Use of Isoquercetin in the Treatment of Prurigo Nodularis.

Atopic dermatitis and prurigo nodularis result from complex interactions between the skin, the immune system, and the external environment. The pruritus associated with these conditions greatly impacts patients' quality of life and lacks uniformly effective treatment. A 57-year-old patient presented with severe atopic dermatitis and subsequent prurigo nodularis refractory to numerous standard therapies. The supplement isoquercetin was initiated and he noted significant, sustained reduction in his pruritus after only four weeks. Isoquercetin is a glycoside derivative with antihistamine properties of quercetin, a natural polyphenol flavonoid found in many plants. It may offer itch relief in patients who have failed more conventional therapies.

J Drugs Dermatol. 2017;16(11):1156-1158.

Changes in nasal flora one year after endoscopic dacryocystorhinostomy.

PURPOSE: This study investigated changes in patient nasal and conjunctival flora one year after endoscopic dacryocystorhinostomy (EDSR). METHODS: The prospective study included 20 patients that underwent EDSR due to chronic dacryocystitis. Conjunctival and nasal cultures were obtained one year after EDSR from both study and control groups. Patient characteristics, chronic illnesses, the severity and duration of complaints, culture results, and the stent removal time were recorded and analyzed. RESULTS: In the study group, the most commonly isolated microorganism in the nasal cultures was coagulase-negative staphylococcus (n = 11), and the second most commonly isolated microorganism was Staphylococcus aureus (n = 7). A total of 11 (55%) of the nasal cultures in the study group showed the presence of multi-drug resistant (MDR) bacteria, as did 2 (10%) of the nasal cultures in the control group (p = 0.007). CONCLUSIONS: One year after EDSR surgery with silicon stent placement, we detected changes in the nasal flora in the operated side compared with the non-operated side. Even though more than half of the nasal cultures in the study group were positive for MDR bacteria, these microorganisms did not cause attacks of dacryocystitis or affect surgical success.

Jute fibre reinforced biodegradable composites using starch as a biological macromolecule: Fabrication and performance evaluation.

The aim of this study is to develop environment friendly packaging and life style materials for replacing conventionally explored hazardous synthetic materials. The study carried out by using raw jute fibre reinforced thermoplastic corn starch (TPCS) is to develop biodegradable flexible composite materials. Flexible composites are prepared by maintaining with different fibre content (30 %, 40 % and 50 wt%). A thin coating of polyurethane based formulation is applied on one side of the developed composite to make it water resistant. Composite samples are examined in terms of their tensile properties, tear resistance, folding endurance, water absorbency, capillary action etc. The results show that flexible composites, having 50 % fibre content have tensile strength of 12.8 MPa and 12 MPa at cross and machine direction respectively compared to 3.1 MPa for the TPCS film. The Water drop test on the coated side of the developed material concluded that there is no water penetration even after 60 min of wetting. The interaction between two hydrophilic components is established with FTIR analysis. The XRD analysis was carried out to find the crystallinity of TPCS, Jute fibre and composite samples. Surface morphology and fibre/matrix interaction is observed by SEM. The detail chemical mechanism involved of fibre matrix interaction also been postulated. The scientific finding shows that the developed flexible material can be suitable for making packaging and life style items.

First report of detection and molecular confirmation of Plasmodium ovale from severe malaria cases in central India.

OBJECTIVE: We report for the first-time detection of Plasmodium ovale in central India. METHODS: From 2010, all hospitalised suspected malaria cases at the malaria clinic of the Regional Medical Research Centre for Tribals in Bastar district, central India, were screened. Plasmodium species were identified by microscopy and species-specific nested PCR of 18s rRNA. RESULTS: Of 256 enrolled cases of confirmed P. falciparum malaria by microscopy, P. ovale infection was detected in three cases (1.2%) by PCR and sequencing. Of these three cases, one had cerebral malaria and another had severe malaria anaemia. In both of these cases, P. ovale infection was mixed with P. falciparum, while in third case the infection was mixed with both P. falciparum and P. vivax. Phylogenetic analysis revealed that these isolates showed closed homology with West African genotypes. CONCLUSION: All three hospitalised patients were originally residents of remote inaccessible forest villages and never moved out of their residence. This finding also has implications in malaria control and elimination as P. ovale causes relapses. This study highlights the need of molecular diagnosis of malaria species for appropriate treatment and control.

Direct observation of broken time-reversal symmetry on the surface of a magnetically doped topological insulator.

We study interference patterns of a magnetically doped topological insulator Bi(2-x)Fe(x)Te(3+d) by using Fourier transform scanning tunneling spectroscopy and observe several new scattering channels. A comparison with angle-resolved photoemission spectroscopy allows us to unambiguously ascertain the momentum-space origin of distinct dispersing channels along high-symmetry directions and identify those originating from time-reversal symmetry breaking. Our analysis also reveals that the surface state survives far above the energy where angle-resolved photoemission spectroscopy finds the onset of continuum bulk bands.

Multifunctional Thio-Stabilized Gold Nanoparticles for Near-Infrared Fluorescence Detection and Imaging of Activated Caspase-3.

BACKGROUND: Gold nanoparticles (AuNPs) are commonly used in nanomedicine because of their unique spectral properties, chemical and biological stability, and ability to quench the fluorescence of organic dyes attached to their surfaces. However, the utility of spherical AuNPs for activatable fluorescence sensing of molecular processes have been confined to resonance-matched fluorophores in the 500 nm to 600 nm spectral range to maximize dye fluorescence quenching efficiency. Expanding the repertoire of fluorophore systems into the NIR fluorescence regimen with emission >800 nm will facilitate the analysis of multiple biological events with high detection sensitivity. OBJECTIVE: The primary goal of this study is to determine if spherical AuNP-induced radiative rate suppression of non-resonant near-infrared (NIR) fluorescent probes can serve as a versatile nanoconstruct for highly sensitive detection and imaging of activated caspase-3 in aqueous media and cancer cells. This required the development of activatable NIR fluorescence sensors of caspase-3 designed to overcome the nonspecific degradation and release of the surface coatings in aqueous media. METHOD: We harnessed the fluorescence-quenching properties and multivalency of spherical AuNPs to develop AuNP-templated activatable NIR fluorescent probes to detect activated caspase-3, an intracellular reporter of early cell death. Freshly AuNPs were coated with a multifunctional NIR fluorescent dye-labeled peptide (LS422) consisting of an RGD peptide sequence that targets αvß3-integrin protein (αvß3) on the surface of cancer cells to mediate the uptake and internalization of the sensors in tumor cells; a DEVD peptide sequence for reporting the induction of cell death through caspase-3 mediated NIR fluorescence enhancement; and a multidentate hexacysteine sequence for enhancing self-assembly and stabilizing the multifunctional construct on AuNPs. The integrin binding affinity of LS422 and caspase-3 kinetics were determined by a radioligand competitive binding and fluorogenic peptide assays, respectively. Detection of intracellular caspase-3, cell viability, and the internalization of LS422 in cancer cells were determined by confocal NIR fluorescence spectroscopy and microscopy. RESULTS: Narrow size AuNPs (13 nm) were prepared and characterized by transmission electron microscopy and dynamic light scattering. When assembled on the AuNPs, the binding constant of LS422 for αvß3 improved 11-fold from 13.2 nM to 1.2 nM. Whereas the catalytic turnover of caspase-3 by LS422-AuNPs was similar to the reference fluorogenic peptide, the binding affinity for the enzyme increased by a factor of 2. Unlike the αvß3 positive, but caspase-3 negative breast cancer MCF-7 cells, treatment of the αvß3 and caspase-3 positive lung cancer A549 cells with Paclitaxel showed significant fluorescence enhancement within 30 minutes, which correlated with caspase-3 specific activation of LS422-AuNPs fluorescence. Incorporation of a 3.5 mW NIR laser source into our spectrofluorometer increased the detection sensitivity by an order of magnitude (limit of detection ~0.1 nM of cypate) and significantly decreased the signal noise relative to a xenon lamp. This gain in sensitivity enabled the detection of substrate hydrolysis at a broad range of inhibitor concentrations without photobleaching the cypate dye. CONCLUSION: The multifunctional AuNPs demonstrate the use of a non-resonant quenching strategy to design activatable NIR fluorescence molecular probes. The nanoconstruct offers a selective reporting method for detecting activated caspase-3, imaging of cell viability, identifying dying cells, and visualizing the functional status of intracellular enzymes. Performing these tasks with NIR fluorescent probes creates an opportunity to translate the in vitro and cellular analysis of enzymes into in vivo interrogation of their functional status using deep tissue penetrating NIR fluorescence analytical methods.

Period multiplication cascade at the order-by-disorder transition in uniaxial random field XY magnets.

Uniaxial random field disorder induces a spontaneous transverse magnetization in the XY model. Adding a rotating driving field, we find a critical point attached to the number of driving cycles needed to complete a limit cycle, the first discovery of this phenomenon in a magnetic system. Near the critical drive, time crystal behavior emerges, in which the period of the limit cycles becomes an integer n > 1 multiple of the driving period. The period n can be engineered via specific disorder patterns. Because n generically increases with system size, the resulting period multiplication cascade is reminiscent of that occurring in amorphous solids subject to oscillatory shear near the onset of plastic deformation, and of the period bifurcation cascade near the onset of chaos in nonlinear systems, suggesting it is part of a larger class of phenomena in transitions of dynamical systems. Applications include magnets, electron nematics, and quantum gases.

Adenomyosis: still largely under-diagnosed.

Underlying adenomyosis is often the cause of treatment failure for patients undergoing Mirena insertion, endometrial ablation and/or hysteroscopic resection for abnormal uterine bleeding and/or pelvic pain. In this cohort of abnormal uterine bleeding, clinicians rarely considered adenomyosis as a differential diagnosis. In such cases, gynaecologists concentrated primarily on menstrual flow. Symptoms of pelvic pain, dyspareunia, pelvic pressure symptoms and type of dysmenorrhoea were not queried. Frequently, no correlation was sought to account for a uterus noted to be enlarged either clinically or at hysteroscopy. Given the limitation of ultrasound scan (USS) in diagnosing adenomyosis, and gynaecologists' reliance on USS findings, adenomyosis often remains undiagnosed before a hysterectomy. An earlier diagnosis of adenomyosis requires a good history, correlation of clinical examination and ultrasound scan findings and a back-up MRI service. Once adenomyosis is suspected, women can be appropriately counselled so that they are fully aware of the possible failure of conservative management. If conservative management is chosen, they should be followed-up and hysterectomy offered for persistent symptoms.

Antibacterial Activities of Clove (Syzygium aromaticum) Extracts Against Three Food Borne Pathogens: Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.

Evaluation of the in vitro antibacterial activity of aqueous and ethanolic extracts isolated from Clove (Syzygium aromaticum) buds against three food borne pathogens, gram-positive Staphylococcus aureus and gram-negative Escherichia coli & Pseudomonas aeruginosa. This interventional study was carried out during the period of July 2018 to June 2019 in the Department of Pharmacology and Therapeutics with the collaboration of Department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh. The antibacterial activity was tested at different concentrations of both extracts of spice by using disc diffusion & broth dilution method. The extracts were prepared by using solvents aqueous & ethanol. The test microorganisms were also tested for their activity against a standard antibiotic Gentamicin (80mg) by broth dilution method and the result was compared with that of Aqueous and Ethanolic extracts. Aqueous and ethanolic extracts of clove had inhibitory activity against the test bacteria. Among different concentrations of the ACE, 500µg/ml & above concentration showed inhibitory effect against Staphylococcus aureus & Escherichia coli and 700µg/ml & above concentration showed inhibitory effect against Pseudomonas aeruginosa. In case of ECE, 500µg/ml & above concentration showed inhibitory effect against aforesaid bacteria. In disc diffusion method, S. aureus was found to be most susceptible to ACE (30.5mm) & Pseudomonas aeruginosa was found to be most susceptible to ECE (38mm). Minimum inhibitory concentrations (MIC) of ECE were lower than ACE for the test bacteria except Staphylococcus aureus where MICs of ACE & ECE were the same. This result was also compared against a standard antibiotic Gentamicin where the MICs of Gentamicin were lower in comparison to MICs of ACE & ECE. The present study showed that aqueous and ethanolic extracts of Clove demonstrated antibacterial effects against food borne pathogens.

Siva is an apoptosis-selective p53 target gene important for neuronal cell death.

p53 plays a central role in neuronal cell death resulting from acute injury or disease. To define the pathway by which p53 triggers apoptosis, we used microarray analysis to identify p53 target genes specifically upregulated during apoptosis but not cell cycle arrest. This analysis identified a small subset of targets highly selective for the p53 apoptotic response, including Siva, a proapoptotic protein whose function is not well understood. Siva's expression pattern suggests that it plays an instructive role in apoptosis, and accordingly, we demonstrate that Siva is essential for p53-dependent apoptosis in cerebellar granule neurons. In addition, we determine that endogenous Siva is associated with the plasma membrane and that Caspase-8 and Bid are important for neuronal apoptosis. Our studies highlight the participation of membrane signaling events in p53's apoptotic program in primary neurons and have significant implications for understanding the mechanisms underlying pathogenesis after neuronal injury and in neurodegenerative diseases.

Chemometrical analysis of proteomics data obtained from three cell types treated with multi-walled carbon nanotubes and TiO2 nanobelts$.

Applications of nanomaterials in biomedical, industrial, and consumer goods areas are expanding rapidly because of their unique physicochemical properties. Hazard assessment of nanosubstances is necessary for the protection of human and ecological health. We studied the proteomics patterns of three cell lines: co-culture of Caco-2 and HT29-MTX cells, primary small airway epithelial cells, and THP-1macrophage-like cells. The cells were exposed at 10 µg and 100 µg concentrations for 3 and 24 hours to multi-walled carbon nanotubes and TiO2 nanobelts (TiO2-NB). The data were analysed with the hierarchical clustering method and principal components analysis. In all cases, time of exposure is the most important factor in separation and clustering of proteomics patterns. Furthermore, the sets of proteins, which are specific for long (24 hours) exposure, are identified.

Mathematical structural descriptors and mutagenicity assessment: a study with congeneric and diverse datasets$.

Quantitative bioactivity and toxicity assessment of chemical compounds plays a central role in drug discovery as it saves a substantial amount of resources. To this end, high-performance computing has enabled researchers and practitioners to leverage hundreds, or even thousands, of computed molecular descriptors for the activity prediction of candidate compounds. In this paper, we evaluate the utility of two large groups of chemical descriptors by such predictive modelling, as well as chemical structure discovery, through empirical analysis. We use a suite of commercially available and in-house software to calculate molecular descriptors for two sets of chemical mutagens - a homogeneous set of 95 amines, and a diverse set of 508 chemicals. Using calculated descriptors, we model the mutagenic activity of these compounds using a number of methods from the statistics and machine-learning literature, and use robust principal component analysis to investigate the low-dimensional subspaces that characterize these chemicals. Our results suggest that combining different sets of descriptors is likely to result in a better predictive model - but that depends on the compounds being modelled and the modelling technique being used.

A quantitative structure-activity relationship (QSAR) study of dermal absorption using theoretical molecular descriptors.

Quantitative structure-activity relationship (QSAR) models were developed for the prediction of dermal absorption based on experimental log Kp data for a diverse set of 101 chemicals obtained from the literature. Molecular descriptors including topostructural (TS), topochemical (TC), shape or three-dimensional (3D) and quantum chemical (QC) indices were calculated. Based on this information, a generic predictive model was created using the diverse set of 101 compounds. In addition, two submodels were prepared for subsets of 79 cyclic and 22 acyclic chemicals. A modified Gram-Schmidt variable reduction algorithm for descriptor thinning was followed by regression analyses using ridge regression (RR), principal components regression (PCR) and partial least squares regression (PLS). The RR results were found to be superior to PLS and PCR regressions. The cross-validated correlation coefficients for the full set and subsets were 0.67-0.87. Computational methods such as QSAR modelling can be used to augment existing data to prioritise chemicals that need to be studied further for toxicological evaluation and risk assessment.

Three dimensional structure-activity relationships (3D-QSAR) for insect repellency of diastereoisomeric compounds: a hierarchical molecular overlay approach.

2-(2-Hydroxyethyl)-1-piperidinecarboxylic acid 1-methylpropyl ester (Picaridin), and 1-(cyclohex-3-ene-1-ylcarbonyl)-2-methylpiperidine (AI3-37220; 220) are alternatives to DEET (N,N-diethyl-3-methylbenzamide), the most popular mosquito repellent. Picaridin and AI3-37220 exhibit polychiral diastereoisomerism and each has four diastereoisomers due to the presence of two asymmetric centers in their molecules. The diastereoisomers of these compounds have differing degrees of mosquito-repellent activity according to quantitative behavioral assays conducted at the United States Department of Agriculture. An insight into the stereochemical requirements for repellency is of great importance in the development of better repellents. Molecular overlay of the optimized geometries of the diastereoisomers was considered as a novel tool for Stereochemical Structure-Activity Relationship (SSAR) modeling. An earlier study using molecular mechanics (MM2) optimized geometries showed good promise. In continuation of this effort and to overcome certain defects in using MM2 geometries, a hierarchical overlay approach was developed. In this method geometry of the low energy conformer of each diastereoisomer was optimized using: the following quantum chemical methods in a graduated manner: (a) semiempirical AM1, (b) Hartree Fock (STO3G, 3-21G, 6-31G, and 6-311G), and (c) Density Functional Theory (B3LYP/6-31G, B3LYP/6-311G). The optimized geometries of different diastereoisomers were overlaid in various user defined combinations to calculate the root mean square distances (RMSD) of the overlaid structures. The RMSD with respect to the most active diastereoisomer (220SS) were found to have a strong relationship with biological potency. Common motifs in shapes and molecular surfaces that are probably critical for effective repellent activity were identified. The hierarchical approach gave valuable information on the quantum chemical level (basis set) at which optimization must be carried out to get the correct order of repellency of the diastereoisomers of Picaridin and 220.

Design and in vitro testing of a floatable gastroretentive tablet of metformin hydrochloride.

Metformin hydrochloride, which is better absorbed in the upper intestine, was formulated as a floating (buoyant) matrix tablet using a gas generating agent (sodium bicarbonate) and a gel forming hydrophilic polymer (hydroxypropyl methylcellulose). The formulation was optimized on the basis of floating ability and in vitro drug release. The resulting formulation produced robust tablets with optimum hardness, consistent weight uniformity and low tablet friability. All tablets but one exhibited satisfactory (gradual and near complete) drug release and buoyancy. In vitro drug release tests of these tablets indicated controlled sustained release of metformin hydrochloride and 96-99% released at the end of 8 h. Two formulations of fabricated tablets containing metformin hydrochloride (500 mg), sodium bicarbonate (75 mg), hydroxypropyl methylcellulose-K 4M (170-180 mg), citric acid (between 15 and 20 mg) and polyvinyl pyrrolidone K90 (32-40 mg) with hardness between 6.8 to 7.5 kg/cm2 showed a floating time of more than 8 h and promising drug release results. The release followed the Higuchi kinetic model, indicating diffusion dominated drug release.

Epidermal growth factor receptor T790M testing in progressed lung cancer: A review of sensitive methods for analysis of tissue and liquid biopsy samples.

Lung cancer is one of the major causes of mortality worldwide and is on the rise in India. The identification of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has paved the way for personalized therapy in lung cancer with EGFR-tyrosine kinase inhibitors (TKIs). Despite the proven efficacy of EGFR-TKIs in patients harboring EGFR mutations, their clinical utility is limited by the development of acquired resistance mechanisms by the tumor cells. T790M mutation accounts for 60% of all resistance mechanisms to EGFR TKIs and is responsible for treatment failure with first- and second-generation TKIs. With the development of novel therapeutic agents such as osimertinib to overcome this resistance mechanism, it is essential to detect patients harboring T790M mutation. There are several limitations with the use of tissue biopsy specimens for molecular testing such as poor quality and quantity of sample, tumor heterogeneity, occurrence of complications, and issues with repeat biopsy. Liquid biopsy offers a noninvasive approach that can be used for diagnostic purposes as well as for monitoring treatment response and evaluation of resistance mechanisms. This review focuses on the methods for molecular testing of tissue and liquid biopsy specimens for EGFR mutations, particularly EGFR T790M mutation.

Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway.

Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.