Optimizing donor site analgesia after bone harvest from iliac crest.

At Queens Medical Centre, Nottingham, alveolar bone grafts (ABG) for patients with cleft lip and palate (CLP) were performed by two surgeons following the same surgical protocol, but with different postoperative iliac crest donor site analgesia: surgeon A used a donor site bolus of levobupivacaine, whilst surgeon B used a donor site epidural catheter (EC) infusing levobupivacaine. A healthcare evaluation was conducted in two phases to establish the effectiveness of analgesia for CLP patients undergoing ABGs. Data were collected prospectively in 2016 and 2018. Cleft patients postoperative to ABG were included. Outcome measures were pain scores at 2, 4, 6, 12, and 24 hours, time to mobilization, and time to food intake. Mean pain scores at the first evaluation were <1 out of 10 for all time points, except 24 hours (score 2.0 for bolus, 1.8 for EC). There was no statistically significant difference between the groups for any of the outcomes measured. As EC conferred no advantage, surgeon B changed to bolus administration and a second evaluation was performed. The mean pain score for the second evaluation was 1.7 and higher pain scores were more common with lower doses of levobupivacaine. The data suggest that bolus injection can produce safe, effective pain control provided an adequate dose is given.

Predicting soil respiration from peatlands.

This study considers the relative performance of six different models to predict soil respiration from upland peat. Predicting soil respiration is important for global carbon budgets and gap filling measured data from eddy covariance and closed chamber measurements. Further to models previously published new models are presented using two sub-soil zones and season. Models are tested using data from the Bleaklow plateau, southern Pennines, UK. Presented literature models include ANOVA using logged environmental data, the Arrhenius equation, modified versions of the Arrhenius equation to include soil respiration activation energy and water table depth. New models are proposed including the introduction of two soil zones in the peat profile, and season. The first new model proposes a zone of high CO(2) productivity related to increased soil microbial CO(2) production due to the supply of labile carbon from plant root exudates and root respiration. The second zone is a deeper zone where CO(2) production is lower with less labile carbon. A final model allows the zone of high CO(2) production to become dormant during winter months when plants will senesce and will vary depending upon vegetation type within a fixed location. The final model accounted for, on average, 31.9% of variance in net ecosystem respiration within 11 different restoration sites whilst, using the same data set, the best fitting literature equation only accounted for 18.7% of the total variance. Our results demonstrate that soil respiration models can be improved by explicitly accounting for seasonality and the vertically stratified nature of soil processes. These improved models provide an enhanced basis for calculating the peatland carbon budgets which are essential in understanding the role of peatlands in the global C cycle.

Evidence of an increase in the incidence of odontogenic sinusitis over the last decade in the UK.

BACKGROUND: Dental disease is a recognised cause of sinusitis. We perceived an increased incidence of sinusitis secondary to dental disease in recent years. This study reviews the incidence of odontogenic sinusitis, its clinical features and treatment. METHODS: Medical records of patients with odontogenic sinusitis were identified using the senior author's clinical database and Hospital Information Support System data (January 2004 to December 2009). RESULTS: Twenty-six patients were identified, nine females and 17 males (age range, 17-73 years). Rhinorrhoea and cacosmia were the commonest symptoms (81 and 73 per cent, respectively), with presence of pus the commonest examination finding (73 per cent). Causative dental pathology included periapical infection (73 per cent), oroantral fistula (23 per cent) and a retained root (4 per cent). In all 26 cases, treatment resulted in complete resolution of symptoms; 21 (81 per cent) required sinus surgery. The number of patients with odontogenic sinusitis undergoing surgery has steadily increased, from no cases in 2004 to 10 in 2009 (accounting for 8 per cent of all patients requiring sinus surgery). Reduced access to dental care may be responsible. CONCLUSION: The incidence of odontogenic sinusitis appears to be increasing. The importance of assessing the oral cavity and dentition in patients with rhinosinusitis is therefore emphasised.

Bayesian sensitivity analysis of a model of the aortic valve.

Understanding the mechanics of the aortic valve has been a focus of attention for many years in the biomechanics literature, with the aim of improving the longevity of prosthetic replacements. Finite element models have been extensively used to investigate stresses and deformations in the valve in considerable detail. However, the effect of uncertainties in loading, material properties and model dimensions has remained uninvestigated. This paper presents a formal statistical consideration of a selected set of uncertainties on a fluid-driven finite element model of the aortic valve and examines the magnitudes of the resulting output uncertainties. Furthermore, the importance of each parameter is investigated by means of a global sensitivity analysis. To reduce computational cost, a Bayesian emulator-based approach is adopted whereby a Gaussian process is fitted to a small set of training data and then used to infer detailed sensitivity analysis information. From the set of uncertain parameters considered, it was found that output standard deviations were as high as 44% of the mean. It was also found that the material properties of the sinus and aorta were considerably more important in determining leaflet stress than the material properties of the leaflets themselves.

Hold, grasp, clutch or grab: consumer grip choices during food container opening.

Society is ageing and sadly that ageing leads to a host of issues, not least a society in which the majority are likely to have some loss of strength and dexterity. This can lead to complications in undertaking everyday tasks such as using transport, bathing or even handling and opening food. Packaging has to provide a multitude of services; to protect and preserve the product, to provide information to the consumer and not least to allow access to the contents. This access to packaging--or 'openability'--has become a significant issue for designers and manufacturers with the change in demographics as described above. Understanding the choices consumers make in how they manipulate packaging can help designers produce packaging that is more able to meet the requirements of modern society. Studies previously undertaken by the authors showed that consumers did use different grips when opening packaging and that certain grips were theoretically more comfortable and stronger than others. This paper outlines a further study whereby consumers were asked to apply the most common grips to a specially designed torque measuring device. Details were taken about the consumers: age, gender, occupation, hand size, plus their preferred grip choice for packaging of this type. The study showed that typically women chose a grip that maximised their opportunity of opening the closure and that this grip choice was more limited than that available for men. This has implications for inclusive design of many everyday products.

Computational model of an infant brain subjected to periodic motion simplified modelling and Bayesian sensitivity analysis.

Non-accidental head injury in infants, or shaken baby syndrome, is a highly controversial and disputed topic. Biomechanical studies often suggest that shaking alone cannot cause the classical symptoms, yet many medical experts believe the contrary. Researchers have turned to finite element modelling for a more detailed understanding of the interactions between the brain, skull, cerebrospinal fluid (CSF), and surrounding tissues. However, the uncertainties in such models are significant; these can arise from theoretical approximations, lack of information, and inherent variability. Consequently, this study presents an uncertainty analysis of a finite element model of a human head subject to shaking. Although the model geometry was greatly simplified, fluid-structure-interaction techniques were used to model the brain, skull, and CSF using a Eulerian mesh formulation with penalty-based coupling. Uncertainty and sensitivity measurements were obtained using Bayesian sensitivity analysis, which is a technique that is relatively new to the engineering community. Uncertainty in nine different model parameters was investigated for two different shaking excitations: sinusoidal translation only, and sinusoidal translation plus rotation about the base of the head. The level and type of sensitivity in the results was found to be highly dependent on the excitation type.

The multi-annual carbon budget of a peat-covered catchment.

This study estimates the complete carbon budget of an 11.4 km(2) peat-covered catchment in Northern England. The budget considers both fluvial and gaseous carbon fluxes and includes estimates of particulate organic carbon (POC); dissolved organic carbon (DOC); excess dissolved CO(2); release of methane (CH(4)); net ecosystem respiration of CO(2); and uptake of CO(2) by primary productivity. All components except CH(4) were measured directly in the catchment and annual carbon budgets were calculated for the catchment between 1993 and 2005 using both extrapolation and interpolation methods. The study shows that: Over the 13 year study period the total carbon balance varied between a net sink of -20 to -91 Mg C/km(2)/yr. The biggest component of this budget is the uptake of carbon by primary productivity (-178 Mg C/km(2)/yr) and in most years the second largest component is the loss of DOC from the peat profile (+39 Mg C/km(2)/yr). Direct exchanges of C with the atmosphere average -89 Mg C/km(2)/yr in the catchment. Extrapolating the general findings of the carbon budget across all UK peatlands results in an approximate carbon balance of -1.2 Tg C/yr (+/-0.4 Pg C/yr) which is larger than previously reported values. Carbon budgets should always be reported with a clear statement of the techniques used and errors involved as this is significant when comparing results across studies.

Cementifying fibroma of the frontal bone: a case report.

Cementifying fibromas are rare fibro-osseous tumours that are usually found in the jaws. We report a 10-year-old boy who presented with a mass in the frontal bone causing frontal bossing and proptosis. The preoperative diagnosis was not clear despite computed tomographic and magnetic resonance imaging. The lesion was resected completely and found to be a cementifying fibroma. It was reconstructed at the same operation and he made a good recovery with no sign of recurrence.

Human thyroid cancer cells as a source of iso-genic, iso-phenotypic cell lines with or without functional p53.

Differentiated thyroid carcinomas (in contrast to the rarer anaplastic form) are unusual among human cancers in displaying a remarkably low frequency of p53 mutation and appear to retain wild-type (wt) p53 function as assessed by the response of derived cell lines to DNA damage. Using one such cell line, K1, we have tested the effect of experimental abrogation of p53 function by generating matched sub-clones stably expressing either a neo control gene, a dominant-negative mutant p53 (143ala) or human papilloma virus protein HPV16 E6. Loss of p53 function in the latter two groups was confirmed by abolition of p53-dependent 'stress' responses including induction of the cyclin/CDK inhibitor p21WAF1 and G1/S arrest following DNA-damage. In contrast, no change was detected in the phenotype of 'unstressed' clones, with respect to any of the following parameters: proliferation rate in monolayer, serum-dependence for proliferation or survival, tumorigenicity, cellular morphology, or tissue-specific differentiation markers. The K1 line therefore represents a 'neutral' background with respect to p53 function, permitting the derivation of functionally p53 + or - clones which are not only iso-genic but also iso-phenotypic. Such a panel should be an ideal tool with which to test the p53-dependence of cellular stress responses, particularly the sensitivity to potential therapeutic agents, free from the confounding additional phenotypic differences which usually accompany loss of p53 function. The results also further support the hypothesis that p53 mutation alone is not sufficient to drive progression of thyroid cancer to the aggressive anaplastic form.

Control of replicative life span in human cells: barriers to clonal expansion intermediate between M1 senescence and M2 crisis.

The accumulation of genetic abnormalities in a developing tumor is driven, at least in part, by the need to overcome inherent restraints on the replicative life span of human cells, two of which-senescence (M1) and crisis (M2)-have been well characterized. Here we describe additional barriers to clonal expansion (Mint) intermediate between M1 and M2, revealed by abrogation of tumor-suppressor gene (TSG) pathways by individual human papillomavirus type 16 (HPV16) proteins. In human fibroblasts, abrogation of p53 function by HPVE6 allowed escape from M1, followed up to 20 population doublings (PD) later by a second viable proliferation arrest state, MintE6, closely resembling M1. This occurred despite abrogation of p21(WAF1) induction but was associated with and potentially mediated by a further approximately 3-fold increase in p16(INK4a) expression compared to its level at M1. Expression of HPVE7, which targets pRb (and p21(WAF1)), also permitted clonal expansion, but this was limited predominantly by increasing cell death, resulting in a MintE7 phenotype similar to M2 but occurring after fewer PD. This was associated with, and at least partly due to, an increase in nuclear p53 content and activity, not seen in younger cells expressing E7. In a different cell type, thyroid epithelium, E7 also allowed clonal expansion terminating in a similar state to MintE7 in fibroblasts. In contrast, however, there was no evidence for a p53-regulated pathway; E6 was without effect, and the increases in p21(WAF1) expression at M1 and MintE7 were p53 independent. These data provide a model for clonal evolution by successive TSG inactivation and suggest that cell type diversity in life span regulation may determine the pattern of gene mutation in the corresponding tumors.

The use of lignocaine in dental practice: results of a survey of a group of general and hospital dental practitioners.

OBJECTIVES: This survey investigated whether dentists using lignocaine with adrenaline used aspiration syringes or warming and assessed their knowledge of appropriate doses of these drugs. METHODS: Sixty-two general dental practitioners (GDPs) and 26 hospital dental practitioners (HDPs) responded to a series of questions asked via telephone or direct interview. RESULTS: Only 3% of dentists interviewed correctly calculated the amount of lignocaine (mg) in 2 ml of 2% lignocaine solution and none knew the safe dose expressed as mg/kg body wt. All dentists were using a cartridge system and had an easily remembered maximum number of cartridges that they would administer. This number varied, but in all cases was within the safe maximum dose recommended by the British National Formulary. The survey also showed that 63% of the GDPs were using self aspirating syringe systems and approximately 50% considered warming the anaesthetic solution prior to injection to be beneficial. CONCLUSION: The results indicate that dentists may be found to be poor at calculating doses but are nevertheless unlikely to give inappropriate amounts of lignocaine to healthy adults. This indicates the relative safety of the cartridge system. The use of the self aspirating syringe is not universal in spite of recommendations for its use. Warming of the anaesthetic solution is popular.

Two new retractors for use in cryotherapy.

Two new instruments are described for use in the cryotherapy of peripheral nerves. They are designed to give good vision and access, protect surrounding tissues and be comfortable to hold.

Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2.

A significant proportion of human cancers express high levels of p53 protein in the absence of an underlying mutation in the gene. Using transformed (Vh1) and non-transformed (FRTL-5) rat thyroid epithelial cell lines as a model, we have examined the mechanisms by which high levels of wild-type p53 may be tolerated. Stable transfection with p53-dependent reporter constructs demonstrated that the 'excess' wild-type p53 in Vh1 cells is not associated with a comparable increase in p53-dependent transcription (though the response to u.v. irradiation is retained). Mdm-2, which binds p53 and inhibits its transactivation activity, is overexpressed in Vh1 cells in the absence of gene amplification and in a p53-dependent manner. Furthermore disruption of p53-mdm-2 complex formation in Vh1 cells by microinjection of an antibody to the p53-binding domain of mdm-2 resulted in a dramatic increase in p53-dependent transcription. Since only a small proportion of the p53 in Vh1 cells was found to be in complex with mdm-2 (the majority of unbound protein being in a latent form), this suggests that mdm-2 selectively binds a pool of p53 that would otherwise be active as a sequence-specific activator of transcription. We suggest that, in some types of tumour, the 'sensitivity' of the p53-driven mdm-2 feedback loop may be sufficient to prevent free, active p53 reaching the level required for growth arrest or apoptosis, making them an ideal target for therapies designed to disrupt p53-mdm-2 interactions.

Spontaneous de-differentiation correlates with extended lifespan in transformed thyroid epithelial cells: an epigenetic mechanism of tumour progression?

Normal thyroid follicular cells, like many highly differentiated epithelia, have limited proliferative capacity. We previously showed that this could be extended by expression of the SV40 large T oncogene, but that immortal lines always lost thyroid-specific differentiation. Detailed analysis now show that clones expressing T undergo 2 mutually exclusive fates. They either (i) remain well-differentiated, in which case they undergo irreversible growth arrest after 5 to 15 p.d., or (ii) spontaneously develop poorly differentiated sub-clones that exhibit greatly extended proliferative life spans (up to 75 p.d.). The frequency of this event (> 3 per 10(4) cell divisions) greatly exceeds that expected from somatic mutation, suggesting an epigenetic basis. This is supported by our finding of rare de-differentiated epithelial cells in normal thyroid that all generate clones with extended life spans, indistinguishable from the above, following introduction of SV40 T. Escape from early mortality in differentiated thyroid epithelium therefore requires not only loss of tumour suppressor gene function (induced here by SV40 T), but also a switch in differentiation programme, with the latter effectively converting the follicular cell into a cell type with increased intrinsic proliferative potential. The analogy between this in vitro model and the progression of thyroid cancer from the well-differentiated to the highly aggressive, anaplastic form suggests that de-differentiation may play a causal rather than a passive role in this critical switch in tumour behaviour.

S phase cell-cycle arrest following DNA damage is independent of the p53/p21(WAF1) signalling pathway.

It is now likely that the cyclin-kinase inhibitor, p21(WAF1/SD11), is a key effector of p53-mediated cell-cycle arrest at the G(1)/S checkpoint following DNA damage. More recently, however, in vitro data has suggested that this pathway may also mediate the acute inhibition of DNA synthesis seen in cells already in S phase. Here we address this question in an intact cell system using normal human diploid fibroblasts in which p53 function is manipulated by expression of a dominant-negative mutant (ala(143)) introduced by a retroviral vector. Induction of DNA strand breaks in normal control fibroblasts by exposure to bleomycin led as expected to G(1)/S cell cycle arrest, induction of p2l(WAF1) and a rapid reduction in the rate of DNA synthesis in cells already in S phase. Stable expression of mutant p53 abrogated the G(1)/S (but not the G(2)/M) cell cycle checkpoint and abolished the induction of p21(WAF1), but had no significant effect on the inhibition of DNA replication in S phase nuclei. We conclude that, despite the in vitro evidence for inhibitory activity on PCNA/polymerase delta, p21(WAF1) induction does not appear to be essential for the acute inhibition of DNA synthesis in the intact cell following strand-break damage in S phase.

Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1.

Although the cyclin-dependent kinase inhibitor p21SDI1 (WAF1/CIP1) has been proposed as the mediator of p53-induced cell cycle arrest following DNA damage, several stimuli now appear to induce SDI1 independent of p53 function. We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fibroblasts using an amphotropic retroviral vector. Following DNA strand break damage induced by bleomycin, both SDI1 induction and G1-S cell cycle arrest are p53 dependent, consistent with SDI1 being the key mediator. In contrast, in cellular senescence (and following UV irradiation), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent. We conclude (a) that redundant pathways exist for induction of SDI1, but that (b) SDI1, while perhaps necessary, is not sufficient for inhibition of cell cycle progression, requiring the cooperation of an additional factor (possibly another cyclin-dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent.

In vitro reconstruction of tumour initiation in a human epithelium.

Knowledge of tumour initiation in human epithelia is limited by sample availability and difficulty in experimental manipulation of human cells. The thyroid is a useful model since, in addition to multiple tumour stages, it presents two distinct 'pathways' of tumorigenesis: 'follicular' tumours, in which ras oncogene mutations occur at high frequency and 'papillary' tumours, associated with ret (or trk) activation. We have used these observations to reconstruct early thyroid tumorigenesis, using amphotropic retroviral vectors. When introduced into normal thyroid epithelial cells, mutant ras induces self-limiting growth of well-demarcated, differentiated colonies--a phenotype consistent with follicular adenoma. Activated ret on the other hand induces smaller, poorly-demarcated colonies with a morphology consistent with early papillary tumours. Mutant p53--which occurs only in the latest stages of thyroid cancer--was without effect. Our results provide the first direct experimental evidence in a human epithelium for alternative initiating oncogenes and their determination of the subsequent 'direction' of tumour development.