Transcutaneous delivery of anti-arthritic agents

There is a substantial clinical need for improved therapeutic systems for the treatment of arthritis. This thesis concerns the development of a novel medication that is applied to the skin directly overlying the areas affected. The system comprises the co-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), plus a non-steroidal anti-inflammatory (NSAID) drug. The source of EPA and DHA is fish oil which contains high proportions of these compounds and, although still largely considered a 'neutraceutical', its therapeutic value is supported by an ever increasing body of evidence, both scientific and anecdotal. The NSAID examined was ketoprofen, a widely used drug, found in a number of topical preparations. Synergistic action involving the two substances would be expected to provide a multi-faceted attack on the aetiology of arthritis. Ketoprofen and EPA/DHA were successfully delivered across full-thickness porcine ear skin in-vitro, although the presence of thickening agent retarded permeation of the latter. The successful delivery of these compounds into the joint capsule of a porcine forelimb was also demonstrated in-vitro. A novel transcutaneous delivery model was developed and used to provide preliminary data for the uptake of EPA into an ex-vivo cartilage ex-plant post transcutaneous permeation. The last three chapters can be considered collectively as an investigation into the unexpected phenomenon of enhancement of EPA/DHA by ketoprofen and two main hypotheses were tested firstly, the formation of a Jt-jc ketoprofen / EPA complex - the existence of which was strongly supported by the NMR/molecular modelling work of Chapter 8 secondly, the ketoprofen inhibition of epidermal enzymes active upon EPA, discussed in Chapters 7 and 9. In summary, the development of a novel dual-action, transcutaneous anti-arthritic formulation is possible and has been supported by this work. Furthermore, a hitherto unknown topical delivery mechanism has been elucidated.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

RETROCAM: A Versatile Optical Imager for Synoptic Studies

We present RETROCAM, an auxiliary CCD camera that can be rapidly inserted into the optical beam of the MDM 2.4m telescope. The speed and ease of reconfiguring the telescope to use the imager and a straightforward user interface permit the camera to be used during the course of other observing programs. This in turn encourages RETROCAM's use for a variety of monitoring projects.Comment: 6 pages, 6 figures, Accepted by A

The Rad4TopBP1 ATR-Activation domain functions in G1/S phase in a chromatin-dependent manner

DNA damage checkpoint activation can be subdivided in two steps: initial activation and signal amplification. The events distinguishing these two phases and their genetic determinants remain obscure. TopBP1, a mediator protein containing multiple BRCT domains, binds to and activates the ATR/ATRIP complex through its ATR-Activation Domain (AAD). We show that Schizosaccharomyces pombe Rad4TopBP1 AAD–defective strains are DNA damage sensitive during G1/S-phase, but not during G2. Using lacO-LacI tethering, we developed a DNA damage–independent assay for checkpoint activation that is Rad4TopBP1 AAD–dependent. In this assay, checkpoint activation requires histone H2A phosphorylation, the interaction between TopBP1 and the 9-1-1 complex, and is mediated by the phospho-binding activity of Crb253BP1. Consistent with a model where Rad4TopBP1 AAD–dependent checkpoint activation is ssDNA/RPA–independent and functions to amplify otherwise weak checkpoint signals, we demonstrate that the Rad4TopBP1 AAD is important for Chk1 phosphorylation when resection is limited in G2 by ablation of the resecting nuclease, Exo1. We also show that the Rad4TopBP1 AAD acts additively with a Rad9 AAD in G1/S phase but not G2. We propose that AAD–dependent Rad3ATR checkpoint amplification is particularly important when DNA resection is limiting. In S. pombe, this manifests in G1/S phase and relies on protein– chromatin interactions

Impairment of Cycling Capacity in the Heat in Well-Trained Endurance Athletes After High-Intensity Short-Term Heat Acclimation

Purpose: to investigate the effects of short-term, high-intensity interval-training (HIIT) heat acclimation (HA). Methods: male cyclists/triathletes were assigned into either an HA (n = 13) or a comparison (COMP, n = 10) group. HA completed 3 cycling heat stress tests (HSTs) to exhaustion (60% Wmax; HST1, pre-HA; HST2, post-HA; HST3, 7 d post-HA). HA consisted of 30-min bouts of HIIT cycling (6 min at 50% Wmax, then 12 × 1-min 100%-Wmax bouts with 1-min rests between bouts) on 5 consecutive days. COMP completed HST1 and HST2 only. HST and HA trials were conducted in 35°C/50% relative humidity. Cycling capacity and physiological and perceptual data were recorded. Results: cycling capacity was impaired after HIIT HA (77.2 [34.2] min vs 56.2 [24.4] min, P = .03) and did not return to baseline after 7 d of no HA (59.2 [37.4] min). Capacity in HST1 and HST2 was similar in COMP (43.5 [8.3] min vs 46.8 [15.7] min, P = .54). HIIT HA lowered resting rectal (37.0°C [0.3°C] vs 36.8°C [0.2°C], P = .05) and body temperature (36.0°C [0.3°C] vs 35.8°C [0.3°C], P = .03) in HST2 compared with HST1 and lowered mean skin temperature (35.4°C [0.5°C] vs 35.1°C [0.3°C], P = .02) and perceived strain on day 5 compared with day 1 of HA. All other data were unaffected. Conclusions: cycling capacity was impaired in the heat after 5 d of consecutive HIIT HA despite some heat adaptation. Based on data, this approach is not recommended for athletes preparing to compete in the heat; however, it is possible that it may be beneficial if a state of overreaching is avoided

Depressive symptoms in asymptomatic stage B heart failure with Type II diabetic mellitus.

BackgroundThe presence of concomitant Type II diabetic mellitus (T2DM) and depressive symptoms adversely affects individuals with symptomatic heart failure (HF).HypothesisIn presymptomatic stage B HF, this study hypothesized the presence of greater inflammation and depressive symptoms in T2DM as compared to non-T2DM Stage B patients.MethodsThis cross-sectional study examined clinical parameters, inflammatory biomarkers, and depressive symptoms in 349 T2DM and non-T2DM men with asymptomatic stage B HF (mean age 66.4 years ±10.1; range 30-91).ResultsFewer diabetic HF patients had left ventricular (LV) systolic dysfunction (P < .05) although more had LV diastolic dysfunction (P < .001). A higher percentage of T2DM HF patients were taking ACE-inhibitors, beta-blockers, calcium channel blockers, statins, and diuretics (P values < .05). T2DM HF patients had higher circulating levels of interleukin-6 (IL-6) (P < .01), tumor necrosis factor-alpha (P < .01), and soluble ST2 (sST2) (P < .01) and reported more somatic/affective depressive symptoms (Beck Depression Inventory II) (P < .05) but not cognitive/affective depressive symptoms (P = .20). Among all patients, in a multiple regression analysis predicting presence of somatic/affective depressive symptoms, sST2 (P = .026), IL-6 (P = .010), B-type natriuretic peptide (P = .016), and sleep (Pittsburgh Sleep Quality Index [P < .001]) were significant predictors (overall model F = 15.39, P < .001, adjusted R2 = .207).ConclusionsSomatic/affective but not cognitive/affective depressive symptoms are elevated in asymptomatic HF patients with T2DM patients. Linkages with elevated inflammatory and cardiac relevant biomarkers suggest shared pathophysiological mechanisms among T2DM HF patients with somatic depression, and these conditions are responsive to routine interventions, including behavioral. Copyright © 2019 John Wiley & Sons, Ltd

SuperCam, a 64-pixel heterodyne imaging array for the 870 micron atmospheric window

We report on the development of SuperCam, a 64 pixel, superheterodyne camera designed for operation in the astrophysically important 870 micron atmospheric window. SuperCam will be used to answer fundamental questions about the physics and chemistry of molecular clouds in the Galaxy and their direct relation to star and planet formation. The advent of such a system will provide an order of magnitude increase in mapping speed over what is now available and revolutionize how observational astronomy is performed in this important wavelength regime. Unlike the situation with bolometric detectors, heterodyne receiver systems are coherent, retaining information about both the amplitude and phase of the incident photon stream. From this information a high resolution spectrum of the incident light can be obtained without multiplexing. SuperCam will be constructed by stacking eight, 1x8 rows of fixed tuned, SIS mixers. The IF output of each mixer will be connected to a low-noise, broadband MMIC amplifier integrated into the mixer block. The instantaneous IF bandwidth of each pixel will be ~2 GHz, with a center frequency of 5 GHz. A spectrum of the central 500 MHz of each IF band will be provided by the array spectrometer. Local oscillator power is provided by a frequency multiplier whose output is divided between the pixels by using a matrix of waveguide power dividers. The mixer array will be cooled to 4K by a closed-cycle refrigeration system. SuperCam will reside at the Cassegrain focus of the 10m Heinrich Hertz telescope (HHT). A prototype single row of the array will be tested on the HHT in 2006, with the first engineering run of the full array in late 2007. The array is designed and constructed so that it may be readily scaled to higher frequencies.Comment: 12 pages, 14 figures, to be published in the Proceedings of SPIE Vol. 6275, "Astronomical Telescopes and Instrumentation, Millimeter and Submillimeter Detectors and Instrumentation for Astronomy III

Comparison of burst detectors for spike trains

Accurate identification of bursting activity is an essential element in the characterization of neuronal network activity. Despite this, no one technique for identifying bursts in spike trains has been widely adopted. Instead, many methods have been developed for the analysis of bursting activity, often on an ad hoc basis. Here we provide an unbiased assessment of the effectiveness of eight of these methods at detecting bursts in a range of spike trains. We suggest a list of features that an ideal burst detection technique should possess and use synthetic data to assess each method in regard to these properties. We further employ each of the methods to reanalyze microelectrode array (MEA) recordings from mouse retinal ganglion cells and examine their coherence with bursts detected by a human observer. We show that several common burst detection techniques perform poorly at analyzing spike trains with a variety of properties. We identify four promising burst detection techniques, which are then applied to MEA recordings of networks of human induced pluripotent stem cell-derived neurons and used to describe the ontogeny of bursting activity in these networks over several months of development. We conclude that no current method can provide "perfect" burst detection results across a range of spike trains; however, two burst detection techniques, the MaxInterval and logISI methods, outperform compared with others. We provide recommendations for the robust analysis of bursting activity in experimental recordings using current techniques.Experimental data collection was supported by the BBSRC (PC, OP, grant number BB/H008608/1). EC was supported by a Wellcome Trust PhD Studentship and NIHR Cambridge Biomedical Research Centre Studentship. CWT was supported by a bursary from the Bridgwater Summer Undergraduate Research programme.This is the final version of the article. It first appeared from the American Physiological Society via https://doi.org/10.1152/jn.00093.201