Organic reactions in ionic liquids:A new method for the synthesis of alkyl aryl sulfones by alkylation of sodium arenesulfinates with unactivated alkyl chlorides

A new method is reported for the synthesis of alkyl aryl sulfones by alkylation of sodium arenesulfinates with unactivated alkyl chlorides using ionic liquid based on 1-butyl-3-methylimidazolium tetrafluoroborate (BmimBF 4) mixed with water (2:1) as reaction media. The ionic liquid can be reused and the procedure gives the sulfones in moderate yields.

Super-hydrophobic surface of bulk carbon nanotubes compacted by spark plasma sintering followed by modification with polytetrofluorethylene

The surfaces of bulk carbon nanotubes compacted by plasma spark sintering have been modified with polytetrofluorethylene, thereby producing a super-hydrophobic surface with a contact angle above 160°. The surface roughness and air trapped in pores and between the polytetrofluorethylene particles are responsible for the super-hydrophobility. The material can be machined into desired shapes with fine and complex channels, allowing internal surfaces to also be super-hydrophobic.

Functional and perceived benefits of wearing coloured filters by patients with age-related macular degeneration

Background: The aim was to investigate the visual effect of coloured filters compared to transmission-matched neutral density filters, in patients with dry age-related macular degeneration. Methods: Visual acuity (VA, logMAR), contrast sensitivity (Pelli-Robson) and colour vision (D15) were recorded for 39 patients (average age 79.1 ± 7.2 years) with age-related macular degeneration, both in the presence and absence of glare from a fluorescent source. Patients then chose their preferred coloured and matched neutral density transmission filters (NoIR). Visual function tests were repeated with the chosen filters, both in the presence and absence of glare from the fluorescent source. Patients trialled the two filters for two weeks each, in random order. Following the trial of each filter, a telephone questionnaire was completed. Results: VA and contrast sensitivity were unaffected by the coloured filters but reduced through the neutral density filters (p < 0.01). VA and contrast sensitivity were reduced by similar amounts, following the introduction of the glare source, both in the presence and absence of filters (p < 0.001). Colour vision error scores were increased following the introduction of a neutral density filter (from 177.6 ± 60.2 to 251.9 ± 115.2) and still further through coloured filters (275.1 ± 50.8; p < 0.001). In the absence of any filter, colour vision error scores increased by 29.1 ± 55.60 units in the presence of glare (F2,107 = 3.9, p = 0.02); however, there was little change in colour vision error scores, in the presence of glare, with either the neutral density or coloured filters. Questionnaires indicated that patients tended to gain more benefit from the coloured filters. Conclusions: Coloured filters had minimal impact on VA and contrast sensitivity in patients with age-related macular degeneration; however, they caused a small reduction in objective colour vision, although this was not registered subjectively by patients. Patients indicated that they received more benefit from the coloured filters compared with neutral density filters. © 2013 The Authors © 2013 Optometrists Association Australia.

Celiac disease-specific TG2-targeted autoantibodies inhibit angiogenesis ex vivo and in vivo in mice by interfering with endothelial cell dynamics

A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2), reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility. © 2013 Kalliokoski et al.

The pharmacology of centrally acting drugs in animals of altered thyroid status

The pharmacological effects of a number of centrally acting drugs have been compared in euthyroid mice and mice made hyperthyroid by pretreatment with sodium-1-thyroxine. The potencies of two barbiturates, pentobarbitone and thiopentone - as indicated by the duration of their hypnotic actions and their acute toxicities - are increased in hyperthyroid mice. An acutely active uncoupler of phosphorylative oxidation is 2, 4-dinitrophenol, an agent which proved to be a potent hypnotic when administered intracerebrally. An attempt has been made to relate the mechanism of action of the barbiturates to the uncoupling effects of thyroxine and 2, 4-dinitrophenol. The pharmacological effects of chlorpromazine, reserpine and amphetamine-like drugs have also been studied in hyperthyroid mice. After pretreatment with thyroxine, mice show a reduced tendency to become hypothermic after chlorpromazine or reserpine; in fact, under suitable laboratory conditions these agents produce a hyperthermic effect. Yet their known depressant effects upon locomotor activity were not substantially altered. Thus it appeared that depression of locomotor activity and hypothermia are not necessarily correlated, an observation at variance with previously held opinion. These results have been discussed in the light of our knowledge of the role of the thyroid gland in thermoregulation. The actions of tremorine and its metabolite, oxotremorine, have also been examined. Hyperthyroid animals are less susceptible to both the hypothermia and tremor produced by these agents. An attempt is made to explain these observations, in view of the known mechanism of action of oxotremorine and the tremorgenic actions that thyroxine may have. A number of experimental methods have been used to study the anti-nociceptive (analgesic) effects of drugs in euthyroid and hyperthyroid mice. The sites and mechanisms of action of these drugs and the known actions of thyroxine have been discussed.

Spinal motor neurite outgrowth over glial scar inhibitors is enhanced by coculture with bone marrow stromal cells

Background context Transplantation of bone marrow cells into spinal cord lesions promotes functional recovery in animal models, and recent clinical trials suggest possible recovery also in humans. The mechanisms responsible for these improvements are still unclear. Purpose To characterize spinal cord motor neurite interactions with human bone marrow stromal cells (MSCs) in an in vitro model of spinal cord injury (SCI). Study design/setting Previously, we have reported that human MSCs promote the growth of extending sensory neurites from dorsal root ganglia (DRG), in the presence of some of the molecules present in the glial scar, which are attributed with inhibiting axonal regeneration after SCI. We have adapted and optimized this system replacing the DRG with a spinal cord culture to produce a central nervous system (CNS) model, which is more relevant to the SCI situation. Methods We have developed and characterized a novel spinal cord culture system. Human MSCs were cocultured with spinal motor neurites in substrate choice assays containing glial scar-associated inhibitors of nerve growth. In separate experiments, MSC-conditioned media were analyzed and added to spinal motor neurites in substrate choice assays. Results As has been reported previously with DRG, substrate-bound neurocan and Nogo-A repelled spinal neuronal adhesion and neurite outgrowth, but these inhibitory effects were abrogated in MSC/spinal cord cocultures. However, unlike DRG, spinal neuronal bodies and neurites showed no inhibition to substrates of myelin-associated glycoprotein. In addition, the MSC secretome contained numerous neurotrophic factors that stimulated spinal neurite outgrowth, but these were not sufficient stimuli to promote spinal neurite extension over inhibitory concentrations of neurocan or Nogo-A. Conclusions These findings provide novel insight into how MSC transplantation may promote regeneration and functional recovery in animal models of SCI and in the clinic, especially in the chronic situation in which glial scars (and associated neural inhibitors) are well established. In addition, we have confirmed that this CNS model predominantly comprises motor neurons via immunocytochemical characterization. We hope that this model may be used in future research to test various other potential interventions for spinal injury or disease states. © 2014 Elsevier Inc. All rights reserved.

Verification of the indoor GPS system, by comparison with calibrated coordinates and by angular reference

This paper details work carried out to verify the dimensional measurement performance of the Indoor GPS (iGPS) system; a network of Rotary-Laser Automatic Theodolites (R-LATs). Initially tests were carried out to determine the angular uncertainties on an individual R-LAT transmitter-receiver pair. A method is presented of determining the uncertainty of dimensional measurement for a three dimensional coordinate measurement machine. An experimental procedure was developed to compare three dimensional coordinate measurements with calibrated reference points. The reference standard used to calibrate these reference points was a fringe counting interferometer with the multilateration technique employed to establish three dimensional coordinates. This is an extension of the established technique of comparing measured lengths with calibrated lengths. The method was found to be practical and able to establish that the expanded uncertainty of the basic iGPS system was approximately 1 mm at a 95% confidence level. Further tests carried out on a highly optimized version of the iGPS system have shown that the coordinate uncertainty can be reduced to 0.25 mm at a 95% confidence level.

Estimation of uncertainty in three-dimensional coordinate measurement by comparison with calibrated points

This paper details a method of estimating the uncertainty of dimensional measurement for a three-dimensional coordinate measurement machine. An experimental procedure was developed to compare three-dimensional coordinate measurements with calibrated reference points. The reference standard used to calibrate these reference points was a fringe counting interferometer with a multilateration-like technique employed to establish three-dimensional coordinates. This is an extension of the established technique of comparing measured lengths with calibrated lengths. Specifically a distributed coordinate measurement device was tested which consisted of a network of Rotary-Laser Automatic Theodolites (R-LATs), this system is known commercially as indoor GPS (iGPS). The method was found to be practical and was used to estimate that the uncertainty of measurement for the basic iGPS system is approximately 1 mm at a 95% confidence level throughout a measurement volume of approximately 10 m × 10 m × 1.5 m. © 2010 IOP Publishing Ltd.

Internet use by patients with bipolar disorder:results from an international multisite survey

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with bipolar disorder diagnosis in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Online information seeking by patients with bipolar disorder:results from an international multisite survey

Background: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. Methods: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. Results: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. Conclusion: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Verification of the indoor gps system by comparison with points calibrated using a network of laser tracker measurements

This paper details a method of determining the uncertainty of dimensional measurement for a three dimensional coordinate measurement machine. An experimental procedure was developed to compare three dimensional coordinate measurements with calibrated reference points. The reference standard used to calibrate these reference points was a fringe counting interferometer with the multilateration technique employed to establish three dimensional coordinates. This is an extension of the established technique of comparing measured lengths with calibrated lengths. Specifically a distributed coordinate measurement device was tested which consisted of a network of Rotary-Laser Automatic Theodolites (R-LATs), this system is known commercially as indoor GPS (iGPS). The method was found to be practical and able to establish that the expanded uncertainty of the basic iGPS system was approximately 1 mm at a 95% confidence level. © Springer-Verlag Berlin Heidelberg 2010.

Reactions of copper macrocycles with antioxidants and HOCl:potential for biological redox sensing

A series of simple copper N(2)S(2) macrocycles were examined for their potential as biological redox sensors, following previous characterization of their redox potentials and crystal structures. The divalent species were reduced by glutathione or ascorbate at a biologically relevant pH in aqueous buffer. A less efficient reduction was also achieved by vitamin E in DMSO. Oxidation of the corresponding univalent copper species by sodium hypochlorite resulted in only partial (~65 %) recovery of the divalent form. This was concluded to be due to competition between metal oxidation and ligand oxidation, which is believed to contribute to macrocycle demetallation. Electrospray mass spectrometry confirmed that ligand oxidation had occurred. Moreover, the macrocyclic complexes could be demetallated by incubation with EDTA and bovine serum albumin, demonstrating that they would be inappropriate for use in biological systems. The susceptibility to oxidation and demetallation was hypothesized to be due to oxidation of the secondary amines. Consequently these were modified to incorporate additional oxygen donor atoms. This modification led to greater resistance to demetallation and ligand oxidation, providing a better platform for further development of copper macrocycles as redox sensors for use in biological systems.

The in vivo susceptibility of Leishmania donovani to sodium stibogluconate is drug specific and can be reversed by inhibiting glutathione biosynthesis

Resistance to pentavallent antimonial (Sb-v) agents such as sodium stibogluconate (SSG) is creating a major problem in the treatment of visceral leishmaniasis. In the present study the in vivo susceptibilities of Leishmania donovani strains, typed as SSG resistant (strain 200011) or SSG sensitive (strain 200016) on the basis of their responses to a single SSG dose of 300 mg of Sb-v/kg of body weight, to other antileishmanial drugs were determined. In addition, the role of glutathione in SSG resistance was investigated by determining the influence on SSG treatment of concomitant treatment with a nonionic surfactant vesicle formulation of buthionine sulfoximine (BSO), a specific inhibitor of the enzyme gamma-glutamylcysteine synthetase which is involved in glutathione biosynthesis, and SSG, on the efficacy of SSG treatment. L. donovani strains that were SSG resistant (strain 200011) and SSG sensitive (strain 200016) were equally susceptible to in vivo treatment with miltefosine, paromomycin and amphotericin B (Fungizone and AmBisome) formulations. Combined treatment with SSG and vesicular BSO significantly increased the in vivo efficacy of SSG against both the 200011 and the 200016 L. donovani strains. However, joint treatment that included high SSG doses was unexpectedly associated with toxicity. Measurement of glutathione levels in the spleens and livers of treated mice showed that the ability of the combined therapy to inhibit glutathione levels was also dependent on the SSG dose used and that the combined treatment exhibited organ-dependent effects. The SSG resistance exhibited by the L. donovani strains was not associated with cross-resistance to other classes of compounds and could be reversed by treatment with an inhibitor of glutathione biosynthesis, indicating that clinical resistance to antimonial drugs should not affect the antileishmanial efficacies of alternative drugs. In addition, it should be possible to identify a treatment regimen that could reverse antimony resistance.

Residue-specific investigation of the relationship between oxidation and activity of a dual specificity phosphatase by mass spectrometry

Redox regulation of signalling pathways is critical in proliferation and apoptosis; redox imbalance can lead to pathologies such as inflammation and cancer. Vaccinia H1-related protein (VHR; DUSP3) is a dual-specificity phosphatase important in controlling MAP kinase activity during cell cycle. the active-site motif contains a cysteine that acts as a nucleophile during catalysis. We used VHR to investigate the effect of oxidation in vitro on phosphatase activity, with the aim of determining how the profile of site-specific modification related to catalytic activity. Recombinant human VHR was expressed in E. coli and purified using a GST-tag. Protein was subjected to oxidation with various concentrations of SIN-1 or tetranitromethane (TNM) as nitrating agents, or HOCl. the activity was assayed using either 3-O-methylfluorescein phosphate with fluorescence detection or PIP3 by phosphate release with malachite green. the sites of oxidation were mapped using HPLC coupled to tandem mass spectrometry on an ABSciex 5600TripleTOF following in-gel digestion. More than 25 different concentration-dependent oxidative modifications to the protein were detected, including oxidations of methionine, cysteine, histidine, lysine, proline and tyrosine, and the % oxidized peptide (versus unmodified peptide) was determined from the extracted ion chromatograms. Unsurprisingly, methionine residues were very susceptible to oxidation, but there was a significant different in the extent of their oxidation. Similarly, tyrosine residues varied greatly in their modifications: Y85 and Y138 were readily nitrated, whereas Y38, Y78 and Y101 showed little modification. Y138 must be phosphorylated for MAPK phosphatase activity, so this susceptibility impacts on signalling pathways. Di- and tri- oxidations of cysteine residues were observed, but did not correlate directly with loss of activity. Overall, the catalytic activity did not correlate with redox state of any individual residue, but the total oxidative load correlated with treatment concentration and activity. This study provides the first comprehensive analysis of oxidation modifications of VHR, and demonstrates both heterogenous oxidant effects and differential residue susceptibility in a signalling phosphatase.

Dimethylsulfoxide oxidizes glutathione in vitro and in human erythrocytes:kinetic analysis by 1H NMR

The interaction of dimethylsulfoxide (Me2SO) with glutathione was investigated under non-equilibrium conditions in solution using 1H NMR and in intact erythrocytes using 1H spin-echo NMR. In solution the reaction was observed to follow second-order kinetics (Rate = k1[glutathione][Me2SO]) at 300 K pH 7.4, ksol = 4.7 × 10-5 mol -1 L1 s-1. In intact erythrocytes the rate constant for the cellular environment, kcell, was found to be slightly larger at 8.1 × 10-5 mol-1 L1 s-1. Furthermore, the reaction of Me2SO with erythrocyte glutathione showed a biphasic dependence on the Me2SO concentration, with little oxidation of glutathione occurring until the Me2SO concentration exceeded 0.5 mol L-1. The results suggest that at lower concentrations, Me2SO can be effectively removed, most probably by reaction with glutathione, which is regenerated by glutathione reductase, although preferential reaction with other cellular components (e.g., membrane or cellular thiols) cannot be ruled out. Thus the concentrations of Me2SO that are commonly used in cryopreservation of mammalian cells (∼1.4 mol L-1) can cause oxidation of intracellular glutathione.