SOLID LIPID NANOPARTICLES AND NANOSTRUCTURED LIPID CARRIERS OF TOLNAFTATE: DESIGN, OPTIMIZATION AND IN-VITRO EVALUATION

Objective: The target of our work is the preparation of tolnaftate (TOL) loaded solid lipid nanoparticles (SLNs) as well as nanostructured lipid carriers (NLCs).Methods: The high shear homogenization method was chosen for the preparation of nanoparticles. The nanoparticle dispersions were prepared using Compritol 888ATO, Tefose 63, Miglyol® 812, Poloxamer188, and Tween80. Particle size (PS), zeta potential (ZP), polydispersity index (PDI), drug entrapment efficiency (EE) and in vitro release study were determined. Differential Scanning Calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. A stability study for 3 mo was performed.Results: The results revealed that NLC and SLN dispersions had spherical shapes with an average size between 41.10±1.92 nm and 98.85±1.01 nm. High entrapment efficiency was obtained with negatively charged zeta potential with PDI value ranging from 0.251±0.012 to 0.759±0.028. The release profiles of all formulations were characterized by a sustained release behavior over 24 h and the release rates increased as the amount of liquid lipid in lipid core increased. Tolnaftate loaded NLC showed more stability than its corresponding SLN.Conclusion: It can be fulfilled from this work that NLCs may represent a promising carrier for tolnaftate delivery offering both sustained release and stability.Â

Nanolipogel Loaded with Tea Tree Oil for the Management of Burn: GC-MS Analysis, In Vitro and In Vivo Evaluation

The GC-MS analysis of tea tree oil (TTO) revealed 38 volatile components with sesquiterpene hydrocarbons (43.56%) and alcohols (41.03%) as major detected classes. TTO efficacy is masked by its hydrophobicity; nanoencapsulation can address this drawback. The results showed that TTO-loaded solid lipid nanoparticles (SLN1), composed of glyceryl monostearate (2% w/w) and Poloxamer188 (5% w/w), was spherical in shape with a core-shell microstructure. TTO-SLN1 showed a high entrapment efficiency (96.26 ± 2.3%), small particle size (235.0 ± 20.4 nm), low polydispersity index (0.31 ± 0.01), and high negative Zeta potential (−32 mV). Moreover, it exhibited a faster active agent release (almost complete within 4 h) compared to other formulated TTO-SLNs as well as the plain oil. TTO-SLN1 was then incorporated into cellulose nanofibers gel, isolated from sugarcane bagasse, to form the ‘TTO-loaded nanolipogel’ which had a shear-thinning behavior. Second-degree thermal injuries were induced in Wistar rats, then the burned skin areas were treated daily for 7 days with the TTO-loaded nanolipogel compared to the unmedicated nanolipogel, the TTO-loaded conventional gel, and the normal saline (control). The measurement of burn contraction proved that TTO-loaded nanolipogel exhibited a significantly accelerated skin healing, this was confirmed by histopathological examination as well as quantitative assessment of inflammatory infiltrate. This study highlighted the success of the proposed nanotechnology approach in improving the efficacy of TTO used for the repair of skin damage induced by burns

EFFECT OF METHYL-Î’-CYCLODEXTRIN COMPLEXATION ON THE HYPOGLYCEMIC AND HYPOLIPIDEMIC EFFECTS OF KHELLIN: EXPERIMENTAL STUDY

Objective: The present work tackled the development and evaluation of inclusion complex of khellin (KH) and methyl-β-cyclodextrin (MβCD). In addition, it tested its possible hypoglycemic and hypolipidemic effects.Methods: Inclusion complexes of KH-MβCD in the presence of water-soluble polymer were prepared by freeze drying (FD), co-evaporation (EV) and kneading methods (KN). The selected ternary complex was characterized by Fourier transform infrared spectrophotometry (FTIR), x-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy [1]. Assessment of the hypoglycemic effect of the selected ternary complex versus the standard drug metformin was studied. Two different doses of the ternary complex were administered orally to streptozotocin (STZ)-induced type 2diabetic rats. Their hypoglycemic and hypolipidemic effects were evaluated by measuring the fasting blood glucose level (BGL), total cholesterol (TC) and triglycerides levels (TG) along the study period.Results: The FD complex showed the highest drug dissolution rate. All the performed characterization analysis confirmed the formation of a KH-MβCD inclusion complex. The in vivo study declared that both doses showed a marked hypoglycemic and hypolipidemic effects compared to metformin.Conclusion: In conclusion, this study points for the first time that the complexation of KH with MβCD could notably improve the dissolution rate and hence the bioavailability of KH. Moreover, this study demonstrated that this compound has a hypoglycemic and hypolipidemic effect. Thus, it can be a promising natural supportive treatment in type 2 diabetes mellitus (T2DM).Â

Contribution of coagulation factor VII R353Q polymorphism to the risk of thrombotic disorders development (venous and arterial): A case-control study

Background: Elevated factor VII (FVII) level is a risk factor for thromboembolic disorders. It was reported that the FVII R353Q polymorphism is associated with variation in plasma FVII levels, where Q allele carriers were more associated with lower levels of FVII than R allele carriers. However, the association between coagulation FVII R353 Q polymorphisms and the risk of thrombosis is uncertain.Aim of the study: Is to investigate the contribution of factor VII R353Q gene polymorphism to the risk of thrombotic disorders development (venous and arterial) in a group of Egyptian patients.Subjects and methods: This study was conducted on 310 subjects: 110 acute myocardial infarction (AMI) patients, 108 deep venous thrombosis (DVT) patients and 92 healthy controls. FVII R353Q genotypes were assessed using restriction fragment length polymorphism analysis.Results: There were no statistically significant differences in the frequency of FVII R353Q polymorphism between each of the AMI and DVT patients and the control group (P = 0.9, 0.1). However the Q allele showed a significantly higher frequency in the AMI group (15.4%) vs. controls (8.7%) (OR: 1.92; 95% CI: 0.98–3.7). Bivariate analysis demonstrated no significant association between FVII R353Q genotypes and different studied risk factors, neither in arterial nor venous thrombosis.Conclusion: FVII R353Q polymorphism did not contribute to an increased risk of thrombosis (arterial and venous); also carrying the Q allele (of R353Q) did not confer protection against acute thrombotic events

Serum interferon-alpha level in first degree relatives of systemic lupus erythematosus patients: Correlation with autoantibodies titers

AbstractBackground and objectivesInterferon-α (IFN-α), a cytokine with both antiviral and immune-regulatory functions, was suggested as a useful tool which can evaluate current systemic lupus erythematosus (SLE) disease activity and identify patients who are at risk of future disease flares. In the current study, serum IFN-α levels and associated demographic, and serological features in Egyptian SLE patients and their first degree relatives (FDRs) in comparison to unrelated healthy controls (UHCs) were examined, in order to identify individuals at the greatest risk for clinical illness.MethodsIn a cross-sectional study, blood samples were drawn from 54 SLE patients, 93 of their FDRs who consented to enroll into the study and 76 UHCs. Measurement of serum IFN-α by a modified ELISA was carried out. Data were analyzed for associations of serum IFN-α levels with autoantibodies titer.ResultsMean serum IFN-α in FDRs was statistically higher than the UHCs and lower than in SLE patients (P<0.0001) and it was correlated with ANA titer (r=0.6, P<0.0001) and anti ds DNA titer (r=0.62, P<0.0001).ConclusionIFN-α is a crucial player in the complicated autoimmune changes that occur in SLE and serum IFN-α can be a useful marker identifying persons who are at risk of future disease development

Exascale Deep Learning to Accelerate Cancer Research

Deep learning, through the use of neural networks, has demonstrated remarkable ability to automate many routine tasks when presented with sufficient data for training. The neural network architecture (e.g. number of layers, types of layers, connections between layers, etc.) plays a critical role in determining what, if anything, the neural network is able to learn from the training data. The trend for neural network architectures, especially those trained on ImageNet, has been to grow ever deeper and more complex. The result has been ever increasing accuracy on benchmark datasets with the cost of increased computational demands. In this paper we demonstrate that neural network architectures can be automatically generated, tailored for a specific application, with dual objectives: accuracy of prediction and speed of prediction. Using MENNDL--an HPC-enabled software stack for neural architecture search--we generate a neural network with comparable accuracy to state-of-the-art networks on a cancer pathology dataset that is also $16\times$ faster at inference. The speedup in inference is necessary because of the volume and velocity of cancer pathology data; specifically, the previous state-of-the-art networks are too slow for individual researchers without access to HPC systems to keep pace with the rate of data generation. Our new model enables researchers with modest computational resources to analyze newly generated data faster than it is collected.Comment: Submitted to IEEE Big Dat

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia

The combination of cytotoxic treatment with strategies for immune activation represents an attractive strategy for tumour therapy. Following reduction of high tumour burden by effective cytotoxic agents, two major immune-stimulating approaches are being pursued. First, innate immunity can be activated by monoclonal antibodies triggering antibody-dependent cellular cytotoxicity. Second, tumour-specific T cell responses can be generated by immunization of patients with peptides derived from tumour antigens and infused in soluble form or loaded onto dendritic cells. The choice of cytotoxic agents for such combinatory regimens is crucial since most substances such as fludarabine are considered immunosuppressive while others such as cyclophosphamide can have immunostimulatory activity. We tested in this study whether fludarabine and/or cyclophosphamide, which represent a very effective treatment regimen for chronic lymphocytic leukaemia, would interfere with a therapeutic strategy of T cell activation. Analysis of peripheral blood samples from patients prior and during fludarabine/cyclophosphamide therapy revealed rapid and sustained reduction of tumour cells but also of CD4+ and CD8+ T cells. This correlated with a significant cytotoxic activity of fludarabine/cyclophosphamide on T cells in vitro. Unexpectedly, T cells surviving fludarabine/cyclophosphamide treatment in vitro had a more mature phenotype, while fludarabine-treated T cells were significantly more responsive to mitogenic stimulation than their untreated counterparts and showed a shift towards TH1 cytokine secretion. In conclusion, fludarabine/cyclophosphamide therapy though inducing significant and relevant T cell depletion seems to generate a micromilieu suitable for subsequent T cell activation

Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg dexamethasone once daily for 5 days or until discharge if sooner) or usual standard of care alone (which included dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality among all randomised participants. On May 11, 2022, the independent data monitoring committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support is ongoing. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio 1·59 [95% CI 1·20–2·10]; p=0·0012). There was also an excess of pneumonia reported to be due to non-COVID infection (64 cases [10%] vs 37 cases [6%]; absolute difference 3·7% [95% CI 0·7–6·6]) and an increase in hyperglycaemia requiring increased insulin dose (142 [22%] vs 87 [14%]; absolute difference 7·4% [95% CI 3·2–11·5]). INTERPRETATION: In patients hospitalised for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. FUNDING: UK Research and Innovation (Medical Research Council), National Institute of Health and Care Research, and Wellcome Trust