Mortality reporting in interventional radiology: experience of a pilot audit with the Scottish Audit of Surgical Mortality.

AIM: To describe the initial pilot phase of the 2009 Scottish Audit of Surgical Mortality (SASM), which includes outcomes and difficulties that arose during any interventional radiology (IR) procedure performed on patients in this audit over an 18 month period. MATERIALS AND METHODS: Approximately 40 consultant interventional radiologists from all units in Scotland elected to participate in the audit. Each response was then peer reviewed after anonymisation of the patient and institution. If a relevant ACON (area for consideration or area of concern) was generated, this was checked by one of the other reviewers before communication with the original reporting radiologist and colleagues. There was then a right of reply by the reporting unit before formal documentation was sent out. RESULTS: Initial results were analysed after 18 months period, during which time 95 forms relating to deaths of surgical inpatients were sent to interventional radiologists identified as having been involved in an IR procedure at some time during the patient's admission. Seventy-one forms had been returned by July 2010, of which 46 had gone through the entire SASM process. From these, 10 ACONs were attributed. Anonymised case vignettes and reports from these were used as educational tools. CONCLUSION: Involvement with SASM is a useful process. Significant safety issues and learning points were identified in the pilot. The majority of ACONs identified by the audit were in patients who had undergone percutaneous biliary interventions.

The structure of a bottlenose dolphin society is coupled to a unique foraging cooperation with artisanal fishermen.

Diverse and localized foraging behaviours have been reported in isolated populations of many animal species around the world. In Laguna, southern Brazil, a subset of resident bottlenose dolphins (Tursiops truncatus) uses a foraging tactic involving cooperative interactions with local, beach-casting fishermen. We used individual photo-identification data to assess whether cooperative and non-cooperative dolphins were socially segregated. The social structure of the population was found to be a fission-fusion system with few non-random associations, typical for this species. However, association values were greater among cooperative dolphins than among non-cooperative dolphins or between dolphins from different foraging classes. Furthermore, the dolphin social network was divided into three modules, clustering individuals that shared or lacked the cooperative foraging tactic. Space-use patterns were not sufficient to explain this partitioning, indicating a behavioural factor. The segregation of dolphins using different foraging tactics could result from foraging behaviour driving social structure, while the closer association between dolphins engaged in the cooperation could facilitate the transmission and learning of this behavioural trait from conspecifics. This unique case of a dolphin-human interaction represents a valuable opportunity to explore hypotheses on the role of social learning in wild cetaceans.

The primary care diagnosis and management of bulimia nervosa and its relevance in the UK Armed Forces.

Bulimia Nervosa is an eating disorder that is frequently seen in the UK Armed Forces population. In this article the diagnosis, management and clinical considerations of managing this condition in Primary Care in the UKArmed Forces are considered. The occupational and operational considerations for the military environment are also discussed.

Normal Tissue Complication Probability Modelling for Toxicity Prediction and Patient Selection in Proton Beam Therapy to the Central Nervous System: A Literature Review.

Normal tissue complication probability (NTCP) models can guide clinical decision making in radiotherapy. In recent years, they have been used for patient selection for proton beam therapy (PBT) for some anatomical tumour sites. This review synthesizes the published evidence regarding the use of NTCP models to predict the toxicity of PBT, for different end points in patients with brain tumours. A search of Medline and Embase using the Patients, Intervention, Comparison, Outcome (PICO) criteria was undertaken. In total, 37 articles were deemed relevant and were reviewed in detail. Nineteen articles on NTCP modelling of toxicity end points were included. Of these, 11 were comparative NTCP studies of PBT versus conventional photon radiotherapy (XRT), which evaluated differences in plan dosimetry and then assumed that XRT-derived literature estimates of NTCP would be applicable to both. Seven papers derived NTCP models based on PBT outcome data, two of which provided model parameters. Among analysed end points, the reduced risk of secondary tumours with PBT as compared with XRT is estimated - through modelling studies - to be considerable and was highlighted by most authors. For other analysed end points, the clinical benefit of PBT mainly depends on tumour location in relation to organs at risk as well as prescription doses. NTCP models can be useful tools for treatment plan comparison. However, most published toxicity data were derived from XRT cohorts; this review has highlighted the need for further studies relating dose-volume parameters to observed toxicity in PBT-treated patients. Specifically, there is a need for PBT-specific NTCP models that can be implemented in the clinical practice. NTCP models built on robust clinical data for the most common radiotherapy toxicities in the brain would potentially redefine the current indications for PBT.

Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. METHODS: The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. RESULTS: Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. CONCLUSION: Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.

Quantum control of the spin-orbit interaction using the Autler-Townes effect.

We have demonstrated quantum control of the spin-orbit interaction based on the Autler-Townes (ac-Stark) effect in a molecular system using a cw optical field. We show that the enhancement of the spin-orbit interaction between a pair of weakly interacting singlet-triplet rovibrational levels, G (1)Π(g)(v=12,J=21,f)-1 (3)Σ(g)(-)(v=1,N=21,f), separated by 750 MHz in the lithium dimer, depends on the Rabi frequency (laser power) of the control laser. The increase in the spin-orbit interaction due to the control field is observed as a change in the spin character of the individual components of the perturbed pair.

Moving inwards, moving outwards, moving upwards: the role of spirituality during the early stages of breast cancer.

The paper reflects on a study which explored the role of spirituality in the lives of women during the first year after being diagnosed with breast cancer. The study utilised a qualitative method (hermeneutic phenomenology) designed to provide rich and thick understanding of women's experiences of breast cancer and to explore possible ways in which spirituality may, or may not, be beneficial in enabling coping and enhancing quality of life. The paper draws on the thinking of David Hay and Viktor Frankl to develop a model of spirituality that includes, but is not defined by, religion and that has the possibility to facilitate effective empirical enquiry. It outlines a threefold movement - inwards, outwards and upwards - that emerged from in-depth interviews with women who have breast cancer. This framework captures something of the spiritual movement that women went through on their cancer journeys and offers some pointers and possibilities for better and more person-centred caring approaches that include recognition of the spiritual dimension of women's experiences for the management of those with breast cancer.

Experimental investigation of the Cs2 a 3Sigma(u)+ triplet ground state: multiparameter Morse long range potential analysis and molecular constants.

We have observed the vibrational levels v(") = 0-40 of the Cs(2) a (3)Sigma(u)(+) state by perturbation facilitated infrared-infrared double resonance excitation and spectrally resolved fluorescence measurements, and derived a multiparameter Morse long range potential and molecular constants based on these data.

Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway.

Following radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.

In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

A New Standard DNA Damage (SDD) Data Format.

Our understanding of radiation-induced cellular damage has greatly improved over the past few decades. Despite this progress, there are still many obstacles to fully understand how radiation interacts with biologically relevant cellular components, such as DNA, to cause observable end points such as cell killing. Damage in DNA is identified as a major route of cell killing. One hurdle when modeling biological effects is the difficulty in directly comparing results generated by members of different research groups. Multiple Monte Carlo codes have been developed to simulate damage induction at the DNA scale, while at the same time various groups have developed models that describe DNA repair processes with varying levels of detail. These repair models are intrinsically linked to the damage model employed in their development, making it difficult to disentangle systematic effects in either part of the modeling chain. These modeling chains typically consist of track-structure Monte Carlo simulations of the physical interactions creating direct damages to DNA, followed by simulations of the production and initial reactions of chemical species causing so-called "indirect" damages. After the induction of DNA damage, DNA repair models combine the simulated damage patterns with biological models to determine the biological consequences of the damage. To date, the effect of the environment, such as molecular oxygen (normoxic vs. hypoxic), has been poorly considered. We propose a new standard DNA damage (SDD) data format to unify the interface between the simulation of damage induction in DNA and the biological modeling of DNA repair processes, and introduce the effect of the environment (molecular oxygen or other compounds) as a flexible parameter. Such a standard greatly facilitates inter-model comparisons, providing an ideal environment to tease out model assumptions and identify persistent, underlying mechanisms. Through inter-model comparisons, this unified standard has the potential to greatly advance our understanding of the underlying mechanisms of radiation-induced DNA damage and the resulting observable biological effects when radiation parameters and/or environmental conditions change.

Opioid inhibition of Ih via adenylyl cyclase.

Opioids are coupled through G proteins to both ion channels and adenylyl cyclase. This study describes opioid modulation of the voltage-dependent cation channel, Ih, in cultured guinea pig nodose ganglion neurons. Forskolin, PGE2, and cAMP analogs shifted the voltage dependence of activation of Ih to more depolarized potentials and increased the inward current at -60 mV. Opioids had no effect on Ih alone, but reversed the effect of forskolin on Ih. This action of opioids was blocked by naloxone. Opioids had no effect on Ih in the presence of cAMP analogs, suggesting that modulation occurs at the level of adenylyl cyclase. The shift in the voltage dependence of Ih by agents that induce inflammation (i.e., PGE2) is one potential mechanism to mediate an increased excitability. Opioid inhibition of adenylyl cyclase and subsequent inhibition of Ih may be a mechanism by which opioids inhibit primary afferent excitability and relieve pain.

Shipping noise in a dynamic sea: a case study of grey seals in the Celtic Sea.

Shipping noise is a threat to marine wildlife. Grey seals are benthic foragers, and thus experience acoustic noise throughout the water column, which makes them a good model species for a case study of the potential impacts of shipping noise. We used ship track data from the Celtic Sea, seal track data and a coupled ocean-acoustic modelling system to assess the noise exposure of grey seals along their tracks. It was found that the animals experience step changes in sound levels up to ~20dB at a frequency of 125Hz, and ~10dB on average over 10-1000Hz when they dive through the thermocline, particularly during summer. Our results showed large seasonal differences in the noise level experienced by the seals. These results reveal the actual noise exposure by the animals and could help in marine spatial planning.

Seabird diving behaviour reveals the functional significance of shelf-sea fronts as foraging hotspots.

Oceanic fronts are key habitats for a diverse range of marine predators, yet how they influence fine-scale foraging behaviour is poorly understood. Here, we investigated the dive behaviour of northern gannets Morus bassanus in relation to shelf-sea fronts. We GPS (global positioning system) tracked 53 breeding birds and examined the relationship between 1901 foraging dives (from time-depth recorders) and thermal fronts (identified via Earth Observation composite front mapping) in the Celtic Sea, Northeast Atlantic. We (i) used a habitat-use availability analysis to determine whether gannets preferentially dived at fronts, and (ii) compared dive characteristics in relation to fronts to investigate the functional significance of these oceanographic features. We found that relationships between gannet dive probabilities and fronts varied by frontal metric and sex. While both sexes were more likely to dive in the presence of seasonally persistent fronts, links to more ephemeral features were less clear. Here, males were positively correlated with distance to front and cross-front gradient strength, with the reverse for females. Both sexes performed two dive strategies: shallow V-shaped plunge dives with little or no active swim phase (92% of dives) and deeper U-shaped dives with an active pursuit phase of at least 3 s (8% of dives). When foraging around fronts, gannets were half as likely to engage in U-shaped dives compared with V-shaped dives, independent of sex. Moreover, V-shaped dive durations were significantly shortened around fronts. These behavioural responses support the assertion that fronts are important foraging habitats for marine predators, and suggest a possible mechanistic link between the two in terms of dive behaviour. This research also emphasizes the importance of cross-disciplinary research when attempting to understand marine ecosystems.

Arachidonic acid stimulates a novel cocaine-sensitive cation conductance associated with the human dopamine transporter.

The dopamine transporter (DAT) exhibits several ionic currents that are either coupled to or uncoupled from the transport of substrate. Second messenger systems have been shown to modulate dopamine (DA) transport, however, the modulation of DAT-associated currents has not been studied in depth. Using the two-electrode voltage-clamp method to record from Xenopus oocytes expressing the human DAT, we examined the effects of arachidonic acid (AA) on membrane currents. AA (10-100 microM) stimulates a novel nonselective cation conductance seen only in oocytes expressing human DA transporter (hDAT). The AA-stimulated conductance is up to 50-fold greater than the current normally elicited by DA, but does not appear to arise from the modulation of previously described hDAT conductances, including the leak current and the current associated with electrogenic transport. In addition, DA dramatically potentiates and cocaine blocks the AA-stimulated DAT current. DA potentiates the AA-induced currents in the absence of sodium and chloride, indicating that these currents arise from processes distinct from those associated with substrate transport. The effects of AA were mimicked by other fatty acids with a rank order of potency correlated with their degree of unsaturation, suggesting that AA directly stimulates the novel cation current. Therefore, AA stimulation of this DAT-associated conductance may provide a novel mechanism for modulation of neuronal signaling.

Change in functional selectivity of morphine with the development of antinociceptive tolerance.

BACKGROUND AND PURPOSE: Opioids, such as morphine, are the most effective treatment for pain but their efficacy is diminished with the development of tolerance following repeated administration. Recently, we found that morphine activated ERK in opioid-tolerant but not in naïve rats, suggesting that morphine activation of µ-opioid receptors is altered following repeated morphine administration. Here, we have tested the hypothesis that µ-opioid receptor activation of ERK in the ventrolateral periaqueductal gray (vlPAG) is dependent on dynamin, a protein implicated in receptor endocytosis. EXPERIMENTAL APPROACH: Rats were made tolerant to repeated microinjections of morphine into the vlPAG. The effects of dynamin on ERK activation and antinociception were assessed by microinjecting myristoylated dominant-negative dynamin peptide (Dyn-DN) or a scrambled control peptide into the vlPAG. Microinjection of a fluorescent dermorphin analogue (DERM-A594) into the vlPAG was used to monitor µ-opioid receptor internalization. KEY RESULTS: Morphine did not activate ERK and Dyn-DN administration had no effect on morphine-induced antinociception in saline-pretreated rats. In contrast, morphine-induced ERK activation in morphine-pretreated rats that was blocked by Dyn-DN administration. Dyn-DN also inhibited morphine antinociception. Finally, morphine reduced DERM-A594 internalization only in morphine-tolerant rats indicating that µ-opioid receptors were internalized and unavailable to bind DERM-A594. CONCLUSIONS AND IMPLICATIONS: Repeated morphine administration increased µ-opioid receptor activation of ERK signalling via a dynamin-dependent mechanism. These results demonstrate that the balance of agonist signalling to G-protein and dynamin-dependent pathways is altered, effectively changing the functional selectivity of the agonist-receptor complex. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Neuronal localization of cholecystokinin mRNA in the rat brain by using in situ hybridization histochemistry.

The distribution of cholecystokinin (CCK) mRNA in the rat brain was determined by means of in situ hybridization histochemistry. Our results demonstrate a widespread distribution of neurons containing CCK mRNA throughout the rat brain. Hybridization-positive neurons were distributed throughout the neocortex, olfactory bulb, claustrum, amygdala, the dentate gyrus and hippocampus proper, and several subnuclei of the thalamus and the hypothalamus. The most abundant and most heavily labeled neurons were found in the endopiriform/piriform cortex, tenia tecta, and the ventral tegmental area. The distribution of neurons positive for CCK mRNA paralleled that of CCK-like immunoreactive neurons. These results detail the distribution of CCK mRNA and clearly identify the existence of CCK-synthesizing neurons in regions such as the paraventricular and supraoptic nuclei of the hypothalamus, where the presence of CCK cell bodies was previously uncertain.

Prosody impairment and associated affective and behavioral disturbances in Alzheimer's disease.

We examined the ability to produce, repeat, and comprehend emotional prosody in 20 patients with Alzheimer's disease (AD) and in 11 elderly normal control subjects. In addition, caregivers of AD patients completed affective and behavioral measures with reference to the patient. Relative to control subjects, comprehension of emotional prosody was marginally impaired in mildly demented AD patients, whereas production, comprehension, and repetition of emotional prosody were significantly impaired in moderately demented AD patients. The moderately demented patients performed significantly poorer than the mildly demented patients on the production and repetition tasks. In contrast, there was no significance difference between the two groups on the prosody comprehension task. Additional analyses revealed an inverse relationship between the ability to correctly produce and repeat emotional prosody and the frequency of agitated behaviors and depressive symptomatology in moderately demented patients. This latter findings suggests that the inability to communicate emotional message is associated with disturbances in mood and behavior in AD patients. Implications for the management of disruptive behavior in agitated and aprosodic AD patients include the development of caregiver sensitivity to unexpressed emotion and caregiver assistance with emotional expression.

The predictive value of progesterone receptor levels in endometrial cancer.

Recent reports have suggested that the presence of progesterone receptor correlates with other well known predictors of a favorable outcome for endometrial cancer patients. To test this hypothesis, we reviewed the records of 154 patients who had undergone a hysterectomy for adenocarcinoma of the endometrium, and pelvic irradiation if poor prognostic factors were present. The 3 year disease-free survival for all clinical Stage I patients was 80%. Patients with progesterone receptor levels greater than or equal to 100 had a 3 year disease-free survival of 93% compared with only a 36% 3 year disease-free survival for patients with progesterone receptor less than 100 (p less than .0001, log rank test). To determine whether elevated progesterone receptor was an independent prognostic factor for disease-free survival in endometrial cancer, or just correlated with the other well-known predictors, bivariate and multivariate analyses were conducted. Our results indicate the progesterone receptor levels are the single most important prognostic indicator of 3 year disease-free survival in clinical Stage I endometrial cancer, with only cervical involvement and peritoneal cytology being significant prognostic variables after adjusting for progesterone receptor levels.