\u3cem\u3eIn Vitro\u3c/em\u3e Determination of Potency of Small Molecule Inhibitors of Arp2/3 Complex

Actin is a key protein building block of actin microfilaments, which are constructed and deconstructed in response to cellular signaling pathways to regulate cellular processes such as motility, division, and endocytosis. Arp2/3 Complex is a 7-subunit protein complex that is in involved in cellular construction of branched actin networks, functioning by attaching to the side of a pre-existing actin filament and nucleating a daughter branch. Overexpression of Arp2/3 complex has been linked to the ability of certain metastatic cancers to proliferate. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. A bulk actin polymerization assay is used as the key method to determine the potency of inhibitor candidates. Structure-activity relationships derived from these results are also discussed

Girding the loins? Direct evidence of the use of a medieval English parchment birthing girdle from biomolecular analysis

In this paper, we describe palaeoproteomic evidence obtained from a stained medieval birth girdle using a previously developed dry non-invasive sampling technique. The parchment birth girdle studied (Wellcome Collection Western MS. 632) was made in England in the late fifteenth century and was thought to be used by pregnant women while giving birth. We were able to extract both human and non-human peptides from the manuscript, including evidence for the use of honey, cereals, ovicaprine milk and legumes. In addition, a large number of human peptides were detected on the birth roll, many of which are found in cervico-vaginal fluid. This suggests that the birth roll was actively used during childbirth. This study is, to our knowledge, the first to extract and analyse non-collagenous peptides from a birth girdle using this sampling method and demonstrates the potential of this type of analysis for stained manuscripts, providing direct biomolecular evidence for active use

Neuromotor control during stair ambulation in individuals with patellofemoral osteoarthritis compared to asymptomatic controls

Patellofemoral OA is characterized by PF pain during activities that load a flexed knee. Stair stepping ability is frequently impaired, yet little is known of the muscular recruitment strategies utilized during this task. Altered recruitment strategies may provide targets for clinical interventions. We aimed to determine if people with PFOA ascend and descend stairs with different muscular recruitment strategies compared to similar aged healthy individuals.Twenty-two people with PFOA and 20 controls were recruited. Electromyographic recordings from gluteus maximus and medius, medial and lateral hamstrings, vastus medialis and lateralis, medial and lateral gastrocnemius and soleus were acquired during stair ascent and descent. Force plate data was acquired to determine timing of foot placements and characterize dynamic stability.Seventeen people with PFOA (59 ± 10 years, 73 ± 13 kg, 167 ± 9 cm) and 15 controls (57 ± 10 years, 73 ± 16 kg, 171 ± 11 cm) had complete data. People with PFOA demonstrated: longer vastii activation duration during descent (lateralis: p = 0.01; medialis: p = 0.02); earlier onset of vastus lateralis for ascent (p

Predictors of pneumococcal carriage and the effect of the 13-valent pneumococcal conjugate vaccination in the Western Australian Aboriginal population

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced to prevent invasive pneumococcal disease (IPD) in Western Australian (WA) Aboriginal people in 2001. PCV13 replaced PCV7 in July 2011, covering six additional pneumococcal serotypes; however, IPD rates remained high in Aboriginal people in WA. Upper respiratory tract pneumococcal carriage can precede IPD, and PCVs alter serotype distribution. Methods: To assess the impact of PCV13 introduction, identify emerging serotypes, and assess risk factors for carriage, nasopharyngeal swabs and information on demographic characteristics, health, medication and living conditions from Aboriginal children and adults across WA from August 2008 to November 2014 were collected. Bacteria were cultured using selective media and pneumococcal isolates were serotyped by Quellung reaction. Risk factors were analysed by multivariable logistic regression. Results: One thousand five hundred swabs pre- and 1385 swabs post-PCV13 introduction were collected. Pneumococcal carriage was detected in 66.8% of children 53.2% of 5–14 year-olds post-PCV13, compared with pre-PCV13 prevalence of 72.2% and 49.4%, respectively. The prevalence of PCV13-non-PCV7 serotypes decreased in children 13.5% pre-PCV13 to 5.8% post-PCV13 (p \u3c 0.01), and from 8.4% to 6.1% in children 5–14 years old (p \u3e 0.05). The most common serotypes post-PCV13 were 11A (prevalence 4.0%), 15B (3.5%), 16F (3.5%), and 19F (3.2%). Risk of detection of pneumococcal carriage increased until age 12 months (odds ratio [OR] 4.19, 95% confidence interval [CI] 2.39–7.33), with nasal discharge (OR 2.49 [95% CI 2.00–3.09]), residence in a remote community (OR 2.21 [95% CI 1.67–2.92]) and household crowding (OR 1.36 [95% CI 1.11–1.67]). Recent antibiotic use was negatively associated with pneumococcal carriage (OR 0.48 [95% CI 0.33–0.69]). Complete resistance to penicillin was present among isolates of serotypes 19A (6.0%), 19F (2.3%) and non-serotypeable isolates (1.9%). Serotype 23F and newly emerged serotype 7B isolates showed high rates of resistance to cotrimoxazole, erythromycin and tetracycline (86.9%, 86.9%, 82.0%, respectively for 23F, 100.0%, 100.0% and 93.3% for 7B). Conclusion: Since PCV13 replaced PCV7, carriage of PCV13-non-PCV7 serotypes decreased significantly among childrenold, those most likely to have received PCV13, and to a lesser extent in older people. Known risk factors for carriage including crowding and young age remain in the Aboriginal population

High Nasopharyngeal Carriage of Non-Vaccine Serotypes in Western Australian Aboriginal People Following 10 Years of Pneumococcal Conjugate Vaccination

BackgroundInvasive pneumococcal disease (IPD) continues to occur at high rates among Australian Aboriginal people. The seven-valent pneumococcal conjugate vaccine (7vPCV) was given in a 2-4-6-month schedule from 2001, with a 23-valent pneumococcal polysaccharide vaccine (23vPPV) booster at 18 months, and replaced with 13vPCV in July 2011. Since carriage surveillance can supplement IPD surveillance, we have monitored pneumococcal carriage in western Australia (WA) since 2008 to assess the impact of the 10-year 7vPCV program. MethodsWe collected 1,500 nasopharyngeal specimens from Aboriginal people living in varied regions of WA from August 2008 until June 2011. Specimens were cultured on selective media. Pneumococcal isolates were serotyped by the quellung reaction. ResultsStreptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were carried by 71.9%, 63.2% and 63.3% respectively of children <5 years of age, and 34.6%, 22.4% and 27.2% of people ≥5 years. Of 43 pneumococcal serotypes identified, the most common were 19A, 16F and 6C in children <5 years, and 15B, 34 and 22F in older people. 7vPCV serotypes accounted for 14.5% of all serotypeable isolates, 13vPCV for 32.4% and 23vPPV for 49.9%, with little variation across all age groups. Serotypes 1 and 12F were rarely identified, despite causing recent IPD outbreaks in WA. Complete penicillin resistance (MIC ≥2µg/ml) was found in 1.6% of serotype 19A (5.2%), 19F (4.9%) and 16F (3.2%) isolates and reduced penicillin susceptibility (MIC ≥0.125µg/ml) in 24.9% of isolates, particularly 19F (92.7%), 19A (41.3%), 16F (29.0%). Multi-resistance to cotrimoxazole, tetracycline and erythromycin was found in 83.0% of 23F isolates. Among non-serotypeable isolates 76.0% had reduced susceptibility and 4.0% showed complete resistance to penicillin.ConclusionsTen years after introduction of 7vPCV for Aboriginal Australian children, 7vPCV serotypes account for a small proportion of carried pneumococci. A large proportion of circulating serotypes are not covered by any currently licensed vaccine

Is impaired knee confidence related to worse kinesiophobia, symptoms, and physical function in people with knee osteoarthritis after anterior cruciate ligament reconstruction?

Objectives: To compare knee confidence and kinesiophobia (fear of re-injury) in those with and without knee osteoarthritis following anterior cruciate ligament reconstruction, and determine whether poorer knee confidence is associated with greater kinesiophobia, worse knee-related symptoms, and functional impairments in those with knee osteoarthritis

Efficacy of nonsurgical interventions for anterior knee pain: Systematic review and meta-analysis of randomized trials

Anterior knee pain is a chronic condition that presents frequently to sports medicine clinics, and can have a long-term impact on participation in physical activity. Conceivably, effective early management may prevent chronicity and facilitate physical activity. Although a variety of nonsurgical interventions have been advocated, previous systematic reviews have consistently been unable to reach conclusions to support their use. Considering a decade has lapsed since publication of the most recent data in these reviews, it is timely to provide an updated synthesis of the literature to assist sports medicine practitioners in making informed, evidence-based decisions. A systematic review and meta-analysis was conducted to evaluate the evidence for nonsurgical interventions for anterior knee pain

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of Intermediate Care Clinics for Diabetes (ICCD) : study protocol for a randomized controlled trial

Background World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. Methods/Design This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or Control group: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients

Single-Leg Squat Performance is Impaired 1 to 2 Years After Hip Arthroscopy

Objective: To evaluate single-leg squat performance 1-2 years after arthroscopy for intra-articular hip pathology compared with control subjects and the nonsurgical limb, and to investigate whether single-leg squat performance on the operated limb was associated with hip muscle strength