Development of Epigallocatechin 3-gallate-Loaded Hydrogel Nanocomposites for Oral Submucous Fibrosis.

Oral submucous fibrosis (OSF) is a chronic progressive disease associated with increased collagen deposition and TGF-ß1 release. The current therapy and management have been a limited success due to low efficacy and adverse drug reactions. This study aimed to evaluate epigallocatechin 3-gallate (EGCG) encapsulated nanoparticles loaded mucoadhesive hydrogel nanocomposite (HNC) for OSF. Developed HNC formulations were evaluated for their permeation behaviour using in vitro as well as ex vivo studies, followed by evaluation of efficacy and safety by in vivo studies using areca nut extract-induced OSF in rats. The disease condition in OSF-induced rats was assessed by mouth-opening and biochemical markers. The optimized polymeric nanoparticles exhibited the required particle size (162.93 ± 13.81 nm), positive zeta potential (22.50 ± 2.94 mV) with better mucoadhesive strength (0.40 ± 0.002 N), and faster permeation due to interactions of the positively charged surface with the negatively charged buccal mucosal membrane. HNC significantly improved disease conditions by reducing TGF-ß1 and collagen concentration without showing toxicity and reverting the fibroid buccal mucosa to normal. Hence, the optimized formulation can be further tested to develop a clinically alternate therapeutic strategy for OSF.

Identification of potential Akt activators: a ligand and structure-based computational approach.

The Akt pathway plays a significant role in various diseases like Alzheimer's, Parkinson's, and Diabetes. Akt is the central protein whose phosphorylation controls many downstream pathways. Binding of small molecules to the PH domain of Akt facilitates its phosphorylation in the cytoplasm and upregulates the Akt pathway. In the current study, to identify Akt activators, ligand-based approaches like 2D QSAR, shape, and pharmacophore-based screening were used, followed by structure-based approaches such as docking, MM-GBSA, ADME prediction, and MD simulation. The top twenty-five molecules from the Asinex gold platinum database found to be active in most 2D QSAR models were used for shape and pharmacophore-based screening. Later docking was performed using the PH domain of Akt1 (PDB: 1UNQ), and 197105, 261126, 253878, 256085, and 123435 were selected based on docking score and interaction with key residues, which were druggable and formed a stable protein-ligand complex. MD simulations of 261126 and 123435 showed better stability and interactions with key residues. To further investigate the SAR of 261126 and 123435, derivatives were downloaded from PubChem, and structure-based approaches were employed. MD simulation of derivatives 12289533, 12785801, 83824832, 102479045, and 6972939 was performed, in which 83824832 and 12289533 showed interaction with key residues for a longer duration of time, proving that they may act as Akt activators.

Identification of phytochemical as a dual inhibitor of PI3K and mTOR: a structure-based computational approach.

Breast cancer is a common form of cancer that affects both men and women. One of the most common types of genomic flaws in cancer is the aberrations in the PI3K/AKT/mTOR pathway. The benefit of dual targeting PI3K as well as mTOR is that the kinase-positive feedback loops are more effectively inhibited. Therefore, in the current study, structure-based models like molecular docking, MM-GBSA, Qikprop, induced fit docking, simulated molecular dynamics (MD), and thermal MM-GBSA were used to identify the phytochemicals from the zinc 15 database, which may inhibit PI3K and mTOR. After docking the phytochemicals with PI3K (PDB 4FA6), ten ligands based on the docking score were selected, among which salvianolic acid C had the highest docking score. Hence, salvianolic acid A was also docked. All the ligands taken showed a binding energy of greater than - 30 kcal/mol. The predicted ADME showed that the ligands have druggable properties. By performing MD of the top five ligands and salvianolic acid A, it was found that ZINC000059728582, ZINC000257545754, ZINC000253532301, and salvianolic acid A form a stable complex with PI3K protein, among which ZINC000014690026 showed interaction with Val 882 for more than 89% of the time. Salvianolic acid A is already proven to suppress tumor growth in acute myeloid leukemia by inhibiting PI3K/AKT pathway, but the exact protein target is unknown. Therefore, the present study identifies new molecules and provides evidence for salvianolic acid A for dual inhibition. Further experiments must be performed both in vitro and in vivo to support the predictions of these computational tools.

Polyphenol-based targeted therapy for oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic, progressive, and precancerous condition mainly caused by chewing areca nut. Currently, OSF therapy includes intralesional injection of corticosteroids with limited therapeutic success in disease management. Therefore, a combined approach of in silico, in vitro and in vivo drug development can be helpful. Polyphenols are relatively safer than other synthetic counterparts. We used selected polyphenols to shortlist the most suitable compound by in silico tools. Based on the in silico results, epigallocatechin-3-gallate (EGCG), quercetin (QUR), resveratrol, and curcumin had higher affinity and stability with the selected protein targets, transforming growth factor beta-1 (TGF-ß1), and lysyl oxidase (LOX). The efficacy of selected polyphenols was studied in primary buccal mucosal fibroblasts followed by in vivo areca nut extract induced rat OSF model. In in vitro studies, the induced fibroblast cells were treated with EGCG and QUR. EGCG was safer at higher concentrations and more efficient in reducing TGF-ß1, collagen type-1A2 and type-3A1 mRNA expression than QUR. In vivo studies confirmed that the EGCG hydrogel was efficient in improving the disease conditions compared to the standard treatment betamethasone injection with significant reduction in TGF-ß1 and collagen concentrations with increase in mouth opening. EGCG can be considered as a potential, safer and efficient phytomolecule for OSF therapy and its mucoadhesive topical formulation help in the improvement of patient compliance without any side effects. Highlights Potential polyphenols were shortlisted to treat oral submucous fibrosis (OSF) using in silico tools Epigallocatechin 3-gallate (EGCG) significantly reduced TGF-ß1 and collagen both in vitro and in vivo EGCG hydrogel enhanced antioxidant defense, modulated inflammation by reducing TGF-ß1 and improved mouth opening in OSF rat model.

In Silico Screening as a Tool to Prepare Drug-Drug Cocrystals of Ibrutinib-Ketoconazole: a Strategy to Enhance Their Solubility Profiles and Oral Bioavailability.

Ibrutinib (IBR) is a biopharmaceutical classification system (BCS) class II drug and an irreversible Bruton's tyrosine kinase (BTK) inhibitor. IBR has an extremely low oral bioavailability due to the activity of the CYP3A4 enzyme. The current intention of the research was to enhance solubility followed by oral bioavailability of IBR using the hot melt extrusion (HME) technique by formulating drug-drug cocrystals (DDCs). Ketoconazole (KET) is an active CYP3A4 inhibitor and was selected based on computational studies and solubility parameter prediction. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), proton nuclear magnetic resonance (1H NMR), and scanning electron microscopy (SEM) evaluations were employed for estimating the formation of IBR-KET DDCs. The IBR-KET DDC system was discovered to have a hydrogen bond (H-bond) and π-π-stacking interactions, in accordance with the computational results. Further, IBR-KET DDCs showed enhanced solubility, stability, powder dissolution, in vitro release, and flow properties. Furthermore, IBR-KET-DDCs were associated with enhanced cytotoxic activity in K562-CCL-243 cancer cell lines when compared with IBR and KET alone. In vivo pharmacokinetic studies have shown an enhanced oral bioavailability of up to 4.30 folds of IBR and 2.31 folds of KET through IBR-KET-DDCs compared to that of the IBR and KET suspension alone. Thus, the prepared IBR-KET-DDCs using the HME technique stand as a favorable drug delivery system that augments the solubility and oral bioavailability of IBR along with KET.

Anomalous coronary artery in Tetralogy of Fallot-Feasibility of right ventricular outflow tract stenting as initial palliation.

This study addresses the outcome of right ventricle outflow tract (RVOT) stenting in Tetralogy of Fallot (ToF) with anomalous coronaries crossing the RVOT. RVOT stenting in ToF patients has emerged as an alternative to Blalock Taussig shunting. This is a single center study of patients who underwent RVOT stenting for symptomatic ToF at Birmingham Children's Hospital between 2005 and 2020. A total of 122 patients underwent RVOT stenting as initial palliation over a 15-year period, 10 patients had anomalous coronaries crossing the RVOT (study group) and 112 not (comparative group). Median age of the study group was 72.5 days (interquartile range [IQR]: 28-103) with a weight of 4.7 kg (IQR: 3.5-4.9). No significant differences were found between the two groups regarding the patients' weights and ages, procedure and screening times, or hospital stay. Four had valve sparing stenting. Oxygen saturations increased from a median of 75.5% (IQR: 70-82) to 94.5% (IQR: 90-95), p < 0.002. Postprocedure median hospital stay was 3 days (IQR: 2-6). Six patients underwent interstage catheterization reintervention and one needed early surgical palliation due to stent suboptimal position. Complete repair could be delayed for a median of 11.1 months (IQR: 5.6-19.2). At surgical repair, the patients had a median age of 12.3 months (IQR: 7.5-25.6) and weight of 7.7 kg (IQR: 6.8-10.8). There were no deaths. RVOT stenting in ToF with anomalous coronaries is safe and effective. Dilatable stents should be used when two-stage delayed conduit repair is the default approach.

Supravalvular pulmonary stenosis: A risk factor for reintervention in Noonan syndrome with pulmonary valve stenosis.

OBJECTIVES: To assess the short- and long-term outcomes of balloon pulmonary valvuloplasty (BPV) in children with Noonan syndrome (NS). BACKGROUND: Pulmonary stenosis (PS) is the most common congenital heart lesion in NS. BPV is the accepted first line treatment in PS. However, BPV in NS patients has been reported to be less effective, without specific factors for the need for reintervention being identified. METHODS: Retrospective case-note review of all patients with NS who underwent BPV between 1985 and 2020. Patients were divided into 2 groups: those with supravalvular pulmonary stenosis (SPS) in addition to valvar PS, and those with isolated valvar PS. RESULTS: A cohort of 54 patients with NS underwent BPV at a median of 275 (interquartile range [IQR]: 108-575) days of age. SPS was present in 32 (59%) patients whereas 22 had (41) isolated PS. The preprocedural invasive gradient was 47 (IQR: 35-69) mmHg, and 44 (IQR: 35-48) mmHg in those with SPS and those without respectively (p = 0.88). Reintervention was required in 22 patients (41%): 17 (77%) with SPS and 5 (23%) without (p = 0.017). Fourteen patients (11 with SPS) required surgical reintervention and 8 (6 with SPS) required further BPV. There was no significant difference in the age at initial BPV, pre- and postprocedural gradients and interval until reintervention between groups. CONCLUSION: This is the largest reported cohort of patients with NS undergoing BPV. Although BPV is often successful, the reintervention rates are high. SPS was a risk factor for reintervention.

Molecular dynamics and structure-based virtual screening and identification of natural compounds as Wnt signaling modulators: possible therapeutics for Alzheimer's disease.

Wnt signaling pathway is an evolutionarily conserved pathway responsible for neurogenesis, axon outgrowth, neuronal polarity, synapse formation, and maintenance. Downregulation of Wnt signaling has been found in patients with Alzheimer's disease (AD). Several experimental approaches to activate Wnt signaling pathway have proven to be beneficial in alleviating AD, which is one of the new therapeutic approaches for AD. The current study focuses on the computational structure-based virtual screening followed by the identification of potential phytomolecules targeting different markers of Wnt signaling like WIF1, DKK1, LRP6, GSK-3ß, and acetylcholine esterase. Initially, screening of 1924 compounds from the plant-based library of Zinc database was done for the selected five proteins using docking approach followed by MM-GBSA calculations. The top five hit molecules were identified for each protein. Based on docking score, and binding interactions, the top two hit molecules for each protein were selected as promising molecules for the molecular dynamic (MD) simulation study with the five proteins. Therefore, from this in silico based study, we report that Mangiferin could be a potential molecule targeting Wnt signaling pathway modulating the LRP6 activity, Baicalin for AChE activity, Chebulic acid for DKK1, ZINC103539689 for WIF1, and Morin for GSk-3ß protein. However, further validation of the activity is warranted based on in vivo and in vitro experiments for better understanding and strong claim. This study provides an in silico approach for the identification of modulators of the Wnt signaling pathway as a new therapeutic approach for AD.

Matrix metalloproteinase enzyme responsive delivery of 5-Fluorouracil using Collagen-I peptide functionalized Dendrimer-Gold nanocarrier.

OBJECTIVE: The aim was to develop matrix metalloproteinase 1 (MMP1) responsive nanoparticle system for the delivery of 5-fluorouracil (5Fu) anticancer drug. SIGNIFICANCE: The MMP1 in the cancer microenvironment-induced drug release have the advantage of targeted drug release and reduce the distribution of drug to the healthy tissues. METHOD: G5 poly(amidoamine) (PAMAM) dendrimer (G5)-coated gold nanoparticles (G5AuNP) were synthesized and loaded with 5Fu. The drug-loaded nanoparticles were further coated with collagen I (Col-I) peptide, which is a substrate for MMP1 enzyme (Col-I 5Fu@G5AuNP). RESULT: The nanoparticles were highly monodispersed with a particle size of 30 nm and showed high drug encapsulation efficiency. The release of drug from the nanoparticles in HEPES buffer pH 7.4 was faster, higher and better controlled when incubated with MMP1 enzyme. The half-maximum inhibitory concentration for Col-I 5Fu@G5AuNP was eight times lower than the 5Fu against MCF-7, suggesting the improved delivery and anticancer activity of 5Fu after encapsulation in the developed enzyme-responsive nanocarrier system. The computed tomography (CT) X-ray attenuation of Col-I@G5AuNP showed a good contrasting property. CONCLUSION: The formulation Col-I 5Fu@G5AuNP has improved anticancer activity than free drug and the CT imaging results are promising for its theranostic applications for breast cancer treatment.

Drug-Carrier Miscibility in Solid Dispersions of Glibenclamide and a Novel Approach to Enhance Its Solubility Using an Effervescent Agent.

The present research aims to investigate the miscibility, physical stability, solubility, and dissolution rate of a poorly water-soluble glibenclamide (GLB) in solid dispersions (SDs) with hydrophilic carriers like PEG-1500 and PEG-50 hydrogenated palm glycerides (Acconon). Mathematical theories such as Hansen solubility parameters, Flory Huggins theory, Gibbs free energy, and the in silico molecular dynamics simulation study approaches were used to predict the drug-carrier miscibility. To increase the solubility further, the effervescence technique was introduced to the conventional solid dispersions to prepare effervescent solid dispersions (ESD). Solid dispersions (SDs) were prepared by microwave, solvent evaporation, lyophilization, and hot melt extrusion (HME) techniques and tested for different characterization parameters. The theoretical and in silico parameters suggested that GLB would show good miscibility with the selected carriers under certain conditions. Intermolecular hydrogen bonding between the drug and carrier(s) was confirmed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Solid-state characterizations like powder X-ray diffraction, differential scanning calorimetry, and microscopy confirm the amorphous nature of SDs. The addition of the effervescent agent improved the amorphous nature, due to which the solubility and drug release rate was increased. In vitro and ex vivo intestinal absorption studies showed improved flux and permeability than the pure drug, suggesting an enhanced drug delivery. The GLB solubility, dissolution, and stability were greatly enhanced by the SD and ESD technology.

Structure-based docking, pharmacokinetic evaluation, and molecular dynamics-guided evaluation of traditional formulation against SARS-CoV-2 spike protein receptor bind domain and ACE2 receptor complex.

There is an urgent need for reliable cure and preventive measures in this hour of the outbreak of SARS-CoV-2. Siddha- and Ayurvedic-based classical formulations have antiviral properties and great potential therapeutic choice in this pandemic situation. In the current study, in silico-based analysis for the binding potential of phytoconstituents from the classical formulations suggested by the Ministry of Ayush (Kabasura Kudineer, Shwas Kuthar Rasa with Kantakari and pippali churna, Talisadi churna) to the interface domain of the SARS-CoV-2 receptor-binding domain and angiotensin-converting enzyme 2 was performed. Maestro software from Schrodinger and tools like Glide Docking, induced fit docking, MM-GBSA, molecular dynamics (MD) simulation, and thermal MM-GBSA was used to analyze the binding of protein PDB ID:6VW1 and the selected 133 ligands in comparison with drug molecules like favipiravir and ribavirin. QikProp-based ADMET evaluation of all the phytoconstituents found them nontoxic and with drug-like properties. Selection of top ten ligands was made based on docking score for further MM-GBSA analysis. After performing IFD of top five molecules iso-chlorogenic acid, taxiphyllin, vasicine, catechin and caffeic acid, MD simulation and thermal MM-GBSA were done. Iso-chlorogenic acid had formed more stable interaction with key residue among all phytoconstituents. Computational-based study has highlighted the potential of the many constituents of traditional medicine to interact with the SARS-CoV-2 RBD and ACE2, which might stop the viral entry into the cell. However, in vivo experiments and clinical trials are necessary for supporting this claim. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11696-021-01917-z.

Stenting of the right ventricular outflow tract as an initial intervention in Tetralogy of Fallot with pulmonary stenosis and major aortopulmonary collateral arteries.

OBJECTIVES: To assess the role of right ventricular outflow tract stenting as the primary intervention in Tetralogy of Fallot with pulmonary stenosis and major aortopulmonary collateral arteries. BACKGROUND: The management of a subset of infants with Tetralogy of Fallot with pulmonary stenosis and major aortopulmonary collateral arteries requires a staged approach including rehabilitation of diminutive native pulmonary arteries, conventionally using an aortopulmonary shunt. We share our experience of pulmonary artery rehabilitation with right ventricular outflow tract stenting. METHODS: Retrospective review of all patients with Tetralogy of Fallot with pulmonary stenosis who underwent right ventricular outflow tract stenting as primary intervention over an 8-year period. RESULTS: Ten patients underwent right ventricular outflow tract stent insertion at a median age of 61 days (interquartile range (IQR) 8.3-155 days). Median weight at stent deployment was 4.2 kg (IQR 3.2-5.7 kg). Oxygen saturations improved from a median of 79% (IQR 76-80%) to 92% (IQR 90-95%), p = 0.012. The median right and left pulmonary artery z score increased from -3.51 (IQR -4.59 to -2.80) and -2.07 (IQR -3.72 to 0.15) to a median of -1.17 (IQR -2.26 to 0.16) p < 0.05, and 0.24 (IQR -1.09 to 1.84) p < 0.05, respectively, at subsequent angiogram. Nine patients underwent further catheterisation. Four patients underwent complete anatomical repair. Only one patient required unifocalisation, as most patients had a native supply to all-important lung segments. CONCLUSION: Right ventricular outflow tract stenting is a useful procedure in the subset of patients with Tetralogy of Fallot with pulmonary stenosis and major aortopulmonary collateral arteries, where native pulmonary arterial growth is required to facilitate repair.

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity.

Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4'-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand-protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1-5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.

Structurally nanoengineered antimicrobial peptide polymers: design, synthesis and biomedical applications.

Antimicrobial resistance not only increases the contagiousness of infectious diseases but also a threat for the future as it is one of the health care concern around the globe. Conventional antibiotics are unsuccessful in combating chronic infections caused by multidrug-resistant (MDR) bacteria, therefore it is important to design and develop novel strategies to tackle this problems. Among various novel strategies, Structurally Nanoengineered Antimicrobial Peptide Polymers (SNAPPs) have been introduced in recent years to overcome this global health care issue and they are found to be more efficient in their performance. Many facile methods are adapted to synthesize complex SNAPPs with required dimensions and unique functionalities. Their unique characteristics and remarkable properties have been exploited for their immense applications in various fields including biomedicine, targeting therapies, gene delivery, bioimaging, and many more. This review article deals with its background, design, synthesis, mechanism of action, and wider applications in various fields of SNAPPs.

Short to medium term outcomes of right ventricular outflow tract stenting as initial palliation for symptomatic infants with complete atrioventricular septal defect with associated tetralogy of Fallot.

OBJECTIVES: To assess the impact of right ventricular outflow tract (RVOT) stenting as the primary palliation in infants with complete atrioventricular septal defect with associated tetralogy of Fallot (cAVSD/TOF). BACKGROUND: Historically, palliation of symptomatic patients with cAVSD/TOF has been achieved through surgical systemic to pulmonary artery shunting. More recently RVOT stenting has evolved as an acceptable alternative in patients with tetralogy of Fallot. METHODS: Retrospective review of all patients with cAVSD/TOF who underwent RVOT stenting as palliation over a 13-year period from two large tertiary referral centers. RESULTS: Twenty-six patients underwent RVOT stenting at a median age of 57 days (interquartile range [IQR] 25.5-106.5). Median weight for stent deployment was 3.7 kg (IQR 2.91-5.5 kg). RVOT stenting improved oxygen saturations from a median of 72% (IQR 70-76%) to 90% (IQR 84-92%), p < .001. There was a significant increase in the median Z-score for both branch pulmonary arteries at median follow-up of 255 days (IQR 60-455). Eight patients required RVOT stent balloon dilatations and 8 patients required re-stenting for progressive desaturation. The median duration between reinterventions was 122 days (IQR 53-294 days). Four patients died during the follow-up period. No deaths resulted from the initial intervention. To date, definitive surgical intervention was achieved in 19 patients (biventricular repair n = 15) at a median age of 369 days (IQR 223-546 days). CONCLUSION: RVOT stenting in cAVSD/TOF is a safe and effective palliative procedure in symptomatic infants, promoting pulmonary artery growth and improving oxygen saturations.

Antimicrobial peptide polymers: no escape to ESKAPE pathogens-a review.

Antimicrobial resistance (AMR) is one of the significant clinical challenges and also an emerging area of concern arising from nosocomial infections of ESKAPE pathogens, which has been on the rise in both the developed and developing countries alike. These pathogens/superbugs can undergo rapid mutagenesis, which helps them to generate resistance against antimicrobials in addition to the patient's non-adherence to the antibiotic regimen. Sticking to the idea of a 'one-size-fits-all' approach has led to the inappropriate administration of antibiotics resulting in augmentation of antimicrobial resistance. Antimicrobial peptides (AMPs) are the natural host defense peptides that have gained attention in the field of AMR, and recently, synthetic AMPs are well studied to overcome the drawbacks of natural counterparts. This review deals with the novel techniques utilizing the bacteriolytic activity of natural AMPs. The effective localization of these peptides onto the negatively charged bacterial surface by using nanocarriers and structurally nanoengineered antimicrobial peptide polymers (SNAPPs) owing to its smaller size and better antimicrobial activity is also described here.

Stenting and overdilating small Gore-Tex vascular grafts in complex congenital heart disease.

BACKGROUND: Gore-Tex® grafts are integral in the management of congenital heart disease. Issues of graft stenosis or somatic outgrowth may precipitate high-risk early surgery, and catheter intervention is a relatively under-reported management option. OBJECTIVES: To assess efficacy, safety, and outcomes of stenting and overdilating small Gore-Tex® vascular grafts with the aim of optimizing surgical timing. METHODS: Retrospective analysis of single-center, 13-year experience of 93 graft stenting interventions or reintervention in 80 patients, with the aim of relieving stenosis ± overdilation, to depose surgical graft revision or optimize surgical timing and candidacy. RESULTS: Median preintervention graft diameter was 52% (IQR 43-63) of nominal size, postintervention this increased to median 102% (IQR 96-120) [P < 0.001]. Overdilation was achieved in 54%; of these, the median final internal lumen was 126% (IQR 113-132) [P < 0.001]. Mean oxygen saturations increased from 69% to 82% [P < 0.001]. Adverse event rate was 14.9%; this includes mortality (3.2%) and atrioventricular conduction block (8.5%). Univariate analysis and logistic regression showed a significant relationship between adverse events and young age [P < 0.01], low weight [P < 0.01], univentricular physiology [P < 0.001], use of femoral venous access alone [P = 0.03], and intervention on a right ventricle to pulmonary artery conduit [P = 0.03]. Within respective indication groups, 74% were bridged to elective cavopulmonary shunt, 95% were bridged to biventricular surgery, and 78% of long-term palliative care patients continue under follow-up. CONCLUSIONS: Gore-Tex® vascular grafts can be stented effectively and expanded beyond nominal diameters by around +26%. This improves oxygen saturations, providing excellent palliation and optimized surgical timing. Adverse events are most frequent in precavopulmonary shunt patients. CONDENSED ABSTRACT: Gore-Tex® grafts are widely used in the palliation of cyanotic congenital heart disease. Grafts may become stenosed and do not allow for somatic growth. Over a 13 year period, graft stenting was performed in 80 patients (93 technically successful interventions, 4 unsuccessful.) Median internal lumen change was +50% (of nominal graft size), mean oxygen saturation change +13%. Over-dilation was performed in more than half of the cohort, with a median gain of +26% on nominal graft size. In precavopulmonary shunt patients, there was a moderate incidence of serious complications. Clinically useful deferral of surgery was achieved for the majority.

Localized In Situ Nanoemulgel Drug Delivery System of Quercetin for Periodontitis: Development and Computational Simulations.

This study was aimed at formulating a bioabsorbable, controlled-release, nanoemulgel of Quercetin, a potent antimicrobial and anti-inflammatory agent for the treatment of periodontitis that could improve its solubility and bioavailability. Screening of components was carried out based on the solubility studies. Nanoemulsion containing cinnamon oil as the oil phase, tween 80 and Carbitol® as the surfactant-cosurfactant mixture (Smix) and water as the aqueous phase containing 125 µg/200 µL of Quercetin was prepared by using spontaneous emulsification method. Nanoemulgel was prepared using 23% w/v poloxamer 407 as gel base. Comprehensive evaluation of the formulated nanoemulgel was carried out, and the optimized formulation was studied for drug release using Franz vertical diffusion cells. The formulated nanoemulgelexhibited a remarkable release of 92.4% of Quercetin at the end of 6 h, as compared to that of pure Quercetin-loaded gel (<3% release). The viscosity of the prepared nanoemulgel was found to be 30,647 ± 0.32 cPs at 37 °C. Also, molecular dynamics (MD) simulation was utilized to understand the gelation process and role of each component in the formulation. The present study revealed that the developed nanoemulgel of Quercetin could be a potential delivery system for clinical testing in periodontitis.

Outcome after transcatheter occlusion of patent ductus arteriosus in infants less than 6 kg: A national study from United Kingdom and Ireland.

OBJECTIVES: This study aimed to report our national experience with transcatheter patent ductus arteriosus (PDA) occlusion in infants weighing <6 kg. BACKGROUND: The technique of transcatheter PDA closure has evolved in the past two decades and is increasingly used in smaller patients but data on safety and efficacy are limited. METHODS: Patients weighing < 6 kg in whom transcatheter PDA occlusion was attempted in 13 tertiary paediatric cardiology units in the United Kingdom and Ireland were retrospectively analyzed to review the outcome and complications. RESULTS: A total of 408 patients underwent attempted transcatheter PDA closure between January 2004 and December 2014. The mean weight at catheterization was 4.9 ± 1.0 kg and mean age was 5.7 ± 3.0 months. Successful device implantation was achieved in 374 (92%) patients without major complication and of these, complete occlusion was achieved in 356 (95%) patients at last available follow-up. Device embolization occurred in 20 cases (5%). The incidence of device related obstruction to the left pulmonary artery or aorta and access related peripheral vascular injury were low. There were no deaths related to the procedure. CONCLUSIONS: Transcatheter closure of PDA can be accomplished in selected infants weighing <6 kg despite the manufacturer's recommended weight limit of 6 kg for most ductal occluders. The embolization rate is higher than previously reported in larger patients. Retrievability of the occluder and duct morphology needs careful consideration before deciding whether surgical ligation or transcatheter therapy is the better treatment option.