Drug-Phospholipid Complex-loaded Matrix Film Formulation for the Enhanced Transdermal Delivery of Quercetin

A novel quercetin-phospholipid-complex(QPLC)-loaded matrix film for improved transdermal delivery of quercetin was developed. The QPLC formulation, prepared using a solvent-evaporation method, was optimized using a central-composite design. The optimized QPLC formulation was characterized by particle size and zeta potential analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (1H-NMR). QPLC formulation was functionally evaluated for solubility and in vitro dissolution of quercetin. Matrix films of pure quercetin (Q-MF)or QPLC QPLC-MF) were prepared using a solvent casting method. The prepared Q-MF and QPLC-MF were characterized for weight uniformity, folding endurance, moisture content, and moisture uptake. The films were also functionally characterized for in vitro diffusion of quercetin through a dialysis membrane and ex vivo permeability of quercetin across rat skin. Finally, the anti-inflammatory activity of the films was evaluated on carrageenan-induced paw edema in Wistar albino rats. The experimental design identified the optimal formulation and process variables for the preparation of QPLC. The validation of the obtained model using these values confirmed the suitability and robustness of the model. The physical-chemical characterization of the prepared QPLC supported the formation of a stable complex. The solubility analysis of QPLC showed a 22-fold increase in quercetin aqueous solubility, compared to pure quercetin. The dissolution results exhibited a significantly higher rate and extent of quercetin dissolution from QPLC compared to that of pure quercetin. The permeability of quercetin from Q-MF and QPLC-MF across rat skin mirrored those obtained from the dissolution studies. Topical application of QPLC-MF exhibited a significant (p\u3c0.05) inhibition of carrageenan-induced paw edema in rats compared to that of Q-MF. This study provides a promising combination approach, i.e., phospholipid-based complexation and transdermal film formulation for improved transdermal delivery of quercetin and similar pharmacologically active phytoconstituents

Preliminary Evaluation of an lytA PCR Assay for Detection of Streptococcus pneumoniae in Urine Specimens from Hospitalized Patients with Community-Acquired Pneumonia

Community acquired pneumonia (CAP) due to Streptococcus pneumoniae still occurs in at risk populations, despite the availability of effective vaccines. Laboratory confirmation of S. pneumoniae remains challenging in cases of CAP despite advances in blood culture techniques and the availability of nucleic acid amplification tests such as PCR-based methods. Urine specimens are an attractive sample type because they are non-invasive compared to bronchial washes or whole blood specimens for patients with CAP. While urine specimens have been used successfully in antigen detection assays, they have not been extensively evaluated for PCR-based assays. In this preliminary study, we evaluated the potential for a real-time PCR assay targeting the S. pneumoniae autolysin gene (lytA) to detect in archived urine samples from patients with CAP. Results indicate that the real time lytA PCR assay on the Luminex ARIES® system shows promise as a screening tool for patients with CAP based on comparison to urine antigen detection assay results

Serum magnesium level and QTc interval prolongation in acute myocardial infarction patients and its correlation with arrhythmias

Background: Arrhythmias commonly occur early in acute myocardial infarction and remain a common cause of sudden death in AMI. Magnesium has been implicated in the pathogenesis of acute myocardial infarction and its complication like arrhythmia. Magnesium improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death. It improves vascular tone, peripheral vascular resistance, after load and cardiac output and reduces cardiac arrhythmias. The objective of this study to investigate the serum magnesium level and QTc interval prolongation in AMI and its correlation with arrhythmias.Methods: In this study, 200 patients of AMI were enrolled. ECG and cardiac parameters were examined. Serum magnesium level is measured and the QTc interval was calculated.Results: MI was more prevalent in the male patients (63.3%) and age group of 41-50 years. Hypertension (35.7%), smoking (34.2%), and diabetes (23.1%) were the major risk factor for MI. Mean serum magnesium level was 1.64±0.37 among those having arrhythmia that is significantly low as compared to those having no arrhythmia among which mean serum magnesium level was 2.28±0.31 (p<0.001). Mean QTc was higher (546.88 ms vs. 404.33ms) in patients documented with arrhythmia compared with those who had no arrhythmia (p<0.001).Conclusions: In acute myocardial infarction, patients with low magnesium levels and prolonged QTc interval are more prone to get arrhythmias. So magnesium treatment can be considered in patients of acute myocardial infarction with low magnesium levels

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Identification of C-C Chemokine Receptor 1 (CCR1) as the Monocyte Hemofiltrate C-C Chemokine (HCC)-1 Receptor

Hemofiltrate C-C chemokine (HCC)-1 is a recently cloned C-C chemokine that is structurally similar to macrophage inflammatory protein (MIP)-1α. Unlike most chemokines, it is constitutively secreted by tissues and is present at high concentrations in normal human plasma. Also atypical for chemokines, HCC-1 is reported not to be chemotactic for leukocytes. In this paper, we have investigated the chemokine receptor usage and downstream signaling pathways of HCC-1. Cross-desensitization experiments using THP-1 cells suggested that HCC-1 and MIP-1α activated the same receptor. Experiments using a panel of cloned chemokine receptors revealed that HCC-1 specifically activated C-C chemokine receptor (CCR)1, but not closely related receptors, including CCR5. HCC-1 competed with MIP-1α for binding to CCR1-transfected cells, but with a markedly reduced affinity (IC50 = 93 nM versus 1.3 nM for MIP-1α). Similarly, HCC-1 was less potent than MIP-1α in inducing inhibition of adenylyl cyclase in CCR1-transfected cells. HCC-1 induced chemotaxis of freshly isolated human monocytes, THP-1 cells, and CCR1-transfected cells, and the optimal concentration for cell migration (100 nM) was ∼100-fold lower than that of MIP-1α (1 nM). These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes

Mapping spot blotch resistance genes in four barley populations

Bipolaris sorokiniana (teleomorph: Cochliobolus sativus) is the fungal pathogen responsible for spot blotch in barley (Hordeum vulgare L.) and occurs worldwide in warmer, humid growing conditions. Current Australian barley varieties are largely susceptible to this disease and attempts are being made to introduce sources of resistance from North America. In this study we have compared chromosomal locations of spot blotch resistance reactions in four North American two-rowed barley lines; the North Dakota lines ND11231-12 and ND11231-11 and the Canadian lines TR251 and WPG8412-9-2-1. Diversity Arrays Technology (DArT)-based PCR, expressed sequence tag (EST) and SSR markers have been mapped across four populations derived from crosses between susceptible parental lines and these four resistant parents to determine the location of resistance loci. Quantitative trait loci (QTL) conferring resistance to spot blotch in adult plants (APR) were detected on chromosomes 3HS and 7HS. In contrast, seedling resistance (SLR) was controlled solely by a locus on chromosome 7HS. The phenotypic variance explained by the APR QTL on 3HS was between 16 and 25% and the phenotypic variance explained by the 7HS APR QTL was between 8 and 42% across the four populations. The SLR QTL on 7HS explained between 52 to 64% of the phenotypic variance. An examination of the pedigrees of these resistance sources supports the common identity of resistance in these lines and indicates that only a limited number of major resistance loci are available in current two-rowed germplasm

Depth Profiles of Residual Stresses in Inconel 718Machined with Uncoated and Coated Tools

567-573Inconel 718 is one of the super-alloy materials, belonging to nickel-chromium alloy family, which has major applications in aerospace sector such as engine parts and turbine components. Durability of these components during engineering performance is affected by residual stresses induced in them in the course of their manufacturing processes. The concept of the present paper is to provide an insight view of induced residual stresses in Inconel 718 work piece, when machined with coated (TiN) and uncoated tools at optimum conditions. For this purpose, turning experiments have been conducted on IN718 material through statistical approach using L9 orthogonal array. Taguchi optimization method is exercised with the emphasis on minimizing the cutting forces resulted during machining. The residual stresses generated in the work piece at the optimum conditions employed for both the tools have been evaluated using XRD method. Conditions such as cutting speed of 60 m/min, feed at 0.068 mm/rev and depth-of-cut of 0.10 mm have been optimized for achieving minimum cutting forces during machining of IN 718 using both coated and uncoated tools. However, tensile stresses on the initial surface layer and compressive stresses in the sub-surface layers are found higher in the work piece material machined with uncoated tool. Surface roughness and temperature developed on the surface of the machined bar are higher in case of uncoated tool than those with coated tool

Development and characterization of a high-throughput in vitro cord formation model insensitive to VEGF inhibition

BACKGROUND: Anti-VEGF therapy reduces tumor blood vessels, however, some vessels always remain. These VEGF insensitive vessels may help support continued tumor growth and metastases. Many in vitro assays examining multiple steps of the angiogenic process have been described, but the majority of these assays are sensitive to VEGF inhibition. There has been little focus on the development of high-throughput, in vitro assays to model the vessels that are insensitive to VEGF inhibition. METHODS: Here, we describe a fixed end-point and kinetic, high-throughput stem cell co-culture model of cord formation. RESULTS: In this system, cords develop within 24 hours, at which point they begin to lose sensitivity to VEGF inhibitors, bevacizumab, and ramucirumab. Consistent with the hypothesis that other angiogenic factors maintain VEGF-independent vessels, pharmacologic intervention with a broad spectrum anti-angiogenic antagonist (suramin), a vascular disrupting agent (combretastatin), or a combination of VEGF and Notch pathway inhibitors reduced the established networks. In addition, we used our in vitro approach to develop an in vivo co-implant vasculogenesis model that connects with the endogenous vasculature to form functional blood vessels. Similar to the in vitro system, over time these vessels become insensitive to VEGF inhibition. CONCLUSION: Together, these models may be used to identify novel drugs targeting tumor vessels that are not sensitive to VEGF inhibition

Colletotrichum blight control in large cardamom (Amomum subulatum Roxb.) nursery

Experiments were conducted in large cardamom (Amomum subulatum Roxb.) nursery using bioagents and chemicals to produce healthy planting materials free from blight caused by Colletotrichum gloeosporioides (Penz.) Sacc. The results indicated that selection of apparently disease free mother plants and treating the rhizome and pseudostem (planting unit) with carbendazim+mancozeb (0.3%) or copper oxychloride (0.3%) would help in reducing the disease incidence in the nursery. Since Sikkim is an organic state, use of copper oxychloride can be recommended. &nbsp

Smooth-muscle-derived WNT5A augments allergen-induced airway remodelling and Th2 type inflammation

Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smooth-muscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4+ T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4+ T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth muscle-derived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling