Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.

Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12) to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase). In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb). This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents.CM is funded by Medical Research Council Grant No G9826026. AR was funded by a British Heart Foundation Centre of Research Excellence-funded Vacation Studentship. CHC is funded by British Heart Foundation Fellowship FS/11/49/28751.This is the final version of the article. It first appeared from PLOS via https://doi.org/10.1371/journal.pone.016300

The first endovascular repair of an acute type A dissection using an endograft designed for the ascending aorta

Endovascular repair has emerged as a potential alternative to emergency open surgical repair for type A dissection in selected patients, with isolated reports describing the results obtained with a range of devices designed originally for the descending aorta. We believe that we present the first reported repair of an acute ascending aortic dissection using an endovascular stent graft manufactured specifically for the ascending aorta

Lessons from Laparoscopic Liver Surgery: A Nine-Year Case Series

Objective. This series describes a developing experience in laparoscopic liver surgery presenting results from 40 procedures including right hemihepatectomy, left lateral lobectomy, and microwave ablation therapy. Methods. Forty patients undergoing laparoscopic liver surgery between September 1997 and November 2006 were included. The data set includes: operative procedure and duration, intraoperative blood loss, conversion to open operation rates, length of hospital stay, complications, mortality, histology of lesions/resection margins, and disease recurrence. Results. Mean age of patient: 59 years, 17/40 male, 23/40 female, 23/40 of lesions were benign, and 17/40 malignant. Operations included: laparoscopic anatomical resections n = 15, nonanatomical resections n = 11, microwave ablations n = 8 and deroofing of cysts n = 7. Median anaesthetic time: 120 minutes (range 40–240), mean blood loss 78 mL and 1/40 conversions to open. Median resection margins were 10 mm (range 1–14) and median length of stay 3 days (range 1–10). Operative and 30-day mortality were zero with no local disease recurrence. Conclusion. Laparoscopic liver surgery appears safe and effective and is associated with reduced hospital stay. Larger studies are required to confirm it is oncologically sound

Inequity in access to transplantation in the UK

Background and objectives Despite the presence of a universal health care system, it is unclear if there is intercenter variation in access to kidney transplantation in the United Kingdom. This study aims to assess whether equity exists in access to kidney transplantation in the United Kingdom after adjustment for patient-specific factors and center practice patterns. Design, setting, participants, & measurements In this prospective, observational cohort study including all 71 United Kingdom kidney centers, incident RRT patients recruited between November 2011 and March 2013 as part of the Access to Transplantation and Transplant Outcome Measures study were analyzed to assess preemptive listing (n=2676) and listing within 2 years of starting dialysis (n=1970) by center. Results Seven hundred and six participants (26%) were listed preemptively, whereas 585 (30%) were listed within 2 years of commencing dialysis. The interquartile range across centers was 6%–33% for preemptive listing and 25%–40% for listing after starting dialysis. Patient factors, including increasing age, most comorbidities, body mass index >35 kg/m2, and lower socioeconomic status, were associated with a lower likelihood of being listed and accounted for 89% and 97% of measured intercenter variation for preemptive listing and listing within 2 years of starting dialysis, respectively. Asian (odds ratio, 0.49; 95% confidence interval, 0.33 to 0.72) and Black (odds ratio, 0.43; 95% confidence interval, 0.26 to 0.71) participants were both associated with reduced access to preemptive listing; however Asian participants were associated with a higher likelihood of being listed after starting dialysis (odds ratio, 1.42; 95% confidence interval, 1.12 to 1.79). As for center factors, being registered at a transplanting center (odds ratio, 3.1; 95% confidence interval, 2.36 to 4.07) and a universal approach to discussing transplantation (odds ratio, 1.4; 95% confidence interval, 1.08 to 1.78) were associated with higher preemptive listing, whereas using a written protocol was associated negatively with listing within 2 years of starting dialysis (odds ratio, 0.7; 95% confidence interval, 0.58 to 0.9). Conclusions Patient case mix accounts for most of the intercenter variation seen in access to transplantation in the United Kingdom, with practice patterns also contributing some variation. Socioeconomic inequity exists despite having a universal health care system

Seasonality of Holocene hydroclimate in the Eastern Mediterranean reconstructed using the oxygen isotope composition of carbonates and diatoms from Lake Nar, central Turkey

A positive shift in the oxygen isotope composition (δ18O) of lake carbonates in the Eastern Mediterranean from the early to late Holocene is usually interpreted as a change to drier (reduced P/E) conditions. However, it has also been suggested that changes in the seasonality of precipitation could explain these trends. Here, Holocene records of δ18O from both carbonates and diatom silica, from Lake Nar in central Turkey, provide insights into palaeoseasonality. We show how Δδ18Olakewater (the difference between spring and summer reconstructed δ18Olakewater) was minimal in the early Holocene and for most of the last millennium, but was greater at other times. For example, between ~4,100-1,600 years BP we suggest that increased Δδ18Olakewater could have been the result of relatively more spring/summer evaporation, amplified by a decline in lake level. In terms of change in annual mean δ18O, isotope mass balance modelling shows that this can be influenced by changes in seasonal P/E as well as inter-annual P/E, but lake level falls inferred from other proxies confirm there was a mid Holocene transition to drier climatic conditions in central Turkey

Response of a low elevation carbonate lake in the Yucatan Peninsula (Mexico) to climatic and human forcings

The importance of climate change, specifically drought, across the Maya region in the northern Neotropics, remains a topic of lively debate. Part of this discussion hinges on the coherency of response to climatic variability across different archives and proxies. In this paper we present a 6600-year palaeolimnological record from Yaal Chac, a carbonate lake (known locally as a cenote) in the northern lowlands of the Yucatan Peninsula, 2‰), but show no covariation with δ13C. A major transition occurs at ca. 4360 cal yr BP, with a change to generally more organic sediments and increased variability in all proxies. Although direct evidence for anthropogenic activity in the Yaal Chac catchment is limited, it seems feasible that human impact was affecting the system. Comparison with other records from the Northern Maya lowlands and the wider region shows little coherence in the mid Holocene, when Yaal Chac seems to have been quite stable, but possibly responsive to increased climatic seasonality, driving the production of seasonal laminae. In the late Holocene, when the climate was generally more variable, there is more coherence between Yaal Chac and other regional records, including the so called Pan Caribbean Dry Period (3500–2500 cal yr BP) and the droughts of the late Pre-Classic period (1800–1600 cal yr BP). The Yaal Chac record shows no evidence of drought at the time of either the Maya ‘hiatus’ or the Maya ‘collapse’ of the Terminal Classic, but does record drying from the 14th to 19th centuries CE, in keeping with other proxy and historical records. This new record from Yaal Chac highlights the spatial variability of responses to climate forcings and the importance of recognising individual system sensitivity

A 6,000-year record of environmental change from the eastern Pacific margin of central Mexico

The transition from the mid- to late-Holocene in MesoAmerica saw increasing complexity in spatial patterns of change. Records from the western part of the region are sparse, with lacustrine sequences affected by long term anthropogenic disturbance or lacking chronological resolution. Here, we present a continuous palaeoecological and geochemical record from Laguna de Juanacatlán, a remote lake in the mountains of the western TMVB. Diatom assemblages, XRF scanning data and bulk organic geochemistry from a well-dated, 7.25-m laminated sequence were combined with summary pollen data from a 9-m partially laminated core to provide a continuous record of catchment and lake ecosystem changes over the last c. 6,000 years. Relatively humid conditions prevailed prior to c. 5.1 cal ka, which supported dense oak-pine forest cover around a deep, stratified lake. A trend towards drier conditions began c. 5.1 cal ka, intensifying after 4.0 cal ka, consistent with weakening of the North American Monsoon. Between 3.0 and 1.2 cal ka, lower lake levels and variable catchment run-off are consistent with increasing ENSO influence observed in the Late Holocene in the neotropics. From 1.2 to 0.9 cal ka, a marked change to catchment stability and more intense stratification reflected drier conditions and / or reduced rainfall variability and possibly warmer temperatures. After 0.9 cal ka, conditions were wetter, with an increase in catchment disturbance associated with the combined effects of climate and human activity. In recent decades, the lake ecosystem has changed markedly, possibly in response to recent climate change as well as local catchment dynamics

A tale of two lakes: a multi-proxy comparison of Lateglacial and Holocene environmental change in Cappadocia, Turkey

Individual palaeoenvironmental records represent a combination of regional-scale (e.g. climatic) and site-specific local factors. Here we compare multiple climate proxies from two nearby maar lake records, assuming that common signals are due to regional-scale forcing. A new core sequence from Nar Lake in Turkey is dated by varves and U–Th to the last 13.8 ka. Markedly dry periods during the Lateglacial stadial, at 4.3–3.7 and at 3.2–2.6 ka BP, are associated with peaks in Mg/dolomite, positive δ18O, elevated diatom-inferred electrical conductivity, an absence of laminated sediments and low Quercus/chenopod ratios. Wet phases occurred during the early–mid Holocene and 1.5–0.6 ka BP, characterized by negative δ18O, calcite precipitation, high Ca/Sr ratios, a high percentage of planktonic diatoms, laminated sediments and high Quercus/chenopod ratios. Comparison with the record from nearby Eski Acıgöl shows good overall correspondence for many proxies, especially for δ18O. Differences are related to basin infilling and lake ontogeny at Eski Acıgöl, which consequently fails to register climatic changes during the last 2 ka, and to increased flux of lithogenic elements into Nar Lake during the last 2.6 ka, not primarily climatic in origin. In attempting to separate a regional signal from site-specific ‘noise’, two lakes may therefore be better than one

Choice of Moisturiser for Eczema Treatment (COMET):feasibility study of a randomised controlled parallel group trial in children recruited from primary care

OBJECTIVES: To determine the feasibility of a randomised controlled trial of ‘leave on’ emollients for children with eczema. DESIGN: Single-centre, pragmatic, 4-arm, observer-blinded, parallel, randomised feasibility trial. SETTING: General practices in the UK. PARTICIPANTS: Children with eczema aged 1 month to <5 years. OUTCOME MEASURES: Primary outcome—proportion of parents who reported use of the allocated study emollient every day for the duration of follow-up (12 weeks). Other feasibility outcomes—participant recruitment and retention, data collection and completeness and blinding of observers to allocation. INTERVENTIONS: Aveeno lotion, Diprobase cream, Doublebase gel, Hydromol ointment. RESULTS: 197 children were recruited—107 by self-referral (mainly via practice mail-outs) and 90 by inconsultation (clinician consenting and randomising) pathways. Participants recruited inconsultation were younger, had more severe Patient-Oriented Eczema Measure scores and were more likely to withdraw than self-referrals. Parents of 20 (10%) of all the randomised participants reported using the allocated emollient daily for 84 days. The use of other non-study emollients was common. Completeness of data collected by parent-held daily diaries and at monthly study visits was good. Daily diaries were liked (81%) but mainly completed on paper rather than via electronic (‘app’) form. Major costs drivers were general practitioner consultations and eczema-related prescriptions. Observer unblinding was infrequent, and occurred at the baseline or first follow-up visit through accidental disclosure. CONCLUSIONS: It is feasible in a primary care setting to recruit and randomise young children with eczema to emollients, follow them up and collect relevant trial data, while keeping observers blinded to their allocation. However, reported use of emollients (study and others) has design implications for future trials. TRIAL REGISTRATION NUMBER: ISRCTN21828118/EudraCT2013-003001-26