Mucoadhesive microspheres of chitosan and polyvinyl alcohol as a carrier for intranasal delivery of insulin: in vitro and in vivo studies

The aim of this study was to investigate the capabilities of chitosan microspheres as drug carrier system in co-formulation with polyvinyl alcohol (PVA), to improve the systemic absorption of intranasal insulin delivery. Insulin loaded microspheres was developed from varying ratio of chitosan solutions along with polyvinyl alcohol (PVA) as additive polymer using spray drying method. Different formulations were developed and morphological studies of the optimized formulas showed that the size range of spherical shaped particulate matters existed from 200 nm to 2 mm. It was clearly observed that physicochemical properties of the microspheres were extensively affected by changing the concentration ratio of the two polymeric materials. In vitro studies of insulin release pattern was performed in various time intervals up to 24 h. It was evident that microspheres made up of chitosan showed initial burst release but slower release as the experiment continued. Microspheres made up of combination of the aforementioned two polymers had instant, sharp and burst drug release. Surprisingly there was no absorption after intranasal delivery of chitosan-PVA microspheres in groups of rats comparing to formulated chitosan microspheres having profound absorption due to their smaller particle size, slower drug release rate and better mucoadhesive properties. Therefore, significant reduction in the plasma blood glucose level for chitosan based optimized formulation was seen right after 4.5 hours compared with control group. The aim of the present study was to fabricate an appropriate application of polymeric microspheres for intranasal delivery of insulin using a novel optimized formulation based on industrial level spray drying technique and to realize the possible barriers in scale up process of its large scale production, considering the effectiveness of polyvinyl alcohol (PVA) and chitosan to increase mucoadhesivness, gelling ability and ultimately effective release behavior pattern of insulin. According to this study, the combination of the polymers used and the mean particle size of formulated microspheres were found to be key factors in insulin drug release resulting for further enhancement of insulin absorption via intranasal route of delivery

Contrast and rate of light intensity decrease control directional swimming in the box jellyfish Tripedalia cystophora (Cnidaria, Cubomedusae)

Box jellyfish respond to visual stimuli by changing the dynamics and frequency of bell contractions. In this study, we determined how the contrast and the dimming time of a simple visual stimulus affected bell contraction dynamics in the box jellyfish Tripedalia cystophora. Animals were tethered in an experimental chamber where the vertical walls formed the light stimuli. Two neighbouring walls were darkened and the contraction of the bell was monitored by high-speed video. We found that (1) bell contraction frequency increased with increasing contrast and decreasing dimming time. Furthermore, (2) when increasing the contrast and decreasing the dimming time pulses with an off-centred opening had a better defined direction and (3) the number of centred pulses decreased. Only weak effects were found on the relative diameter of the contracted bell and no correlation was found for the duration of bell contraction. Our observations show that visual stimuli modulate swim speed in T. cystophora by changing the swim pulse frequency. Furthermore, the direction of swimming is better defined when the animal perceives a high-contrast, or fast dimming, stimulus

Mathematically modelling the dynamics of cholesterol metabolism and ageing

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the UK. This conditionbecomes increasingly prevalent during ageing; 34.1% and 29.8% of males and females respectively, over 75years of age have an underlying cardiovascular problem. The dysregulation of cholesterol metabolism isinextricably correlated with cardiovascular health and for this reason low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol (HDL-C) are routinely used as biomarkers of CVD risk. Theaim of this work was to use mathematical modelling to explore how cholesterol metabolism is affectedby the ageing process. To do this we updated a previously published whole-body mathematical model ofcholesterol metabolism to include an additional 96 mechanisms that are fundamental to this biologicalsystem. Additional mechanisms were added to cholesterol absorption, cholesterol synthesis, reversecholesterol transport (RCT), bile acid synthesis, and their enterohepatic circulation. The sensitivity of themodel was explored by the use of both local and global parameter scans. In addition, acute cholesterolfeeding was used to explore the effectiveness of the regulatory mechanisms which are responsible formaintaining whole-body cholesterol balance. It was found that our model behaves as a hypo-responderto cholesterol feeding, while both the hepatic and intestinal pools of cholesterol increased significantly.The model was also used to explore the effects of ageing in tandem with three different cholesterolester transfer protein (CETP) genotypes. Ageing in the presence of an atheroprotective CETP genotype,conferring low CETP activity, resulted in a 0.6% increase in LDL-C. In comparison, ageing with a genotypereflective of high CETP activity, resulted in a 1.6% increase in LDL-C. Thus, the model has illustrated theimportance of CETP genotypes such as I405V, and their potential role in healthy ageing

Retracing the history and planning the future of the red squirrel (Sciurus vulgaris) in Ireland using non-invasive genetics

The Eurasian red squirrel’s (Sciurus vulgaris) history in Ireland is largely unknown, but the original population is thought to have been driven to extinction by humans in the 17th Century, and multiple records exist for its subsequent reintroduction in the 19th 4 Century. However, it is currently unknown how these reintroductions affect the red squirrel population today, or may do so in the future. In this study, we report on the development of a DNA toolkit for the non-invasive genetic study of the red squirrel. Non-invasively collected red squirrel samples were combined with other samples collected throughout Ireland and previously published mitochondrial DNA (mtDNA) data from Ireland, Great Britain and continental Europe to give an insight into population genetics and historical introductions of the red squirrel in Ireland. Our findings demonstrate that the Irish red squirrel population is on a national scale quite genetically diverse, but at a local level contains relatively low levels of genetic diversity and evidence of genetic structure. This is likely an artefact of the introduction of a small number of genetically similar animals to specific sites. A lack of continuous woodland cover in Ireland has prevented further mixing with animals of different origins that may have been introduced even to neighbouring sites. Consequently, some of these genetically isolated populations are or may in the future be at risk of extinction. The Irish red squirrel population contains mtDNA haplotypes of both a British and Continental European origin, the former of which are now extinct or simply not recorded in contemporary Great Britain. The Irish population is therefore important in terms of red squirrel conservation not only in Ireland, but also for Great Britain, and should be appropriately managed

Evaluating home-based personalised virtual reality physiotherapy rehabilitation compared with usual care in the treatment of pain for people with knee osteoarthritis: protocol for a randomised feasibility study

Introduction Home-based physiotherapy is a current approach to manage knee osteoarthritis (OA). However, adherence to physiotherapy is poor. Non-immersive virtual reality (VR) has shown promise in improving self-efficacy and adherence in other clinical conditions. A non-immersive VR-based home physiotherapy system named Sensor-based Physiotherapy Intervention with Virtual Reality (SPIN-VR) for knee OA has been developed, integrating physiotherapy exercises into engaging games that adjust in difficulty based on real-time performance. This approach aims to enhance exercise adherence by making physiotherapy more enjoyable and personalised. To evaluate the feasibility of this intervention, a randomised controlled trial is being conducted. Method and analysis This single-centre, open-label, randomised controlled feasibility trial will evaluate the SPIN-VR system over 12 weeks compared with usual care physiotherapy for knee OA. 50 participants will be randomly assigned to either the SPIN-VR or usual care group, with follow-ups at 12 and 24 weeks post randomisation. The primary outcomes will be a description of feasibility of recruitment, patient willingness to be randomised, the completeness of outcome measures and patient adherence to the intervention. Secondary outcomes include evaluations of muscle strength, endurance, aerobic capacity, exercise technique, central pain processing and self-reported pain mechanisms and moderators. Participants in the intervention arm will be interviewed after 12 weeks to capture their experience in using the VR system. Ethics and dissemination This protocol was approved by the Wales Research Ethics Committee 3. Research findings will be disseminated in open-access peer-reviewed journals, to researchers and health professionals through conference presentations, to patients and the public by organising webinars and a seminar. Trial registration number NCT06639867

Limited diversity associated with duplicated class II MHC-DRB genes in the red squirrel population in the United Kingdom compared with continental Europe

The red squirrel (Sciurus vulgaris) population in the United Kingdom has declined over the last century and is now on the UK endangered species list. This is the result of competition from the eastern grey squirrel (S. carolinensis) which was introduced in the 19th century. However, recent evidence suggests that the rate of population decline is enhanced by squirrelpox disease, caused by a viral infection carried asymptomatically by grey squirrels but to which red squirrels are highly susceptible. Population genetic diversity provides some resilience to rapidly evolving or exotic pathogens. There is currently no data on genetic diversity of extant UK squirrel populations with respect to genes involved in disease resistance. Diversity is highest at loci involved in the immune response including genes clustered within the major histocompatibility complex (MHC). Using the class II DRB locus as a marker for diversity across the MHC region we genotyped 110 red squirrels from locations in the UK and continentalEurope. Twenty four Scvu-DRB alleles at two functional loci; Scvu-DRB1 and Scvu- DRB2, were identified. High levels of diversity were identified at both loci in the continental populations. In contrast, no diversity was observed at the Scvu-DRB2 locus in the mainland UK population while a high level of homozygosity was observed at the Scvu-DRB1 locus. The red squirrel population in the UK appears to lack the extensive MHC diversity associated with continental populations, a feature which may have contributed to their rapid decline

Women’s, partners’ and healthcare providers’ views and experiences of assisted vaginal birth: a systematic mixed methods review

Background When certain complications arise during the second stage of labour, assisted vaginal delivery (AVD), a vaginal birth with forceps or vacuum extractor, can effectively improve outcomes by ending prolonged labour or by ensuring rapid birth in response to maternal or fetal compromise. In recent decades, the use of AVD has decreased in many settings in favour of caesarean section (CS). This review aimed to improve understanding of experiences, barriers and facilitators for AVD use. Methods Systematic searches of eight databases using predefined search terms to identify studies reporting views and experiences of maternity service users, their partners, health care providers, policymakers, and funders in relation to AVD. Relevant studies were assessed for methodological quality. Qualitative findings were synthesised using a meta-ethnographic approach. Confidence in review findings was assessed using GRADE CERQual. Findings from quantitative studies were synthesised narratively and assessed using an adaptation of CERQual. Qualitative and quantitative review findings were triangulated using a convergence coding matrix. Results Forty-two studies (published 1985–2019) were included: six qualitative, one mixed-method and 35 quantitative. Thirty-five were from high-income countries, and seven from LMIC settings. Confidence in the findings was moderate or low. Spontaneous vaginal birth was most likely to be associated with positive short and long-term outcomes, and emergency CS least likely. Views and experiences of AVD tended to fall somewhere between these two extremes. Where indicated, AVD can be an effective, acceptable alternative to caesarean section. There was agreement or partial agreement across qualitative studies and surveys that the experience of AVD is impacted by the unexpected nature of events and, particularly in high-income settings, unmet expectations. Positive relationships, good communication, involvement in decision-making, and (believing in) the reason for intervention were important mediators of birth experience. Professional attitudes and skills (development) were simultaneously barriers and facilitators of AVD in quantitative studies. Conclusions Information, positive interaction and communication with providers and respectful care are facilitators for acceptance of AVD. Barriers include lack of training and skills for decision-making and use of instruments

Effects of membrane depolarization and changes in extracellular [K+] on the Ca2+ transients of fast skeletal muscle fibers. Implications for muscle fatigue

Repetitive activation of skeletal muscle fibers leads to a reduced transmembrane K+ gradient. The resulting membrane depolarization has been proposed to play a major role in the onset of muscle fatigue. Nevertheless, raising the extracellular K+ (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{K}}_{\text{o}}^{ + }$$\end{document}) concentration (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$[ {\text{K}}^{ + } ]_{\text{o}}$$\end{document}) to 10 mM potentiates twitch force of rested amphibian and mammalian fibers. We used a double Vaseline gap method to simultaneously record action potentials (AP) and Ca2+ transients from rested frog fibers activated by single and tetanic stimulation (10 pulses, 100 Hz) at various \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$[ {\text{K}}^{ + } ]_{\text{o}}$$\end{document} and membrane potentials. Depolarization resulting from current injection or raised \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$[ {\text{K}}^{ + } ]_{\text{o}}$$\end{document} produced an increase in the resting [Ca2+]. Ca2+ transients elicited by single stimulation were potentiated by depolarization from −80 to −60 mV but markedly depressed by further depolarization. Potentiation was inversely correlated with a reduction in the amplitude, overshoot and duration of APs. Similar effects were found for the Ca2+ transients elicited by the first pulse of 100 Hz trains. Depression or block of Ca2+ transient in response to the 2nd to 10th pulses of 100 Hz trains was observed at smaller depolarizations as compared to that seen when using single stimulation. Changes in Ca2+ transients along the trains were associated with impaired or abortive APs. Raising \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$[ {\text{K}}^{ + } ]_{\text{o}}$$\end{document} to 10 mM potentiated Ca2+ transients elicited by single and tetanic stimulation, while raising \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$[ {\text{K}}^{ + } ]_{\text{o}}$$\end{document} to 15 mM markedly depressed both responses. The effects of 10 mM \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{K}}_{\text{o}}^{ + }$$\end{document} on Ca2+ transients, but not those of 15 mM \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{K}}_{\text{o}}^{ + }$$\end{document}, could be fully reversed by hyperpolarization. The results suggests that the force potentiating effects of 10 mM \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{K}}_{\text{o}}^{ + }$$\end{document} might be mediated by depolarization dependent changes in resting [Ca2+] and Ca2+ release, and that additional mechanisms might be involved in the effects of 15 mM \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{K}}_{\text{o}}^{ + }$$\end{document} on force generation

Interventions to reduce unnecessary caesarean sections in healthy women and babies

Optimising the use of caesarean section (CS) is of global concern. Underuse leads to maternal and perinatal mortality and morbidity. Conversely, overuse of CS has not shown benefits and can create harm. Worldwide, the frequency of CS continues to increase, and interventions to reduce unnecessary CSs have shown little success. Identifying the underlying factors for the continuing increase in CS use could improve the efficacy of interventions. In this Series paper, we describe the factors for CS use that are associated with women, families, health professionals, and health-care organisations and systems, and we examine behavioural, psychosocial, health system, and financial factors. We also outline the type and effects of interventions to reduce CS use that have been investigated. Clinical interventions, such as external cephalic version for breech delivery at term, vaginal breech delivery in appropriately selected women, and vaginal birth after CS, could reduce the frequency of CS use. Approaches such as labour companionship and midwife-led care have been associated with higher proportions of physiological births, safer outcomes, and lower health-care costs relative to control groups without these interventions, and with positive maternal experiences, in high-income countries. Such approaches need to be assessed in middle-income and low-income countries. Educational interventions for women should be complemented with meaningful dialogue with health professionals and effective emotional support for women and families. Investing in the training of health professionals, eliminating financial incentives for CS use, and reducing fear of litigation is fundamental. Safe, private, welcoming, and adequately resourced facilities are needed. At the country level, effective medical leadership is essential to ensure CS is used only when indicated. We conclude that interventions to reduce overuse must be multicomponent and locally tailored, addressing women’s and health professionals’ concerns, as well as health system and financial factors