Stabilization of long-looped i-motif DNA by polypyridyl ruthenium complexes

A spectroscopic study of the interactions of Λ- and Δ-[Ru(phen)2(dppz)]2+ with i-motif DNA containing thymine loops of various lengths. In the presence of i-motifs, the luminescence of the Λ enantiomer was enhanced much more than the Δ. Despite this, the effect of each enantiomer on i-motif thermal stability was comparable. The sequences most affected by [Ru(phen)2(dppz)]2+ were those with long thymine loops; this suggests that long-looped i-motifs are attractive targets for potential transition metal complex drugs and should be explored further in drug design

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Comparative Skull Morphology of Uropeltid Snakes (Alethinophidia: Uropeltidae) with Special Reference to Disarticulated Elements and Variation

Uropeltids form a diverse clade of highly derived, fossorial snakes that, because of their phylogenetic position among other alethinophidian lineages, may play a key role in understanding the early evolution of cranial morphology in snakes. We include detailed osteological descriptions of crania and mandibles for eight uropeltid species from three nominal genera (Uropeltis, Rhinophis, and Brachyophidium) and emphasize disarticulated elements and the impact of intraspecific variation on previously proposed morphological characters used for phylogenetic analysis. Preliminary analysis of phylogenetic relationships strongly supports a clade composed exclusively of species of Plectrurus, Uropeltis, and Rhinophis. However, monophyly of each of those genera and Melanophidium is not upheld. There is moderate support that Sri Lankan species (e.g., Rhinophis and Uropeltis melanogaster) are monophyletic with respect to Indian uropeltids. Previously proposed characters that are phylogenetically informative include the shape of the nasals, length of the occipital condyle, level of development of the posteroventral process of the dentary, and participation of the parietal in the optic foramen. Additionally, thirty new features that may be systematically informative are identified and described, but were not verified for their utility. Such verification must await availability of additional disarticulated cranial material from a larger sample of taxa. All characters require further testing through increased focus on sources and patterns of intraspecific variation, inclusion of broader taxonomic samples in comparative studies, and exploration of skeletal development, sexual dimorphism, and biogeographic patterns. Additionally, trends in the relative enlargement of the sensory capsules, reduction in cranial ossification and dentition, fusion of elements, and the appearance of novel morphological conditions, such as the structure and location of the suspensorium, may be related to fossoriality and miniaturization in some uropeltid taxa, and may complicate analysis of relationships within Uropeltidae and among alethinophidian snakes

Host Plant Induced Variation in Gut Bacteria of Helicoverpa armigera

Helicoverpa are important polyphagous agricultural insect pests and they have a worldwide distribution. In this study, we report the bacterial community structure in the midgut of fifth instar larvae of Helicoverpa armigera, a species prevalent in the India, China, South Asia, South East Asia, Southern & Eastern Africa and Australia. Using culturable techniques, we isolated and identified members of Bacillus firmus, Bacillus niabense, Paenibacillus jamilae, Cellulomonas variformis, Acinetobacter schindleri, Micrococcus yunnanesis, Enterobacter sp., and Enterococcus cassiliflavus in insect samples collected from host plants grown in different parts of India. Besides these the presence of Sphingomonas, Ralstonia, Delftia, Paracoccus and Bacteriodetes was determined by culture independent molecular analysis. We found that Enterobacter and Enterococcus were universally present in all our Helicoverpa samples collected from different crops and in different parts of India. The bacterial diversity varied greatly among insects that were from different host plants than those from the same host plant of different locations. This result suggested that the type of host plant greatly influences the midgut bacterial diversity of H. armigera, more than the location of the host plant. On further analyzing the leaf from which the larva was collected, it was found that the H. armigera midgut bacterial community was similar to that of the leaf phyllosphere. This finding indicates that the bacterial flora of the larval midgut is influenced by the leaf surface bacterial community of the crop on which it feeds. Additionally, we found that laboratory made media or the artificial diet is a poor bacterial source for these insects compared to a natural diet of crop plant

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Imaging tumour hypoxia with positron emission tomography.

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.Cancer Research UK (CRUK) funded the National Cancer Research Institute (NCRI) PET Research Working party to organise a meeting to discuss imaging cancer with hypoxia tracers and Positron Emission Tomography. IF was funded by CRUK and is also supported by the Chief Scientific Office. ALH is supported by CRUK and the Breast Cancer Research Foundation. RM is funded by NIHR Cambridge Biomedical Research Centre.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc2014610a.html

Killing Hypoxic Cell Populations in a 3D Tumor Model with EtNBS-PDT

An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations

Identification of a Novel Calotropis procera Protein That Can Suppress Tumor Growth in Breast Cancer through the Suppression of NF-κB Pathway

10.1371/journal.pone.0048514PLoS ONE712

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of  80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency