A bridged loop gap resonator (BLGR) for small animal imaging by 1.5 T MRI systems.

A bridged loop gap resonator (BLGR) was developed as a transmit and receive coil for a mobile insert to be used for small animal proton imaging by 1.5 T MRI devices. The insert system has its own gradient system, radio frequency (RF) transmit and receive coil, and control and signal processing unit. The reflection S11 and transmission S21 parameters, quality factor (Q), sensitivity, signal to noise ratio (SNR), and maps of the static (B0) and RF (B1) magnetic flux densities were measured. The RF coil was developed starting from a loop gap resonator (LGR) for a balanced LGR and a shielded balanced LGR for a shielded bridged balanced LGR. The purpose of developing this device is to minimize the influence of the sample and surroundings on the RF coil parameters. The final design of the BLGR does not require retuning after a sample change. A 3D image of a mouse in formalin was acquired with a fast low angle shot (FLASH) MRI sequence. The SNR was calculated from one FLASH image. The signal for SNR calculation was acquired from a gadolinium-doped water sample and the noise from the air outside of the sample. This article verifies that the BLGR is viable for small animal nuclear magnetic resonance imaging at 1.5 T and is independent of sample size and material.

Insights into possibilities for grouping and read-across for nanomaterials in EU chemicals legislation.

This paper presents a comprehensive review of European Union (EU) legislation addressing the safety of chemical substances, and possibilities within each piece of legislation for applying grouping and read-across approaches for the assessment of nanomaterials (NMs). Hence, this review considers both the overarching regulation of chemical substances under REACH (Regulation (EC) No 1907/2006 on registration, evaluation, authorization, and restriction of chemicals) and CLP (Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures) and the sector-specific pieces of legislation for cosmetic, plant protection and biocidal products, and legislation addressing food, novel food, and food contact materials. The relevant supporting documents (e.g. guidance documents) regarding each piece of legislation were identified and reviewed, considering the relevant technical and scientific literature. Prospective regulatory needs for implementing grouping in the assessment of NMs were identified, and the question whether each particular piece of legislation permits the use of grouping and read-across to address information gaps was answered.

Correction to: The help for people with money, employment or housing problems (HOPE) intervention: pilot randomised trial with mixed methods feasibility research.

[This corrects the article DOI: 10.1186/s40814-018-0365-6.].

The help for people with money, employment or housing problems (HOPE) intervention: pilot randomised trial with mixed methods feasibility research.

BACKGROUND: Job loss, austerity measures, financial difficulties and house repossession contribute to the risk of self-harm and suicide during recessions. Navigating the benefits system and accessing sources of welfare and debt advice is a difficult experience for vulnerable people, further contributing to their distress. Whilst there is some evidence that advice-type interventions can lead to financial gain, there is mixed evidence for their effectiveness in improving mental health in those experiencing financial difficulties. There have been no interventions targeting those who have self-harmed due to economic hardship. METHODS: Our aim was to determine the feasibility and acceptability of a brief psychosocial intervention (the 'HOPE' service) for people presenting to hospital emergency departments (ED) following self-harm or in acute distress because of financial, employment or welfare (benefit) difficulties. Nineteen people consented to random allocation to the intervention or control arm on a 2:1 basis. Participants randomised to the intervention arm (n = 13) received up to six sessions of 1:1 support provided by community support staff trained in Motivational Interviewing (MI). Control participants (n = 6) received a one-off session signposting them to relevant support organisations. Fourteen participants were followed up after 3 months. Participants and mental health workers took part in qualitative interviews. The acceptability of outcome measures including the PHQ-9, GAD-7, repeat self-harm, EQ5D-5 L and questions about debt, employment and welfare benefits were explored. RESULTS: Interviews indicated the main benefits of the service as the resolution of specific financial problems and receiving support when participants were feeling most vulnerable. Randomisation was acceptable to most participants although not always fully understood and control participants could be disappointed. Recruitment was slow (1-2 per month). The outcome measures were acceptable and appeared sensitive to change. DISCUSSION: The HOPE intervention is feasible and acceptable. There was evidence of need and it is a relatively inexpensive intervention. Refining aspects of the intervention would be straightforward. A full-scale RCT would be feasible, if broadened eligibility criteria led to increased recruitment and improvements were made to staff training and support. TRIAL REGISTRATION: ISRCTN58531248.

Vaccine-Associated Maintenance of Epithelial Integrity Correlated With Protection Against Virus Entry.

To identify the mechanisms by which human immunodeficiency virus type 1 (HIV-1) might penetrate the epithelial barrier during sexual transmission to women and the mechanisms of vaccine-associated protection against entry, we characterized early epithelial responses to vaginal inoculation of simian immunodeficiency virus strain mac251 (SIVmac251) in naive or SIVmac239Δnef-vaccinated rhesus macaques. Vaginal inoculation induced an early stress response in the cervicovaginal epithelium, which was associated with impaired epithelial integrity, damaged barrier function, and virus and bacterial translocation. In vaccinated animals, early stress responses were suppressed, and the maintenance of epithelial barrier integrity correlated with prevention of virus entry. These vaccine-protective effects were associated with a previously described mucosal system for locally producing and concentrating trimeric gp41 antibodies at the mucosal interface and with formation of SIV-specific immune complexes that block the stress responses via binding to the epithelial receptor FCGR2B and subsequent inhibitory signaling. Thus, blocking virus entry may be one protective mechanism by which locally concentrated non-neutralizing Ab might prevent HIV sexual transmission to women.

Vaccine-modified NF-kB and GR signaling in cervicovaginal epithelium correlates with protection.

Cervicovaginal epithelium plays a critical role in determining the outcome of virus transmission in the female reproductive tract (FRT) by initiating or suppressing transmission-facilitating mucosal immune responses in naïve and SIVmac239Δnef-vaccinated animals, respectively. In this study, we examined the very early responses of cervical epithelium within 24 h after vaginal exposure to SIV in naive and SIVmac239Δnef-vaccinated rhesus macaques. Using both ex vivo and in vivo experimental systems, we found that vaginal exposure to SIV rapidly induces a broad spectrum of pro-inflammatory responses in the epithelium associated with a reciprocal regulation of NF-kB and glucocorticoid receptor (GR) signaling pathways. Conversely, maintenance of high-level GR expression and suppression of NF-kB expression in the epithelium were associated with an immunologically quiescent state in the FRT mucosa and protection against vaginal challenge in SIVmac239Δnef-vaccinated animals. We show that the immunologically quiescent state is induced by FCGR2B-immune complexes interactions that modify the reciprocal regulation of NF-kB and GR signaling pathways. Our results suggest that targeting the balance of NF-kB and GR signaling in early cervicovaginal epithelium responses could moderate mucosal inflammation and target cell availability after vaginal infection, thereby providing a complementary approach to current prevention strategies.

How extreme dieting becomes compulsive: A novel hypothesis for the role of anxiety in the development and maintenance of anorexia nervosa.

The US National Institute of Mental Health's Research Domain Criteria (NIMH RDoC) advocates the study of features common to psychiatric conditions. This transdiagnostic approach has recently been adopted into the study of anorexia nervosa (AN), an illness that can be considered compulsive in nature. This has led to the development of an account of AN that identifies key roles for the heightened reinforcement of starvation, leading to its excessive repetition, and goal-directed system dysfunction. Considering models of illness in other compulsive disorders, we extend the existing account to explain the emergence of reinforcement and goal-directed system abnormalities in AN, proposing that anxiety is central to both processes. As such we emphasise the particular importance of the anxiolytic effects of starvation, over other reinforcing outcomes, in encouraging the continuation of starvation within a model that proposes a number of mechanisms by which anxiety operates in the development and maintenance of AN. We suggest the psychopathology of AN mediates the relationship between the anxiolytic effects of starvation and excessive repetition of starvation, and that compulsive starvation has reciprocal effects on its determinants. We thus account for the emergence of symptoms of AN other than compulsive starvation, and for the relationship between different features of the disorder. By extending and adapting an existing explanation of AN, we provide a richer aetiological model that invites new research questions and could inform novel approaches to prevention and treatment.

HOPE: Help fOr People with money, employment, benefit or housing problems: study protocol for a randomised controlled trial.

BACKGROUND: Self-harm and suicide increase in times of economic recession. Factors including job loss, austerity measures, financial difficulties and house repossession contribute to the risk. Vulnerable individuals commonly experience difficulties in navigating the benefits system and in accessing the available sources of welfare and debt advice, and this contributes to their distress. Our aim is to determine the feasibility and acceptability of a brief psychosocial intervention (the "HOPE" service) for people presenting to hospital emergency departments (ED) following self-harm or in acute distress because of financial, employment, or welfare (benefit) difficulties. METHOD: A pilot study including randomisation will be employed to determine whether it is possible to undertake a full-scale trial. Twenty people presenting to the ED who have self-harmed, have suicidal thoughts and depression and/or are in crisis and where financial, employment or benefit problems are cited as contributory factors will be asked to consent to random allocation to the intervention or control arm on a 2:1 basis. People who require secondary mental health follow-up will be excluded. Those randomised to the intervention arm will receive up to six sessions with a mental health worker who will provide practical help with financial and other problems. The mental health worker will use the motivational interviewing method in their interactions with participants. Control participants will receive one session signposting them to existing relevant support organisations. Participants will be followed up after 3 months. Participants and the mental health workers will take part in qualitative interviews to enable refinement of the intervention. The acceptability of outcome measures including the PHQ-9, GAD-7, repeat self-harm, EQ5D-5L and questions about debt, employment and welfare benefits will be explored. DISCUSSION: This study will assess whether a full-scale randomised trial of this novel intervention to prevent self-harm among those distressed because of financial difficulties is feasible, including the acceptability of randomisation, potential rate of recruitment and the acceptability of outcome measures. TRIAL REGISTRATION: ISRCTN58531248.

Assessment of colorectal length using the electromagnetic capsule tracking system: a comparative validation study in healthy subjects.

AIM: We aimed to determine colorectal length with the 3D-Transit system by describing a 'centreline' of capsule movement and comparing it with known anatomy, as determined by magnetic resonance imaging (MRI). Further, we aimed to test the day-to-day variation of colorectal length assessed with the system. METHOD: The 3D-Transit system consists of electromagnetic capsules that can be tracked as they traverse the gastrointestinal tract. Twenty-five healthy subjects were examined with both 3D-Transit and MRI. Another 21 healthy subjects were examined with 3D-Transit on two consecutive days. RESULTS: Computation of colorectal length from capsule passage was possible for 60 of the 67 3D-Transit recordings. The length of the colorectum measured with MRI and 3D-Transit was 95 (75-153) cm and 99 (77-147) cm, respectively (P = 0.15). The coefficient of variation (CV) between MRI and 3D-Transit was 7.8%. Apart from the caecum/ascending colon being 26% (P = 0.002) shorter on MRI, there were no other differences in total or segmental colorectal lengths between methods (all P > 0.05). The length of the colorectum measured with 3D-Transit on two consecutive days was 102 (73-119) cm and 103 (75-123) cm (P = 0.67). The CV between days was 7.3%. CONCLUSION: The 3D-Transit system allows accurate and reliable determination of colorectal length compared with MRI-derived colorectal length and between days. Antegrade or retrograde capsule movement relative to this centreline, as well as the length and speed of movements, may be determined by future studies to allow better classification and treatment in patients with dysmotility.

Minute Impurities Contribute Significantly to Olfactory Receptor Ligand Studies: Tales from Testing the Vibration Theory.

Several studies have attempted to test the vibrational hypothesis of odorant receptor activation in behavioral and physiological studies using deuterated compounds as odorants. The results have been mixed. Here, we attempted to test how deuterated compounds activate odorant receptors using calcium imaging of the fruit fly antennal lobe. We found specific activation of one area of the antennal lobe corresponding to inputs from a specific receptor. However, upon more detailed analysis, we discovered that an impurity of 0.0006% ethyl acetate in a chemical sample of benzaldehyde-d5 was entirely responsible for a sizable odorant-evoked response in Drosophila melanogaster olfactory receptor cells expressing dOr42b. Without gas chromatographic purification within the experimental setup, this impurity would have created a difference in the responses of deuterated and nondeuterated benzaldehyde, suggesting that dOr42b be a vibration sensitive receptor, which we show here not to be the case. Our results point to a broad problem in the literature on use of non-GC-pure compounds to test receptor selectivity, and we suggest how the limitations can be overcome in future studies.

Analysis of 2D NMR relaxation data using Chisholm approximations.

To analyze 2D NMR relaxation data based on a discrete delta-like relaxation map we extended the Padé-Laplace method to two dimensions. We approximate the forward Laplace image of the time domain signal by a Chisholm approximation, i.e. a rational polynomial in two dimensions. The poles and residues of this approximation correspond to the relaxation rates and weighting factors of the underlying relaxation map. In this work we explain the principle ideas of our algorithm and demonstrate its applicability. Therefore we compare the inversion results of the Chisholm approximation and Tikhonov regularization method as a function of SNR when the investigated signal is based on a given discrete relaxation map. Our algorithm proved to be reliable for SNRs larger than 50 and is able to compete with the Tikhonov regularization method. Furthermore we show that our method is also able to detect the simulated relaxation compartments of narrow Gaussian distributions with widths less or equal than 0.05s-1. Finally we investigate the resolution limit with experimental data. For a SNR of 750 the Chisholm approximation method was able to resolve two relaxation compartments in 8 of 10 cases when both compartments differ by a factor of 1.7.

A simple metal staining procedure for identification and visualization of single cells by LA-ICP-MS.

High lateral resolution of metal detection in single cells by use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) demands powerful staining methods. In this work different staining procedures for the single cell analysis with LA-ICP-MS were optimized. An iridium intercalator was utilized to stain the cell nuclei whereas the whole cell was stained by the use of maleimido-mono-amide-DOTA (mDOTA) complexing lanthanide(iii) ions. The content of the artificially introduced metals per cell was quantified using a matrix matched calibration approach based on cellulose membranes onto which standards were spotted by a microarray spotter. Absolute metal stain amounts in the range of 2.34 to 9.81 femtomole per cell were determined. The metal staining procedures allow direct identification and visualization of single cells and their cell compartments by element microscopy without the use of bright field images of the sample.

Inelastic non-Newtonian flow over heterogeneously slippery surfaces.

In this study, we investigated inelastic non-Newtonian fluid flow over heterogeneously slippery surfaces. First, we simulated the flow of aqueous xanthan gum solutions over a bubble mattress, which is a superhydrophobic surface consisting of transversely positioned no-slip walls and no-shear gas bubbles. The results reveal that for shear-thinning fluids wall slip can be increased significantly, provided that the system is operated in the shear-thinning regime. For a 0.2 wt% xanthan gum solution with a power-law index of n=0.4, the numerical results indicate that wall slip can be enhanced 3.2 times when compared to a Newtonian liquid. This enhancement factor was also predicted from a theoretical analysis, which gave an expression for the maximum slip length that can be attained over flat, heterogeneously slippery surfaces. Although this equation was derived for a no-slip/no-shear unit length that is much larger than the typical size of the system, we found that it can also be used to predict the enhancement in the regime where the slip length is proportional to the size of the no-shear region or the bubble width. The results could be coupled to the hydrodynamic development or entrance length of the system, as maximum wall slip is only reached when the fluid flow can fully adapt to the no-slip and no-shear conditions at the wall.

Epithelium-innate immune cell axis in mucosal responses to SIV.

In the SIV (simian immunodeficiency virus)-rhesus macaque model of HIV-1 (human immunodeficiency virus type I) transmission to women, one hallmark of the mucosal response to exposure to high doses of SIV is CD4 T-cell recruitment that fuels local virus expansion in early infection. In this study, we systematically analyzed the cellular events and chemoattractant profiles in cervical tissues that precede CD4 T-cell recruitment. We show that vaginal exposure to the SIV inoculum rapidly induces chemokine expression in cervical epithelium including CCL3, CCL20, and CXCL8. The chemokine expression is associated with early recruitment of macrophages and plasmacytoid dendritic cells that are co-clustered underneath the cervical epithelium. Production of chemokines CCL3 and CXCL8 by these cells in turn generates a chemokine gradient that is spatially correlated with the recruitment of CD4 T cells. We further show that the protection of SIVmac239Δnef vaccination against vaginal challenge is correlated with the absence of this epithelium-innate immune cell-CD4 T-cell axis response in the cervical mucosa. Our results reveal a critical role for cervical epithelium in initiating early mucosal responses to vaginal infection, highlight an important role for macrophages in target cell recruitment, and provide further evidence of a paradoxical dampening effect of a protective vaccine on these early mucosal responses.

Regional gastrointestinal transit times in severe ulcerative colitis.

BACKGROUND: Gastrointestinal (GI) dysmotility may present secondary to inflammatory bowel disease. The main aim of this study was to investigate GI motility in ulcerative colitis (UC) patients during severe disease activity. METHODS: Twenty patients with severe UC were studied with a novel telemetric capsule system (3D-Transit) designed for minimally invasive, ambulatory assessment of total and regional GI transit times. Ten patients were available for follow-up during remission. Data were compared to those of 20 healthy subjects (HS). KEY RESULTS: Total GI transit time was significantly longer in patients with severe UC (median 44.5 h [range 9.9-102.7 h]) than in HS (median 27.6 h [range 9.6-56.4 h]) (p = 0.032). Additionally, during severe UC, transit time was prolonged through the proximal colon (p = 0.003) and there were strong trends toward longer than normal small intestinal transit time (HS: median 4.9 h [range 3.4-8.3 h] vs severe UC patients: median 5.9 h [range 3.9-11.9 h]; p = 0.053) and colorectal transit times (HS: median 18.2 h [range 1.5-43.7] vs severe UC patients: median 34.9 h [range 0.4-90.9 h]; p = 0.056). Our data further indicate that total GI and colorectal transit times may be prolonged in UC during early remission. CONCLUSIONS & INFERENCES: Total GI transit times are significantly prolonged during severe UC.

Pilot study trialling a new ambulatory method for the clinical assessment of regional gastrointestinal transit using multiple electromagnetic capsules.

BACKGROUND: Gastrointestinal (GI) motor disorders often involve several regions of the GI tract. Therefore, easy and safe assessment of whole gut and regional motility is valuable for more precise diagnosis. 3D-Transit is a novel method for ambulatory evaluation of total and regional gastrointestinal transit times (GITT) based on the anatomical localization of ingestible electromagnetic capsules. The main purpose of this study was to test the performance of the 3D-Transit system. METHODS: Twenty healthy volunteers each ingested three electromagnetic capsules over a period of two consecutive days. Standard radio-opaque markers (ROM) were also ingested to assess the agreement between total GITT obtained with both methods. KEY RESULTS: Investigations were well-tolerated and three capsules could be tracked simultaneously with minimal data loss (Capsule 1: median: 0.2% of time (range 0-25.3%). Region specific contraction patterns were identified and used for computation of total and regional GITT in all subjects. Inter-observer agreement was 100% for total GITT (median variation 0%) but less for regional GITT. Day-to-day and diurnal variations were significant for total and regional GITT. Total GITT assessed by 3D-Transit capsules were moderately well-correlated to those assessed with standard ROM (Spearman's rho = 0.7). CONCLUSIONS & INFERENCES: 3D-transit is a well-tolerated and minimal invasive ambulatory method for assessment of GI motility. By providing both total and regional transit times, the 3D-Transit system holds great promise for future clinical studies of GI function in health and disease.

Apparent rate constant mapping using hyperpolarized [1-(13)C]pyruvate.

Hyperpolarization of [1-13C]pyruvate in solution allows real-time measurement of uptake and metabolism using MR spectroscopic methods. After injection and perfusion, pyruvate is taken up by the cells and enzymatically metabolized into downstream metabolites such as lactate, alanine, and bicarbonate. In this work, we present comprehensive methods for the quantification and interpretation of hyperpolarized 13C metabolite signals. First, a time-domain spectral fitting method is described for the decomposition of FID signals into their metabolic constituents. For this purpose, the required chemical shift frequencies are automatically estimated using a matching pursuit algorithm. Second, a time-discretized formulation of the two-site exchange kinetic model is used to quantify metabolite signal dynamics by two characteristic rate constants in the form of (i) an apparent build-up rate (quantifying the build-up of downstream metabolites from the pyruvate substrate) and (ii) an effective decay rate (summarizing signal depletion due to repetitive excitation, T1-relaxation and backward conversion). The presented spectral and kinetic quantification were experimentally verified in vitro and in vivo using hyperpolarized [1-13C]pyruvate. Using temporally resolved IDEAL spiral CSI, spatially resolved apparent rate constant maps are also extracted. In comparison to single metabolite images, apparent build-up rate constant maps provide improved contrast by emphasizing metabolically active tissues (e.g. tumors) and suppression of high perfusion regions with low conversion (e.g. blood vessels). Apparent build-up rate constant mapping provides a novel quantitative image contrast for the characterization of metabolic activity. Its possible implementation as a quantitative standard will be subject to further studies.

Control of slippage with tunable bubble mattresses.

Tailoring the hydrodynamic boundary condition is essential for both applied and fundamental aspects of drag reduction. Hydrodynamic friction on superhydrophobic substrates providing gas-liquid interfaces can potentially be optimized by controlling the interface geometry. Therefore, establishing stable and optimal interfaces is crucial but rather challenging. Here we present unique superhydrophobic microfluidic devices that allow the presence of stable and controllable microbubbles at the boundary of microchannels. We experimentally and numerically examine the effect of microbubble geometry on the slippage at high resolution. The effective slip length is obtained for a wide range of protrusion angles, θ, of the microbubbles into the flow, using a microparticle image velocimetry technique. Our numerical results reveal a maximum effective slip length, corresponding to a 23% drag reduction at an optimal θ ≈ 10°. In agreement with the simulation results, our measurements correspond to up to 21% drag reduction when θ is in the range of -2° to 12°. The experimental and numerical results reveal a decrease in slip length with increasing protrusion angles when >/~ 10°. Such microfluidic devices with tunable slippage are essential for the amplified interfacial transport of fluids and particles.

The C-terminal domain of the Uup protein is a DNA-binding coiled coil motif.

The bacterial Uup protein belongs to the REG subfamily of soluble ATP-binding cassette (ABC) ATPases, and is implicated in precise excision of transposons. In Escherichia coli, the uup gene encodes a 72 kDa polypeptide that comprises two ABC domains, separated by a linker region, and a 12kDa C-terminal domain (CTD). Uup binds double-stranded DNA with no sequence specificity, and we previously demonstrated that the CTD domain is a crucial region that participates in DNA-binding activity. We report herein the NMR structure of Uup CTD, consisting of an intramolecular antiparallel two-stranded coiled coil motif. Structural comparison with analogous coiled coil domains reveals that Uup CTD contains an atypical 3(10)-helix in the α-hairpin region that contributes to the hydrophobic core. Using NMR titration experiments, we identified residues of the CTD domain involved in the binding to double-stranded DNA. These residues are located on two opposite surfaces at the base of the coiled coil, formed by the N- and C-terminal extremities, where a strictly conserved proline residue induces an overwinding of the coiled coil. Finally, preliminary analysis of NMR spectra recorded on distinct Uup constructs precludes a fully flexible positioning of the CTD domain in full-length Uup. These structural data are the first reported for a non-ATPase domain within ABC REG subfamily.