Extending the SAFT-gamma Mie approach to model benzoic acid, diphenylamine, and mefenamic acid: Solubility prediction and experimental measurement

The prediction of the solubility of active pharmaceutical ingredients (APIs) is a significant challenge which is of importance in pharmaceutical applications and solvent selection. Here, we extend the table of group interactions (3 like interactions, 47 unlike interactions) of the SAFT-γ Mie group-contribution equation of state to model the phase behaviour and solubility of mefenamic acid, a nonsteroidal anti-inflammatory drug, in a range of solvents. In addition to mefenamic acid, we also consider its molecular synthons: benzoic acid and diphenylamine. New experimental solubility data are presented for the three molecules in a range of solvents, and three new SAFT-γ Mie functional groups are defined (aCCOOH, aCNHaC and CH3CO) and characterised, together with their interactions with solvent groups. Literature data for the vapour pressure, single-phase density, saturation density, vapourisation enthalpy, bubble temperature, dew temperature, and bubble pressure are used to characterise the new group interactions. Solubility data are used to characterise the new group-group interactions only if there are no other experimental data available. The transferability and predictive accuracy of the new models are assessed by comparing the theoretical predictions with the experimental solubility data. Our comparison includes alcohols, ketones, and esters as families of solvents and mixed-solvent solubility predictions

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

A transcriptomic snapshot of early molecular communication between Pasteuria penetrans and Meloidogyne incognita

© The Author(s). 2018Background: Southern root-knot nematode Meloidogyne incognita (Kofoid and White, 1919), Chitwood, 1949 is a key pest of agricultural crops. Pasteuria penetrans is a hyperparasitic bacterium capable of suppressing the nematode reproduction, and represents a typical coevolved pathogen-hyperparasite system. Attachment of Pasteuria endospores to the cuticle of second-stage nematode juveniles is the first and pivotal step in the bacterial infection. RNA-Seq was used to understand the early transcriptional response of the root-knot nematode at 8 h post Pasteuria endospore attachment. Results: A total of 52,485 transcripts were assembled from the high quality (HQ) reads, out of which 582 transcripts were found differentially expressed in the Pasteuria endospore encumbered J2 s, of which 229 were up-regulated and 353 were down-regulated. Pasteuria infection caused a suppression of the protein synthesis machinery of the nematode. Several of the differentially expressed transcripts were putatively involved in nematode innate immunity, signaling, stress responses, endospore attachment process and post-attachment behavioral modification of the juveniles. The expression profiles of fifteen selected transcripts were validated to be true by the qRT PCR. RNAi based silencing of transcripts coding for fructose bisphosphate aldolase and glucosyl transferase caused a reduction in endospore attachment as compared to the controls, whereas, silencing of aspartic protease and ubiquitin coding transcripts resulted in higher incidence of endospore attachment on the nematode cuticle. Conclusions: Here we provide evidence of an early transcriptional response by the nematode upon infection by Pasteuria prior to root invasion. We found that adhesion of Pasteuria endospores to the cuticle induced a down-regulated protein response in the nematode. In addition, we show that fructose bisphosphate aldolase, glucosyl transferase, aspartic protease and ubiquitin coding transcripts are involved in modulating the endospore attachment on the nematode cuticle. Our results add new and significant information to the existing knowledge on early molecular interaction between M. incognita and P. penetrans.Peer reviewedFinal Published versio

Studying the association between musculoskeletal disorders, quality of life and mental health. A primary care pilot study in rural Crete, Greece

<p>Abstract</p> <p>Background</p> <p>The burden of musculoskeletal disorders (MSD) on the general health and well-being of the population has been documented in various studies. The objective of this study was to explore the association between MSD and the quality of life and mental health of patients and to discuss issues concerning care seeking patterns in rural Greece.</p> <p>Methods</p> <p>Patients registered at one rural Primary Care Centre (PCC) in Crete were invited to complete the Nordic Musculoskeletal Questionnaire (NMQ) for the analysis of musculoskeletal symptoms, together with validated instruments for measuring health related quality of life (SF-36) and mental distress (GHQ-28).</p> <p>Results</p> <p>The prevalence rate of MSD was found to be 71.2%, with low back and knee pain being the most common symptoms. Most conditions significantly impaired the quality of life, especially the physical dimensions of SF-36. Depression was strongly correlated to most MSD (<it>p </it>< 0.001). Multiple logistic analyses revealed that patients who consulted the PCC due to MSD were likely to have more mental distress or impaired physical functioning compared to those who did not.</p> <p>Conclusion</p> <p>Musculoskeletal disorders were common in patients attending the rural PCC of this study and were associated with a poor quality of life and mental distress that affected their consultation behaviour.</p

Surgical treatment for acromioclavicular joint osteoarthritis: patient selection, surgical options, complications, and outcome

Osteoarthritis is one of the most common causes of pain originating from the acromioclavicular (AC) joint. An awareness of appropriate diagnostic techniques is necessary in order to localize clinical symptoms to the AC joint. Initial treatments for AC joint osteoarthritis, which include non-steroidal anti-inflammatory drugs (NSAIDS) and corticosteroids, are recommended prior to surgical interventions. Distal clavicle excision, the main surgical treatment option, can be performed by various surgical approaches, such as open procedures, direct arthroscopic, and indirect arthroscopic techniques. When choosing the best surgical option, factors such as avoidance of AC ligament damage, clavicular instability, and post-operative pain must be considered. This article examines patient selection, complications, and outcomes of surgical treatment options for AC joint osteoarthritis

The feeding tube of cyst nematodes: characterisation of protein exclusion

Plant parasitic nematodes comprise several groups; the most economically damaging of these are the sedentary endoparasites. Sedentary endoparasitic nematodes are obligate biotrophs and modify host root tissue, using a suite of effector proteins, to create a feeding site that is their sole source of nutrition. They feed by withdrawing host cell assimilate from the feeding site though a structure known as the feeding tube. The function, composition and molecular characteristics of feeding tubes are poorly characterised. It is hypothesised that the feeding tube facilitates uptake of host cell assimilate by acting as a molecular sieve. Several studies, using molecular mass as the sole indicator of protein size, have given contradictory results about the exclusion limits of the cyst nematode feeding tube. In this study we propose a method to predict protein size, based on protein database coordinates in silico. We tested the validity of these predictions using travelling wave ion mobility spectrometry--mass spectrometry, where predictions and measured values were within approximately 6%. We used the predictions, coupled with mass spectrometry, analytical ultracentrifugation and protein electrophoresis, to resolve previous conflicts and define the exclusion characteristics of the cyst nematode feeding tube. Heterogeneity was tested in the liquid, solid and gas phase to provide a comprehensive evaluation of three proteins of particular interest to feeding tube size exclusion, GFP, mRFP and Dual PI. The data and procedures described here could be applied to the design of plant expressed defence compounds intended for uptake into cyst nematodes. We also highlight the need to assess protein heterogeneity when creating novel fusion proteins

Increasing capacity for the treatment of common musculoskeletal problems: A non-inferiority RCT and economic analysis of corticosteroid injection for shoulder pain comparing a physiotherapist and orthopaedic surgeon

Background Role substitution is a strategy employed to assist health services manage the growing demand for musculoskeletal care. Corticosteroid injection is a common treatment in this population but the efficacy of its prescription and delivery by physiotherapists has not been established against orthopaedic standards. This paper investigates whether corticosteroid injection given by a physiotherapist for shoulder pain is as clinically and cost effective as that from an orthopaedic surgeon. Methods A double blind non-inferiority randomized controlled trial was conducted in an Australian public hospital orthopaedic outpatient service, from January 2013 to June 2014. Adults with a General Practitioner referral to Orthopaedics for shoulder pain received subacromial corticosteroid and local anaesthetic injection prescribed and delivered independently by a physiotherapist or a consultant orthopaedic surgeon. The main outcome measure was total Shoulder Pain and Disability Index (SPADI) score at baseline, six and 12 weeks, applying a non-inferiority margin of 15 points. Secondary outcomes tested for superiority included pain, shoulder movement, perceived improvement, adverse events, satisfaction, quality of life and costs. Results 278 participants were independently assessed by the physiotherapist and the orthopaedic surgeon, with 64 randomised (physiotherapist 33, orthopaedic surgeon 31). There were no significant differences in baseline characteristics between groups. Non-inferiority of injection by the physiotherapist was declared from total SPADI scores at 6 and 12 weeks (upper limit of the 95% one-sided confidence interval 13.34 and 7.17 at 6 and 12 weeks, respectively). There were no statistically significant differences between groups on any outcome measures at 6 or 12 weeks. From the perspective of the health funder, the physiotherapist was less expensive. Conclusions Corticosteroid injection for shoulder pain, provided by a suitably qualified physiotherapist is at least as clinically effective, and less expensive, compared with similar care delivered by an orthopaedic surgeon. Policy makers and service providers should consider implementing this model of care

Study protocol: a mixed methods feasibility study for a loaded self-managed exercise programme for patellofemoral pain

Background: Patellofemoral pain (PFP) is one of the most common forms of knee pain in adults under the age of 40, with a prevalence of 23% in the general population. The long-term prognosis is poor, with only one third of people pain-free 1 year after diagnosis. The biomedical model of pain in relation to persistent PFP has recently been called into question. It has been suggested that interventions for chronic musculoskeletal conditions should consider alternative mechanisms of action, beyond muscles and joints. Modern treatment therapies should consider desensitising strategies, with exercises that target movements and activities patients find fearful and painful. High-quality research on exercise prescription in relation to pain mechanisms, not directed at specific tissue pathology, and dose response clearly warrants further investigation. Our primary aim is to establish the feasibility and acceptability of conducting a definitive RCT which will evaluate the clinical and cost-effectiveness of a loaded self-managed exercise programme for people with patellofemoral pain. Method: This is a single-centred, multiphase, sequential, mixed-methods trial that will evaluate the feasibility of running a definitive large-scale randomised controlled trial of a loaded self-managed exercise programme versus usual physiotherapy. Initially, 8–10 participants with a minimum 3-month history of PFP will be recruited from an NHS physiotherapy waiting list and interviewed. Participants will be invited to discuss perceived barriers and facilitators to exercise engagement, and the meaning and impact of PFP. Then, 60 participants will be recruited in the same manner for the main phase of the feasibility trial. A web-based service will randomise patients to a loaded self-managed exercise programme or usual physiotherapy. The loaded self-managed exercise programme is aimed at addressing lower limb knee and hip weakness and is positioned within a framework of reducing fear/avoidance with an emphasis on self-management. Baseline assessment will include demographic data, average pain within the last week (VAS), fear avoidance behaviours, catastrophising, self-efficacy, sport and leisure activity participation, and general quality of life. Follow-up will be 3 and 6 months. The analysis will focus on descriptive statistics and confidence intervals. The qualitative components will follow a thematic analysis approach. Discussion: This study will evaluate the feasibility of running a definitive large-scale trial on patients with patellofemoral pain, within the NHS in the UK. We will identify strengths and weaknesses of the proposed protocol and the utility and characteristics of the outcome measures. The results from this study will inform the design of a multicentre trial

Trends of the Major Porin Gene (ompF) Evolution: Insight from the Genus Yersinia

OmpF is one of the major general porins of Enterobacteriaceae that belongs to the first line of bacterial defense and interactions with the biotic as well as abiotic environments. Porins are surface exposed and their structures strongly reflect the history of multiple interactions with the environmental challenges. Unfortunately, little is known on diversity of porin genes of Enterobacteriaceae and the genus Yersinia especially. We analyzed the sequences of the ompF gene from 73 Yersinia strains covering 14 known species. The phylogenetic analysis placed most of the Yersinia strains in the same line assigned by 16S rDNA-gyrB tree. Very high congruence in the tree topologies was observed for Y. enterocolitica, Y. kristensenii, Y. ruckeri, indicating that intragenic recombination in these species had no effect on the ompF gene. A significant level of intra- and interspecies recombination was found for Y. aleksiciae, Y. intermedia and Y. mollaretii. Our analysis shows that the ompF gene of Yersinia has evolved with nonrandom mutational rate under purifying selection. However, several surface loops in the OmpF porin contain positively selected sites, which very likely reflect adaptive diversification Yersinia to their ecological niches. To our knowledge, this is a first investigation of diversity of the porin gene covering the whole genus of the family Enterobacteriaceae. This study demonstrates that recombination and positive selection both contribute to evolution of ompF, but the relative contribution of these evolutionary forces are different among Yersinia species

Development of an In Vivo RNAi Protocol to Investigate Gene Function in the Filarial Nematode, Brugia malayi

Our ability to control diseases caused by parasitic nematodes is constrained by a limited portfolio of effective drugs and a paucity of robust tools to investigate parasitic nematode biology. RNA interference (RNAi) is a reverse-genetics tool with great potential to identify novel drug targets and interrogate parasite gene function, but present RNAi protocols for parasitic nematodes, which remove the parasite from the host and execute RNAi in vitro, are unreliable and inconsistent. We have established an alternative in vivo RNAi protocol targeting the filarial nematode Brugia malayi as it develops in an intermediate host, the mosquito Aedes aegypti. Injection of worm-derived short interfering RNA (siRNA) and double stranded RNA (dsRNA) into parasitized mosquitoes elicits suppression of B. malayi target gene transcript abundance in a concentration-dependent fashion. The suppression of this gene, a cathepsin L-like cysteine protease (Bm-cpl-1) is specific and profound, both injection of siRNA and dsRNA reduce transcript abundance by 83%. In vivo Bm-cpl-1 suppression results in multiple aberrant phenotypes; worm motility is inhibited by up to 69% and parasites exhibit slow-moving, kinked and partial-paralysis postures. Bm-cpl-1 suppression also retards worm growth by 48%. Bm-cpl-1 suppression ultimately prevents parasite development within the mosquito and effectively abolishes transmission potential because parasites do not migrate to the head and proboscis. Finally, Bm-cpl-1 suppression decreases parasite burden and increases mosquito survival. This is the first demonstration of in vivo RNAi in animal parasitic nematodes and results indicate this protocol is more effective than existing in vitro RNAi methods. The potential of this new protocol to investigate parasitic nematode biology and to identify and validate novel anthelmintic drug targets is discussed