English fifteenth century book structures

In discussing fifteenth century book structures the thesis describes those collections from which it's survey (of over three hundred bindings) was drawn. It explores the physical archaeology of the book, and considers the context of book production in the late medieval period. The technical skills of the bookbinder are considered in detail, as are the tools, materials and technologies used. The demise of the wooden boarded medieval book is compared with the great age of Romanesque bookbinding. In focusing on the collections held by Cambridge libraries, it was inevitable that there should be a strong concentration on the work of bookbinders from that city, but those from Oxford and London are well represented. The work of a number of provincial binders is also given attention. Many of the books studied were undergoing conservation work whilst being surveyed, and this has provided much information which would otherwise have never been revealed. In particular it was possible to make a detailed study of sewing techniques, and of the changing materials used in the making of sewings. Utilising a microcomputer with a powerful spreadsheet programme, the survey of three hundred books explores all aspects of English fifteenth century binding in wooden boards. Each book was catalogued in terms of nearly three hundred questions in computerised format, and the results were turned into graphs for percentage interpretation. In addition every book was recorded on a detailed survey form, supported by photographs, drawings and diagrams to provide as full a set of details as possible. The results were scrutinised to consider the impact of the growing use of paper and of the invention of printing with movable type. The cultural, social and economic demands of the medieval age are brought together as aspects which influenced the development of the book structure. The way in which books were made and used is considered in depth. The impact of mainstream historical developments in politics, religion and education are also factors which played a vital role in the history of the book during this period. The codex (in original condition) is a "time capsule", to quote Christopher Clarkson, and this research seeks to explore book production in one of the most vital centuries of its history

The effects of Tumour necrosis factor-alpha and Interleukin-1-beta on intracellular calcium handling and contractility in sheep ventricular myocytes

Proinflammatory cytokines such as TNF-α and IL-1β are implicated in the pathogenesis of inflammatory disease states such as sepsis. In sepsis, myocardial depression is a leading cause of death. To design novel therapeutic targets, it is essential that we understand how these cytokines mediate the cellular basis of this cardiac dysfunction. Previous studies, including Greensmith and Nirmalan (2013), demonstrate that perturbed intracellular calcium handling and contractility can account for many aspects of myocardial depression. However, many of these studies suffer important limitations in that (A) small mammal models were used in which the translational relevance is questionable and (B) it remains unclear how proinflammatory cytokines affect certain key aspects of cellular function. To address this, we re-characterised the effects of TNF-α and IL-1β on intracellular calcium handling using a large animal model then investigated their effects on the ryanodine receptor (RyR) and myofilament sensitivity to calcium.Sheep ventricular myocytes were used for all experiments. All procedures used accord with the Animals (Scientific Procedures) Act, UK, 1986 and Directive 2010/63/EU of the European Parliament. Intracellular calcium and contractility dynamics were measured by epi-fluorescent photometry and video sarcomere detection respectively. In all experiments, cells were separately exposed to 50 ng/ml TNF-α and IL-1β acutely. When required, cells were excited using field stimulation at a rate of 0.5 Hz. To indicate changes to RyR properties, intracellular Ca2+ waves were facilitated using 0.3 mM Ouabain and 5 mM Ca2+. SR Ca2+ content was estimated using the amplitude of 10 mM caffeine-evoked Ca2+ transients. TNF-α and IL-1β decreased SR Ca2+ content by 27 and 41 % respectively accounting for a 17 and 24 % decrease of systolic calcium. Only with TNF-α did this reduction in systolic Ca2+ translate to reduced systolic shortening (20 %). We observed no negative effect on the rate of systolic or caffeine-evoked Ca2+ decay. TNF-α and IL-1β decreased Ca2+ wave amplitude by 46 and 34 % and increased frequency by 38 and 28 %. Both cytokines reduced SR Ca2+ threshold for waves. In saponin-permeabilised cells the degree of sarcomere shortening over equivalent calcium ranges was attenuated.These findings confirm that in sheep, TNF-α and IL-1β decrease SR Ca2+ content leading to reduced systolic Ca2+. The increase of Ca2+ wave frequency and decrease of amplitude suggests both cytokines increase ryanodine receptor open probability; confirmed by a decreased SR Ca2+ threshold for waves. So while the reduction of SR Ca2+ content does not appear to be SERCA-dependent increased RyR leak may contribute. The loss of contractile response to increased Ca2+ suggests that both cytokines reduce myofilament Ca2+ sensitivity. These findings advance our understanding of cytokine-mediated cardiac intracellular Ca2+ dysregulation and provide additional cellular substrates for myocardial depression in sepsi

Topical delivery of hexamidine

Hexamidine diisethionate (HEX D) has been used for its biocidal actions in topical preparations since the 1950s. Recent data also suggest that it plays a beneficial role in skin homeostasis. To date, the extent to which this compound penetrates the epidermis has not been reported nor how its topical delivery may be modulated. In the present work we set out to characterise the interaction of HEX D with the skin and to develop a range of simple formulations for topical targeting of the active. A further objective was to compare the skin penetration of HEX D with its corresponding dihydrochloride salt (HEX H) as the latter has more favourable physicochemical properties for skin uptake. Candidate vehicles were evaluated by in vitro Franz cell permeation studies using porcine skin. Initially, neat solvents were investigated and subsequently binary systems were examined. The solvents and chemical penetration enhancers investigated included glycerol, dimethyl isosorbide (DMI), isopropyl alcohol (IPA), 1,2-pentanol (1,2-PENT), polyethylene glycol (PEG) 200, propylene glycol (PG), propylene glycol monolaurate (PGML) and Transcutol®P (TC). Of a total of 30 binary solvent systems evaluated only 10 delivered higher amounts of active into the skin compared with the neat solvents. In terms of topical efficacy, formulations containing PGML far surpassed all other solvents or binary combinations. More than 70% of HEX H was extracted from the skin following application in PG:PGML (50:50). Interestingly, the same vehicle effectively promoted skin penetration of HEX D but demonstrated significantly lower uptake into and through the skin (30%). The findings confirm the unpredictable nature of excipients on delivery of actives with reference to skin even where there are minor differences in molecular structures. We also believe that they underline the ongoing necessity for fundamental studies on the interaction of topical excipients with the skin

Evaluating short-term musculoskeletal pain changes in desk-based workers receiving a workplace sitting-reduction intervention

This paper explores changes in musculoskeletal pain among desk-based workers over three months of a workplace-delivered, sitting-reduction intervention. Participants (n = 153, 46% female; mean ± SD aged 38.9 ± 8.0 years) were cluster-randomized (n = 18 work teams) to receive an organizational change intervention, with or without an activity tracker. A modified Nordic Musculoskeletal Questionnaire assessed pain intensity (0–9; none–worst possible) in the neck, upper and lower back, upper and lower extremities, and in total. The activPAL3 (7 days, 24 h/day protocol) measured sitting and prolonged sitting in =30 min bouts at work. Mixed models adjusting for cluster and intervention arm examined changes in pain (n = 104), and their associations with reductions in sitting and prolonged sitting (h/10 h at work) (n = 90). Changes in pain were nonsignificant (p = 0.05) and small for total pain (-0.06 [95% CI: -0.27, 0.16]) and for each body area (-0.26 [-0.66, 0.15] for upper back to 0.09 [-0.39, 0.56] for lower back). Sitting reduction was associated with reduced lower back pain (-0.84 [-1.44, -0.25] per hour, p = 0.005); other effects were small and non-significant. No substantial average changes in pain were seen; some improvement in lower back pain might be expected with larger sitting reductions. Larger samples and diverse interventions are required for more definitive evidence

Preparation and characterisation of hexamidine salts

Hexamidine diisethionate (HEX D) has been used in the personal care industry and in a number of over-the-counter (OTC) drug products as an antimicrobial agent since the 1950's. Recently, the compound has also been investigated for its beneficial effects on skin health. Surprisingly, there is only limited information describing the physicochemical properties of this compound in the literature. The objective of this work was therefore to conduct a comprehensive programme of characterisation of HEX D as well as its dihydrochloride salt (HEX H). HEX H was prepared from HEX D by a simple acid addition reaction. Both salts were characterised using Nuclear Magnetic Resonance (NMR), Differential scanning calorimetry (DSC), and Thermogravimetric analysis (TGA). A new high performance liquid chromatographic method was developed and validated for both compounds. The pH in aqueous solution as well as respective distribution coefficients between octanol and pH 7.4 buffer were also determined. Finally, solubility and short term stability studies were conducted in a range of solvents. NMR analysis confirmed the preparation of HEX H from HEX D. Thermal analysis indicated the melting points of HEX D and HEX H were 225°C and 266°C respectively. HPLC analysis confirmed the purity of both salts. LogD values at pH 7.4 were -0.74 for HEX D and -0.70 for HEX H respectively. The physicochemical properties of two HEX salts have been established using a range of analytical approaches. Detailed solubility and stability data have also been collated. This information will be useful in the design of novel formulations for targeted delivery of these compounds to the skin

Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank-Starling response.

The Frank-Starling mechanism allows the amount of blood entering the heart from the veins to be precisely matched with the amount pumped out to the arterial circulation. As the heart fills with blood during diastole, the myocardium is stretched and oxidants are produced. Here we show that protein kinase G Iα (PKGIα) is oxidant-activated during stretch and this form of the kinase selectively phosphorylates cardiac phospholamban Ser16-a site important for diastolic relaxation. We find that hearts of Cys42Ser PKGIα knock-in (KI) mice, which are resistant to PKGIα oxidation, have diastolic dysfunction and a diminished ability to couple ventricular filling with cardiac output on a beat-to-beat basis. Intracellular calcium dynamics of ventricular myocytes isolated from KI hearts are altered in a manner consistent with impaired relaxation and contractile function. We conclude that oxidation of PKGIα during myocardial stretch is crucial for diastolic relaxation and fine-tunes the Frank-Starling response

A systematic review of correlates of sedentary behaviour in adults aged 18–65 years: a socio-ecological approach

Background: Recent research shows that sedentary behaviour is associated with adverse cardio-metabolic consequences even among those considered sufficiently physically active. In order to successfully develop interventions to address this unhealthy behaviour, factors that influence sedentariness need to be identified and fully understood. The aim of this review is to identify individual, social, environmental, and policy-related determinants or correlates of sedentary behaviours among adults aged 18-65 years. Methods: PubMed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between January 2000 and September 2015. The search strategy was based on four key elements and their synonyms: (a) sedentary behaviour (b) correlates (c) types of sedentary behaviours (d) types of correlates. Articles were included if information relating to sedentary behaviour in adults (18-65 years) was reported. Studies on samples selected by disease were excluded. The full protocol is available from PROSPERO (PROSPERO 2014:CRD42014009823). Results: 74 original studies were identified out of 4041: 71 observational, two qualitative and one experimental study. Sedentary behaviour was primarily measured as self-reported screen leisure time and total sitting time. In 15 studies, objectively measured total sedentary time was reported: accelerometry (n = 14) and heart rate (n = 1). Individual level factors such as age, physical activity levels, body mass index, socio-economic status and mood were all significantly correlated with sedentariness. A trend towards increased amounts of leisure screen time was identified in those married or cohabiting while having children resulted in less total sitting time. Several environmental correlates were identified including proximity of green space, neighbourhood walkability and safety and weather. Conclusions: Results provide further evidence relating to several already recognised individual level factors and preliminary evidence relating to social and environmental factors that should be further investigated. Most studies relied upon cross-sectional design limiting causal inference and the heterogeneity of the sedentary measures prevented direct comparison of findings. Future research necessitates longitudinal study designs, exploration of policy-related factors, further exploration of environmental factors, analysis of inter-relationships between identified factors and better classification of sedentary behaviour domains

Effect of Duration and Amplitude of Direct Current When Lidocaine is Delivered by Iontophoresis

Dosage for the galvanic stimulation for iontophoresis varies. Clinicians manipulate the duration or the amplitude of the current, but it is not known which is more effective. We compared the anesthetic effect of lidocaine HCL (2%) by manipulating the current parameters on 21 healthy volunteers (age: 21.2 ± 4.2, height 170.7 ± 10.2 cm, mass 82.1 ± 19.2 kg). Three conditions were administered in a random order using a Phoresor II® with 2 mL, 2% lidocaine HCL in an iontophoresis electrode. (1) HASD (40 mA*min): High amplitude (4 mA), short duration (10 min); (2) LALD (40 mA.min): Low amplitude (2 mA), long duration (20 min); (3) Sham condition (0 mA, 20 min). Semmes-Weinstein monofilament (SWM) scores were taken pre and post intervention to measure sensation changes. Two-way ANOVA with repeated measures was used to compare sensation. Both iontophoresis treatments: LALD (4.2 ± 0.32 mm) and HASD (4.2 ± 0.52 mm) significantly increased SWM scores, indicating an increase in anesthesia, compared to the sham condition (3.6 ± 0.06 mm) p \u3c 0.05. Neither LALD nor HASD was more effective and there was no difference in anesthesia with the sham. Lidocaine delivered via iontophoresis reduces cutaneous sensation. However, there was no benefit in either a HASD or LALD treatment