bluuebunny/crossref_metadata_2025 huggingface dataset:
Interoception beyond homeostasis: affect, cognition and mental health
Authors: Tsakiris Manos , Critchley Hugo
Published: October 2016

Interoception refers to the sensing of the internal state of one's body. Interoception is distinct from the processing of sensory information concerning external (non-self) stimuli (e.g. vision, hearing, touch and smell) and is the afferent axis to internal (autonomic and hormonal) physiological control. However, the impact of interoception extends beyond homeostatic/allostatic reflexes: it is proposed to be fundamental to motivation, emotion (affective feelings and behaviours), social cognition and self-awareness. This view is supported by a growing body of experimental evidence that links peripheral physiological states to mental processes. Within this framework, the representation of self is constructed from early development through continuous integrative representation of biological data from the body, to form the basis for those aspects of conscious awareness grounded on the subjective sense of being a unique individual. This theme issue of the
Philosophical Transactions of the Royal Society B
draws together state-of-the-art knowledge concerning theoretical, experimental and clinical facets of interoception with the emphasis on cognitive and affective neuroscience. The multidisciplinary and cross-disciplinary perspectives represented in this theme issue disseminate and entrench knowledge about interoception across the scientific community and provide a reference for the conceptualization and further study of interoception across behavioural sciences.
Feeling, learning from and being aware of inner states: interoceptive dimensions in neurodegeneration and stroke
Authors: García-Cordero Indira , Sedeño Lucas , de la Fuente Laura , Slachevsky Andrea , Forno Gonzalo , Klein Francisco , Lillo Patricia , Ferrari Jesica , Rodriguez Clara , Bustin Julian , Torralva Teresa , Baez Sandra , Yoris Adrian , Esteves Sol , Melloni Margherita , Salamone Paula , Huepe David , Manes Facundo , García Adolfo M. , Ibañez Agustín
Published: October 2016

Interoception is a complex process encompassing multiple dimensions, such as accuracy, learning and awareness. Here, we examined whether each of those dimensions relies on specialized neural regions distributed throughout the vast interoceptive network. To this end, we obtained relevant measures of cardiac interoception in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal brain damage: behavioural variant fronto-temporal dementia (bvFTD), Alzheimer's disease (AD) and fronto-insular stroke. Neural correlates of the three dimensions were examined through structural and functional resting-state imaging, and online measurements of the heart-evoked potential (HEP). The three patient groups presented deficits in interoceptive accuracy, associated with insular damage, connectivity alterations and abnormal HEP modulations. Interoceptive learning was differentially impaired in AD patients, evidencing a key role of memory networks in this skill. Interoceptive awareness results showed that bvFTD and AD patients overestimated their performance; this pattern was related to abnormalities in anterior regions and associated networks sub-serving metacognitive processes, and probably linked to well-established insight deficits in dementia. Our findings indicate how damage to specific hubs in a broad fronto-temporo-insular network differentially compromises interoceptive dimensions, and how such disturbances affect widespread connections beyond those critical hubs. This is the first study in which a multiple lesion model reveals fine-grained alterations of body sensing, offering new theoretical insights into neuroanatomical foundations of interoceptive dimensions.

This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.
Interoception, homeostatic emotions and sympathovagal balance
Authors: Strigo Irina A. , Craig Arthur D. (Bud)
Published: October 2016

We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as
homeostatic emotions
. We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans.

This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.
An active inference theory of allostasis and interoception in depression
Authors: Barrett Lisa Feldman , Quigley Karen S. , Hamilton Paul
Published: October 2016

In this paper, we integrate recent theoretical and empirical developments in predictive coding and active inference accounts of interoception (including the Embodied Predictive Interoception Coding model) with working hypotheses from the theory of constructed emotion to propose a biologically plausible unified theory of the mind that places metabolism and energy regulation (i.e. allostasis), as well as the sensory consequences of that regulation (i.e. interoception), at its core. We then consider the implications of this approach for understanding depression. We speculate that depression is a disorder of allostasis, whose myriad symptoms result from a ‘locked in’ brain that is relatively insensitive to its sensory context. We conclude with a brief discussion of the ways our approach might reveal new insights for the treatment of depression.

This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.
Using Machine Learning to Parse Breast Pathology Reports
Authors: Yala Adam , Barzilay Regina , Salama Laura , Griffin Molly , Sollender Grace , Bardia Aditya , Lehman Constance , Buckley Julliette M. , Coopey Suzanne B. , Polubriaginof Fernanda , Garber Judy E. , Smith Barbara L. , Gadd Michele A. , Specht Michelle C. , Gudewicz Thomas M. , Guidi Anthony , Taghian Alphonse , Hughes Kevin S.
Published: October 2016

1

Purpose

Extracting information from Electronic Medical Record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest.

Methods

We collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital (MGH), Brigham and Womens Hospital (BWH), and Newton-Wellesley Hospital (NWH), covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6,295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably.

Results

The model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports.

Conclusions

Our learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from this data.
Genomic plasticity and rapid host switching promote the evolution of generalism in the zoonotic pathogenCampylobacter
Authors: Woodcock Dan J. , Krusche Peter , Strachan Norval J. C. , Forbes Ken J. , Cohan Frederick M. , Méric Guillaume , Sheppard Samuel K.
Published: October 2016

Horizontal gene transfer accelerates bacterial adaptation to novel environments, allowing selection to act on genes that have evolved in multiple genetic backgrounds. This can lead to ecological specialization. However, little is known about how zoonotic bacteria maintain the ability to colonize multiple hosts whilst competing with specialists in the same niche. Here we develop a stochastic evolutionary model and show how genetic transfer of niche specifying genes and the opportunity for host transition can interact to promote the emergence of host generalist lineages of the zoonotic bacteriumCampylobacter. Using a modelling approach we show that increasing levels of recombination enhance the efficiency with which selection can fix combinations of beneficial alleles, speeding adaptation. We then show how these predictions change in a multi-host system, with low levels of recombination, consistent with realr/mestimates, increasing the standing variation in the population, allowing a more effective response to changes in the selective landscape. Our analysis explains how observed gradients of host specialism and generalism can evolve in a multihost system through the transfer of ecologically important loci among coexisting strains.
Clear: Composition of Likelihoods for Evolve And Resequence Experiments
Authors: Iranmehr Arya , Akbari Ali , Schlötterer Christian , Bafna Vineet
Published: October 2016

The advent of next generation sequencing technologies has made whole-genome and whole-population sampling possible, even for eukaryotes with large genomes. With this development, experimental evolution studies can be designed to observe molecular evolution “in-action” via Evolve-and-Resequence (E&R) experiments. Among other applications, E&R studies can be used to locate the genes and variants responsible for genetic adaptation. Existing literature on time-series data analysis often assumes large population size, accurate allele frequency estimates, and wide time spans. These assumptions do not hold in many E&R studies.

In this article, we propose a method-Composition of Likelihoods for Evolve-And-Resequence experiments (Clear)–to identify signatures of selection in small population E&R experiments. Cleartakes whole-genome sequence of pool of individuals (pool-seq) as input, and properly addresses heterogeneous ascertainment bias resulting from uneven coverage. Clearalso provides unbiased estimates of model parameters, including population size, selection strength and dominance, while being computationally efficient. Extensive simulations show that Clearachieves higher power in detecting and localizing selection over a wide range of parameters, and is robust to variation of coverage. We applied Clearstatistic to multiple E&R experiments, including, data from a study ofD. melanogasteradaptation to alternating temperatures and a study of outcrossing yeast populations, and identified multiple regions under selection with genome-wide significance.
Examining the interaction between TGFBR3 and ESRRA in ovarian cancer prognosis
Authors: Passey Alun , Brown Robert , Wilhelm-Benartzi Charlotte S.
Published: October 2016

The authors found that ESRRA when co-expressed at high levels with TGFβR3 may be prognostic for serous ovarian cancer overall survival in data from the Cancer Genome Atlas; however, this result was not validated in further datasets. A cell line was also identified in this study for future functional investigation of interactions between ESRRA and TGFβR3 in the context of oestrogen signaling in order to further elucidate their potential roles as prognostic biomarkers for serous ovarian cancer.

FUNDING SUPPORT

This work was supported by Cancer Research UK program A6689 (RB and CSWB) and the Medical Research Council (AP)

CONFLICT OF INTEREST DISCLOSURES

The authors have declared no conflicts of interest.

AUTHOR CONTRIBUTIONS

CSWB designed the study. AP, CSWB, and RB developed the methodology. AP and CSWB collected the data. AP, CSWB, and RB wrote the manuscript. CSWB is responsible for the overall content.
Using predictive specificity to determine when gene set analysis is biologically meaningful
Authors: Ballouz Sara , Pavlidis Paul , Gillis Jesse
Published: October 2016

Gene set analysis, which translates gene lists into enriched functions, is among the most common bioinformatic methods. Yet few would advocate taking the results at face value. Not only is there no agreement on the algorithms themselves, there is no agreement on how to benchmark them. In this paper, we evaluate the robustness and uniqueness of enrichment results as a means of assessing methods even where correctness is unknown. We show that heavily annotated (“multifunctional”) genes are likely to appear in genomics study results and drive the generation of biologically non-specific enrichment results as well as highly fragile significances. By providing a means of determining where enrichment analyses report non-specific and non-robust findings, we are able to assess where we can be confident in their use. We find significant progress in recent bias correction methods for enrichment and provide our own software implementation. Our approach can be readily adapted to any pre-existing package.
Multiplexed computations in retinal ganglion cells of a single type
Authors: Deny Stephane , Ferrari Ulisse , Mace Emilie , Yger Pierre , Caplette Romain , Picaud Serge , Tkačik Gašper , Marre Olivier
Published: October 2016

In the early visual system, cells of the same type perform the same computation in di↵erent places of the visual field. How these cells code together a complex visual scene is unclear. A common assumption is that cells of the same type will extract a single stimulus feature to form a feature map, but this has rarely been observed directly. Using large-scale recordings in the rat retina, we show that a homogeneous population of fast OFF ganglion cells simultaneously encodes two radically different features of a visual scene. Cells close to a moving object code linearly for its position, while distant cells remain largely invariant to the object’s position and, instead, respond non-linearly to changes in the object’s speed. Cells switch between these two computations depending on the stimulus. We developed a quantitative model that accounts for this effect and identified a likely disinhibitory circuit that mediates it. Ganglion cells of a single type thus do not code for one, but two features simultaneously. This richer, flexible neural map might also be present in other sensory systems.
Expressing an RbcS Antisense Gene in Transgenic Flaveria bidentis Leads to an Increased Quantum Requirement for CO2 Fixed in Photosystems I and II
Authors: Siebke K. , von Caemmerer S. , Badger M. , Furbank R. T.
Published: October 2016

It was previously shown with concurrent measurements of gas exchange and carbon isotope discrimination that the reduction of ribulose-1,5-bisphosphate carboxylase/oxygenase by an antisense gene construct in transgenic Flaveria bidentis (a C4 species) leads to reduced CO2 assimilation rates, increased bundle-sheath CO2 concentration, and leakiness (defined as the ratio of CO2 leakage to the rate of C4 acid decarboxylation; S. von Caemmerer, A. Millegate, G.D. Farquhar, R.T. Furbank [1997] Plant Physiol 113: 469–477). Increased leakiness in the transformants should result in an increased ATP requirement per mole of CO2 fixed and a change in the ATP-to-NADPH demand. To investigate this, we compared measurements of the quantum yield of photosystem I and II ([phi]PSI and [phi]PSII) with the quantum yield of CO2 fixation ([phi]CO2) in control and transgenic F. bidentis plants in various conditions. Both [phi]PSI/[phi]CO2 and [phi]PSII/[phi]CO2 increased with a decrease in ribulose-1,5-bisphosphate carboxylase/oxygenase content, confirming an increase in leakiness. In the wild type the ratio of [phi]PSI to [phi]PSII was constant at different irradiances but increased with irradiance in the transformants, suggesting that cyclic electron transport may be higher in the transformants. To evaluate the relative contribution of cyclic or linear electron transport to extra ATP generation, we developed a model that links leakiness, ATP/NADP requirements, and quantum yields. Despite some uncertainties in the light distribution between photosystem I and II, we conclude from the increase of [phi]PSII/[phi]CO2 in the transformants that cyclic electron transport is not solely responsible for ATP generation without NADPH production.
Characterization of Blue Light Signal Transduction Chains That Control Development and Maintenance of Sexual Competence in Chlamydomonas reinhardtii
Authors: Pan J. M. , Haring M. A. , Beck C. F.
Published: October 2016

Blue light induces the differentiation of Chlamydomonas reinhardtii pregametes to gametes. The light-induced conversion of pregametes to gametes is protein synthesis dependent and proceeds only after a lag phase. Upon incubation in the dark, gametes lost their mating ability, resulting in dark-inactivated gametes. Reillumination rapidly restored mating competence and this was shown to be independent of protein synthesis. Apparently, differentiation and maintenance of gametic competence are both regulated by light. Whether one or two light-activated signal pathways are involved was investigated using pharmacological compounds that affect signal transduction. Compounds that affected pregamete-to-gamete conversion affected the expression of a gamete-specific gene in a similar fashion. Other drugs affected only dark-inactivated gametes, suggesting that reactivating gametes requires a separate signaling pathway. Combined treatments provided evidence for the consecutive action of a phosphatase and a protein kinase C-like kinase in the light-induced reactivation process.
Evidence for the Presence of a Porin in the Membrane of Glyoxysomes of Castor Bean
Authors: Reumann S. , Bettermann M. , Benz R. , Heldt H. W.
Published: October 2016

Glyoxysomes of endosperm tissue of castor bean (Ricinus communis L.) seedlings were solubilized in a detergent and added to a lipid bilayer. Conductivity measurements revealed that the glyoxysomal preparation contained a porin-like channel. Using an electrophysiological method, which we established for semiquantitative determination of porin activity, we were able to demonstrate that glyoxysomal membranes purified by sucrose density gradient centrifugation contain an integral membrane protein with porin activity. The porin of glyoxysomes was shown to have a relatively small single-channel conductance of about 330 picosiemens in 1 M KCl and to be strongly anion selective. Thus, the glyoxysomal porin differs from the other previously characterized porins in the outer membrane of mitochondria or plastids, but is similar to the porin of spinach (Spinacia oleracea L.) leaf peroxisomes. Our results suggest that, in analogy to the porin of leaf peroxisomes, the glyoxysomal porin facilitates the passage of small metabolites, such as succinate, citrate, malate, and aspartate, through the membrane.
Temporal Changes in State Transitions and Photosystem Organization in the Unicellular, Diazotrophic Cyanobacterium Cyanothece sp. ATCC 51142
Authors: Meunier P. C. , Colon-Lopez M. S. , Sherman L. A.
Published: October 2016

The unicellular Cyanobacterium Cyanothece sp. ATCC 51142, grown under alternating 12-h light/12-h dark conditions, temporally separated N2 fixation from photosynthesis. The regulation of photosynthesis was studied using fluorescence spectra and kinetics to determine changes in state transitions and photosystem organization. The redox poise of the plastoquinone (PQ) pool appeared to be central to this regulation. Respiration supported N2 fixation by oxidizing carbohydrate granules, but reduced the PQ pool. This induced state 2 photosystem II monomers and lowered the capacity for O2 evolution. State 2 favored photosystem I trimers and cyclic electron transport, which could stimulate N2 fixation; the stimulation suggested an ATP limitation to N2 and CO2 fixation. The exhaustion of carbohydrate granules at around 6 h in the dark resulted in reduced respiratory electron flow, which led to a more oxidized PQ pool and produced a sharp transition from state 2 to state 1. This transient state 1 returned to state 2 in the remaining hours of darkness. In the light phase, photosystem II dimerization correlated with increased phycobilisome coupling to photosystem II (state 1) and increased rates of O2 evolution. However, dark adaptation did not guarantee state 2 and left photosystem I centers in a mostly monomeric state at certain times.
Crystal and geometry-optimized structure, and Hirshfeld surface analysis of 1-(2-bromoethyl)indoline-2,3-dione
Authors: Sharmila N. , Sundar T. V. , Sathish G. , Venkatesan P.
Published: October 2016

In the title compound, C10H8BrNO2, the isatin (1H-indole-2,3-dione) moiety is nearly planar (r.m.s. deviation = 0.026 Å). In the crystal, molecules are linked by C—H...O hydrogen bonds, forming layers parallel to the ab plane, and enclosing R
4
4(24) loops. There are a low percentage (19.3%) of intermolecular H...H contacts in the structure, as estimated by the analysis of Hirshfeld surfaces. This could be due to the presence of the Br atom, present in the bromoethylene group, which makes ca 18.7% Br...H contacts.
3-Chloro-r-2,c-6-bis(4-fluorophenyl)-3-methylpiperidin-4-one
Authors: Arulraj R. , Sivakumar S. , Thiruvalluvar A. , Kaur Manpreet , Jasinski Jerry P.
Published: October 2016

The title compound, C18H16ClF2NO, contains one independent molecule in the asymmetric unit, with the piperidin-4-one ring adopting a slightly distorted chair conformation and an equatorial orientation of all the substituents except chlorine. A single weak intermolecular C—H...O interaction influences the crystal packing, forming infinite one-dimensional zigzag chains along the a axis. The structure was refined as a two-component inversion twin.
Fire prevents woody encroachment only at higher‐than‐historical frequencies in a South African savanna
Authors: Case Madelon F. , Staver A. Carla
Published: October 2016

Woody encroachment is a pervasive challenge facing savanna and grassland managers world‐wide. Proposed drivers of the phenomenon range from local changes in fire, herbivory and direct human impacts, to global changes in climate or atmospheric [CO2] that may be accelerating woody growth. The relative influences of local versus global drivers and their interactions are largely unknown, but will determine the extent to which management can limit woody encroachment locally.

We examined recent woody encroachment in Hluhluwe–iMfolozi Park in South Africa from 2007 to 2014. Vegetation transects were distributed across broad gradients in rainfall, herbivore use intensity and fire frequency, on a variety of soils.

Density of medium trees (2–4 m tall) increased dramatically (by 46%) in seven years, while densities of small and large trees remained constant. Increases in medium tree density were largest on sandy soils, where fires were infrequent and where grazing pressure increased.

Tree density increased even where recent fire frequency was similar to historical fire regimes. These potentially widespread increases, unexplained by changes in local disturbance history, suggest the possible influence of drivers outside the scope of local control.

Synthesis and applications. Fire can provide a limited buffer against generalized woody encroachment in savannas, but may only prevent further encroachment where managers can increase fire frequency. Grazing, which can limit fire frequency and intensity, may come increasingly into conflict with efforts to control woody encroachment, presenting a stark choice for savanna managers between maintenance of short‐term grazer population productivity and longer‐term prevention of woody encroachment.
Evidence‐based occupational therapy for people with dementia and their families: What clinical practice guidelines tell us and implications for practice
Authors: Laver Kate , Cumming Robert , Dyer Suzanne , Agar Meera , Anstey Kaarin J , Beattie Elizabeth , Brodaty Henry , Broe Tony , Clemson Lindy , Crotty Maria , Dietz Margaret , Draper Brian , Flicker Leon , Friel Meg , Heuzenroeder Louise , Koch Susan , Kurrle Sue , Nay Rhonda , Pond Dimity , Thompson Jane , Santalucia Yvonne , Whitehead Craig , Yates Mark
Published: October 2016

Background/aim

The first evidence‐based Clinical Practice Guidelines and Principles of Care for People with Dementia in Australia have been released. The Guidelines detail a number of important evidence‐based recommendations for occupational therapists. The aim of this paper is (1) to provide an overview of Guideline development, and (2) to describe the evidence supporting a recommendation for occupational therapy. Common characteristics of effective occupational therapy programmes for people with dementia are described.

Methods

Guideline development involved adaptation of existing high‐quality guidelines developed overseas and 17 systematic reviews to ensure that the most recent high‐quality evidence was included. One of the systematic reviews involved examining the evidence for interventions to promote independence in people with dementia. Specifically, we looked at the evidence for occupational therapy and its effect on activities of daily living, quality of life and carer impact.

Results

A total of 109 recommendations are included in the Guidelines. Occupational therapy was found to significantly increase independence in activities of daily living and improve quality of life. Effective occupational therapy programmes involve: environmental assessment, problem solving strategies, carer education and interactive carer skills training.

Conclusion

Occupational therapists working with people with dementia in community settings should ensure that their time is spent on those aspects of intervention that are shown to be effective.
Bacillus Spores in the Food Industry: A Review on Resistance and Response to Novel Inactivation Technologies
Authors: Soni Aswathi , Oey Indrawati , Silcock Pat , Bremer Phil
Published: October 2016

The importance and challenges presented by Bacillus spores in the food industry are briefly outlined with a focus on Bacillus cereus. The structure and the mechanism of resistance exhibited by Bacillus spores are described, and the steps involved in their germination are included. Novel technologies, using no or only mild heat treatments, to inactivate Bacillus spores are covered, including ultraviolet radiation, pulsed electric field, and high‐pressure processing, both as stand‐alone techniques or techniques as part of a hurdle approach.
Prehospital ketamine use by paramedics in the Australian Capital Territory: A 12 month retrospective analysis
Authors: Hollis Gregory J , Keene Toby M , Ardlie Rory M , Caldicott David GE , Stapleton Stuart G
Published: October 2016

Objective

The aim of this study was to describe prehospital use of ketamine by ACT Ambulance Service, and frequency of endotracheal intubation.

Methods

This was a retrospective study of patients receiving prehospital ketamine between 1 January and 31 December 2013. Episodes were identified from the prehospital electronic patient care records, then linkage to ED records at two receiving hospitals. Demographics, dose, indication and occasions of intubation were analysed.

Results

A total of 163 episodes were identified; 10 of these were excluded because of lack of identifying data or missing records (age 1–97 years [mean: 43, standard deviation: 21.7], 56% men). Median total dose was 60 mg (interquartile range 70; 5–400 mg) in three doses (interquartile range 3; 1–14 mg). For patients with a weight recorded (63%), median dose was 0.73 mg/kg. Indications were analgesia 68%, agitation/combative 25%, rapid sequence intubation 5% and others 2%. A total of 26 patients were endotracheally intubated, 11 prehospital (seven as an intended rapid sequence intubation and four combative patients with return of spontaneous circulation) and 15 in the ED. Of ED intubations, 10 were trauma patients and five were drug ingestion related. Patients receiving ketamine for combativeness were more likely to be intubated than those receiving it for analgesia (25 vs 7.2%; odds ratio: 3.46; 95% confidence interval: 1.12, 10.71). In those with a weight recorded, the mg/kg dose was not associated with subsequent intubation.

Conclusions

Median dose for analgesia was comparable with other studies; dose for sedation was less than reported elsewhere. Intubation rate for patients receiving prehospital ketamine was 17%. Further study is recommended to assess the ED course of the non‐intubated group of patients, and consideration should be given to non‐weight‐based methods of dose selection.
Urinary collecting system invasion is associated with poor survival in patients with clear‐cell renal cell carcinoma
Authors: Bailey George C. , Boorjian Stephen A. , Ziegelmann Matthew J. , Westerman Mary E. , Lohse Christine M. , Leibovich Bradley C. , Cheville John C. , Thompson R. Houston
Published: October 2016

Objectives

To evaluate the prognostic significance of urinary collecting system invasion (UCSI) in a large series of patients with clear‐cell renal cell carcinoma (RCC).

Materials and Methods

Patients with clear‐cell RCC treated with nephrectomy between 2001 and 2010 were reviewed from a prospectively maintained registry. One urological pathologist re‐reviewed all slides. Cancer‐specific survival was estimated using the Kaplan–Meier method, and associations of UCSI with death from RCC were evaluated using Cox models.

Results

Of the 859 patients with clear‐cell RCC, 58 (6.8%) had UCSI. At last follow‐up, 310 patients had died from RCC at a median of 1.8 years after surgery. The median follow‐up for patients alive at last follow‐up was 8.2 years. The estimated cancer‐specific survival at 10 years after surgery for patients with UCSI was 17%, compared with 60% for patients without UCSI (P < 0.001). In a multivariable model, UCSI remained independently associated with an increased risk of death from RCC (hazard ratio 1.5; P = 0.018). Further, among patients with pT3 RCC, those with USCI had survival outcomes similar to those of patients with pT4 RCC.

Conclusions

Collecting system invasion is associated with poor prognosis among patients with clear‐cell RCC. If validated, consideration should be given to including UCSI in future staging systems.
Virtue male sling for post‐prostatectomy stress incontinence: a prospective evaluation and mid‐term outcomes
Authors: Ferro Matteo , Bottero Danilo , D'Elia Carolina , Matei Deliu Victor , Cioffi Antonio , Cozzi Gabriele , Serino Alessandro , Cordima Giovanni , Bianchi Roberto , Incarbone Piero Giacomo , Brescia Antonio , Musi Gennaro , Fusco Ferdinando , Detti Serena , Mirone Vincenzo , de Cobelli Ottavio
Published: October 2016

Objective

To evaluate the efficacy and safety of the Virtue® male sling (Coloplast, Humlebaek, Denmark) in a cohort of patients affected by post‐prostatectomy stress urinary incontinence (SUI).

Methods

All 29 consecutive patients treated with a Virtue male sling at our Institution between July 2012 and October 2013 were included in the present prospective, non‐randomized study. Patients were evaluated preoperatively and at 1, 3, 6, 12, 24 and 36 months after surgery using a 24‐h pad weight test, the International Consultation on Incontinence short‐form questionnaire (ICIQ‐SF), Urinary Symptom Profile (USP) questionnaire, a bladder diary, uroflowmetry and the Patient Global Impression of Improvement (PGI‐I) and Patient Global Impression of Severity questionnaires.

Results

The mean patient age was 65.5 years. A total of 72.4% of patients had preoperative mild incontinence (1–2 pads/day), while nine patients used 3–5 pads/day. There were a total of 17 complications, which occurred in 29 patients (58.6%); all were Clavien–Dindo grade I. At 12‐month follow‐up patients showed a significant improvement in 24‐h pad test (128.6 vs 2.5 g), number of pads per day (2 vs 0), ICIQ‐SF score (14.3 vs 0.9) and USP score for SUI (4 vs 0), and outcomes remained stable at 36 months. At last follow‐up, the median score on the PGI‐I questionnaire was 1 (very much better).

Conclusion

The Virtue male sling is an effective treatment option for low to moderate post‐prostatectomy incontinence.
Stay or Go? Ecuadorian Immigrants in Spain in Times of Crisis
Authors: IGLESIAS MARTÍNEZ JUAN
Published: October 2016

This article studies how the economic crisis affects Ecuadorian immigrants' decisions on staying in Spain or returning to their home country. Before the crisis, Ecuadorians were one of the most significant migrant groups in Spain in terms of volume and degree of settlement. The crisis has destabilised their situation and modified their migratory projects in different ways. This article presents the three main choices facing Ecuadorian immigrants during the crisis: permanence, wait and see, and return/re‐migration. The analysis focuses on how the decision‐making process is carried out and on the different factors that lead Ecuadorians to choose each option.
MiR‐133b inhibits growth of human gastric cancer cells by silencing pyruvate kinase muscle‐splicer polypyrimidine tract‐binding protein 1
Authors: Sugiyama Taro , Taniguchi Kohei , Matsuhashi Nobuhisa , Tajirika Toshihiro , Futamura Manabu , Takai Tomoaki , Akao Yukihiro , Yoshida Kazuhiro
Published: October 2016

The metabolism in tumor cells shifts from oxidative phosphorylation to glycolysis even in an aerobic environment. This phenomenon is known as the Warburg effect. This effect is regulated mainly by polypyrimidine tract‐binding protein 1 (PTBP1), which is a splicer of the mRNA for the rate‐limiting enzymes of glycolysis, pyruvate kinase muscle 1 and 2 (PKM1 and PKM2). In the present study, we demonstrated that miR‐133b reduced PTBP1 expression at translational level and that the expression levels of miR‐133b were significantly downregulated in gastric cancer clinical samples and human cell lines, whereas the protein expression level of PTBP1 was upregulated in 80% of the 20 clinical samples of gastric cancer examined. Ectopic expression of miR‐133b and knockdown of PTBP1 in gastric cancer cells inhibited cell proliferation through the induction of autophagy by the switching of PKM isoform expression from PKM2‐dominant to PKM1‐dominant. The growth inhibition was partially canceled by an autophagy inhibitor 3‐MA or a reactive oxygen species scavenger N‐acetylcysteine. These findings indicated that miR‐133b acted as a tumor‐suppressor through negative regulation of the Warburg effect in gastric cancer cells.
Effect of AKT3 expression on MYC‐ and caspase‐8‐dependent apoptosis caused by polo‐like kinase inhibitors in HCT 116 cells
Authors: Nonomiya Yuma , Noguchi Kohji , Tanaka Noritaka , Kasagaki Takahiro , Katayama Kazuhiro , Sugimoto Yoshikazu
Published: October 2016

Polo‐like kinase (PLK) is a cell‐cycle regulator that is overexpressed in several cancer cell types. Polo‐like kinase is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536‐resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We showed that PLKi‐induced caspase‐8 activation was attenuated in the BI 2536‐resistant cell lines. We also showed that the expression of P‐glycoprotein (P‐GP) and AKT3 was upregulated, whereas that of MYC was downregulated in some BI 2536‐resistant cell lines. Expression of P‐GP conferred resistance to PLKis, and PLKi‐induced apoptosis was dependent on MYC and caspase‐8 in HCT 116 cells. We also showed for the first time that AKT3 suppressed BI 6727‐induced caspase‐8 activation and conferred resistance to PLKis. Collectively, these results indicate that MYC, caspase‐8, P‐GP, and AKT3 play critical roles in PLKi‐induced apoptosis. Therefore, they are candidate biomarkers of the pharmacological efficacy of PLKis.
Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells
Authors: Hirashita Yuka , Tsukamoto Yoshiyuki , Yanagihara Kazuyoshi , Fumoto Shoichi , Hijiya Naoki , Nakada Chisato , Uchida Tomohisa , Matsuura Keiko , Kodama Masaaki , Okimoto Tadayoshi , Daa Tsutomu , Seike Masataka , Iha Hidekatsu , Shirao Kuniaki , Murakami Kazunari , Moriyama Masatsugu
Published: October 2016

Gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, therefore, targeting of the RTK/KRAS downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. We assembled a panel of 48 GC cell lines and screened predictors of responsiveness to inhibition of the RAF/MEK/ERK pathway, one of the RTK/KRAS downstream pathways. We found that GC cells with MET amplification or KRAS mutation, but not amplification, tended to be sensitive to MEK inhibition. However, several cell lines without RTK/KRAS alterations also showed high sensitivity to MEK inhibition. We then focused on the phosphorylation of RTK/KRAS downstream molecules to screen for predictors’ sensitivity to MEK inhibition. We found that the phosphorylation level of mammalian target of rapamycin complex 1 (mTORC1) downstream molecules, including p70S6K, 4EBP1, and S6, was significantly associated with sensitivity to MEK inhibition in GC cells (P < 0.05), suggesting that mTORC1 activity is related to the sensitivity to MEK inhibition. Furthermore, the change in mTORC1 activity after MEK inhibition was also significantly associated with this sensitivity (P < 0.001). Among the mTORC1 downstream molecules, the change in S6 phosphorylation (pS6) showed the most significant correlation with sensitivity. Using xenograft models derived from highly sensitive and resistant cell lines, we found specific reduction of pS6 in xenografts from highly sensitive cell lines after 6 h of treatment with an MEK inhibitor. Thus, our data suggest the potential clinical applicability of an MEK inhibitor for a proportion of GC patients who could be selected on the basis of pS6 change after MEK inhibition.
Novel 3‐D cell culture system for in vitro evaluation of anticancer drugs under anchorage‐independent conditions
Authors: Aihara Ayako , Abe Natsuki , Saruhashi Koichiro , Kanaki Tatsuro , Nishino Taito
Published: October 2016

Anticancer drug discovery efforts have used 2‐D cell‐based assay models, which fail to forecast in vivo efficacy and result in a lower success rate of clinical approval. Recent 3‐D cell culture models are expected to bridge the gap between 2‐D and in vivo models. However, 3‐D cell culture methods that are available for practical anticancer drug screening have not yet been fully attained. In this study, we screened several polymers for their ability to suspend cells or cell spheroids homogeneously in a liquid medium without changing the viscosity behavior, and identified gellan gum (FP001), as the most potent polymer. FP001 promoted cell dispersion in the medium and improved the proliferation of a wide range of cancer cell lines under low attachment conditions by inhibiting the formation of large‐sized spheroids. In addition, cancer cells cultured with FP001‐containing medium were more susceptible to inhibitors of epidermal growth factor (EGF) signaling than those cultured under attachment conditions. We also showed that ligands of the EGF receptor family clearly enhance proliferation of SKOV3 ovarian carcinoma cells under anchorage‐independent conditions with FP001. Consistent with this result, the cells grown with FP001 showed higher EGF receptor content compared with cells cultured under attachment conditions. In conclusion, we developed a novel 3‐D cell culture system that is available for high throughput screening of anticancer agents, and is suitable for evaluation of molecular‐targeted anticancer drugs. Three‐dimensional cell culture using FP001 will be of value in the development of useful technologies for anticancer drug discovery.
Synthesis and preliminary evaluation of a 18F‐labeled ethisterone derivative [18F]EAEF for progesterone receptor targeting
Authors: Wu Xiaowei , You Linyi , Zhang Deliang , Gao Mengna , Li Zijing , Xu Duo , Zhang Pu , Huang Lumei , Zhuang Rongqiang , Wu Hua , Zhang Xianzhong
Published: October 2016

To develop a novel progesterone receptor‐targeting probe for positron emission tomography imaging, an ethisterone derivative [18F]EAEF was designed and prepared in high decay‐corrected radiochemical yield (30–35%) with good radiochemical purity (>98%). [18F]EAEF is a lipophilic tracer (logP = 0.53 ± 0.06) with very good stability in saline and serum. In the biodistribution study, high radioactivity accumulation of [18F]EAEF were found in uterus (5.73 ± 1.83% ID/g) and ovary (4.05 ± 0.73% ID/g) at 2 hr postinjection (p.i.), which have high progesterone receptor expression after treated with estradiol, while the muscle background has very low uptake (0.50 ± 0.17% ID/g). For positron emission tomography imaging, [18F]EAEF showed high uptake in progesterone receptor‐positive MCF‐7 tumor (3.15 ± 0.07% ID/g at 2 hr p.i.) with good tumor to muscle ratio (2.90), and obvious lower tumor uptakes were observed in MCF‐7 with EAEF blocking (1.84 ± 0.05% ID/g at 2 hr p.i.) or in progesterone receptor‐negative MDA‐MB‐231 tumor (1.80 ± 0.03% ID/g at 2 hr p.i.). Based on the good stability and specificity of [18F]EAEF, it may be a good candidate for imaging progesterone receptor and worth further investigation.
Is there an optimal preoperative management strategy for phaeochromocytoma/paraganglioma?
Authors: Challis B.G. , Casey R.T. , Simpson H.L. , Gurnell M.
Published: October 2016

Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine secreting neuroendocrine tumours that predispose to haemodynamic instability. Currently, surgery is the only available curative treatment, but carries potential risks including hypertensive and hypotensive crises, cardiac arrhythmias, myocardial infarction and stroke, due to tumoral release of catecholamines during anaesthetic induction and tumour manipulation. The mortality associated with surgical resection of PPGL has significantly improved from 20–45% in the early 20th century (Apgar & Papper, AMA Archives of Surgery, 1951, 62, 634) to 0–2·9% in the early 21st century (Kinney et al. Journal of Cardiothoracic and Vascular Anesthesia, 2002, 16, 359), largely due to availability of effective pharmacological agents and advances in surgical and anaesthetic practice. However, surgical resection of PPGL still poses significant clinical management challenges. Preoperatively, alpha‐adrenoceptor blockade is the mainstay of management, although various pharmacological strategies have been proposed, based largely on reports derived from retrospective data sets. To date, no consensus has been reached regarding the ‘ideal’ preoperative strategy due, in part, to a paucity of data from high‐quality evidence‐based studies comparing different treatment regimens. Here, based on the available literature, we address the Clinical Question: Is there an optimal preoperative management strategy for PPGL?
A Say‐Barber‐Biesecker‐Young‐Simpson variant of Ohdo syndrome with a KAT6B 10‐base pair palindromic duplication: A recurrent mutation causing a severe phenotype mixed with genitopatellar syndrome
Authors: Niida Yo , Mitani Yusuke , Kuroda Mondo , Yokoi Ayano , Nakagawa Hiroyasu , Kato Akiko
Published: October 2016

The Say‐Barber‐Biesecker‐Young‐Simpson variant of Ohdo syndrome (SBBYSS) (MIM# 603736) and genitopatellar syndrome (GPS) (MIM#606170) are allelic diseases caused by KAT6B mutation. Genotype–phenotype correlation is assumed, but a few patients manifest overlapping features of both syndromes. Here we report the case of a boy with SBBYSS. He had a KAT6B mutation previously reported in typical SBBYSS, but he also manifested severe developmental delay, as well as genital features and laryngomalacia requiring tracheostomy that conformed to GPS.
The effect of implant macro‐thread design on implant stability in the early post‐operative period: a randomized, controlled pilot study
Authors: McCullough Jeffrey J. , Klokkevold Perry R.
Published: October 2016

Introduction

Available literature suggests there is a transient drop in implant stability from approximately week 0 to week 3–4 as a result of peri‐implant bone remodeling as it transitions from a primary, mechanical stability to a secondary, biological stability. Research investigating the influence of macro‐thread design on this process is scant.

Aim

The specific aim of this study was to evaluate the role of macro‐thread design on implant stability in the early post‐operative healing period using resonance frequency analysis (RFA).

Material and methods

Seven patients, each missing at least two posterior teeth in the same arch, were included in the study. Three patients qualified for four implants resulting in a total of 10 matched pairs. All sites were healed (>6 months), non‐grafted sites with sufficient bone to place implants. Each site in a matched pair was randomly assigned to receive either a control (Megagen EZ Plus Internal; EZ) or test (Megagen AnyRidge; AR) implant. The test implant incorporates a novel thread design with a wide thread depth and increased thread pitch. RFA was used to determine implant stability quotient (ISQ) values for each implant at the time of placement and weekly for the first 8 weeks.

Results

Implants consistently achieved a relatively high insertion torque (30–45 N/cm) and high initial ISQ value (79.8 ± 1.49). Baseline ISQ values for test (AR; 79.55 ± 1.61) and control (EZ; 80.05 ± 1.37) implants were similar. A general pattern of stability from baseline through all eight follow‐up evaluations was observed for the test implants. A pattern of decreasing ISQ values was observed for the control implants across the early follow‐up evaluations up to week four, where the value plateaued. There was a statistically significant main effect due to implant type (P < 0.01) and a statistically significant interaction between implant type and time (P < 0.01), indicating that the test and control implants performed differently at certain time points.

Conclusions

Within the limitations of this study, macro‐thread design appears to play a role in implant stability in the early post‐operative healing period as assessed by RFA. These findings may have important implications related to immediate or early loading protocols.