The beta-subunit of human chorionic gonadotrophin exists as a homodimer

The free beta-subunit of human chorionic gonadotrophin (hCGbeta) is well recognised as a product of many epithelial tumours. Recently, it has been shown that this ectopic production may have a functional relationship to tumour growth. The growth-promoting activity of hCGbeta may be explained by its structural similarity to a family of growth factors which all contain the same distinct topological fold known as the cystine-knot motif. Since the other members of this family all exhibit their activities as homo- and heterodimers, it is possible that the same may be true for hCGbeta. Using size-exclusion chromatography, low stringency SDS-PAGE and matrix assisted laser desorption/ionisation (MALDI) time-of-flight (TOF) mass spectrometry (MS) we have shown that pure preparations of hCGbeta contain hCGbetabeta homodimers. Size-exclusion chromatography revealed asymmetric elution profiles with a forward peak corresponding to the size-exclusion characteristic of a globular protein with an approximate mass of 44-54 kDa and a late shoulder centered around an elution position expected for a globular protein of approximately 29 kDa. Two immunoreactive hCGbeta species, of approximately 32 and 64 kDa, were clearly resolved by SDS-PAGE and Western blotting. When analysed by MALDI-TOF MS a |mf23 kDa monomer and a |mf46 kDa dimer were identified. Formation of hCGbetabeta homodimers is consistent with the behaviour of other cystine-knot growth factors and strengthens the inclusion of the glycoprotein hormones within this superfamily. It has yet to be determined whether it is this dimeric molecular species that is responsible for growth-promoting activity of hCGbeta preparations in tumours

IMPECCABLE: Integrated Modeling PipelinE for COVID Cure by Assessing Better LEads

The drug discovery process currently employed in the pharmaceutical industry typically requires about 10 years and $2–3 billion to deliver one new drug. This is both too expensive and too slow, especially in emergencies like the COVID-19 pandemic. In silico methodologies need to be improved both to select better lead compounds, so as to improve the efficiency of later stages in the drug discovery protocol, and to identify those lead compounds more quickly. No known methodological approach can deliver this combination of higher quality and speed. Here, we describe an Integrated Modeling PipEline for COVID Cure by Assessing Better LEads (IMPECCABLE) that employs multiple methodological innovations to overcome this fundamental limitation. We also describe the computational framework that we have developed to support these innovations at scale, and characterize the performance of this framework in terms of throughput, peak performance, and scientific results. We show that individual workflow components deliver 100 × to 1000 × improvement over traditional methods, and that the integration of methods, supported by scalable infrastructure, speeds up drug discovery by orders of magnitudes. IMPECCABLE has screened ∼ 1011 ligands and has been used to discover a promising drug candidate. These capabilities have been used by the US DOE National Virtual Biotechnology Laboratory and the EU Centre of Excellence in Computational Biomedicine

MRI Pattern Recognition in Multiple Sclerosis Normal-Appearing Brain Areas

Objective Here, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing­remitting type) in lesioned areas, areas of normal­appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques. Methods A lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information. Results Among regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10−13). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10−7). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10−10). Interpretation We identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale

Effect of thong style flip-flops on children’s barefoot walking and jogging kinematics

BACKGROUND: Thong style flip-flops are a popular form of footwear for children. Health professionals relate the wearing of thongs to foot pathology and deformity despite the lack of quantitative evidence to support or refute the benefits or disadvantages of children wearing thongs. The purpose of this study was to compare the effect of thong footwear on children’s barefoot three dimensional foot kinematics during walking and jogging. METHODS: Thirteen healthy children (age 10.3 ± 1.6 SD years) were recruited from the metropolitan area of Sydney Australia following a national press release. Kinematic data were recorded at 200 Hz using a 14 camera motion analysis system (Cortex, Motion Analysis Corporation, Santa Rosa, USA) and simultaneous ground reaction force were measured using a force platform (Model 9281B, Kistler, Winterthur, Switzerland). A three-segment foot model was used to describe three dimensional ankle, midfoot and one dimensional hallux kinematics during the stance sub-phases of contact, midstance and propulsion. RESULTS: Thongs resulted in increased ankle dorsiflexion during contact (by 10.9°, p; = 0.005 walk and by 8.1°, p; = 0.005 jog); increased midfoot plantarflexion during midstance (by 5.0°, p; = 0.037 jog) and propulsion (by 6.7°, p; = 0.044 walk and by 5.4°, p;= 0.020 jog); increased midfoot inversion during contact (by 3.8°, p;= 0.042 jog) and reduced hallux dorsiflexion during walking 10% prior to heel strike (by 6.5°, p; = 0.005) at heel strike (by 4.9°, p; = 0.031) and 10% post toe-off (by 10.7°, p; = 0.001). CONCLUSIONS: Ankle dorsiflexion during the contact phase of walking and jogging, combined with reduced hallux dorsiflexion during walking, suggests a mechanism to retain the thong during weight acceptance. Greater midfoot plantarflexion throughout midstance while walking and throughout midstance and propulsion while jogging may indicate a gripping action to sustain the thong during stance. While these compensations exist, the overall findings suggest that foot motion whilst wearing thongs may be more replicable of barefoot motion than originally thought

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18–50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene–placebo difference 0·16 pu, 95% CI –0·39 to 0·71; p=0·55). Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. Funding: Multiple Sclerosis Society of the United Kingdom

Wellsprings of a 'World War': An early English attempt to conquer Canada during King William's war, 1688-97

This is the author's PDF version of an article published in Journal of Imperial and Commonwealth History© 2006. The definitive version is available at www.tandf.co.uk/journals/FICHThis article discusses the military history of the early years of King William's War, 1688-97, including an early attempt to conquer French Canada in 1690 by Sir William Phips. The article places this within differeing interpretations of the military historiography of early modern colonial America.This article was submitted to the RAE2008 for the University of Chester - History

A Risk Score for Predicting Multiple Sclerosis

Multiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible. Siblings of people with MS have an increased risk of both MS and demonstrating asymptomatic changes in keeping with MS. We set out to develop an MS risk score integrating both genetic and environmental risk factors. We used this score to identify siblings at extremes of MS risk and attempted to validate the score using brain MRI.78 probands with MS, 121 of their unaffected siblings and 103 healthy controls were studied. Personal history was taken, and serological and genetic analysis using the illumina immunochip was performed. Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. Scores were initially calculated using log odds ratio from the HLA-DRB1*1501 allele only, secondly using data from all MS-associated SNPs identified in the 2011 GWAS. Subjects with extreme risk scores underwent validation studies. MRI was performed on selected individuals.There was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p<0.0005). Unaffected siblings had a risk score intermediate to people with MS and controls (p<0.0005). The best performing risk score generated an AUC of 0.82 (95%CI 0.75–0.88).The risk score demonstrates an AUC on the threshold for clinical utility. Our score enables the identification of a high-risk sibling group to inform pre-symptomatic longitudinal studies

Physiotherapy alone or in combination with corticosteroid injection for acute lateral epicondylitis in general practice: A protocol for a randomised, placebo-controlled study

<p>Abstract</p> <p>Background</p> <p>Lateral epicondylitis is a painful condition responsible for loss of function and sick leave for long periods of time. In many countries, the treatment guidelines recommend a wait-and-see policy, reflecting that no conclusions on the best treatment can be drawn from the available research, published studies and meta-analyses.</p> <p>Methods/Design</p> <p>Randomized double blind controlled clinical trial in a primary care setting. While earlier trials have either compared corticosteroid injections to physical therapy or to naproxen orally, we will compare the clinical effect of physiotherapy alone or physiotherapy combined with corticosteroid injection in the initial treatment of acute tennis elbow. Patients seeing their general practitioner with lateral elbow pain of recent onset will be randomised to one of three interventions: 1: physiotherapy, corticosteroid injection and naproxen or 2: physiotherapy, placebo injection and naproxen or 3: wait and see treatment with naproxen alone. Treatment and assessments are done by two different doctors, and the contents of the injection is unknown to both the treating doctor and patient. The primary outcome measure is the patient's evaluation of improvement after 6, 12, 26 and 52 weeks. Secondary outcome measures are pain, function and severity of main complaint, pain-free grip strength, maximal grip strength, pressure-pain threshold, the patient's satisfaction with the treatment and duration of sick leave.</p> <p>Conclusion</p> <p>This article describes a randomized, double blind, controlled clinical trial with a one year follow up to investigate the effects of adding steroid injections to physiotherapy in acute lateral epicondylitis.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT00826462</p

Duty, desire or indifference? A qualitative study of patient decisions about recruitment to an epilepsy treatment trial

BACKGROUND: Epilepsy is a common neurological condition, in which drugs are the mainstay of treatment and drugs trials are commonplace. Understanding why patients might or might not opt to participate in epilepsy drug trials is therefore of some importance, particularly at a time of rapid drug development and testing; and the findings may also have wider applicability. This study examined the role of patient perceptions in the decision-making process about recruitment to an RCT (the SANAD Trial) that compared different antiepileptic drug treatments for the management of new-onset seizures and epilepsy. METHODS: In-depth interviews with 23 patients recruited from four study centres. All interviews were tape-recorded and transcribed; the transcripts were analysed thematically using a qualitative data analysis package. RESULTS: Of the nineteen informants who agreed to participate in SANAD, none agreed for purely altruistic reasons. The four informants who declined all did so for very specific reasons of self-interest. Informants' perceptions of the nature of the trial, of the drugs subject to trial, and of their own involvement were all highly influential in their decision-making. Informants either perceived the trial as potentially beneficial or unlikely to be harmful, and so agreed to participate; or as potentially harmful or unlikely to be beneficial and so declined to participate. CONCLUSION: Most patients applied 'weak altruism', while maintaining self-interest. An emphasis on the safety and equivalence of treatments allowed some patients to be indifferent to the question of involvement. There was evidence that some participants were subject to 'therapeutic misconceptions'. The findings highlight the individual nature of trials but nonetheless raise some generic issues in relation to their design and conduct

Reproducibility over a 1-month period of 1H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients

N-acetylaspartate/creatine (NAA/Cr) ratios, assessed with proton magnetic resonance spectroscopy, are increasingly used as a surrogate marker for axonal dysfunction and degeneration in multiple sclerosis (MS). The purpose of this study was to test short-time reproducibility of NAA/Cr ratios in patients with clinically stable MS. In 35 MS patients we analysed NAA/Cr ratios obtained with 1H-MR spectroscopic imaging at the centrum semiovale either with lateral ventricles partially included (group 1; n=15) or more cranially with no ventricles included (group 2; n=20). To test short-term reproducibility of the NAA/Cr measurements, patients were scanned twice 4 weeks apart. We determined mean NAA/Cr and Cho/Cr ratios of 12 grey matter and 24 white matter voxels. Mean NAA/Cr ratios of both the white and grey matter did not change after 4 weeks. Overall 4-week reproducibility of the NAA/Cr ratio, expressed as coefficient of variation, was 4.8% for grey matter and 3.5% for white matter. Reproducibility of cranial scanning of the ventricles was slightly better than with cerebrospinal fluid included. Our study shows good short-term reproducibility of NAA/Cr ratio measurements in the centrum semiovale, which supports the reliability of this technique for longitudinal studies