Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing.

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

A Highly Selective Pyrene Appended Oxacalixarene Receptor for MNA and 4-NP Detection: an Experimental and Computational Study.

A novel pyrene-substituted oxacalixarene was designed and synthesized as a selective probe for the simultaneous detection of MNA and 4-NP. Utilizing 1H-NMR, 13C-NMR, and FT-IR analysis techniques, its structure was characterized. The binding property of BPOC to a variety of NACs, including 1,3-DNB, 2,3-DNT, 2,4-DNT, 2,6-DNT, 4-NP, 4-NT, and PA, revealed that the sensor binds to MNA and 4-NP with remarkable selectivity. Binding constant reveals lower detection limits of MNA is 0.2 µM and 0.3 µM for 4-NP. Using docking and density functional theory (DFT), computational insights were provided for investigating the stability and spectroscopic analysis of the inclusion complex. From molecular docking study, we observed the best docking score of BPOC with 4-NT and MNA complex. The calculations supplement the findings significantly and clarify the structural geometry and mode of interactions in supramolecular complexation. In an MTT experiment on human PBMC to check for cytotoxicity, this chemical was found to influence 1 × 105 cell viability dose-dependently.

Procedural and short-term results of electroanatomic-mapping-guided ganglionated plexus ablation by first-time operators: A multicenter study.

INTRODUCTION: Single-center observational studies have shown promising results with fragmented electrogram (FE)-guided ganglionated plexus (GP) ablation in patients with vagally mediated bradyarrhythmia (VMB). We aimed to compare the acute procedural characteristics during FE-guided GP ablation in patients with VMB performed by first-time operators and those of a single high-volume operator. METHODS AND RESULTS: This international multicenter cohort study included data collected over 2 years from 16 cardiac hospitals. The primary operators were classified according to their prior GP ablation experience: a single high-volume operator who had performed > 50 GP ablation procedures (Group 1), and operators performing their first GP ablation cases (Group 2). Acute procedural characteristics and syncope recurrence were compared between groups. Forty-seven consecutive patients with VMB who underwent FE-guided GP ablation were enrolled, n = 31 in Group 1 and n = 16 in Group 2. The mean number of ablation points in each GP was comparable between groups. The ratio of positive vagal response during ablation on the left superior GP was higher in Group 1 (90.3% vs. 62.5%, p = .022). Ablation of the right superior GP increased heart rate acutely without any vagal response in 45 (95.7%) cases. The procedure time was longer in group 2 (83.4 ± 21 vs. 118.0 ± 21 min, respectively, p < .001). Over a mean follow-up duration of 8.0 ± 3 months (range 2-24 months), none of the patients suffered from syncope. CONCLUSION: This multi-center pilot study shows for the first time the feasibility of FE-guided GP ablation across a large group of procedure-naïve operators.

Synthetic and Medicinal Perspective of 1,2,4-Triazole as Anticancer Agents.

Cancer is still one of the leading causes of death worldwide. Many researchers are working to design and develop heterocyclic-based drugs with the potential to treat cancer at various stages. There is always an unmet need to discover new anticancer drugs to treat different types of cancer. Based on literature reports, it was evident that hybrid 1,2,4-triazoles exhibit a wide spectrum of biological potential (particularly potent anticancer activity), as compared to the corresponding monocyclic compounds. In this review, we summarized fused/hybrid 1,2,4-triazole and poly-functionalized 1,2,4-triazoles as anticancer agents. Triazole may be fused with other heterocyclic scaffolds like pyrimidine, pyridine, piperidine, quinoxaline, quinazoline, thiadiazine, indole, phthalazine etc. A clear explanation of the method of synthesis, structure-activity relationship, and in vitro results plus the inhibitory concentration of new molecules are focused on in this review article.

Assessment of prevalence and characteristics of asthma-COPD overlap among patients with chronic airflow obstruction.

Given the paucity of research on asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) and the high prevalence of co-morbidities and healthcare utilization associated with it, the current study looked at the prevalence of ACO and its clinico-radiological phenotype in patients with chronic airflow obstruction. The study was conducted at a tertiary care hospital in North India. Patients over 40 with COPD or asthma were screened for inclusion in the ACO, asthma, and COPD groups. The ACO and COPD groups were further investigated. The clinical characteristics, lung functions, health-related quality of life, and radiological features of both groups were investigated and compared. ACO was discovered in 16.3% of patients with chronic airflow obstruction (asthma and COPD). The most commonly observed symptoms at presentation in the evaluated ACO patients (n=77) were shortness of breath, wheezing, cough, and expectoration (mean age at presentation: 57.9; mean duration of illness: 8.62 years). Exacerbation rates in ACO patients were significantly higher than in COPD patients (p<0.001). The ACO group had a significantly greater mean change in FEV1 post-bronchodilator in millilitres (ml) and percentage (379.61 ml and 37.72%) than the COPD group (p<0.001). The proportion of patients with emphysema was lower in the ACO group than in the COPD group (p<0.001). The ACO and COPD groups did not differ significantly in major airway wall thickness (p=0.3), but the COPD group had a significantly higher proportion of patients with vascular attenuation and distortion (p<0.001). Patients with COPD had a higher degree of hyperinflation, according to high resolution computed tomography (HRCT) indices. This study found that patients with ACO have a distinct phenotype in terms of clinical presentation and HRCT features. More research on the radiological features of ACO is required to identify the anatomical abnormalities involved in the disease's pathogenesis and to validate the radiological features of ACO.

Utilization of Chlorella pyrenoidosa for Remediation of Common Effluent Treatment Plant Wastewater in Coupling with Co-relational Study: An Experimental Approach.

Earlier investigations on biological methods of wastewater treatment have revealed that algal based wastewater treatment could be a green, cost effective and efficient approach for the removal of heavy metals. So, this study aimed to assess the potential of microalga Chlorella pyrenoidosa for remediation of heavy metals (Cr, Cu, Pb, Zn, Cd, Mn, and Ni) from varying concentration (25%, 50%, 75 and 100%) of wastewater collected from Common Effluent Treatment Plant. Heavy metals such as Cr, Cu, Pb, Zn, Cd, Mn, and Ni have been removed significantly from the wastewater, with percentage removal ranging from 73%, 60%, 75%, 66%, 87%, 83%, and 74% with 50% test solution, 57%, 59%, 70%, 56%, 72%, 66%, and 62% with 75% test solution, and 47%, 55%, 56%, 71%, 61%, 77%, and 72% with 100% test solution respectively. Studies on biochemical assay (protein, carbohydrate, and pigment) of Chlorella pyrenoidosa were also an important part of the present investigation to understand the interaction of heavy metals with algal biochemical compounds using Pearson correlation co-efficient. Biomass grown in CETP wastewater can be used for synthesis of various fruitful value-added end products like bio-diesel, pharmaceutical products, cosmetic products, bio-adsorbent etc.

Microtubule associated proteins as targets for anticancer drug development.

The dynamic equilibrium of tubulin-microtubule is an essential aspect of cell survivality. Modulation of this dynamics has become an important target for the cancer drug development. Tubulin exists in the alpha-beta dimer form which polymerizes to form microtubule and further depolymerizes back to tubulin dimer. The microtubule plays an essential role in mitosis and cell multiplication. Antitubulin drugs disturb the microtubule dynamics which is essentially required for DNA segregation and cell division during mitosis so killing the cancerous cells. Microtubule Associated Proteins (MAPs) interact with cellular cytoskeletal microtubules. MAPs bind to the either polymerized or depolymerized tubulin dimers within the cell and mostly causing stabilization of microtubules. Some of the tubulin binding drugs are in clinical use and others in clinical trial. MAPs inhibitors are also in clinical trial. Post-translational modification of lysine-40 either in histone or in alpha tubulin has an important role in gene expression and is balanced between histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDAC inhibitors have the anticancer properties to form a drug for the treatment of cancer. They act by inducing cell cycle arrest and cell death. Some of the HDAC inhibitors are approved to be used as anticancer drug while others are under different phases of clinical trial. The present review updates on various MAPs, their role in cancer progression, MAPs inhibitors and their future prospects.

Midterm clinical and radiologic survivorship of a stemless total shoulder arthroplasty.

AIM: The aim of this study was to evaluate the clinical and radiologic outcomes of stemless total shoulder arthroplasty (TSA) in patients with glenohumeral arthritis. PATIENTS AND METHODS: This is a retrospective case series of all patients who underwent a TSA with Affinis Short prosthesis during the period 2010-2017. Seventy-two TSAs were performed within our unit, in 62 patients (45 females and 17 males), with 10 patients having bilateral TSAs with this prosthesis. The mean follow-up was 3.9 years (2-8.7 years). Patients were evaluated clinically with the Oxford Shoulder Score, range of movement assessment, and a numerical patient satisfaction score. Follow-up radiographs were evaluated by 2 reviewers assessing for lucency and assigned a Lazarus grade. RESULTS: Six patients were lost to follow-up prior to their 2-year review. At last follow-up, the mean forward elevation was 157° (80°-180°), abduction was 150° (60°-180°), and external rotation was 39° (20°-60°). The mode internal rotation was to the lumbar spine, with 95% of patients achieving internal rotation to L5 or higher. The mean Oxford Shoulder Score was 45 (18-48). The mean patient satisfaction score was 4.93/5. No humeral lucencies were observed. Sixty-four percent (n=47) of the glenoids were Lazarus grade 0, showing no evidence of radiolucency. The remaining patients were Lazarus grade 1-3, although none were progressive and all patients were asymptomatic. No patients were revised for aseptic loosening. Four patients underwent revision: 1 for infection, 1 for heterotrophic ossification and stiffness, and 2 for rotator cuff failure. CONCLUSION: Midterm follow-up results indicate good clinical and radiologic survivorship for this stemless TSA. Our findings suggest good patient function and satisfaction, and no patients have required revision for aseptic loosening. Further follow-up is required to determine long-term survivorship.

Structural and clinical impact of anti-allergy agents: An overview.

Allergic disorders are markedly rising in industrialized countries. The identification of compounds that trigger the immunoglobulin E (IgE)-dependent allergic reaction remain the means to improve the quality of life by limiting patient's exposure to critical allergens. Information concerning the treatment and onset of allergic disorders including atopic dermatitis, allergic rhinitis, and bronchial asthma has been provided by the research over the past decade. Recent studies also indicated that allergic inflammation is associated closely with their exacerbation and progression and indeed is the basic pathophysiology of allergic diseases. As a result of immunological and molecular biological studies our understanding of the mechanism of allergic inflammation with regard to therapeutic agents has improved. While much effort has been paid to developing a new anti-allergic agent, the allergic disease has yet to be completely conquered. The more extensive research will allow the development of new therapeutics to combat allergic diseases. Currently, with respect to mechanism of action anti-allergy drugs are classified into five types including histamine H1 antagonists, leukotriene antagonists, Th2 cytokine inhibitors, thromboxane A2 inhibitors and mediator-release inhibitors. The use of two or more anti-allergy agents together is not acknowledged at present, but this will be the subject of research in the future because with different mechanisms of action anti-allergy agents used at the same time will theoretically increase their effects. This review article focuses on anti-allergy agents highlighting their applications, clinical trials and recent advancement on drugs.

Recent synthetic and medicinal perspectives of tryptanthrin.

Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.

Synthetic and medicinal perspective of thiazolidinones: A review.

In the modern scenario, thiazolidinone scaffold has emerged as a very potent scaffold as per its clinical significance concerned. It has attracted the keen interest of the researchers due to its great diversity in biological activities. Thiazolidinones are the saturated form of thiazole, called thiazolidine with a carbonyl group. The 1,3-thiazolidin-4-ones possess wide range of pharmacological activities such as anti-cancer, anti-diabetic, anti-microbial, anti-viral, anti-inflammatory and anti-convulsant. In the past few years, various newer synthetic approaches have been designed to synthesize diverse scaffolds to explore the various types of biological activities. In this review, an attempt has been made by the authors to summarize various synthetic strategies for thiazolidinone derivatives as well as their biological significance.

Water-Promoted Regiospecific Azidolysis and Copper-Catalyzed Azide-Alkyne Cycloaddition: One-Pot Synthesis of 3-Hydroxy-1-alkyl-3-[(4-aryl/alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-ones.

An efficient, eco-friendly, base free, one-pot, sequential protocol was developed for epoxide azidolysis and copper-catalyzed azide-alkyne cycloaddition using water as the solvent for the synthesis of 3-hydroxy-1-alkyl-3-[(4-aryl/alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-ones. The optimized reaction conditions have been generalized in the case of aromatic as well as aliphatic alkyne partners to afford good yields and high regioselectivity.

Vermiremediation of heavy metals in wastewater sludge from paper and pulp industry using earthworm Eisenia fetida.

This work presents the results of removing heavy metals from paper mill wastewater (PMS) sludge spiked with cow dung (CD) employing Eisenia fetida. A total of seven set-ups were prepared: CD (100 percent), PMS: CD (1:3), PMS:CD (1:2), PMS:CD (1:1), PMS (100 percent), PMS:CD (3:1) and PMS:CD (2:1) and changes in chemical parameters were observed for 60 days. Vermistabilization caused the significant decrease in the level of Cd (32-37 percent), Cr (47.3-80.9 percent), Cu (68.8-88.4 percent), and Pb (95.3-97.5 percent) and substantial increase in EC, total-N, available P and K at the end. At the end, the tissues of inoculated worms showed the high load (mg kg(-1), dry biomass) of Pb (8.81-9.69), Cd (2.31-2.71), Cr (20.7-35.9) and Cu (9.94-11.6), respectively which indicated bioaccumulation of metals by worms. The PMS:CD (2:1 and/or 3:1) appeared to be suitable waste mixture in terms of high metal removal and earthworm growth rates. Bioaccumulation, as quantified using BCF, was in the order: Cd>Cr>Pb>Cu. Results suggested vermiremediation as appropriate technology for bioremediation of heavy metals from PMS.

Synthetic and Clinical Perspectives of Evotaz: An Overview.

Viruses cause a variety of diseases in the human body. Antiviral agents are used to prevent the production of disease-causing viruses. These agents obstruct and kill the virus's translation and replication. Because viruses share the metabolic processes of the majority of host cells, finding targeted medicines for the virus is difficult. In the ongoing search for better antiviral agents, the USFDA approved EVOTAZ, a new drug discovered for the treatment of Human Immunodeficiency Virus (HIV). It is a once-daily (OD) fixed-dose combination of Cobicistat, a cytochrome P450 (CYP) enzyme inhibitor, and Atazanavir, a protease inhibitor. The combination drug was created in such a way that it can inhibit both CYP enzymes and proteases at the same time, resulting in the virus's death. The drug is not effective in children under the age of 18; however, it is still being studied for various parameters. This review article focuses on EVOTAZ's preclinical and clinical aspects, as well as its efficacy and safety profiles.

A sustainable strategic approach for N-alkylation of amines with activation of alcohols triggered via a hydrogen auto-transfer reaction using a Pd(II) complex: evidence for metal-ligand cooperativity.

This work describes a new well-defined, air-stable, phosphine free palladium(II) [Pd(L)Cl] (1) catalyst. This catalyst was utilized for N-alkylation of amines and indole synthesis where H2O was found to be the by-product. A broad range of aromatic amines were alkylated using this homogeneous catalyst with a catalyst loading of 0.1 mol%. Greener aromatic and aliphatic primary alcohols were utilized and a hydrogen auto-transfer strategy via a metal-ligand cooperative approach was investigated. The precursor of the antihistamine-containing drug molecule tripelennamine was synthesized on a gram scale for large-scale applicability of the current synthetic methodology. A number of control experiments were performed to investigate the possible reaction pathway and the outcomes of these experiments indicated the azo-chromophore as a hydrogen reservoir during the catalytic cycle.

Cardioneuroablation for the management of patients with recurrent vasovagal syncope and symptomatic bradyarrhythmias: the CNA-FWRD Registry.

BACKGROUND: Cardioneuroablation has been emerging as a potential treatment alternative in appropriately selected patients with cardioinhibitory vasovagal syncope (VVS) and functional AV block (AVB). However the majority of available evidence has been derived from retrospective cohort studies performed by experienced operators. METHODS: The Cardioneuroablation for the Management of Patients with Recurrent Vasovagal Syncope and Symptomatic Bradyarrhythmias (CNA-FWRD) Registry is a multicenter prospective registry with cross-over design evaluating acute and long-term outcomes of VVS and AVB patients treated by conservative therapy and CNA. RESULTS: The study is a prospective observational registry with cross-over design for analysis of outcomes between a control group (i.e., behavioral and medical therapy only) and intervention group (Cardioneuroablation). Primary and secondary outcomes will only be assessed after enrollment in the registry. The follow-up period will be 3 years after enrollment. CONCLUSIONS: There remains a lack of prospective multicentered data for long-term outcomes comparing conservative therapy to radiofrequency CNA procedures particularly for key outcomes including recurrence of syncope, AV block, durable impact of disruption of the autonomic nervous system, and long-term complications after CNA. The CNA-FWRD registry has the potential to help fill this information gap.

Mechanisms of ranolazine's dual protection against atrial and ventricular fibrillation.

Coronary artery disease and heart failure carry concurrent risk for atrial fibrillation and life-threatening ventricular arrhythmias. We review evidence indicating that at therapeutic concentrations, ranolazine has potential for dual suppression of these arrhythmias. Mechanisms and clinical implications are discussed.

Antiarrhythmic drugs 2013: state of the art.

Antiarrhythmic drugs are widely used, but are of modest efficacy and have important side effects. However, even with the advance of catheter ablation for atrial fibrillation and ventricular tachycardia, antiarrhythmic drugs remain an important tool for treating arrhythmias. Antiarrhythmic drug development has remained slow despite much effort given our limited understanding of what role various ionic currents play in arrhythmogenesis and how they are modified by arrhythmias. This review will focus on promising new antiarrhythmic drugs undergoing clinical investigation or currently approved for clinical use, including amiodarone analogues, agents with novel ionic targets, and new drug combinations.