CRF [diabetes, hypertension, elevated low-density cholesterol (LDL-C) and smoking] whereas others - specific metabolic risk factors - MRF [high-density lipoprotein cholesterol (HDL-C), body-mass index (BMI), waist-hip ratio (WHR), and triglycerides, and HbA1c get less attention. METHODS: This is a prospective case-control observational study from 15 tertiary care hospitals in India. CRF and MRF in patients presenting with first incidence of ACS (n = 2153) were compared with matched controls (n = 1210). RESULTS: Propensity score matching (PSM) yielded 1193 cases and matched 1210 controls. Risk factor prevalence in cases vs. controls were CRF: hypertension - 39.4% vs 16.4% (p < 0.0001), diabetes - 42.6% vs 12.7% (p < 0.0001), smoking - 28.3% vs 9.3% (p < 0.0001) and elevated LDL-C - 70.2% vs 57.9% (p < 0.0001). MRF: High BMI - 54.7% vs 55.1% (p = 0.84), increased waist: hip ratio 79.5% vs 63.6% (p < 0.0001), high HbA1c - 37.8% vs 14.9% (p < 0.0001), low HDL-C - 56.2% vs 42.8% (p < 0.0001) and elevated triglycerides - 49.7% vs 44.2% (p = 0.007). Adjusted Odds ratios by multivariate analysis were CRF: hypertension - 2.3 (p < 0.001), diabetes - 4.7 (p < 0.001), high LDL-C - 3.3 (p < 0.001) and smoking- 6.3 (p < 0.001). MRF: High waist: hip ratio - 2.4 (p < 0.001) high HbA1c - 3.2 (p < 0.001), low HDL-C 2.2 (p < 0.001) and elevated triglycerides - 0.878 p = 0.17. CONCLUSION: In India, the risk of ACS conferred by specific metabolic risk factors (High waist: hip ratio, Low HDL-C and High HbA1c) is comparable to that caused by CRF.

Computational Molecular Modeling Studies of Some Mycobacterium Tuberculosis Alanine Racemase Inhibitors.

Alanine racemase is a pyridoxal-5'-phosphate dependent bacterial enzyme that provides the essential peptidoglycan precursor D-alanine, utilized for cell wall synthesis. This enzyme is ubiquitous throughout bacteria, including Mycobacterium tuberculosis, making it an attractive target for antibacterial drug discovery. We investigated the binding mode of twenty five reported Mycobacterium tuberculosis alanine racemase inhibitors. The results obtained from molecular docking studies emphasized the importance of inhibitor interaction with Lys42, Tyr46, Arg140, His172 and Tyr175 residues at the catalytic binding pocket of alanine racemase enzyme. The predicted binding free energies showed that van der Waals and nonpolar solvation interactions are the driving force for binding of inhibitors. Molecular dynamics simulation studies of four such inhibitor-alanine racemase systems were further explored to study the inhibition mechanism. The quantum chemical parameters calculated at the B3LYP/6-31G**++ level of theory indicated that the inhibitors must have low values of the lowest unoccupied molecular orbital energy and high values of electrostatic potential for stronger interactions. We expect that this study can provide significant theoretical guidance for design of potent Mycobacterium tuberculosis alanine racemase inhibitors in future.

On the Electrophysiology and Mapping of Intramural Arrhythmic Focus.

BACKGROUND: Conventional mapping of focal ventricular arrhythmias relies on unipolar electrogram characteristics and early local activation times. Deep intramural foci are common and associated with high recurrence rates following catheter-based radiofrequency ablation. We assessed the accuracy of unipolar morphological patterns and mapping surface indices to predict the site and depth of ventricular arrhythmogenic focal sources. METHODS: An experimental beating-heart model used Langendorff-perfused, healthy swine hearts. A custom 56-pole electrode array catheter was positioned on the left ventricle. A plunge needle was placed perpendicular in the center of the grid to simulate arrhythmic foci at variable depths. Unipolar electrograms and local activation times were generated. Simulation models from 2 human hearts were also included with grids positioned simultaneously on the endocardium-epicardium from multiple left ventricular, septal, and outflow tract sites. RESULTS: A unipolar Q or QS complex lacks specificity for superficial arrhythmic foci, as this morphology pattern occupies a large surface area and is the predominant pattern as intramural depth increases without developing a R component. There is progressive displacement from the arrhythmic focus to the surface exit as intramural focus depth increases. A shorter total activation time over the overlying electrode array, larger surface area within initial 20 ms activation, and a dual surface breakout pattern all indicate a deep focus. CONCLUSIONS: Displacement from the focal intramural origin to the exit site on the mapping surface could lead to erroneous lesion delivery strategies. Traditional unipolar electrogram features lack specificity to predict the intramural arrhythmic source; however, novel endocardial-epicardial mapping surface indices can be used to determine the depth of arrhythmic foci.

Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation.

BACKGROUND: Proarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the concomitant effects on membrane voltage dynamics have not been evaluated yet. METHODS: After baseline optical mapping, Langendorff-perfused rabbit hearts treated with azumolene, or vehicle, were subjected to global ischemia-reperfusion (I/R) followed by two episodes of long-duration ventricular fibrillation (LDVF). Simultaneous dual epicardial calcium transient (CaT) and voltage dynamics were studied optically. RESULTS: Pre-treatment with azumolene was associated with higher CaT amplitude alternans ratios (0.94 ± 0.02 vs. 0.78 ± 0.03 in control hearts, at 6 Hz; p = 0.005; and action potential amplitude alternans ratio (0.95 ± 0.02 vs. 0.78 ± 0.04 at 6.0 Hz; p = 0.02), and reduction of action potential duration (APD80) dispersion (9.0 ± 4.8 msec vs. 19.3 ± 6.6 msec at 6.0 Hz p = 0.02) and optical action potential upstroke rise time (26.3 ± 2.6 msec in control vs. 13.8 ± 0.6 msec at 6.0 Hz, p = 0.02) after LDVF. No change in action potential duration (APD) was noted with azumolene treatment. CONCLUSION: In a model of ischemic recurrent LDVF, treatment with azumolene led to reduction of cardiac alternans, i.e., calcium and voltage alternans. Unlike conventional anti-arrhythmic agents, reduction of action potential upstroke rise time and preservation of action potential duration following azumolene treatment may reduce the proarrhythmia risk.

Role of Purkinje-muscle junction in early ventricular fibrillation in a porcine model: Beyond the trigger concept.

BACKGROUND: The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied; however, its involvement after onset and in early maintenance of VF is controversial. AIM: We studied the role of the Purkinje-muscle junctions (PMJ) on epicardial-endocardial activation gradients during early VF. METHODS: In a healthy, porcine, beating-heart Langendorff model [control, n = 5; ablation, n = 5], simultaneous epicardial-endocardial dominant frequent mapping was used (224 unipolar electrograms) to calculate activation rate gradients during the onset and early phase of VF. Selective Purkinje ablation was performed using Lugol's solution, followed by VF re-induction and mapping and finally, histological evaluation. RESULTS: Epicardial activation rates were faster than endocardial rates for both onset and early VF. After PMJ ablation, activation rates decreased epicardially and endocardially for both onset and early VF [Epi: 9.7 ± 0.2 to 8.3 ± 0.2 Hz (p <.0001) and 10.9 ± 0.4 to 8.8 ± 0.3 Hz (p < .0001), respectively; Endo: 8.2 ± 0.3 Hz to 7.4 ± 0.2 Hz (p < .0001) and 7.0 ± 0.4 Hz to 6.6 ± 0.3 Hz (p = .0002), respectively]. In controls, epicardial-endocardial activation rate gradients during onset and early VF were 1.7 ± 0.3 Hz and 4.5 ± 0.4 Hz (p < .001), respectively. After endocardial ablation of PMJs, these gradients were reduced to 0.9 ± 0.3 Hz (onset VF, p < .001) and to 2.2 ± 0.3 Hz (early VF, p <.001). Endocardial-epicardial Purkinje fiber arborization and selective Purkinje fiber extinction after only endocardial ablation (not with epicardial ablation) was confirmed on histological analysis. CONCLUSIONS: Beyond the trigger paradigm, PMJs determine activation rate gradients during onset and during early maintenance of VF.

Exploring the role and lived experiences of people with disabilities working in the agricultural sector in northern Nigeria

It is estimated that over 75.0% of households in sub-Saharan Africa are involved in agriculture, and the majority of the poor in rural areas rely on agriculture for their livelihoods. One billion people living with disabilities in low- and middle-income countries are argued to make up the poorest of the poor, yet to our knowledge, no literature has captured the livelihood of people living with disabilities in the context of farming in Nigeria, specifically northern Nigeria where most of the households are involved in agriculture and related activities. Objectives: This article reports on findings from a study that sought to understand disability in the context of northern Nigerian farming, with a particular focus on the role and lived experiences of people living with disabilities working in the agricultural sector. Method: A survey questionnaire was developed and captured the experiences of 1067 people living with disabilities working in the agricultural sector across five states (Adamawa, Bauchi, Jigawa, Kaduna and Yobe) in northern Nigeria. Results: Findings indicate that people with disabilities are actively participating in agricultural activities for several reasons, which specifically included 'forced to and for survival'. When participants reported needing care, this was predominantly provided by family members. Findings also showed that participants with disabilities experienced several economic and sociocultural challenges because of their impairments. Conclusion: This study adds to the very limited literature on farmers living with disabilities in sub-Saharan Africa and so highlights the need for more research to be conducted with farmers living with disabilities in Nigeria, particularly female farmers living with disabilities. These will provide more evidence pertaining to the experiences of farmers living with disabilities in order to provide effective disability- and gender-inclusive agricultural and entrepreneurship programmes in Nigeria. Contribution: The results of this research reveal important insights relating to the experiences of farmers living with disabilities in northern Nigeria, which can contribute to informing future developmental projects to achieve effective inclusion and actively benefit people living with disabilities

Autologous Bone Marrow-Derived Chondrocytes for Patients with Knee Osteoarthritis: A Randomized Controlled Trial.

RESULTS: There were a total of 60 patients who were followed up. Three patients in Group II were removed from the analysis as they underwent total knee arthroplasty (TKA). A notably significant improvement was noticed in the ABMDC group on all scores of VAS and MKSSSF with P < 0.0001. The control group continued to be dissatisfied with the treatment they were taking. CONCLUSIONS: This study reveals that a single injection of 5 million of ABMDC was efficient in reducing the symptoms, improving the functional score and betterment of QOL.