The readability and reliability of online information about adenoidectomy.

OBJECTIVE: There is limited understanding amongst patients and parents of paediatric patients regarding adenoidectomy. Most patients access health-related information online. The aim of this study was to assess the suitability of online information on adenoidectomy. METHOD: The term 'adenoid' was used to search Google, and the first 50 websites identified were screened. For each website, the readability and quality were assessed. RESULTS: Of the 41 websites that met the inclusion criteria, the mean readability scores corresponded to 'difficult to read' and university-level reading categories. For the quality of the websites, the mean score corresponded to 'fair' with 39 per cent of the websites containing either 'poor' or 'very poor' quality data. The ENT UK information is one of the most readable and reliable online resources. CONCLUSION: The online information on adenoidectomy is largely set at an inappropriate readability level and of variable quality. Surgeons should consider assisting their patients with online searches regarding adenoidectomy.

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy.

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

A policy of day-case sinonasal surgery is safe, well tolerated and cost-effective.

OBJECTIVE: Practices vary regarding the timing of discharge after sinonasal surgery. This study aimed to examine the cost-effectiveness of same-day discharge compared to next-day discharge after sinonasal surgery. METHODS: A retrospective single-surgeon audit of sinonasal surgery over a 12-month period was performed. Demographic and clinical details, including distance travelled home, timing of discharge, hospital re-presentation, and complications, were collected and compared between the same-day discharge and next-day discharge groups. A cost-effectiveness analysis was performed. RESULTS: A total of 181 patients were identified; 117 underwent day-case surgery, of which 6 re-presented to the emergency department. Sixty-four patients stayed overnight after surgery, and six of those patients re-presented to the emergency department. The per patient cost was $3262 for day-case sinonasal surgery and $5050 for those admitted overnight after surgery (p < 0.001). CONCLUSION: Routine same-day discharge after sinonasal surgery is achievable, safe and cost-effective.

Cellular rescue in a zebrafish model of congenital muscular dystrophy type 1A.

Laminins comprise structural components of basement membranes, critical in the regulation of differentiation, survival and migration of a diverse range of cell types, including skeletal muscle. Mutations in one muscle enriched Laminin isoform, Laminin alpha2 (Lama2), results in the most common form of congenital muscular dystrophy, congenital muscular dystrophy type 1A (MDC1A). However, the exact cellular mechanism by which Laminin loss results in the pathological spectrum associated with MDC1A remains elusive. Here we show, via live tracking of individual muscle fibres, that dystrophic myofibres in the zebrafish model of MDC1A maintain sarcolemmal integrity and undergo dynamic remodelling behaviours post detachment, including focal sarcolemmal reattachment, cell extension and hyper-fusion with surrounding myoblasts. These observations imply the existence of a window of therapeutic opportunity, where detached cells may be "re-functionalised" prior to their delayed entry into the cell death program, a process we show can be achieved by muscle specific or systemic Laminin delivery. We further reveal that Laminin also acts as a pro-regenerative factor that stimulates muscle stem cell-mediated repair in lama2-deficient animals in vivo. The potential multi-mode of action of Laminin replacement therapy suggests it may provide a potent therapeutic axis for the treatment for MDC1A.

Effectiveness of extensive sinus surgery with post-operative medical management for chronic rhinosinusitis.

OBJECTIVE: To prospectively assess treatment outcomes of chronic rhinosinusitis patients undergoing functional endoscopic sinus surgery and post-operative medical treatment over a prolonged follow-up period. METHODS: Patients undergoing functional endoscopic sinus surgery in the tertiary referral practice of a single surgeon were studied prospectively. Symptoms were scored by patients pre-operatively and over a minimum follow-up period of 12 months. RESULTS: The study comprised 200 non-consecutive patients. The median pre-operative symptom score was 16 (out of a maximum of 25) (95 per cent confidence interval = 15 to 17). Symptom scores reduced to a median of 7 (95 per cent confidence interval = 6 to 8) after 12 months of follow up (p < 0.0001). The median symptom score improved for all symptoms and across all patient subgroups. CONCLUSION: Extensive functional endoscopic sinus surgery offers significant and durable symptom improvement in patients with chronic rhinosinusitis refractory to medical treatment. This improvement extends to all patient subgroups. Prolonged medical therapy is recommended after functional endoscopic sinus surgery.

Analysing regenerative potential in zebrafish models of congenital muscular dystrophy.

The congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of muscle disorders. Clinically hypotonia is present from birth, with progressive muscle weakness and wasting through development. For the most part, CMDs can mechanistically be attributed to failure of basement membrane protein laminin-α2 sufficiently binding with correctly glycosylated α-dystroglycan. The majority of CMDs therefore arise as the result of either a deficiency of laminin-α2 (MDC1A) or hypoglycosylation of α-dystroglycan (dystroglycanopathy). Here we consider whether by filling a regenerative medicine niche, the zebrafish model can address the present challenge of delivering novel therapeutic solutions for CMD. In the first instance the readiness and appropriateness of the zebrafish as a model organism for pioneering regenerative medicine therapies in CMD is analysed, in particular for MDC1A and the dystroglycanopathies. Despite the recent rapid progress made in gene editing technology, these approaches have yet to yield any novel zebrafish models of CMD. Currently the most genetically relevant zebrafish models to the field of CMD, have all been created by N-ethyl-N-nitrosourea (ENU) mutagenesis. Once genetically relevant models have been established the zebrafish has several important facets for investigating the mechanistic cause of CMD, including rapid ex vivo development, optical transparency up to the larval stages of development and relative ease in creating transgenic reporter lines. Together, these tools are well suited for use in live-imaging studies such as in vivo modelling of muscle fibre detachment. Secondly, the zebrafish's contribution to progress in effective treatment of CMD was analysed. Two approaches were identified in which zebrafish could potentially contribute to effective therapies. The first hinges on the augmentation of functional redundancy within the system, such as upregulating alternative laminin chains in the candyfloss fish, a model of MDC1A. Secondly high-throughput small molecule screens not only provide effective therapies, but also an alternative strategy for investigating CMD in zebrafish. In this instance insight into disease mechanism is derived in reverse. Zebrafish models are therefore clearly of critical importance in the advancement of regenerative medicine strategies in CMD. This article is part of a Directed Issue entitled: Regenerative Medicine: The challenge of translation.

If you don't know where you are going, you can't tell if you have arrived: defining goals for drug safety announcements.

One of the responses available to drug regulators facing a potential drug safety issue is to release a "Dear Doctor" letter describing the problem. Although numerous such safety alerts are issued every year, we know almost nothing about their effectiveness in improving patient outcomes. The article by Reber et al. in this issue is important because it is one of the few studies to examine the effect of such safety alerts on physician behavior.

Materials characterization and histological analysis of explanted polypropylene, PTFE, and PET hernia meshes from an individual patient.

During its tenure in vivo, synthetic mesh materials are exposed to foreign body responses, which can alter physicochemical properties of the material. Three different synthetic meshes comprised of polypropylene, expanded polytetrafluoroethylene (ePTFE), and polyethylene terephthalate (PET) materials were explanted from a single patient providing an opportunity to compare physicochemical changes between three different mesh materials in the same host. Results from infrared spectroscopy demonstrated significant oxidation in polypropylene mesh while ePTFE and PET showed slight chemical changes that may be caused by adherent scar tissue. Differential scanning calorimetry results showed a significant decrease in the heat of enthalpy and melt temperature in the polypropylene mesh while the ePTFE and PET showed little change. The presence of giant cells and plasma cells surrounding the ePTFE and PET were indicative of an active foreign body response. Scanning electron micrographs and photo micrographs displayed tissue entrapment and distortion of all three mesh materials.

Group therapy for adolescents with repeated self harm: randomised controlled trial with economic evaluation.

OBJECTIVE: To examine the effectiveness and cost-effectiveness of group therapy for self harm in young people. DESIGN: Two arm, single (assessor) blinded parallel randomised allocation trial of a group therapy intervention in addition to routine care, compared with routine care alone. Randomisation was by minimisation controlling for baseline frequency of self harm, presence of conduct disorder, depressive disorder, and severity of psychosocial stress. PARTICIPANTS: Adolescents aged 12-17 years with at least two past episodes of self harm within the previous 12 months. Exclusion criteria were: not speaking English, low weight anorexia nervosa, acute psychosis, substantial learning difficulties (defined by need for specialist school), current containment in secure care. Setting Eight child and adolescent mental health services in the northwest UK. INTERVENTIONS: Manual based developmental group therapy programme specifically designed for adolescents who harm themselves, with an acute phase over six weekly sessions followed by a booster phase of weekly groups as long as needed. Details of routine care were gathered from participating centres. MAIN OUTCOME MEASURES: Primary outcome was frequency of subsequent repeated episodes of self harm. Secondary outcomes were severity of subsequent self harm, mood disorder, suicidal ideation, and global functioning. Total costs of health, social care, education, and criminal justice sector services, plus family related costs and productivity losses, were recorded. RESULTS: 183 adolescents were allocated to each arm (total n = 366). Loss to follow-up was low (<4%). On all outcomes the trial cohort as a whole showed significant improvement from baseline to follow-up. On the primary outcome of frequency of self harm, proportional odds ratio of group therapy versus routine care adjusting for relevant baseline variables was 0.99 (95% confidence interval 0.68 to 1.44, P = 0.95) at 6 months and 0.88 (0.59 to 1.33, P = 0.52) at 1 year. For severity of subsequent self harm the equivalent odds ratios were 0.81 (0.54 to 1.20, P = 0.29) at 6 months and 0.94 (0.63 to 1.40, P = 0.75) at 1 year. Total 1 year costs were higher in the group therapy arm (£21,781) than for routine care (£15,372) but the difference was not significant (95% CI -1416 to 10782, P = 0.132). CONCLUSIONS: The addition of this targeted group therapy programme did not improve self harm outcomes for adolescents who repeatedly self harmed, nor was there evidence of cost effectiveness. The outcomes to end point for the cohort as a whole were better than current clinical expectations. Trial registration ISRCTN 20496110.

A fitness based analysis of Daisyworld.

The Gaia hypothesis [Lovelock, J., Margulis, L., 1974. Atmospheric homeostasis: the Gaia hypothesis. Tellus 26, 1], that the earth functions as a self-regulating system, has never sat particularly comfortably with ideas in mainstream biology [Anon, 2002. In pursuit of arrogant simplicities. Nature 416, 247]. A lack of any clear role for evolution in the model has led to claims of teleology-that self-regulation emerges because it is pre-ordained to do so [Doolittle, W.F., 1981. Is nature really motherly? CoEvol. Q. 58-63; Dawkins, R., 1979. The Extended Phenotype. Oxford University Press, Oxford]. The Daisyworld parable [Watson, A.J., Lovelock, J.E., 1983. Biological homeostasis of the global environment--the parable of Daisyworld. Tellus B 35, 284], a simple mathematical illustration of Gaia, went some way to addressing these critiques but, despite recent success in incorporating natural selection [Stocker, S.,1995. Regarding mutations in Daisyworld models. J. Theor. Biol. 175, 495; Lenton, T.M., 1998. Gaia and natural selection. Nature 394, 439; Lenton, T.M., Lovelock, J.E., 2001. Daisyworld revisited: quantifying biological effects on planetary self-regulation. Tellus B 53, 288; Wood, A.J., Ackland, G.J., Lenton, T.M., 2006. Mutation of albedo and growth response leads to oscillations in a spatial Daisyworld. J. Theor. Biol. 242, 188], it remains a widely held view that the ideas are inconsistent with biological principles. We show that standard methodology from quantitative genetics can be used to predict the stationary states and dynamic behaviour of Daisyworlds. The system regulates its temperature due to the low-level evolutionary dynamics of competition between the thermally coupled daisies, no higher level principle is invoked. A reconciliation of Gaia with evolutionary theory may allow further development of evolutionary arguments for the existence of global self-regulatory systems.

The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.

Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.

An updated 'Essex' by 'Forrest' linkage map and first composite interval map of QTL underlying six soybean traits.

DNA marker maps based on single populations are the basis for gene, loci and genomic analyses. Individual maps can be integrated to produce composite maps with higher marker densities if shared marker orders are consistent. However, estimates of marker order in composite maps must include sets of markers that were not polymorphic in multiple populations. Often some of the pooled markers were not codominant, or were not correctly scored. The soybean composite map was composed of data from five separate populations based on northern US germplasm but does not yet include 'Essex' by 'Forrest' recombinant inbred line (RIL) population (E x F) or any southern US soybean cultivars. The objectives were, to update the E x F map with codominant markers, to compare marker orders among this map, the Forrest physical map and the composite soybean map and to compare QTL identified by composite interval maps to the earlier interval maps. Two hundred and thirty seven markers were used to construct the core of the E x F map. The majority of marker orders were consistent between the maps. However, 19 putative marker inversions were detected on 12 of 20 linkage groups (LG). Eleven marker distance compressions were also found. The number of inverted markers ranged from 1 to 2 per LG. Thus, marker order inversions may be common in southern compared to northern US germplasm. A total of 61 QTL among 37 measures of six traits were detected by composite interval maps, interval maps and single point analysis. Seventeen of the QTL found in composite intervals had previously been detected among the 29 QTL found in simple interval maps. The genomic locations of the known QTL were more closely delimited. A genome sequencing project to compare Southern and Northern US soybean cultivars would catalog and delimit inverted regions and the associated QTL. Gene introgression in cultivar development programs would be accelerated.

Mutation of albedo and growth response produces oscillations in a spatial Daisyworld.

We extended a two-dimensional cellular automaton (CA) Daisyworld to include mutation of optimal growth temperature as well as mutation of albedo. Thus, the organisms (daisies) can adapt to prevailing environmental conditions or evolve to alter their environment. We find the resulting system oscillates with a period of hundreds of daisy generations. Weaker and less regular oscillations exist in previous daisyworld models, but they become much stronger and more regular here with mutation in the growth response. Despite the existence of a particular combination of mean albedo and optimum individual growth temperature which maximises growth, we find that this global state is unstable with respect to mutations which lower absolute growth rate, but increase marginal growth rate. The resulting system oscillates with a period that is found to decrease with increasing death rate, and to increase with increasing heat diffusion and heat capacity. We speculate that the origin of this oscillation is a Hopf bifurcation, previously predicted in a zero-dimensional system.

Equilibrium statistical mechanics of a grain boundary.

In this article we introduce, develop, and discuss the theoretical calculations required for the exact solution of a recently reported phase transition, the geodesic to zigzag transition. In this scenario the interfacial transition emerges from geometric competition between a geodesic, shortest path, configuration and a zigzag configuration which is able to reduce its energy by binding to a centrally positioned defect line. From a technical point of view the transition is unusual as it is described by a change from saddle dominated behavior to pole dominated behavior of the integral representing the partition function ratio. We also establish the precise fluctuation behavior of the interface by computing the spin magnetization at any point in the system.

Is the Rehydrin TrDr3 from Tortula ruralis associated with tolerance to cold, salinity, and reduced pH? Physiological evaluation of the TrDr3-orthologue, HdeD from Escherichia coli in response to abiotic stress.

We have employed EST analysis in the resurrection moss Tortula ruralis to discover genes that control vegetative desiccation tolerance and describe the characterization of the EST-derived cDNA TrDr3 ( Tortula ruralis desiccation-stress related). The deduced polypeptide TRDR3 has a predicted molecular mass of 25.5 kDa, predicted pI of 6.7, and six transmembrane helical domains. Preliminary expression analyses demonstrate that the TrDr3 transcript ratio increases in response to slow desiccation relative to the hydrated control in both total and polysomal mRNA (mRNP fraction), which classifies TrDr3 as a rehydrin. Bioinformatic searches of the electronic databases reveal that Tortula TRDR3 shares significant similarities to the hdeD gene product ( HNS- dependent expression) from Escherichia coli. The function of the HdeD protein in E. coli is unknown, but it is postulated to be involved in a mechanism of acid stress defence. To establish the role of E. coli HdeD in abiotic stress tolerance, we determined the log survival percentage from shaking cultures of wild-type bacteria and the isogenic hdeD deletion strain (Delta hdeD) in the presence of low temperature (28 degrees C), elevated NaCl (5 % (w/v)), or decreased pH (4.5), or all treatments simultaneously. The Delta hdeD deletion strain was less sensitive, as compared to wild-type E. coli, in response to decreased pH ( p > 0.009), and the combination of all three stresses ( p > 0.0001).

Wetting effects at a grain boundary.

We consider a tier of weakened bonds along the center line of a two-dimensional Ising ferromagnet strip as a model of a grain boundary. When an interface traverses such a strip at an angle, whether or not there is a continuous pinning-depinning transition at subcritical temperature depends on this angle and the degree of bond weakening. We also study the relaxation of such a system to its equilibrium state using continuous time Monte Carlo simulation with Kawasaki dynamics; this reveals a matter transport mechanism confined to the grain boundary.

Relaxation dynamics of a system with a grain boundary.

Recently an interesting phase transition scenario in the context of a planar Ising system with a grain boundary was revealed [Phys. Rev. Lett. 93, 076101 (2004)]]. In this paper we study in more detail the relaxation dynamics of this system and show how the grain boundary acts as a guide spatially confining matter transport. This is done by performing simulations using the continuous time Monte Carlo algorithm with Kawasaki dynamics. We also set up the problem as a solid-on-solid model and formulate corresponding Langevin equations for the dynamics in two cases, with and without matter conservation.

A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade.

BACKGROUND: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. METHODS AND RESULTS: Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. CONCLUSIONS: There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.

Ten year experience with Aspire (Tissuemed) porcine bioprosthesis: single centre experience.

BACKGROUND: Aspire (Tissuemed) bioprosthesis is a third generation porcine bioprosthesis. 10-year outcome of this bioprosthesis is unknown. METHODS: We report our experience of 139 consecutive prosthesis implanted between 1990-1998. The clinical outcome was reviewed retrospectively. RESULTS: 126 patients (67 males and 59 females), mean age 68.4+/-8.4 years underwent 139 valve replacements. Sites of valve implantation included the aortic in 77 patients (61%); mitral in 35 patients (27%); aortic+mitral in 13 patients (10%) and tricuspid in 1 patient (0.8%). 32/126 patients (25%) also underwent concomitant coronary artery bypass grafting (CABG). 30-day mortality for the whole group was 8.7% (11/126) with no valve related deaths. Follow up was 98.4% complete with a mean follow up of 6.1+/-3.3 years (766 patient-years, range 0-10.2 years). Overall 10-year actuarial survival was 41+/-7% (AVR 49+/-10%, MVR 29+/-11%) and this was influenced by pre-operative poor left ventricular function (EF<30%) (p=0.007) and pre-operative NYHA class III/IV (p=0.001). Overall estimated 10-year actuarial freedom from valve related events (Kaplan-Meier) and valve related events expressed as linearised rates (%/patient-year) were: freedom from structural valve failure 97+/-2% (0.26%/patient-year); non-structural dysfunction 98+/-1% (0.13%/patient-year); freedom from prosthetic valve endocarditis 94+/-3% (0.39%/patient-year); freedom from significant haemorrhagic event 82+/-6% (1.33%/patient-year); freedom from thrombo-embolism 90+/-3% (0.91%/patient-year) and freedom from re-operation was 93+/-3% (0.52%/patient-year). CONCLUSION: In our experience Aspire (Tissuemed) porcine bioprosthesis functions satisfactorily at 10-years with low valve related complications. Further follow-up will determine its long-term durability.