Controlling electron emission from the photoactive yellow protein chromophore by substitution at the coumaric acid group

Understanding how the interactions between a chromophore and its surrounding protein control the function of a photoactive protein remains a challenge. Here, we present the results of photoelectron spectroscopy measurements and quantum chemistry calculations aimed at investigating how substitution at the coumaryl tail of the photoactive yellow protein chromophore controls competing relaxation pathways following photoexcitation of isolated chromophores in the gas phase with ultraviolet light in the range 350-315 nm. The photoelectron spectra are dominated by electrons resulting from direct detachment and fast detachment from the 2(1)ππ* state but also have a low electron kinetic energy component arising from autodetachment from lower lying electronically excited states or thermionic emission from the electronic ground state. We find that substituting the hydrogen atom of the carboxylic acid group with a methyl group lowers the threshold for electron detachment but has very little effect on the competition between the different relaxation pathways, whereas substituting with a thioester group raises the threshold for electron detachment and appears to 'turn off' the competing electron emission processes from lower lying electronically excited states. This has potential implications in terms of tuning the light-induced electron donor properties of photoactive yellow protein

The relationship between reductions in knee loading and immediate pain response whilst wearing lateral wedged insoles in knee osteoarthritis

Studies of lateral wedge insoles (LWIs) in medial knee osteoarthritis (OA) have shown reductions in the average external knee adduction moment (EKAM) but no lessening of knee pain. Some treated patients actually experience increases in the EKAM which could explain the overall absence of pain response. We examined whether, in patients with painful medial OA, reductions in the EKAM were associated with lessening of knee pain. Each patient underwent gait analysis whilst walking in a control shoe and two LWI's. We evaluated the relationship between change in EKAM and change in knee pain using Spearman Rank Correlation coefficients and tested whether dichotomizing patients into biomechanical responders (decreased EKAM) and non-responders (increased EKAM) would identify those with reductions in knee pain. In 70 patients studied, the EKAM was reduced in both LWIs versus control shoe (−5.21% and −6.29% for typical and supported wedges, respectively). The change in EKAM using LWIs was not significantly associated with the direction of knee pain change. Further, 54% were biomechanical responders, but these persons did not have more knee pain reduction than non-responders. Whilst LWIs reduce EKAM, there is no clearcut relationship between change in medial load when wearing LWIs and corresponding change in knee pain

The photoionization dynamics of the three structural isomers of dichloroethene

Using tunable vacuum-UV radiation from a synchrotron, the threshold photoelectron spectrum, threshold photoelectron photoion coincidence spectrum and ion breakdown diagram of the 1,1, cis-1,2 and trans-1,2 isomers of C$_2$H$_2$Cl$_2$ have been recorded in the range 9-23 eV. The energies of the peaks in the threshold photoelectron spectrum are in good agreement with outer-valence Greens function caculations. The major difference between the isomers, both predicted and observed experimentally is that the F and G states of C$_2$H$_2$Cl$_2^+$ are approximately degenerate for 1,1 and trans-1,2, but well separated for the cis-1,2 isomer. The ground and low-lying valence states of C$_2$H$_2$Cl$_2^+$ are bound, with higher-lying states dissociating to C$_2$H$_2$Cl$^+$ or C$_2$H$_2^+$. The translational kinetic energy release into C$_2$H$_2$Cl$^+$ + Cl is determined as a function of energy. Isolated-state behaviour for the low-lying electronic states of C$_2$H$_2$Cl$_2^+$ becomes more statistical as the energy increases

Clinical and instrumental evaluation of Botulinum Toxin type A safety profile in post stroke spasticity rehabilitation treatment

Post stroke spasticity (PSS) occurs approximately in 30% of stroke survivors. Spasticity varies from a subtle neurological sign to a gross increase in tone causing immobility of joints. PSS is associated with several complications, increasing care needs and utilisation of healthcare resources. Botulinum toxin type A (BoNT-A) has been considered as an effective and safe treatment for focal spasticity in stroke survivors, with low prevalence of complications, reversibility of effect, and efficacy in reducing spastic hypertonia. Recent studies estimated that a significant percentage of patients affected by PSS could benefit from higher doses than those permitted by current country directives. However, at present time, there is no general consensus on the maximum dose of BoNT-A in terms of safety and clinical interchangeability among the three commercially approved products (abobotulinumtoxinA, onabotulinumtoxinA, incobotulinumtoxinA). In light of these considerations, the aim of this thesis is to investigate the safety profile of BoNT-A high doses in the treatment of post stroke spasticity. In our research activity we investigated the clinical effect of this treatment in severely affected patients, focusing on both clinical and instrumental assessment of systemic effects of BoNT-A

The efficacy of a lateral wedge insole for painful medial knee osteoarthritis after prescreening : a randomized clinical trial

OBJECTIVE: Lateral wedge shoe insoles decrease medial knee loading, but trials have shown no effect on pain in medial knee osteoarthritis (OA). However, insoles' loading effects are inconsistent, and they can increase patellofemoral loading. We hypothesized that insoles would reduce pain in preselected patients. METHODS: In persons with painful medial knee OA, we excluded those with patellofemoral OA and those with pain <4/10. We further excluded participants who, in a gait laboratory using lateral wedges, did not show at least a 2% reduction in knee adduction moment (KAM) compared with their shoes and a neutral insole. We then randomized subjects to lateral wedge vs. neutral insole for 8 week periods separated by an 8 week washout. Primary outcome was knee pain over the past week (0-10) and secondary outcomes nominated activity pain and KOOS pain. We carried out mixed model analyses adjusted for baseline pain. RESULTS: Of 83 participants, 21 (25%) were excluded because of insufficient reduction in KAM. Of 62 included, mean age was 64.2 years (SD 9.1); 37.1% were women. Lateral wedge insoles produced a greater reduction in knee pain than neutral insoles (difference 0.7 on 0-10 scale; 95%CI 0.1, 1.2; p = 0.02). Secondary outcomes showed mixed findings. CONCLUSIONS: In persons prescreened to eliminate those with patellofemoral OA and biomechanical non-responders, lateral wedge insoles reduced knee pain, but the effect of treatment was small and is likely of clinical significance in only a minority of patients. Targeting patients may identify those who respond to this treatment

Assessment of bone marrow oedema-like lesions using MRI in patellofemoral knee osteoarthritis: comparison of different MRI pulse sequences

Objective: To compare bone marrow oedema-like lesion (BML) volume in subjects with symptomatic patellofemoral (PF) knee osteoarthritis (OA) using four different MRI sequences and to determine reliability of BML volume assessment using these sequences and their correlation with pain. Methods: 76 males and females (mean age 55.8 years) with symptomatic patellofemoral knee OA had 1.5 T MRI scans. PD fat suppressed (FS), STIR, contrast-enhanced (CE) T1W FS, and 3D T1W fast field echo (FFE) sequences were obtained. All sequences were assessed by one reader, including repeat assessment of 15 knees using manual segmentation and the measurements were compared. We used random-effects panel linear regression to look for differences in the log-transformed BML volume (due to positive skew in the BML volume distribution) between sequences and to determine associations between BML volumes and knee pain. Results: 58 subjects had PF BMLs present on at least one sequence. Median BML volume measured using T1W FFE sequence was significantly smaller (224.7 mm3, interquartile range [IQR] 82.50–607.95) than the other three sequences. BML volume was greatest on the CE sequence (1129.8 mm3, IQR 467.28–3166.02). Compared to CE sequence, BML volumes were slightly lower when assessed using PDFS (proportional difference = 0.79; 95% confidence interval [CI] 0.62, 1.01) and STIR sequences (proportional difference = 0.85; 95% CI 0.67, 1.08). There were strong correlations between BML volume on PDFS, STIR, and CE T1W FS sequences (ρs = 0.98). Correlations were lower between these three sequences and T1W FFE (ρs = 0.80–0.81). Intraclass correlation coefficients were excellent for proton density fat-suppressed, short-tau inversion recovery, and CE T1W FS sequences (0.991–0.995), while the ICC for T1W FFE was good at 0.88. We found no significant association between BML volumes assessed using any of the sequences and knee pain. Conclusion: T1W FFE sequences were less reliable and measured considerably smaller BML volume compared to other sequences. BML volume was larger when assessed using the contrast enhanced T1W FS though not statistically significantly different from BMLs when assessed using PDFS and STIR sequences. Advances in knowledge: This is the first study to assess BMLs by four different MRI pulse sequences on the same data set, including different fluid sensitive sequences and gradient echo type sequence

Patients with perianal Crohn's fistulas experience delays in accessing anti-TNF therapy due to slow recognition, diagnosis and integration of specialist services: lessons learned from three referral centres.

AIM: Crohn's anal fistula should be managed by a multidisciplinary team. There is no clearly defined 'patient pathway' from presentation to treatment. The aim of this study was to describe the patient route from presentation with symptomatic Crohn's anal fistula to starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Case note review was undertaken at three hospitals with established inflammatory bowel disease services. Patients with Crohn's anal fistula presenting between 2010 and 2015 were identified through clinical coding and local databases. Baseline demographics were captured. Patient records were interrogated to identify route of access, and clinical contacts during the patient pathway. RESULTS: Seventy-nine patients were included in the study, of whom 54 (68%) had an established diagnosis of Crohn's disease (CD). Median time from presentation to anti-TNF therapy was 204 days (174 vs 365 days for existing and new diagnosis of CD, respectively; P = 0.019). The mean number of surgical outpatient attendances, operations and MRI scans per patient was 1.03, 1.71 and 1.03, respectively. Patients attended a mean of 1.49 medical clinics. Seton insertion was the most common procedure, accounting for 48.6% of all operations. Where care episodes ('clinical events per 30 days') were infrequent this correlated with prolongation of the pathway (r = -0.87; P < 0.01). CONCLUSION: This study highlights two key challenges in the treatment pathway: (i) delays in diagnosis of underlying CD in patients with anal fistula and (ii) the pathway to anti-TNF therapy is long, suggesting issues with service design and delivery. These should be addressed to improve patient experience and outcome

Foot and ankle biomechanics play a role in biomechanical response to lateral wedge insoles

Lateral wedge insoles have consistently shown to reduce the external knee adduction moment (EKAM) in medial knee osteoarthritis (OA) patients; although there is evidence that certain patients have a paradoxical increase in EKAM. This may be a key factor in determining clinical response and thus identifying and understanding why these patients increase EKAM is critical for prescribing the correct treatment for these patients. Previous evidence has suggested that foot and ankle biomechanics play a role in reducing EKAM by shifting the centre of foot pressure (COFP) laterally and increasing the valgus orientation of the calcaneus, which shortens the lever arm in respect of the knee, thus reducing the EKAM. To date, patients have been studied irrespective of biomechanical response to lateral wedge insoles. In this study we investigated whether dynamic ankle biomechanics can assist in identifying and explaining why some patients increase EKAM and other decrease EKAM when wearing a lateral wedge

The efficacy of intra-articular steroids in hip osteoarthritis: a systematic review

© 2016 Osteoarthritis Research Society International Objective International guidelines recommend intra-articular steroid injections (IASIs) in the management of hip osteoarthritis (OA), though these recommendations are extrapolated primarily from studies of knee OA. The aim of this systematic review was to assess the efficacy of IASI on pain in hip OA. Methods MEDLINE, EMBASE, AMED, CINAHL Plus, Web of Science and the Cochrane Central Register of Controlled Trials were searched to May 2015. Randomised controlled trials (RCTs) assessing the efficacy of hip IASI on pain were included. Pre-specified data was extracted using a standardised form. Quality was assessed using the Jadad score. Results Five trials met the inclusion criteria. All had a small number of participants (≤101). All studies reported some reduction in pain at 3–4 weeks post-injection compared to control. Based on data from individual trials the treatment effect size was large at 1 week post-injection but declined thereafter. A significant (moderate effect size) reduction in pain was reported in two trials up to 8 weeks following IASI. Pooled results of two trials (n = 90) showed an increased likelihood of meeting the Outcome measures in Rheumatology Clinical Trials (OMERACT)–Osteoarthritis Research Society International (OARSI) response criteria at 8 weeks post-IASI, odds ratio 7.8 (95% confidence interval (CI): 2.7–22.8). The number needed to treat to achieve one OMERACT–OARSI responder at 8 weeks post-injection was 2.4 (95% CI: 1.7–4.2). Hip IASI appear to be generally well tolerated. Conclusions Hip IASI may be efficacious in short-term pain reduction in those with hip OA though the quality of the evidence was relatively poor. Further large, methodologically rigorous trials are required to verify whether intra-articular corticosteroids are beneficial and for how long