Patients with tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are hypersensitive to Toll-like receptor 9 stimulation.

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor 1 (TNF-R1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition Toll-like receptor (TLR)-9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: serum levels of 15 proinflammatory cytokines were measured to assess the initial inflammatory status. Interleukin (IL)-1ß, IL-6, IL-8, IL-17, IL-22, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor (TGF)-ß were significantly elevated in TRAPS patients' sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR-9 ligand (ODN2006) triggered significantly greater up-regulation of proinflammatory signalling intermediates [TNF receptor-associated factor (TRAF 3), IL-1 receptor-associated kinase-like 2 (IRAK2), Toll interacting protein (TOLLIP), TRAF6, phosphorylated transforming growth factor-ß-activated kinase 1 (pTAK), transforming growth factor-ß-activated kinase-binding protein 2 (TAB2), phosphorylated TAK 2 (pTAB2), IFN-regulatory factor 7 (IRF7), receptor interacting protein (RIP), nuclear factor kappa B (NF-κB) p65, phosphorylated NF-κB p65 (pNF-κB p65) and mitogen-activated protein kinase kinase (MEK1/2)] in TRAPS patients' PBMCs. This up-regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide-ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS and highlights the need for novel pathway-specific therapeutic treatments for this disease.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

[{"text": "\"BACKGROUND:\r\nInfantile wheezing is a common problem, but there are no guidelines for the evaluation of infants with recurrent or persistent wheezing that is not relieved or prevented by standard therapies.\r\n\r\nMETHODS:\r\nAn American Thoracic Society-sanctioned guideline development committee selected clinical questions related to uncertainties or controversies in the diagnostic evaluation of wheezing infants. Members of the committee conducted pragmatic evidence syntheses, which followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The evidence syntheses were used to inform the formulation and grading of recommendations.\r\n\r\nRESULTS:\r\nThe pragmatic evidence syntheses identified few studies that addressed the clinical questions. The studies that were identified constituted very low-quality evidence, consisting almost exclusively of case series with risk of selection bias, indirect patient populations, and imprecise estimates. The committee made conditional recommendations to perform bronchoscopic airway survey, bronchoalveolar lavage, esophageal pH monitoring, and a swallowing study. It also made conditional recommendations against empiric food avoidance, upper gastrointestinal radiography, and gastrointestinal scintigraphy. Finally, the committee recommended additional research about the roles of infant pulmonary function testing and food avoidance or dietary changes, based on allergy testing.\r\n\r\nCONCLUSIONS:\r\nAlthough infantile wheezing is common, there is a paucity of evidence to guide clinicians in selecting diagnostic tests for recurrent or persistent wheezing. Our committee made several conditional recommendations to guide clinicians; however, additional research that measures clinical outcomes is needed to improve our confidence in the effects of various diagnostic interventions and to allow advice to be provided with greater confidence.\"", "_i": "en"}]

Publication of surgeon specific outcome data: a review of implementation, controversies and the potential impact on surgical training.

Government-mandated publication of named surgeon-specific outcome data (SSD) has recently been introduced across nine surgical speciality areas in England. This move is the first time that such national data has been released in any country, and it promises to provide a significant advancement in health service transparency. Data is derived from nine preexisting national surgical audit databases. However, eight of these were not originally designed for this purpose, and there is considerable controversy surrounding data quality, risk adjustment, patient use and interpretation, and surgeons' subsequent case selection. Concerns also surround the degree to which these results truly reflect the individual consultant, or the wider hospital team and accompanying resources. The potential impact on surgical training has largely been overlooked. This paper investigated the background to SSD publication and controversies surrounding this, the potential impact on surgical training and the response to these concerns from medical and surgical leaders. As SSD collection continues to be refined, the most appropriate outcomes measurements need to be established, and risk adjustment requires ongoing improvement and validation. Prospective evaluation of changes in surgical training should be undertaken, as any degradation of will have both short and long-term consequences for patients and surgeons alike. It is important that the literature supporting the safety of supervised trainee practice is also promoted in order to counterbalance any potential concerns that might detract from trainee operating opportunities. Finally, it is important that outcomes data is communicated to patients in the most meaningful way in order to facilitate their understanding and interpretation given the complexities of the data and analysis involved.

Association of Surgeons in Training conference: Belfast 2014.

The Association of Surgeons in Training (ASiT) is a professional body and registered charity working to promote excellence in surgical training for the benefit of junior doctors and patients alike. ASiT is independent of the National Health Service (NHS), Surgical Royal Colleges, and specialty associations and represents trainees in all ten surgical specialties. ASiT was delighted to welcome all four surgical Royal College Presidents and over 650 delegates to Belfast for ASiT 2014. With a theme of Marginal Gains, the conference programme explored collaboration, simulation training and human factors, complimented by debates including the Shape of Training Review (ShOT), several focussed parallel sessions and ten subsidised pre-conference training courses. Almost £4000 was awarded by the incoming President, Mr Vimal Gokani, to delegates across more than 30 prizes for delegates who presented the highest scoring academic work from over 1200 submitted abstracts.

Sudden collapses in the heat in patients on angiotensin type 2 receptor blockers.

CONTEXT: A clinical case report is presented of some patients taking angiotensin type 2 receptor blockers (AT2RB) who collapsed without warning whilst being active outdoors in the heat. ISSUES: It is not possible to recognise hypotension due to the heat by testing in a controlled environment such as a doctor's office. Many people taking AT2RBs may be thus misdiagnosed and inappropriately treated. LESSONS LEARNED: Sudden collapse in a patient on AT2RB who is active in the heat should alert the physician to the possible cause of extreme sensitivity to low-grade volume depletion.

Disinfection of flexible fibre-optic endoscopes out-of-hours: confidential telephone survey of ENT units in England - 10 years on.

OBJECTIVE: To audit out-of-hours flexible endoscope disinfection practice in England and compare the findings with a previously published first audit cycle, with the 2005 ENT UK guidelines as the key intervention. METHODS: A telephone survey of the 104 ENT units in England was conducted out-of-hours, replicating the first cycle. The on-call clinician answered questions concerning access to flexible endoscopes, training, disinfection procedures and record keeping. Information regarding the clinician's trainee grade and their cross-covering duties was also acquired. Responses were compared to the first cycle results and published guidance. RESULTS: In total, 72 of the 104 units agreed to participate. The on-call clinician cleaned the flexible endoscope in 43 per cent of units. However, adequate training in disinfection only occurred in a minority of units (37 per cent), though this was an improvement from the first cycle (12 per cent). Furthermore, 27 per cent of units used an inadequate method of disinfection out-of-hours. One confounding factor may be the increase in cross-cover out-of-hours, with 68 per cent of respondents covering one or more other specialties. CONCLUSION: An overall moderate improvement in the safety of out-of-hours endoscopy in the past 10 years cannot obscure the urgent need for universal compliance with national guidelines.

The baton exchange during the 4 x 100 m relay: a mathematical analysis.

Using mathematical analysis, we examined the three baton exchanges that occur during a 4 x 100 m relay. Identical representative 100 m running performances were assumed for each of four elite male athletes, and the calculations were made for optimal or near-optimal positions of the baton exchanges and starting positions of the athletes running the second, third and fourth legs as determined by Ward-Smith and Radford (2002). In this paper, we focus on the calculation of the checkmark position and demonstrate the complexity of the baton exchange process. The results of the mathematical analysis show that, for optimal performance, the checkmark should be located differently for each of the three exchanges in a single race, and is further affected bylane draw and free distance (the distance between the runners at the baton exchange). For a representative free distance of 1 m at each exchange, the checkmark distance ranges from a minimum of 11.04 m at the third exchange in Lane 1 to 12.20 m for the first exchange in Lane 8. Failure by teams and their coaches to consider adequately the complexities of the baton exchanges may help explain why 25.5% of teams in recent World Championships were disqualified or did not finish.

British running performances in the eighteenth century.

Our aims were to improve our understanding of human performance before 1850 and to put nineteenth- and twentieth-century performances into a broader historical context. Consequently, 536 foot-races performed in Britain in the 'long' eighteenth century were identified, 53 of which were analysed in detail. The best performances at the end of the eighteenth century were compared with those at the end of the nineteenth and twentieth centuries. The data for the nineteenth century were marginally better than those for the eighteenth century up to 20 nm, but beyond that Thomas Carlisle's time, set in about 1740, of 2 hours for 21 miles was outstanding. Current records are shown to be better than earlier records at all distances from 5 km up to the marathon, the superiority being most pronounced from 15 km upwards.

Distinct antigenic features of linear epitopes at the N-terminus and C-terminus of 65 kDa glutamic acid decarboxylase (GAD65): implications for autoantigen modification during pathogenesis.

Autoantibodies to 65 kDa glutamic acid decarboxylase (GAD65) are produced in many patients with autoimmune polyendocrine syndrome type II (APS-II) or stiff-man syndrome (SMS) and are heterogeneous in their epitope specificities, recognizing both conformational and linear determinants. Major linear epitopes of GAD, which are recognized by autoantibodies in a minority of these patients, occur in the N-terminal and C-terminal regions. We have investigated antibody recognition of the N- and C-termini of GAD65 in relation to their structural features as an approach to understanding what modifications to the native GAD structure may occur that facilitate the generation of antibodies specific to linear epitopes in these regions during the autoimmune pathogenesis. A monoclonal antibody specific to the N-terminus of GAD65 bound both native and denatured GAD in ELISA, whereas monoclonal and polyclonal antibodies specific to the C-terminus of GAD bound only denatured GAD. These antibodies were epitope mapped using random peptide phage-display libraries and the epitopes related to a previously proposed structural model of GAD65. This has led us to propose that the alpha-helical secondary structure of the C-terminus of GAD65 must be denatured to generate linear epitopes. In contrast, the N-terminus is both surface exposed and linear in the native structure, but may be masked by membrane interactions, which must be broken to facilitate recognition by B cells.

A mathematical analysis of the 4 x 100 m relay.

In this study, we examined aspects of the 4 x 100 m relay that are amenable to mathematical analysis. We looked at factors that affect the time required to complete the relay, focusing on the performance of elite male athletes. Factors over which the individual athletes, and the team coach, can exercise some control are: the starting positions of the runners on legs 2, 3 and 4, the positions at which baton exchanges occur, the free distances at the baton exchanges and the running order of the athletes. The lane draw is shown to have an important influence on the relay time, although it is outside the control of the team coach. Teams drawn in the outside lanes benefit from the inverse relation between bend radius of curvature and running speed. For teams composed of athletes with different times over 100 m, we show that the fastest relay times are achieved with the fastest athlete taking the first leg, with the slowest two runners allocated to the final two legs.

Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus.

The generation of an autoimmune response against islet beta-cells is central to the pathogenesis of type 1 diabetes mellitus, and this response is driven by the stimulation of autoreactive lymphocytes by components of the beta-cells themselves. Reactive oxygen species (ROS) have been implicated in the beta-cell destruction which leads to type 1 diabetes and may modify beta-cell components so as to enhance their immunogenicity. We investigated the effects of oxidation reactions catalysed by copper or iron on the major beta-cell autoantigen glutamic acid decarboxylase (GAD). Lysates of purified rat islets were exposed to copper or iron sulphate with or without hydrogen peroxide or ascorbic acid. Immunostaining showed that these treatments generated high molecular weight covalently linked aggregates containing GAD. These are not formed by intermolecular disulphide bonds between cysteine residues since they cannot be resolved into monomeric form when electrophoresed under extreme reducing conditions. There was no modification of insulin or pro-insulin by ROS. The same oxidative changes to GAD could be induced in viable islet cells treated with copper sulphate and hydrogen peroxide, and thus the modifications are not an artefact of the catalysed oxidation of cell-free lysates. Sera from patients with type 1 diabetes and stiffman syndrome containing GAD antibodies reacted predominantly with the highest molecular weight modified protein band of GAD: normal human sera did not precipitate GAD. Thus, oxidatively modified aggregates of GAD react with serum antibodies of type 1 diabetes patients and some SMS patients: this is consistent with oxidative modifications of autoantigens being relevant to the pathogenesis of type 1 diabetes.

A rare and serious consequence of a rat bite.

Contact with rat saliva or faeces can lead to infection with Streptobacillus moniliformis and the condition known as 'rat bite fever'. We report a case of septic arthritis of the hip due to this organism following a bite on the finger of a 14-year-old boy from a rat for sale in a pet shop. The case was successfully treated by arthrotomy, drainage and joint lavage followed by administration of penicillin. Septic arthritis of the hip due to S. moniliformis has not been previously described and this case highlights a possible danger of keeping rats as pets.

Energy conversion rates during sprinting with an emphasis on the performance of female athletes.

Computed results from a mathematical model of the bioenergetics of sprinting, which incorporates a three-equation representation of anaerobic metabolism, were compared with measured distance-time data for female athletes from the finals of the 100-m event at the World Championships of 1987. The computed results closely model the performance of the competitors over the course of the entire race. The three main contributions to anaerobic metabolism were investigated and comparisons were made between male and female sprinters. Whereas the time constants for adenosine triphosphate (ATP) and phosphocreatine utilization for the two sexes were found to be similar, for oxygen-independent glycolysis the time constants of the female athletes were found to be higher. The maximum powers generated by female athletes during ATP conversion and glycolysis were only slightly lower than the figures found for male athletes, but the value for phosphocreatine utilization was substantially lower. The lower value for phosphocreatine utilization might explain the more pronounced fall-off in running speed over the latter stages of a race that female athletes experience in comparison with men. Although anaerobic sources dominate energy provision for both male and female sprinters, the calculations show that the latter make greater use of aerobic energy supplies.

Investigation of the kinetics of anaerobic metabolism by analysis of the performance of elite sprinters.

The principal motivation for the present work was the study of the kinetics of anaerobic metabolism. A new mathematical model of the bioenergetics of sprinting, incorporating a three-equation representation of anaerobic metabolism, is developed. Results computed using the model are compared with measured data from the mens' finals of the 100m event at the 1987 World Championships. The computed results closely predict the overall average performance of the competitors over the course of the entire race. Further calculations show the three-equation model of anaerobic metabolism to be a significant improvement over the previous one-equation model. Representative values of time constants that govern the rate of anaerobic energy release have been determined for elite male athletes. For phosphocreatine utilisation, values for lambda(2)=0. 20s(-1) and psi(2)=3.0s(-1) are consistent with data previously reported in the literature. New values of lambda(3)=0.033s(-1) and psi(3)=0.34s(-1) are proposed as offering an improved representation of the kinetics of oxygen-independent glycolysis. For the first time, tentative values for the time constants of ATP utilisation, lambda(1)=0.9s(-1) and psi(1)=20s(-1), are suggested. The maximum powers developed during sprinting by oxygen-independent glycolysis, PCr utilisation and endogenous ATP utilisation were calculated as 34. 1, 30.1 and 16.6Wkg(-1), respectively, with an overall maximum anaerobic power of 51.6Wkg(-1). Sample calculations show the mathematical model can be used in principle to derive data on the kinetics of anaerobic metabolism of individual athletes.