Heterogeneity after harmonisation: A retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries.

PURPOSE: Database heterogeneity can impact effect estimates. Harmonisation provided by common protocols and common data models (CDMs) can increase the validity of pharmacoepidemiologic research. In a case study measuring the changes in the safety and effectiveness of stroke prevention therapy after the introduction of direct oral anticoagulants (DOACs), we performed an international comparison. METHODS: Using data from Stockholm, Denmark, Scotland and Norway, harmonised with a common protocol and CDM, two calendar-based cohorts were created: 2012 and 2017. Patients with a diagnosis code of atrial fibrillation 5 years preceding the 1-year cohort window were included. DOAC, vitamin K antagonist and aspirin treatment were assessed in the 6 months prior to the start of each year while strokes and bleeds were assessed during the year. A Poisson regression generated incidence rate ratios (IRRs) to compare outcomes from 2017 to 2012 adjusted for changes in individual-level baseline characteristics. RESULTS: In 280 359 patients in the 2012 cohort and 356 779 in the 2017 cohort, treatment with OACs increased on average from 45% to 65%, while treatment with aspirin decreased from 30% to 10%. In all countries except Scotland, there were decreases in the risk of stroke and no changes in bleeding risk, after adjustment for changes in baseline characteristics. In Scotland, major bleeding (IRR 1.09, 95% confidence interval [CI] [1.00; 1.18]) and intracranial haemorrhage (IRR 1.31, 95% CI [1.13; 1.52]) increased from 2012 to 2017. CONCLUSIONS: Stroke prevention therapy improved from 2012 to 2017 with a corresponding reduction in stroke risk without increasing the risk of bleeding in all countries, except Scotland. The heterogeneity that remains after methodological harmonisation can be informative of the underlying population and database.

Post-mortem computed tomography in the investigation of conflict and terrorist related deaths: UK military experience of developing a multidisciplinary service.

This paper discusses the introduction, development and utility of post-mortem imaging relating specifically to conflict-related and terrorist-related deaths and considers the use of computed tomography (CT) in the investigations. We demonstrate how a multi-disciplinary approach involving direct communication between forensic pathologist and radiologist can maximise evidential yield, reduce the need for unnecessary dissection and further our understanding of such injuries. This summarises our shared experience of hundreds of cases, each having been individually discussed and reviewed, and has helped shape our understanding of conflict injury as well as contributing to the development of mitigation strategies and adaptations to protective equipment. A series of clinical cases are presented to demonstrate some of the strengths and weaknesses of the process.

The enhanced recovery after surgery (ERAS) Greenie Board: a Navy-inspired quality improvement tool.

The United States Navy uses a visual feedback system for pilots, named 'the Greenie Board', to improve flight manoeuvres on aircraft carriers. Given that increased compliance with enhanced recovery after surgery protocols reduces postoperative complications, we decided to apply a similar feedback system to our institutional enhanced recovery programme. We undertook a prospective 12-month audit of 194 patients assigned to our enhanced recovery programme and evaluated adherence to the anaesthesia-related components of our protocol, before and after implementing a Greenie Board. A compliance score was calculated by summing points for adherence to: intra-operative antibiotic prophylaxis; temperature management; goal-directed intravenous fluid therapy; postoperative nausea and vomiting prophylaxis; and postoperative fluid restriction. The score for each patient was then colour-coded and anonymously displayed for each anaesthetist on a Greenie Board within the operating theatre suite. Protocol adherence improved significantly following introduction, with 'Green' scores (acceptable compliance) increasing from 33% to 72% of patients (p < 0.0001). The greatest improvement was seen with anti-emetic prophylaxis (49% to 70%, p = 0.004) with a consequent reduction in postoperative nausea and vomiting (OR 0.42, 95% CI 0.19-0.88, p = 0.021). We did not observe a decrease in other postoperative complications nor hospital length of stay. We conclude that this US Navy-inspired feedback system is an easily implemented, low-cost quality improvement tool that significantly improved adherence to intra-operative components of our enhanced recovery protocol. The system lends itself to global scaling to drive quality improvement in healthcare delivery and would be suited to institutions without electronic medical records, including low-resource countries.

Does preliminary optimisation of an anatomically correct skull-brain model using simple simulants produce clinically realistic ballistic injury fracture patterns?

Ballistic head injury remains a significant threat to military personnel. Studying such injuries requires a model that can be used with a military helmet. This paper describes further work on a skull-brain model using skulls made from three different polyurethane plastics and a series of skull 'fills' to simulate brain (3, 5, 7 and 10% gelatine by mass and PermaGel™). The models were subjected to ballistic impact from 7.62 × 39 mm mild steel core bullets. The first part of the work compares the different polyurethanes (mean bullet muzzle velocity of 708 m/s), and the second part compares the different fills (mean bullet muzzle velocity of 680 m/s). The impact events were filmed using high speed cameras. The resulting fracture patterns in the skulls were reviewed and scored by five clinicians experienced in assessing penetrating head injury. In over half of the models, one or more assessors felt aspects of the fracture pattern were close to real injury. Limitations of the model include the skull being manufactured in two parts and the lack of a realistic skin layer. Further work is ongoing to address these.

An overview of systematic reviews on the public health consequences of social isolation and loneliness.

OBJECTIVES: Social isolation and loneliness have been associated with ill health and are common in the developed world. A clear understanding of their implications for morbidity and mortality is needed to gauge the extent of the associated public health challenge and the potential benefit of intervention. STUDY DESIGN: A systematic review of systematic reviews (systematic overview) was undertaken to determine the wider consequences of social isolation and loneliness, identify any differences between the two, determine differences from findings of non-systematic reviews and to clarify the direction of causality. METHODS: Eight databases were searched from 1950 to 2016 for English language reviews covering social isolation and loneliness but not solely social support. Suitability for inclusion was determined by two or more reviewers, the methodological quality of included systematic reviews assessed using the a measurement tool to assess systematic reviews (AMSTAR) checklist and the quality of evidence within these reviews using the grading of recommendations, assessment, development and evaluations (GRADE) approach. Non-systematic reviews were sought for a comparison of findings but not included in the primary narrative synthesis. RESULTS: Forty systematic reviews of mainly observational studies were identified, largely from the developed world. Meta-analyses have identified a significant association between social isolation and loneliness with increased all-cause mortality and social isolation with cardiovascular disease. Narrative systematic reviews suggest associations with poorer mental health outcomes, with less strong evidence for behavioural and other physical health outcomes. No reviews were identified for wider socio-economic or developmental outcomes. CONCLUSIONS: This systematic overview highlights that there is consistent evidence linking social isolation and loneliness to worse cardiovascular and mental health outcomes. The role of social isolation and loneliness in other conditions and their socio-economic consequences is less clear. More research is needed on associations with cancer, health behaviours, and the impact across the life course and wider socio-economic consequences. Policy makers and health and local government commissioners should consider social isolation and loneliness as important upstream factors impacting on morbidity and mortality due to their effects on cardiovascular and mental health. Prevention strategies should therefore be developed across the public and voluntary sectors, using an asset-based approach.

Using experimental and computational energy equilibration to understand hierarchical self-assembly of Fmoc-dipeptide amphiphiles.

Despite progress, a fundamental understanding of the relationships between the molecular structure and self-assembly configuration of Fmoc-dipeptides is still in its infancy. In this work, we provide a combined experimental and computational approach that makes use of free energy equilibration of a number of related Fmoc-dipeptides to arrive at an atomistic model of Fmoc-threonine-phenylalanine-amide (Fmoc-TF-NH2) which forms twisted fibres. By using dynamic peptide libraries where closely related dipeptide sequences are dynamically exchanged to eventually favour the formation of the thermodynamically most stable configuration, the relative importance of C-terminus modifications (amide versus methyl ester) and contributions of aliphatic versus aromatic amino acids (phenylalanine F vs. leucine L) is determined (F > L and NH2 > OMe). The approach enables a comparative interpretation of spectroscopic data, which can then be used to aid the construction of the atomistic model of the most stable structure (Fmoc-TF-NH2). The comparison of the relative stabilities of the models using molecular dynamic simulations and the correlation with experimental data using dynamic peptide libraries and a range of spectroscopy methods (FTIR, CD, fluorescence) allow for the determination of the nanostructure with atomistic resolution. The final model obtained through this process is able to reproduce the experimentally observed formation of intertwining fibres for Fmoc-TF-NH2, providing information of the interactions involved in the hierarchical supramolecular self-assembly. The developed methodology and approach should be of general use for the characterization of supramolecular structures.

Redesign and commissioning of sexual health services in England - a qualitative study.

OBJECTIVES: Responsibility for the commissioning of sexual and reproductive health (SRH) services transferred from the National Health Service to local authorities in England in 2013. This transfer prompted many local authorities to undertake new procurements of these SRH services. This study was undertaken to capture some of the lessons learnt in order to inform future commissioning and system redesign. STUDY DESIGN: A qualitative study was carried out involving semi-structured interviews. METHODS: Interviews were conducted with 13 local authority sexual health commissioners in Yorkshire and the Humber from 11 interviews. Thematic analysis was used to identify themes from transcripts of the interviews with the 13 participants. RESULTS: Key themes identified were as follows: the challenge and complexity to those new to clinical commissioning; the prerequisites of robust infrastructural inputs to undertake the process, including technical expertise, a dependable project team, with clarity over the timescales and the budget; the requirement for good governance, stakeholder engagement and successful management of relationships with the latter; and the need to focus on the outcomes, aiming for value for money and improved system performance. CONCLUSIONS: Several key issues emerged from our study that significantly influenced the outcome of the redesign and commissioning process for sexual health services. An adapted model of the Donabedian evaluation framework was developed to provide a tool to inform future system redesign. Our model helps identify the key determinants for successful redesign in this context which is essential to both mitigate potential risks and maximize the likelihood of successful outcomes. Our model may have wider applications.

Died of wounds: a mortality review.

OBJECTIVES: Combat casualty care is a complex system involving multiple clinicians, medical interventions and casualty transfers. Improving the performance of this system requires examination of potential weaknesses. This study reviewed the cause and timing of death of casualties deemed to have died from their injuries after arriving at a medical treatment facility during the recent conflicts in Iraq and Afghanistan, in order to identify potential areas for improving outcomes. METHODS: This was a retrospective review of all casualties who reached medical treatment facilities alive, but subsequently died from injuries sustained during combat operations in Afghanistan and Iraq. It included all deaths from start to completion of combat operations. The UK military joint theatre trauma registry was used to identify cases, and further data were collected from clinical notes, postmortem records and coroner's reports. RESULTS: There were 71 combat-related fatalities who survived to a medical treatment facility; 17 (24%) in Iraq and 54 (76%) in Afghanistan. Thirty eight (54%) died within the first 24 h. Thirty-three (47%) casualties died from isolated head injuries, a further 13 (18%) had unsurvivable head injuries but not in isolation. Haemorrhage following severe lower limb trauma, often in conjunction with abdominal and pelvic injuries, was the cause of a further 15 (21%) deaths. CONCLUSIONS: Severe head injury was the most common cause of death. Irrespective of available medical treatment, none of this group had salvageable injuries. Future emphasis should be placed in preventative strategies to protect the head against battlefield trauma.

Isolated popliteus tendon injury does not lead to abnormal laxity in posterior-stabilised total knee arthroplasty.

PURPOSE: The popliteus tendon is crucial to postero-lateral stability and prone to iatrogenic injury intra-operatively. Its role in the stability of the replaced knee remains contentious. The aim of this study was to use computer navigation to quantify the effect of popliteus sectioning on the 'envelope of laxity' (EoL) offered by a posterior-stabilised (PS) total knee arthroplasty (TKA) and compare with that of the native knee. METHODS: Loaded cadaveric legs were mounted on a purpose built rig. EoL was measured in 3 degrees of freedom using computer navigation. Knees were subjectively stressed in varus/valgus, internal/external rotation and anterior draw. This was performed preoperatively, during TKA and after sectioning of the popliteus tendon. Real-time data were recorded at 0°, 30°, 60° and 90° of flexion as the operating surgeon stressed the knee in 3 degrees of freedom to its subjective endpoint. Mixed-effect modelling was used to quantify the effects of intervention on degree of laxity. RESULTS: In all conditions, there was an increase in laxity with knee flexion. Insertion of a PS TKA resulted in increased constraint, particularly in rotation. Sectioning of the popliteus did not result in a significant increase in knee laxity to 90º of knee flexion. However, at deeper flexion angles, tendon sectioning overcame the constraints of the implant resulting in a significant increase in rotatory and varus/valgus laxity towards the native condition. CONCLUSION: These findings support the view that certain current designs of PS knee replacement can constrain the knee in flexion in the absence of postero-lateral deficiency. For this implant, isolated sectioning of the popliteus tendon did not substantially generate abnormal knee laxity.

Using computerised surface wound mapping to compare the potential medical effectiveness of Enhanced Protection Under Body Armour Combat Shirt collar designs.

INTRODUCTION: Protecting the neck from explosively propelled fragments has traditionally been achieved through a collar attached to the ballistic vest. An Enhanced Protection Under Body Armour Combat Shirt (EP-UBACS) collar has been identified as an additional method of providing neck protection but limited evidence as to its potential medical effectiveness exists to justify its procurement. METHOD: Entry wound locations and resultant medical outcomes were determined using Abbreviated Injury Scale (AIS) for all fragmentation neck wounds sustained by UK soldiers between 01 January 2010 and 31 December 2011. Data were prospectively entered into a novel computerised tool base and comparisons made between three EP-UBACS neck collar designs in terms of predicted reduction in AIS scores. RESULTS: All collars reduced AIS scores, with the greatest reduction provided by designs incorporating increased standoff from the neck and an additional semi-circle of ballistic material underneath the collar at the front and back. DISCUSSION: This technique confirms that reinforcing the neck collar of an EP-UBACS would be expected to reduce injury severity from neck wounds. However, without knowledge of entry wound locations for injuries to other body areas as well as the use of AIS scores without clinical or pathological verification its further use in the future may be limited. The ability to overlay any armour design onto a standardised human was potentially the most useful part of this tool and we would recommend developing this technique using underlying anatomical structures and not just the skin surface.

A novel automated test battery reveals enduring behavioural alterations and cognitive impairments in survivors of murine pneumococcal meningitis.

Pneumococcal meningitis, caused by Streptococcus pneumoniae infection, is a major form of lethal bacterial meningitis. Survivors are predisposed to developing lifelong disabling sequelae, including cognitive impairment, psychological problems and motor deficits. In our experimental model, ventricular inoculation of 10(5) colony-forming units of S. pneumoniae type 3 caused 90% of mice to develop life-threatening meningitis within 48 h. Antibiotic treatment with ceftriaxone 20 h post infection reduced the incidence of severe meningitis to <10%. At the time of treatment, upregulation of pro-inflammatory cytokines was detected, including interleukin-1ß, interleukin-6 and tumour necrosis factor. We evaluated the long-term behavioural and cognitive sequelae in control mice and those surviving meningitis using an automated system (the IntelliCage) in which mice perform a range of behavioural and spatial tasks to obtain water rewards from conditioning units in their home cage. Surviving mice showed a number of altered behaviours relative to controls, including (i) hypoexploration when first exposed to the IntelliCage, (ii) altered activity patterns (fewer visits to conditioning stations during the light phase and more in the dark phase), (iii) avoidance of light (a constant or flashing LED stimulus), (iv) impaired spatial learning (a complex patrolling task), and (v) impaired discrimination reversal learning. Overall these results suggest photophobia and weakened learning ability in post-meningitic mice, particularly on tasks engaging hippocampal and prefrontal neural substrates. This study also demonstrates a standardised and comprehensive battery of tests that can be readily used to investigate neurological sequelae in undisturbed mice residing in a complex home cage environment.

Brain endothelial cells increase the proliferation of Plasmodium falciparum through production of soluble factors.

We here describe the novel finding that brain endothelial cells in vitro can stimulate the growth of Plasmodium falciparum through the production of low molecular weight growth factors. By using a conditioned medium approach, we show that the brain endothelial cells continued to release these factors over time. If this mirrors the in vivo situation, these growth factors potentially would provide an advantage, in terms of enhanced growth, for sequestered parasitised red blood cells in the brain microvasculature. We observed this phenomenon with brain endothelial cells from several sources as well as a second P. falciparum strain. The characteristics of the growth factors included: <3 kDa molecular weight, heat stable, and in part chloroform soluble. Future efforts should be directed at identifying these growth factors, since blocking their production or actions might be of benefit for reducing parasite load and, hence, malaria pathology.

The Mortality Peer Review Panel: a report on the deaths on operations of UK Service personnel 2002-2013.

INTRODUCTION: Review of adverse outcomes is an essential element of healthcare governance. For each operational death, the post-mortem is attended by a member of Academic Department of Military Emergency Medicine and the case is assessed by a Mortality Peer Review Panel comprised of Defence Professors and other clinical and technical experts. METHODS: A search was conducted of the Joint Theatre Trauma Registry (JTTR) for all UK military death reviews held from January 2002 to November 2013 and the judgement made by the Mortality Peer Review panel. Cases are awarded a 'salvageability' rating between S1 (salvageable) and S4 (not salvageable). Cases graded S1-3 are then assessed further for tactical, clinical or equipment factors that affected the outcome. RESULTS: There were 621 deaths recorded on the JTTR and 517 (83.3%) were due to hostile action. The Killed in Action to Died of Wounds ratio is 6.28 : 1. Explosive mechanisms of injury were responsible for 55.65% of combat deaths and penetrating mechanisms 28.71%. An average of 10.56 injuries was recorded per casualty and the mean number of body regions affected was 3.34. The Peer Review Panel decided that 91.1% cases were not salvageable (S4); this figure is 93.5% if the deaths due to hostile action are considered separately. CONCLUSIONS: The severity of modern military trauma is overwhelming in nature and, along with trauma scoring systems, clinical peer review is an essential part of healthcare governance. The process also helps inform and direct research within clinical and force protection fields.

Sequence-Dependent Melting and Refolding Dynamics of RNA UNCG Tetraloops Using Temperature-Jump/Drop Infrared Spectroscopy.

Time-resolved temperature-jump/drop infrared (IR) spectroscopy has been used to measure the impact of stem base sequence on the melting and refolding dynamics of ribonucleic acid (RNA) tetraloops. A series of three 12-nucleotide RNA hairpin sequences were studied, each featuring a UACG tetraloop motif and a double-stranded stem containing four base pairs. In each case, the stem comprised three GC pairs plus a single AU base pair inserted at the closing point of the loop (RNAloop), in the middle of the stem (RNAmid), or at the stem terminus (RNAend). Results from analogous DNA tetraloop (TACG) sequences were also obtained. Inclusion of AU or AT base pairs in the stem leads to faster melting of the stem-loop structure compared to a stem sequence featuring four GC base pairs while refolding times were found to be slower, consistent with a general reduction in stem-loop stability caused by the AU/AT pair. Independent measurement of the dynamic timescales for melting and refolding of ring vibrational modes of guanine (GR) and adenine (AR) provided position-specific insight into hairpin dynamics. The GR-derived data showed that DNA sequences melted more quickly (0.5 ± 0.1 to 0.7 ± 0.1 µs at 70 °C) than analogous RNA sequences (4.3 ± 0.4 to 4.4 ± 0.3 µs at 70 °C). Position-sensitive data from the AR modes suggests that DNA hairpins begin melting from the terminal end of the stem toward the loop while RNA sequences begin melting from the loop. Refolding timescales for both RNA and DNA hairpins were found to be similar (250 ± 50 µs at 70 °C) except for RNAend and DNAloop which refolded much more slowly (746 ± 36 and 430 ± 31 µs, respectively), showing that the refolding pathway is significantly impaired by the placement of AU/AT pairs at different points in the stem. We conclude that conformational changes of analogous pairs of RNA and DNA tetraloops proceed by different mechanisms.

Associated injuries in casualties with traumatic lower extremity amputations caused by improvised explosive devices.

BACKGROUND: Improvised explosive devices (IEDs) pose a significant threat to military personnel, often resulting in lower extremity amputation and pelvic injury. Immediate management is haemorrhage control and debridement, which can involve lengthy surgery. Computed tomography is necessary to delineate the extent of the injury, but it is unclear whether to perform this during or after surgery. METHODS: The UK Joint Theatre Trauma Registry was searched to identify all UK service personnel who had a traumatic lower extremity amputation following IED injury between January 2007 and December 2010. Data were collected on injury pattern and survival. RESULTS: There were 169 patients who sustained 278 traumatic lower extremity amputations: 69 were killed in action, 16 died from their wounds and 84 were wounded in action, but survived. The median (interquartile range) Injury Severity Score was 75 (21) for those killed in action, 46 (23) for those who died from wounds and 29 (12) for survivors. There were significantly more severe head, chest and abdominal injuries (defined as a body region Abbreviated Injury Scale score of 3 or more) in patients who were killed in action than in those reaching hospital (P < 0·001). Hindquarter amputations were the most lethal, with a mortality rate of 95 per cent. Of the 100 casualties who reached hospital alive, there were nine thoracotomies, one craniotomy and 34 laparotomies. All head or torso injuries that required immediate operation were clinically apparent on admission. CONCLUSION: Higher levels of amputation were associated with greater injury burden and mortality. Intraoperative computed tomography had little value in identifying clinically significant covert injuries.

Measuring RNA UNCG Tetraloop Refolding Dynamics Using Temperature-Jump/Drop Infrared Spectroscopy.

Determining the structural dynamics of RNA and DNA is essential to understanding their cellular function, but direct measurement of strand association or folding remains experimentally challenging. Here we illustrate a temperature-jump/drop method able to reveal refolding dynamics. Time-resolved temperature-jump/drop infrared spectroscopy is used to measure the melting and refolding dynamics of a 12-nucleotide RNA sequence comprising a UACG tetraloop and a four-base-pair double-stranded GC stem, comparing them to an equivalent DNA (TACG) sequence. Stem-loop melting occurred an order of magnitude more slowly in RNA than DNA (6.0 ± 0.1 µs versus 0.8 ± 0.1 µs at 70 °C). In contrast, the refolding dynamics of both sequences occurred on similar time scales (200 µs). While the melting and refolding dynamics of RNA and DNA hairpins both followed Arrhenius temperature dependences, refolding was characterized by an apparent negative activation energy, consistent with a mechanism involving multiple misfolded intermediates prior to zipping of the stem base pairs.

Biochemical characteristics and inhibitor selectivity of mouse indoleamine 2,3-dioxygenase-2.

The first step in the kynurenine pathway of tryptophan catabolism is the cleavage of the 2,3-double bond of the indole ring of tryptophan. In mammals, this reaction is performed independently by indoleamine 2,3-dioxygenase-1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and the recently discovered indoleamine 2,3-dioxygenase-2 (IDO2). Here we describe characteristics of a purified recombinant mouse IDO2 enzyme, including its pH stability, thermal stability and structural features. An improved assay system for future studies of recombinant/isolated IDO2 has been developed using cytochrome b (5) as an electron donor. This, the first description of the interaction between IDO2 and cytochrome b (5), provides further evidence of the presence of a physiological electron carrier necessary for activity of enzymes in the "IDO family". Using this assay, the kinetic activity and substrate range of IDO2 were shown to be different to those of IDO1. 1-Methyl-D-tryptophan, a current lead IDO inhibitor used in clinical trials, was a poor inhibitor of both IDO1 and IDO2 activity. This suggests that its immunosuppressive effect may be independent of pharmacological inhibition of IDO enzymes, in the mouse at least. The different biochemical characteristics of the mouse IDO proteins suggest that they have evolved to have distinct biological roles.

Long-term management of the liver transplant patient: recommendations for the primary care doctor.

No official document has been published for primary care physicians regarding the management of liver transplant patients. With no official source of reference, primary care physicians often question their care of these patients. The following guidelines have been approved by the American Society of Transplantation and represent the position of the association. The data presented are based on formal review and analysis of published literature in the field and the clinical experience of the authors. These guidelines address drug interactions and side effects of immunosuppressive agents, allograft dysfunction, renal dysfunction, metabolic disorders, preventive medicine, malignancies, disability and productivity in the workforce, issues specific to pregnancy and sexual function, and pediatric patient concerns. These guidelines are intended to provide a bridge between transplant centers and primary care physicians in the long-term management of the liver transplant patient.

CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscle.

BACKGROUND: CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression. METHODS: CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-alpha and/or IFN-gamma was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. RESULTS: Interferon-gamma and TNF-alpha synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-gamma reduced TNF-alpha-induced OX40L expression to a similar extent in both cell types. TNF-alpha and IFN-gamma induced CD40 via nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-kappaB and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-kappaB, but these were not statistically significant. The reduced OX40L expression with TNF-alpha and IFN-gamma involved extracellular regulated kinase 1/2 activation. CONCLUSION: Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-gamma may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.

Highly efficient light-emitting diodes with microcavities.

One-dimensional microcavities are optical resonators with coplanar reflectors separated by a distance on the order of the optical wavelength. Such structures quantize the energy of photons propagating along the optical axis of the cavity and thereby strongly modify the spontaneous emission properties of a photon-emitting medium inside a microcavity. This report concerns semiconductor light-emitting diodes with the photon-emitting active region of the light-emitting diodes placed inside a microcavity. These devices are shown to have strongly modified emission properties including experimental emission efficiencies that are higher by more than a factor of 5 and theoretical emission efficiencies that are higher by more than a factor of 10 than the emission efficiencies in conventional light-emitting diodes.