Azoniaspiro salts: towards bridging the gap between room-temperature ionic liquids and molten salts.

In a continued effort to improve the suitability of ionic liquids in applications operating at raised temperatures, novel spirocyclic 'azoniaspiro' salts (with cations derived from five-, six-, seven-and eight-membered rings) are prepared and characterised. The structural and thermal properties of these salts are compared against those of established analogues. The stable geometries and ion pairing behaviour of these species are investigated via a combined experimental/computational approach, employing X-ray crystallography and Density Functional Theory (DFT) methods. Subsequently, the thermal stabilities of these organic salts are characterised and compared using a broad range of techniques. Hyphenated Thermogravimetry-Mass Spectrometry investigations enable complex mechanisms underlying thermal decomposition to be elucidated. Lastly, transition state structures are optimised, corresponding to plausible decomposition mechanisms of the azoniaspiro salt, 6-azoniaspiro[6.5]dodecanium chloride, and one prototypical monocyclic species 1-butyl-1-methylpiperidinium chloride, using DFT. The observed improved thermal stabilities of the azoniaspiro salts, and their potential higher-temperature stable-liquid ranges, render them promising candidates for future ionic liquid applications

An exploration of parents’ preferences for foot care in juvenile idiopathic arthritis: a possible role for the discrete choice experiment

Background: An increased awareness of patients’ and parents’ care preferences regarding foot care is desirable from a clinical perspective as such information may be utilised to optimise care delivery. The aim of this study was to examine parents’ preferences for, and valuations of foot care and foot-related outcomes in juvenile idiopathic arthritis (JIA).<p></p> Methods: A discrete choice experiment (DCE) incorporating willingness-to-pay (WTP) questions was conducted by surveying 42 parents of children with JIA who were enrolled in a randomised-controlled trial of multidisciplinary foot care at a single UK paediatric rheumatology outpatients department. Attributes explored were: levels of pain; mobility; ability to perform activities of daily living (ADL); waiting time; referral route; and footwear. The DCE was administered at trial baseline. DCE data were analysed using a multinomial-logit-regression model to estimate preferences and relative importance of attributes of foot care. A stated-preference WTP question was presented to estimate parents’ monetary valuation of health and service improvements.<p></p> Results: Every attribute in the DCE was statistically significant (p < 0.01) except that of cost (p = 0.118), suggesting that all attributes, except cost, have an impact on parents’ preferences for foot care for their child. The magnitudes of the coefficients indicate that the strength of preference for each attribute was (in descending order): improved ability to perform ADL, reductions in foot pain, improved mobility, improved ability to wear desired footwear, multidisciplinary foot care route, and reduced waiting time. Parents’ estimated mean annual WTP for a multidisciplinary foot care service was £1,119.05.<p></p> Conclusions: In terms of foot care service provision for children with JIA, parents appear to prefer improvements in health outcomes over non-health outcomes and service process attributes. Cost was relatively less important than other attributes suggesting that it does not appear to impact on parents’ preferences.<p></p&gt

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Genome-Wide Compensatory Changes Accompany Drug- Selected Mutations in the Plasmodium falciparum crt Gene

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well in culture, which may reflect adaptive changes in the parasite genome to compensate for the mutations in PfCRT. Using three isogenic clones that have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K), we investigated changes in gene expression in these parasites grown with and without CQ. We also conducted hybridizations of genomic DNA to identify copy number (CN) changes in parasite genes. RNA transcript levels from 45 genes were significantly altered in one or both mutants relative to the parent line, 106/1K76. Most of the up-regulated genes are involved in invasion, cell growth and development, signal transduction, and transport activities. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH such as the V-type H+ pumping pyrophosphatase 2 (PfVP2), Ca2+/H+ antiporter VCX1, a putative drug transporter and CN changes in pfmdr1. These changes may represent adaptations to altered functionality of PfCRT, a predicted member of drug/metabolite transporter superfamily found on the parasite food vacuole (FV) membrane. Further investigation of these genes may shed light on how the parasite compensates for functional changes accompanying drug resistance mutations in a gene coding for a membrane/drug transporter

Calcium Uptake and Proton Transport by Acidocalcisomes of Toxoplasma gondii

Acidocalcisomes are acidic calcium stores found in diverse organisms, being conserved from bacteria to humans. They possess an acidic matrix that contains several cations bound to phosphates, which are mainly present in the form of short and long polyphosphate chains. Their matrix is acidified through the action of proton pumps such as a vacuolar proton ATPase and a vacuolar proton pyrophosphatase. Calcium uptake occurs through a Ca2+/H+ countertransporting ATPase located in the membrane of the organelle. Acidocalcisomes have been identified in a variety of microorganisms, including Apicomplexan parasites such as Plasmodium and Eimeria species, and in Toxoplasma gondii. We report the purification and characterization of an acidocalcisome fraction from T. gondii tachyzoites after subcellular fractionation and further discontinuous iodixanol gradient purification. Proton and calcium transport activities in the fraction were characterized by fluorescence microscopy and spectrophotometric methods using acridine orange and arsenazo III, respectively. This work will facilitate the understanding of the function of acidocalcisomes in Apicomplexan parasites, as we can now isolate highly purified fractions that could be used for proteomic analysis to find proteins that may clarify the biogenesis of these organelles

Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used

Transcranial Low-Level Laser Therapy Improves Neurological Performance in Traumatic Brain Injury in Mice: Effect of Treatment Repetition Regimen

Low-level laser (light) therapy (LLLT) has been clinically applied around the world for a spectrum of disorders requiring healing, regeneration and prevention of tissue death. One area that is attracting growing interest in this scope is the use of transcranial LLLT to treat stroke and traumatic brain injury (TBI). We developed a mouse model of severe TBI induced by controlled cortical impact and explored the effect of different treatment schedules. Adult male BALB/c mice were divided into 3 broad groups (a) sham-TBI sham-treatment, (b) real-TBI sham-treatment, and (c) real-TBI active-treatment. Mice received active-treatment (transcranial LLLT by continuous wave 810 nm laser, 25 mW/cm[superscript 2], 18 J/cm[superscript 2], spot diameter 1 cm) while sham-treatment was immobilization only, delivered either as a single treatment at 4 hours post TBI, as 3 daily treatments commencing at 4 hours post TBI or as 14 daily treatments. Mice were sacrificed at 0, 4, 7, 14 and 28 days post-TBI for histology or histomorphometry, and injected with bromodeoxyuridine (BrdU) at days 21–27 to allow identification of proliferating cells. Mice with severe TBI treated with 1-laser Tx (and to a greater extent 3-laser Tx) had significant improvements in neurological severity score (NSS), and wire-grip and motion test (WGMT). However 14-laser Tx provided no benefit over TBI-sham control. Mice receiving 1- and 3-laser Tx had smaller lesion size at 28-days (although the size increased over 4 weeks in all TBI-groups) and less Fluoro-Jade staining for degenerating neurons (at 14 days) than in TBI control and 14-laser Tx groups. There were more BrdU-positive cells in the lesion in 1- and 3-laser groups suggesting LLLT may increase neurogenesis. Transcranial NIR laser may provide benefit in cases of acute TBI provided the optimum treatment regimen is employed.National Institutes of Health (U.S.) (Grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense. Congressionally Directed Medical Research Programs (W81XWH-09-1-0514)United States. Air Force Office of Scientific Research. Military Photomedicine Program (FA9550-11-1-0331

Multiple host-switching of Haemosporidia parasites in bats

<p>Abstract</p> <p>Background</p> <p>There have been reported cases of host-switching in avian and lizard species of <it>Plasmodium </it>(Apicomplexa, Haemosporidia), as well as in those infecting different primate species. However, no evidence has previously been found for host-swapping between wild birds and mammals.</p> <p>Methods</p> <p>This paper presents the results of the sampling of blood parasites of wild-captured bats from Madagascar and Cambodia. The presence of Haemosporidia infection in these animals is confirmed and cytochrome <it>b </it>gene sequences were used to construct a phylogenetic analysis.</p> <p>Results</p> <p>Results reveal at least three different and independent Haemosporidia evolutionary histories in three different bat lineages from Madagascar and Cambodia.</p> <p>Conclusion</p> <p>Phylogenetic analysis strongly suggests multiple host-switching of Haemosporidia parasites in bats with those from avian and primate hosts.</p

Effects of Blood Collection Conditions on Ovarian Cancer Serum Markers

Evaluating diagnostic and early detection biomarkers requires comparing serum protein concentrations among biosamples ascertained from subjects with and without cancer. Efforts are generally made to standardize blood processing and storage conditions for cases and controls, but blood sample collection conditions cannot be completely controlled. For example, blood samples from cases are often obtained from persons aware of their diagnoses, and collected after fasting or in surgery, whereas blood samples from some controls may be obtained in different conditions, such as a clinic visit. By measuring the effects of differences in collection conditions on three different markers, we investigated the potential of these effects to bias validation studies.We analyzed serum concentrations of three previously studied putative ovarian cancer serum biomarkers-CA 125, Prolactin and MIF-in healthy women, women with ovarian cancer undergoing gynecologic surgery, women undergoing surgery for benign ovary pathology, and women undergoing surgery with pathologically normal ovaries. For women undergoing surgery, a blood sample was collected either in the clinic 1 to 39 days prior to surgery, or on the day of surgery after anesthesia was administered but prior to the surgical procedure, or both. We found that one marker, prolactin, was dramatically affected by collection conditions, while CA 125 and MIF were unaffected. Prolactin levels were not different between case and control groups after accounting for the conditions of sample collection, suggesting that sample ascertainment could explain some or all of the previously reported results about its potential as a biomarker for ovarian cancer.Biomarker validation studies should use standardized collection conditions, use multiple control groups, and/or collect samples from cases prior to influence of diagnosis whenever feasible to detect and correct for potential biases associated with sample collection

Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet improves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet: A meta-analysis of clinical studies

BACKGROUND: Irritable bowel syndrome (IBS) and functional digestive tract disorders, e.g. functional bloating, carbohydrate maldigestion and intolerances, are very common disorders frequently causing significant symptoms that challenge health care systems. A low Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols (FODMAP) diet is one of the possible therapeutic approaches for decreasing abdominal symptoms and improving quality of life. OBJECTIVES: We aimed to meta-analyze data on the therapeutic effect of a low-FODMAP diet on symptoms of IBS and quality of life and compare its effectiveness to a regular, standard IBS diet with high FODMAP content, using a common scoring system, the IBS Symptom Severity Score (IBS-SSS). METHODS: A systematic literature search was conducted in PubMed, EMBASE and the Cochrane Library as well as in the references in a recent meta-analysis. Adult patients diagnosed with IBS according to the Rome II, Rome III, Rome IV or NICE criteria were included in the analysis. STATISTICAL METHODS: Mean differences with 95% confidence intervals were calculated from studies that contained means, standard deviation (SD) or mean differences and SD of differences and p-values. A random effect model was used because of the heterogeneity (Q test (chi2) and I2 indicator). A p-value of less than 0.05 was chosen to indicate a significant difference. RESULTS: The literature search yielded 902 publications, but only 10 were eligible for our meta-analysis. Both regular and low-FODMAP diets proved to be effective in IBS, but post-diet IBS-SSS values were significantly lower (p = 0.002) in the low-FODMAP group. The low-FODMAP diet showed a correlation with the improvement of general symptoms (by IBS-SSS) in patients with IBS. CONCLUSIONS: This meta-analysis provides high-grade evidence of an improved general symptom score among patients with irritable bowel syndrome who have maintained a low-FODMAP diet compared to those on a traditional IBS diet, therefore showing its superiority to regular IBS dietary therapy. These data suggest that a low-FODMAP diet with dietitian control can be a candidate for first-line therapeutic modality in IBS. Because of a lack of data, well-planned randomized controlled studies are needed to ascertain the correlation between improvement of separate key IBS symptoms and the effect of a low-FODMAP diet