17 research outputs found
Nailfold capillaroscopy for day-to-day clinical use: construction of a simple scoring modality as a clinical prognostic index for digital trophic lesions
No full textObjective Construction of a simple nailfold videocapillaroscopic (NVC) scoring modality as a prognostic index for digital trophic lesions for day-to-day clinical use.
Methods An association with a single simple (semi)quantitatively scored NVC parameter, mean score of capillary loss, was explored in 71 consecutive patients with systemic sclerosis (SSc), and reliable reduction in the number of investigated fields (F32-F16-F8-F4). The cut-off value of the prognostic index (mean score of capillary loss calculated over a reduced number of fields) for present/future digital trophic lesions was selected by receiver operating curve (ROC) analysis.
Results Reduction in the number of fields for mean score of capillary loss was reliable from F32 to F8 (intraclass correlation coefficient of F16/F32: 0.97; F8/F32: 0.90). Based on ROC analysis, a prognostic index (mean score of capillary loss as calculated over F8) with a cut-off value of 1.67 is proposed. This value has a sensitivity of 72.22/70.00, specificity of 70.59/69.77, positive likelihood ratio of 2.46/2.32 and a negative likelihood ratio of 0.39/0.43 for present/future digital trophic lesions.
Conclusions A simple prognostic index for digital trophic lesions for daily use in SSc clinics is proposed, limited to the mean score of capillary loss as calculated over eight fields (8 fingers, 1 field per finger)
Reliability of the qualitative and semiquantitative nailfold videocapillaroscopy assessment in a systemic sclerosis cohort : a two-centre study
No full textObjective Investigation of the reliability of the qualitative and semiquantitative scoring of nailfold videocapillaroscopy (NVC) assessment between two raters in a systemic sclerosis (SSc) cohort.
Methods Two raters from different centres blindly assessed the NVC images of 71 consecutive patients with SSc qualitatively as belonging to the scleroderma spectrum (SDS) category ('early', 'active', 'late' scleroderma pattern or 'scleroderma-like' pattern) or to the 'normal' category and semiquantitatively by calculating the mean score for capillary loss, giant capillaries, microhaemorrhages and capillary ramifications. Inter-rater/intrarater agreement was assessed by calculation of the proportion of agreement and by. coefficients. Rater agreement of mean score values of hallmark parameters was assessed by intraclass correlation coefficients.
Results The inter-rater/intrarater proportion of agreement to qualitatively assess an image as belonging to the SDS category or not was 90% and 96%, whereas the agreement to distinguish between only 'early', 'active' and 'late' scleroderma NVC patterns was 62% and 81%. The agreement of the semiquantitative scoring, as assessed by intraclass correlation coefficient, was 0.96 and 0.95 for capillary loss, 0.84 and 0.95 for giant capillaries, 0.90 and 0.95 for microhaemorrhages and 0.64 and 0.95 for capillary ramifications.
Conclusions This is the first study to demonstrate reliability of the qualitative and semiquantitative NVC assessment in an SSc cohort between raters at different centres. Reliability of NVC assessment is essential for use of this tool in multicentre SSc trials
Spatiotemporal evolution of early innate immune responses triggered by neural stem cell grafting
No full textINTRODUCTION: Transplantation of neural stem cells (NSCs) is increasingly suggested to become part of future therapeutic approaches to improve functional outcome of various central nervous system disorders. However, recently it has become clear that only a small fraction of grafted NSCs display long-term survival in the (injured) adult mouse brain. Given the clinical invasiveness of NSC grafting into brain tissue, profound characterisation and understanding of early post-transplantation events is imperative to claim safety and efficacy of cell-based interventions.
METHODS: Here, we applied in vivo bioluminescence imaging (BLI) and post-mortem quantitative histological analysis to determine the localisation and survival of grafted NSCs at early time points post-transplantation.
RESULTS: An initial dramatic cell loss (up to 80% of grafted cells) due to apoptosis could be observed within the first 24 hours post-implantation, coinciding with a highly hypoxic NSC graft environment. Subsequently, strong spatiotemporal microglial and astroglial cell responses were initiated, which stabilised by day 5 post-implantation and remained present during the whole observation period. Moreover, the increase in astrocyte density was associated with a high degree of astroglial scarring within and surrounding the graft site. During the two-week follow up in this study, the NSC graft site underwent extensive remodelling with NSC graft survival further declining to around 1% of the initial number of grafted cells.
CONCLUSIONS: The present study quantitatively describes the early post-transplantation events following NSC grafting in the adult mouse brain and warrants that such intervention is directly associated with a high degree of cell loss, subsequently followed by strong glial cell responses
Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial
No full textCopyright @ Queen’s Printer and Controller of HMSO 2012. This work was produced by Sharples et al. under the terms of a commissioning contract issued by the Secretary of State for Health.Objective: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. Design: A prospective, international, open-label, randomised controlled study, with a trialbased economic analysis. Setting: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals,Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK.
Participants: Inclusion criteria: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for
endosonography and surgery; and no evidence of metastatic disease. Exclusion criteria: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging.
Interventions: Study patients were randomised to either surgical staging alone (n = 118) or
endosonography followed by surgical staging if endosonography was negative (n = 123).
Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical
staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy.
Main outcome measures: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost–utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective.
Results: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm.
Resource use was similar between the groups in all other items. The 6-month cost of the
endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI –£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI –0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective.
Conclusions: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUSFNA or EBUS-TBNA by suitably trained chest physicians.This project was funded by the NIHR Health Technology Assessment programm
Selective non-steroidal glucocorticoid receptor agonists attenuate inflammation but do not impair intestinal epithelial cell restitution in vitro
No full textIntroduction: Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile.
Methods: The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis.
Results: Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348.
Conclusion: Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing. The fact that SEGRAs did not have a similar effect on cell restitution might be due to a different modulation of EGF/ERK1/2 MAPK signalling
Estudo da abordagem diagnóstica e terapêutica de pacientes com neoplasia intraepitelial cervical grau III no Hospital Universitário da Universidade Federal de Santa Catarina.
No full textTrabalho de Conclusão de Curso - Universidade Federal de Santa Catarina. Curso de Medicina. Departamento de Tocoginecologia
Trade liberalisation in small open economies : the case of Kenya
No full textThe object of this thesis is to determine the consequences
of trade liberalisation on the Kenyan economy. This is done by
simulating the effects of tariff reduction, devaluation of domestic
currency and export subsidies. In addition, the effects of
quantitative controls and markup pricing are simulated. The structure
of the economy is modelled through the specification of alternative
closure rules.
Policy changes are simulated using a computable general
equilibrium model (CGE). A nine sector model based on a Social
Accounting Matrix is constructed using the TV-approach to modelling
introduced by Drud, Grais and Pyatt (1986). We depart from
neoclassical models, and therefore other CGE models of Kenya, by
assuming product differentiation between domestic goods and imports
and between gross output sales to domestic and export markets. Our
model is essentially Keynesian but for comparative purposes,
neoclassical closures are specified in some simulations.
In general, the basic argument for or against trade
liberalisation concerns its contribution to economic growth. The
neoclassicals argue that by improving efficient allocation of
resources, liberalisation stimulates higher economic growth. The
structuralists, on the other hand, argue that because of structural
rigidities in LDC economies and because of unfavourable international
conditions, liberalisation will have minimal effect on economic growth.
CGE models are useful in sorting out these arguments. It should be
noted however that the assumptions underlying these models often
reflect the modeller's view about the structure of the economy. The
usefulness of CGE models for policy purposes will therefore depend on
how realistic they reflect the structure of the economy being
modelled.
The results of our model show that the gains from trade
liberalisation, in terms of the growth of real GDP, are low. This
applies to both neoclassical and Keynesian closures. However, it is
shown that changes in returns to factors, consumption levels and
aggregate price levels, depending on the closure adopted, are
significant. This is also true for the policy effects on exports,
imports and on the prices and quantities at the sectoral level. These
results reinforce the view that for policy purposes it is important
that the model being used reflects the structure of the economy under
consideration. It also means that it will not make sense to have
tailor made policy recommendations for all LDCs
Post-larval development in deep-sea echinoderms
No full textThe post-larval phase is an essential period in the life history of marine invertebrates; vulnerable to high mortality, it ultimately influences the distribution and abundance of adult populations. The post metamorphic ontogenesis of thirty species of deep-sea echinoderms, belonging to three classes (Ophiuroidea, Asteroidea and Echinoidea), is described using scanning electron microscopy. The life history of Ophiocten gracilis is also examined as a case study for future research on post-larval organisms. The analysis of development in ophiuroids reveals that species can be identified from a very early post metamorphic stage, even in congeneric species, contrary to the findings of other authors. The ontogeny of homologous structures is similar within related groups, but may give rise to different adult structures indifferent taxa. The mouth papillae within the ophiurids are serially homologous, originating from the jaw, but the fourth mouth papilla may have a different origin. In the families Ophiactidae, Ophiacanthidae and Amphilepididae examined, the mouth papillae have different origins, as, for instance, the adoral shieldspine or tentacle scale. Data on the post-larval development of Ophiura affinis suggest that this species is more closely related to the genus Ophiocten and a change in the generic status is proposed. Ophiocten gracilis is a bathyal brittle star occurring on both sides of the North Atlantic and its life history is studied in the eastern side of the North Atlantic. In this area, O. gracilis spawns in February/March of each year producing a large number of eggs. Fecundity is estimated to be around 40,000 eggs/ind, with the population of the Hebridean Slope being able to produce probably up to 16 million eggs/m2. Post-larvae start settling in May and numbers settling reached over 3,200 post-larvae/m2. The settling speed of post-larvae in the water column is estimated to be around 500 m/day, settling faster in warmer than colder water. Settling speeds appear to be similar for post-larvae ranging from 0.6 to 0.9 mm in disk diameter. Size at settlement is around 0.6 mm in disk diameter and 5-6 arm segments. The settlement of post-larval O. gracilis on the bottom of the Hebridean Slope also represented a considerable fraction of the particulate organic carbon (POC) flux in the area, reaching over 7% of the total daily flux. This is likely to have a considerable impact in the benthic community as competition and predation and as an additional food source for demersal and benthic organisms. The occurrence of post-larvae of O. gracilis in sediment traps also represented a large problem for POC flux measurements, with ophiuroids consuming part of the flux. In future works with sediment traps, such errors must be taken into account and ophiuroids must be included in the total POC flux. The deep-sea juvenile asteroids of the NE Atlantic could be distinguished to species level from a very early stage of development. The ontogenesis of Porcellanaster ceruleus shows that this species is likely to undergo a shift in habitat and diet during the juvenile phase. This is evidenced by the appearance of the epiproctal cone, the changing of the furrow and apical spines, the early development of the cribriform organ adjacent to the madreporite and the appearance of sediment in the stomach. P. ceruleus is probably a predator on meiofauna and small macrofaunal organisms during the early stages of life, changing to a burrowed life style ingesting sediment particles. Most juvenile sea stars analysed during the present study showed wider bathymetric distribution than their adult counterparts, suggesting that events occurring during the early stages of life are important for the maintenance of the local population structure and diversity in the deep NE Atlantic.The post-metamorphic development of three deep-sea spatangoid echinoids is very similar, but the morphology and formation of fascioles facilitate the distinction of the species examined. Whereas in Hemiaster expergitus and Spatangus raschi the fascioles present in the post-larvae develop to form the adult fascioles, in Brissopsis lyrifera post-larvae there is a juvenile fasciole, which disappears during ontogenesis giving way to the adult fascioles. The function of the juvenile fasciole is unknown in B.lyrifera. The development of the periproct in all spatangoids examined is similar to that described by other authors, with the periproct being initially endocyclic and migrating towards the rear of the animal as development progresses. Post-larvae of the genus Echinus could not be separated into different species, which may be linked to the recent diversification of the genus in the North Atlantic. The widespread settlement of echinoderm post-larvae reported in the present thesis and in other works is thought to have been very important for the colonization of the deep-sea through the supply of stages to deeper areas and selection of pressure adapted animals and subsequent speciation
Strategies to manage post-exercise glycaemia in type 1 diabetes
No full textFor patients with type 1 diabetes, a fear of hypoglycaemia and a concern over a loss of control with wider diabetes management are the most salient barriers to exercise participation and adherence. A large proportion of patients report a lack of advice for preventing post-exercise hypoglycaemia, and many feel largely uninformed about insulin administration and carbohydrate intake around aerobic-based exercise. Presently, recommendations within the literature are based predominantly on anecdotal and observational, but not empirical or interventional data. Therefore, this thesis aimed to develop a strategy that enables patients to effectively self-manage glycaemia following exercise, supported by evidence pertaining to the deeper physiological implications and consequences.
Study one (chapter 3) revealed that under conditions of reduced pre-exercise rapid-acting insulin dose, it is also necessary to reduce post-exercise rapid-acting insulin administration by 50% to prevent early-onset hypoglycaemia (≤ 8 hours post-exercise). Consequently, some patients experienced post-prandial hyperglycaemia with this intervention, although this was not associated with any other metabolic, counter-regulatory hormonal, or inflammatory disturbances. The results of study two (chapter 4) demonstrate that post-exercise meal composition, under conditions of reduced pre- and post-exercise rapid-acting insulin dose, carry important implications for post-prandial glycaemia. Specifically, consumption of low GI post-exercise carbohydrates normalise post-prandial hyperglycaemia, whilst protection from early onset hypoglycaemia is maintained. In addition, post-exercise meal composition heavily influences inflammatory markers; a high GI meal results in a pronounced inflammatory response, but a low GI meal completely prevented any rise in measured inflammatory markers. Lastly, study three (chapter 5) assessed the efficacy of a combined basal-bolus insulin reduction and low GI carbohydrate post-exercise feeding strategy. A 20% reduction in basal insulin provided full protection from hypoglycaemia for a total of 24 hours after exercise. Furthermore, ketonaemia did not increase to clinically meaningful levels, nor did inflammatory markers rise above concentrations seen at rest or when exercising under usual basal dose. No other metabolic or counter-regulatory hormonal disturbances were observed following a combined dose reduction to basal-bolus insulin and low GI carbohydrate post-exercise feeding.
Collectively, this thesis has shown that acute prandial adjustments in rapid-acting insulin and carbohydrate feeding, in combination with alterations in basal dose, are effective for managing post-exercise glycaemia and protecting patients from hypoglycaemia for a total of 24 hours after exercise. Moreover, this strategy aims to maintain euglycaemia by reducing post-prandial hyperglycaemia. This is not associated with clinically significant rises in ketonaemia, nor does it induce inflammatory, counter-regulatory hormonal, or other metabolic disturbances. Clinicians are advised to tailor these recommendations to a patient’s individual exercise preferences, fitness and exercise ability, level of diabetes management, and treatment regimen
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
No full textClinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection
