A Genomic Point Mutation in the Extracellular Domain of the Thyrotropin Receptor in Patients with Graves’ Ophthalmopathy

Orbital and pretibial fibroblasts are targets of autoimmune attack in Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD). The fibroblast autoantigen involved in these peripheral manifestations of Graves' disease and the reason for the association of GO and PTD with hyperthyroidism are unknown. RNA encoding the full-length extracellular domain of the TSH receptor has been demonstrated in orbital and dermal fibroblasts from patients with GO and normal subjects, suggesting a possible antigenic link between fibroblasts and thyrocytes. RNA was isolated from cultured orbital, pretibial, and abdominal fibroblasts obtained from patients with severe GO (n = 22) and normal subjects (n = 5). RNA was reverse transcribed, and the resulting cDNA was amplified by the polymerase chain reaction, using primers spanning overlapping regions of the entire extracellular domain of the TSH receptor. Nucleotide sequence analysis showed an A for C substitution in the first position of codon 52 in 2 of the patients, both of whom had GO, PTD, and acropachy. Genomic DNA isolated from the 2 affected patients, and not from an additional 12 normal subjects, revealed the codon 52 mutation by direct sequencing and AciI restriction enzyme digestions. In conclusion, we have demonstrated the presence of a genomic point mutation, leading to a threonine for proline amino acid shift in the predicted peptide, in the extracellular domain of the TSH receptor in two patients with severe GO, PTD, acropachy, and high thyroid-stimulating immunoglobulin levels. RNA encoding this mutant product was demonstrated in the fibroblasts of these patients. We suggest that the TSH receptor may be an important fibroblast autoantigen in GO and PTD, and that this mutant form of the receptor may have unique immunogenic properties

Cast versus functional brace in the rehabilitation of patients treated non-operatively for a rupture of the Achilles tendon: protocol for the UK study of tendo achilles rehabilitation (UK STAR) multi-centre randomised trial

INTRODUCTION Achilles tendon rupture affects over 11 000 people yearly in the UK, and the incidence is increasing. Controversy remains with regard to the best rehabilitation strategy for these patients. In operatively treated patients, functional bracing provides better outcomes compared with plaster casts. However, the role of functional bracing in non-operatively managed patients is unclear. This is the protocol for a multicentre randomised trial of plaster cast immobilisation versus functional bracing for patients with a non-operatively managed Achilles tendon rupture. METHODS AND ANALYSIS All adults presenting with a primary rupture of the Achilles tendon will be screened. Non-operatively treated patients will be eligible to take part in the trial. Broad eligibility criteria will ensure that the results of the study can be generalised to the wider patient population. Randomisation will be on a 1:1 basis. Both rehabilitation strategies are widely used within the National Health Service. Standardised protocols will be followed, and details of plaster material and brace will be as per the site's usual practice.A minimum of 330 patients will be randomised to obtain 90% power to detect a difference of 8 points in Achilles Tendon Total Rupture Score at 9 months. Quality of life and resource use will be collected at 3, 6 and 9 months. The differences between treatment groups will be assessed on an intention-to-treat basis. The results of the trial-based economic evaluation will be expressed in terms of incremental cost per quality-adjusted life-year gained. ETHICS AND DISSEMINATION The National Research Ethic Committee approved this study on 18 March 2016 (16/SC/0109).The National Institute for Health Research Health Technology Assessment monograph and a manuscript to a peer-reviewed journal will be submitted on completion of the trial (summer 2019). The results of this trial will substantially inform clinical practice on the clinical and cost-effectiveness of the treatment of this injury. This study has been registered on the International Standard Randomised Controlled Trial Number registry with reference no ISRCTN62639639

Quantum critical points in ferroelectric relaxors : stuffed tungsten bronze K3Li2Ta5O15 and lead pyrochlore (Pb2Nb2O7)

We have synthesized ceramic specimens of the tetragonal tungsten bronze K3Li2Ta5O15 (KLT) and characterized its phase transition via X-ray diffraction, dielectric permittivity, resonant ultrasonic spectroscopy, and heat capacity measurements. The space group of KLT is reported as both P4/mbm and Cmmm with the orthorhombic distortion occurring when there are higher partial pressures of volatile K and Li used inside the closed crucibles for the solid state synthesis. The data show strong relaxor behavior, with the temperature at which the two dielectric relative permittivity peaks decreasing, with 104 ≥ Tm1 ≥ 69 K and 69 ≥ Tm2 ≥ 46 K as probe frequency f is reduced from 1 MHz to 316 Hz. F tests show that the data satisfies a Vogel-Fulcher model better than Arrhenius with an extrapolated freezing temperature for ε’ and ε” of Tf1 = +15.8 and –11.8 K and Tf2 = –5.0 and –15.0 K for f -> 0 (tending to dc). This difference between Tf from real and imaginary values, albeit counterintuitive, is mandatory, according to the theory of Tagantsev. Therefore, by tuning frequency, the transition could be shifted to absolute zero, suggesting KLT has a relaxor-type quantum critical point. In addition, we have reanalyzed the conflicting literature for Pb2Nb2O7 pyrochlore which suggests that this also has a relaxor-type quantum critical point since the freezing temperature from the Vogel-Fulcher fitting is below absolute zero. Since the transition temperature evidenced in the dielectric data at approximately 100 kHz shifts below 0 K for very low frequencies, this transition would not be seen with heat capacity data collected in the zero-frequency (dc) limit. Both of these materials show promise for possible new relaxor-type quantum critical points with non-perovskite based structures.Publisher PDFPeer reviewe

Rehabilitation strategy after non-surgical treatment of Achilles tendon rupture : UKSTAR, a multicentre RCT

Background Achilles tendon rupture affects > 11,000 people each year in the UK, leading to prolonged periods away from work, sports and social activities. Traditionally, the ruptured tendon is held still in a plaster cast for ≥ 8 weeks. Functional bracing is an alternative treatment that allows patients to mobilise earlier, but there is little evidence about how bracing affects patients’ recovery. Objectives To measure the Achilles Tendon Rupture Score, quality of life, complications and resource use of patients receiving non-operative treatment for an Achilles tendon rupture treated with plaster cast compared with those treated with functional bracing. Design This was a multicentre, randomised, pragmatic, two-group superiority trial. Setting The setting was 39 NHS hospitals. Participants A total of 540 adult patients treated non-operatively for Achilles tendon rupture were randomised from July 2016 to May 2018. Exclusion criteria included presenting after 14 days, having had previous rupture and being unable to complete questionnaires. Interventions A total of 266 participants had a plaster cast applied, with their toes initially pointing to the floor. The cast was changed over 8 weeks to bring the foot into a walking position. A total of 274 patients had a functional brace that facilitated immediate weight-bearing. The foot position was adjusted within the brace over the same 8-week period. Main outcome measures Achilles Tendon Rupture Score is patient reported and assesses symptoms and physical activity related to the Achilles tendon (score 0–100, with 100 being the best possible outcome). The secondary outcomes were quality of life, complications and resource use at 8 weeks and at 3, 6 and 9 months. Results Participants had a mean age of 48.7 years, were predominantly male (79%) and had ruptured their tendon during sports (70%). Over 93% of participants completed follow-up. There was no statistically significant difference in Achilles Tendon Rupture Score at 9 months post injury (–1.38, 95% confidence interval –4.9 to 2.1). There was a statistically significant difference in Achilles Tendon Rupture Score at 8 weeks post injury in favour of the functional brace group (5.53, 95% confidence interval 2.0 to 9.1), but not at 3 or 6 months post injury. Quality of life showed the same pattern, with a statistically significant difference at 8 weeks post injury but not at later time points. Complication profiles were similar in both groups. Re-rupture of the tendon occurred 17 times in the plaster cast group and 13 times in the functional brace group. There was no difference in resource use. Conclusions This trial provides strong evidence that early weight-bearing in a functional brace provides similar outcomes to traditional plaster casting and is safe for patients receiving non-operative treatment of Achilles tendon rupture. The probability that functional bracing is cost-effective exceeds 95% for the base-case imputed analysis, assuming a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. On average, functional brace is associated with lower costs (–£103, 95% confidence interval –£290 to £84) and more quality-adjusted life-years (0.015, 95% confidence interval –0.0013 to 0.030) than plaster cast

An international study evaluating elemental analysis

A statistical study on elemental analysis for 5 small organic compounds at 18 independent service providers across multiple countries demonstrates variation in the returned results that is outside journal guidelines (0.4%) in greater than 10% of measurements. The results indicate that a deviation of 0.4% is not a realistic journal requirement with the variability attributed to random error

Quantum critical points in ferroelectric relaxors: Stuffed tungsten bronze K3Li2Ta5O15 and lead pyrochlore ( Pb2Nb2O7 )

We have synthesized ceramic specimens of the tetragonal tungsten bronze K3Li2Ta5O15 (KLT) and characterized its phase transition via x-ray diffraction, dielectric permittivity, resonant ultrasonic spectroscopy, and heat capacity measurements. The space group of KLT is reported as both P4/mbm and Cmmm with the orthorhombic distortion occurring when there are higher partial pressures of volatile K and Li used inside the closed crucibles for the solid state synthesis. The data show strong relaxor behavior, with the temperature at which the two dielectric relative permittivity peaks decreasing, with 104≥Tm1≥69K and 69≥Tm2≥46K as probe frequency f is reduced from 1 MHz to 316 Hz. F tests show that the data satisfies a Vogel-Fulcher model better than Arrhenius with an extrapolated freezing temperature for ɛ′ and ɛ′′ of Tf1=+15.8 and −11.8K and Tf2=−5.0 and −15.0K for f→0 (tending to dc). This difference between Tf from real and imaginary values, albeit counterintuitive, is mandatory, according to the theory of Tagantsev. Therefore, by tuning frequency, the transition could be shifted to absolute zero, suggesting KLT has a relaxor-type quantum critical point. In addition, we have reanalyzed the conflicting literature for Pb2Nb2O7 pyrochlore which suggests that this also has a relaxor-type quantum critical point since the freezing temperature from the Vogel-Fulcher fitting is below absolute zero. Since the transition temperature evidenced in the dielectric data at approximately 100 kHz shifts below 0 K for very low frequencies, this transition would not be seen with heat capacity data collected in the zero-frequency (dc) limit. Both of these materials show promise for possible new relaxor-type quantum critical points with nonperovskite based structures

Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements: A Prospective Cohort Study

Background Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency. Objective To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM). Design Prospective cohort study. Methods 305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression. Results 22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass. Conclusion Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM

Maternal Perception of Reduced Fetal Movements Is Associated with Altered Placental Structure and Function

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). DFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency. To date there have been no studies of placental structure in cases of DFM.To determine whether maternal perception of reduced fetal movements (RFM) is associated with abnormalities in placental structure and function.Placentas were collected from women with RFM after 28 weeks gestation if delivery occurred within 1 week. Women with normal movements served as a control group. Placentas were weighed and photographs taken. Microscopic structure was evaluated by immunohistochemical staining and image analysis. System A amino acid transporter activity was measured as a marker of placental function. Placentas from all pregnancies with RFM (irrespective of outcome) had greater area with signs of infarction (3.5% vs. 0.6%; p<0.01), a higher density of syncytial knots (p<0.001) and greater proliferation index (p<0.01). Villous vascularity (p<0.001), trophoblast area (p<0.01) and system A activity (p<0.01) were decreased in placentas from RFM compared to controls irrespective of outcome of pregnancy.This study provides evidence of abnormal placental morphology and function in women with RFM and supports the proposition of a causal association between placental insufficiency and RFM. This suggests that women presenting with RFM require further investigation to identify those with placental insufficiency

Evaluating the Potential Effectiveness of Compensatory Mitigation Strategies for Marine Bycatch

Conservationists are continually seeking new strategies to reverse population declines and safeguard against species extinctions. Here we evaluate the potential efficacy of a recently proposed approach to offset a major anthropogenic threat to many marine vertebrates: incidental bycatch in commercial fisheries operations. This new approach, compensatory mitigation for marine bycatch (CMMB), is conceived as a way to replace or reduce mandated restrictions on fishing activities with compensatory activities (e.g., removal of introduced predators from islands) funded by levies placed on fishers. While efforts are underway to bring CMMB into policy discussions, to date there has not been a detailed evaluation of CMMB's potential as a conservation tool, and in particular, a list of necessary and sufficient criteria that CMMB must meet to be an effective conservation strategy. Here we present a list of criteria to assess CMMB that are tied to critical ecological aspects of the species targeted for conservation, the range of possible mitigation activities, and the multi-species impact of fisheries bycatch. We conclude that, overall, CMMB has little potential for benefit and a substantial potential for harm if implemented to solve most fisheries bycatch problems. In particular, CMMB is likely to be effective only when applied to short-lived and highly-fecund species (not the characteristics of most bycatch-impacted species) and to fisheries that take few non-target species, and especially few non-seabird species (not the characteristics of most fisheries). Thus, CMMB appears to have limited application and should only be implemented after rigorous appraisal on a case-specific basis; otherwise it has the potential to accelerate declines of marine species currently threatened by fisheries bycatch