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The trion represents a localized group of neurons with three levels of firing activity. Networks of a small number of trions (with structured interactions and firing dependent on activity at two previous discrete time steps) support a repertoire of hundreds of quasistable, periodic firing patterns (which can be learned). We report striking phenomena with variation in temperature T: There exist a series of phase transitions at precise values T(n), giving new repertoires of periodic firing patterns, and the average time for any initial firing configuration to project onto a firing pattern shows a quite sharp change at each T(n). Near a phase transition, in a Monte Carlo simulation, the temporal evolution wanders back and forth between sets of these firing patterns in contrast to the more structured sequential evolutions far from a T(n). © 1991 The American Physical Society.

We developed a cooperative model of the cortical column incorporating an idealized subunit, the trion (which represents a localized group of neurons), and a discrete time step for firing. We found that networks composed of a small number of trions (with symmetric interactions) supported up to thousands of quasi-stable, periodic firing patterns (MPs) which could be selected out with only small changes in interaction strengths using a Hebb-type algorithm. Here we report a study of the associative recall properties showing striking features: By considering all possible initial firing patterns (for a given set of network connections), we find 1) It takes on the average only 2-5 time steps to recall an MP. 2) Many of the MPs can be individually accessed by thousands of different initial patterns. The variety of examples presented illustrate the rich, general nature of the model.

There have been a considerable number of papers proposing composite models for leptons and quarks. Recently, Glück and Lipkin have stated that reproducing the observed magnetic moments of these fermions presents a serious difficulty for these composite models. We show for a renormalizable theory that, in contrast to Glück's and Lipkin's nonrelativistic arguments, a deeply bound system (with heavy constituent particle masses mc) of (total) spin 1/2, charge e and mass m has the magnetic moment (e/2m) [1 + “usual” (QED + QCD + weak) corrections +O (m/mc) “new” bindng corrections]. Although there remains the considerable dynamical problem of obtaining “light” bound fermions from heavy constituents, there is no separate, additional magnetic moment difficulty. © 1980, All rights reserved.

Motivated by V. B. Mountcastle's organizational principle for neocortical function, and by M. E. Fisher's model of physical spin systems, we introduce a cooperative model of the cortical column incorporating an idealized substructure, the trion, which represents a localized group of neurons. Computer studies reveal that typical networks composed of a small number of trions (with symmetric interactions) exhibit striking behavior--e.g., hundreds to thousands of quasistable, periodic firing patterns, any of which can be selected out and enhanced with only small changes in interaction strengths by using a Hebb-type algorithm.

We formulate a model in which a light pointlike composite fermion is obtained dynamically from two heavy relativistic constituents bound by strong, short-range forces with the bound-state mass as low as one-tenth the sum of the constituent masses, while still obtaining the correct Dirac moment for this bound state (a factor of 5 greater than that of the constituents). Other static properties and details of the spectrum are investigated. © 1981 The American Physical Society.

In sidewise dispersion calculations of the anomalous magnetic moments of the nucleon, the intermediate πN strong states involved are the S11 and P11, both of which are highly inelastic at low energies. These inelastic effects have not previously been included in a systematic manner consistent with unitarity in order to ensure a real absorptive part. We present a multichannel ND-1 formalism for the strong scattering and photoproduction which gives a unitary result for the anomalous moments. The strong form factor is given simply in terms of D-1. Explicit calculations demonstrate that contributions to the dispersion integrals far beyond W∼1500 MeV will be necessary in determining μ. © 1974 The American Physical Society.

Recent experiments at SPEAR indicate an unexpectedly large number of 1 - states in the energy range 3.9-4.4 GeV. We show how the existence of exotic cq̄c̄q mesons can account for these states as well as the rise in R and the missing ψ(3.7) decays. The width of these states does not require that they lie above the, as yet unobserved, DD̄ threshold. Predictions of the model are readily testable. © 1976 The American Physical Society.

High energy γ's observed from Cygnus X-3 have been explained by assuming that protons emitted by a pulsar are accelerated to 1017 eV in its polar field and then collide with the atmosphere of its companion star. Recognizing that ν's are produced by this mechanism the IMB and other experimental groups are currently searching for them. It is shown how the hypothesis of the pulsar being strange matter might be tested by observation of the ν flux. Metastable strange droplets stripped from the pulsar (and accelerated) by electrodynamic fields yield ν's, by decay and by collisions with the companion's atmosphere, with qualitatively different details than those produced by the proton collisions. Further, searching is suggested for ν's produced by this decay mechanism from nearby pulsars with no companion in future, large detectors. The decays may be rapid enough to see the pulsar frequency in the neutrino signal. © 1986.

One of the best tests for compositeness of leptons or quarks is the presence of an anomalous magnetic moment F2. We determine limits on F2 for the, from e+e-+- at PETRA, of F2

The left-hand discontinuities in the partial-wave amplitudes for - scattering are assumed to be dominated by the exchange of the meson in a form suggested by the Regge representation for a resonance. This Regge behavior provides the necessary high-energy cutoff and allows the ND equations to be solved. The partial-wave I=1 amplitudes are calculated for noninteger angular momenta l

The determination of the S-wave ππ phase shifts δ0I at low energy from the analysis of πN→(2π)N is examined critically from the standpoint of the one-pion-exchange model with absorptive corrections. It is found that: (1) The value of δ0I depends strongly on the P-wave phase shifts, which cannot be unambiguously determined, at mππ

The results obtained by Coulter and Shaw in describing dynamical effects in two overlapping resonances are generalized by showing that they are contained in the Wigner-Weisskopf treatment of decaying states. © 1970 The American Physical Society.

Absorptive corrections applied to the peripheral model have provided a relatively successful interpretation of a variety of high-energy production processes. There exist, however, a number of difficulties associated with these calculations. We consider the reaction πN→ρN, which is dominated by π exchange, in order to study the following three ambiguities: (i) the actual dependence of the absorptive corrections on the initial- and final-state elastic-scattering phase shifts, (ii) the role of a form factor, and (iii) the numerical values of the final-state elastic-scattering phase shifts. The comparison of our calculation with the experimental data, in particular the density matrix of the ρ, leads to the following results. The j=12 partial waves must be totally suppressed by the absorptive corrections and the form factor must play a very minor role in order to fit the observed deviation of the ρ's density matrix from that predicted by the exchange of a π in the peripheral model. (A form factor cuts down the low partial waves in a manner which leaves the density matrix unmodified from the simple peripheral model and thus reduces the effect of absorption corrections on the density matrix.) We expect any form factor associated with π exchange to have a weak t dependence, since there exists no resonance with the appropriate quantum numbers (to couple to the π) with energy 1.3 BeV. It is plausible that form factors (in addition to the absorptive corrections), while unimportant for π exchange, may play a significant role in vector exchange (since there seems to be an abundance of high-spin resonances). © 1965 The American Physical Society.

A fit to recent extensive data for the reaction π-+p→π++π-+n at incident π- momentum ∼4 BeVc and final two-pion center-of-mass energy mππ∼mρ was made. The peripheral model with absorption was used in the fit. The asymmetry in the final two-pion distribution θπ gives a quantitative determination of the π-π, S-wave, I=0 scattering amplitude. A constant phase shift of ∼+60°gives as good a fit the to data as a resonance ε0 (at 730 MeV with a width of 90 MeV), proposed by Durand and Chiu. A negative phase shift of ∼-60°is ruled out by examining the distribution in θπ as a function of mππ. © 1967 The American Physical Society.

Two important problems involved in obtaining solutions of partial wave dispersion relations (by the N D method) are having (i) the correct threshold behavior, and (ii) an acceptable high energy behavior. Various physical and numerical approximations have been made to insure (i) and (ii). We numerically investigate the sensitivity of the solutions of the N D equations to these approximations. For this purpose, we consider J = 1 π-π scattering, employing elastic unitarity and assuming that the left hand cut is dominated by the exchange of the ρ{variant} resonance. Two significant features we find are: (a) The values of the cutoffs needed to product a resonance are quite sensitive to the input "strength" of the left hand cut, e.g., a change of the input width of the ρ{variant} by a factor of two changed the value for a "straight cutoff" to produce a resonance at a given energy by a factor of ten. Due to the results of (a) we wish to emphasize the possible danger in employing a single cutoff in the calculations of SU3 multiplets. (b) If one introduces a pole on the left hand cut in order to insure the threshold behavior (i), then the ranges in values for the cutoffs (to insure (ii)) for which any resonance occurs are extremely narrow. On the other hand, a solution in which the phase shift does not become large is insensitive to the position of this pole. © 1965.

STUDY DESIGN: Single-blinded, randomized, posttest only design. OBJECTIVE: To help contribute to the body of evidence in defining the validity of functional capacity evaluations. BACKGROUND: Functional capacity evaluations (FCEs) are tests used to help determine an individual's readiness to return to work. Most FCEs incorporate indicators of effort within the evaluation. Published evidence validating the use of these indicators is limited. METHODS AND MEASURES: Forty-nine injured and noninjured individuals 18 to 65 years of age participated in this study. The participants were randomly assigned to 1 of 2 groups: 100% effort or 50% effort. Raters were blinded to participant group. The Blankenship Version 6.0 software was used to analyze the data and a Blankenship FCE validity profile was scored. A score of 70% or greater was deemed a valid FCE as adopted by the Blankenship protocol. RESULTS: The sensitivity of the FCE components tested was demonstrated to be 80% and specificity was 84.2%. The positive likelihood ratio was 5 and the negative likelihood ratio was 0.2. A receiver operating characteristic (ROC) curve demonstrated the 70% cut-off value for scoring the FCE was optimal. CONCLUSION: Four components of the Blankenship FCE system demonstrated good sensitivity and specificity for detecting submaximal effort. However, clinicians should note that false positives (maximum effort identified as submaximal effort) may occur and scores of 'equivocal' are not scored in the 'criteria passed' category. The rater should be aware that this method of scoring could potentially influence a client's overall FCE score. [ABSTRACT FROM AUTHOR]

A recent study (Johnson et al., 1998) reported an improvement on a visual-spatial task after listening to an excerpt of a Mozart sonata in one subject with Alzheimer's disease (AD). The aim of the present study was to replicate this finding in a larger group. Seventeen mildly demented subjects diagnosed with AD were asked to solve a visual-spatial task before and after a control (i.e., 10 minutes of silence) and experimental (i.e., 10 minutes of a Mozart piano sonata) condition on different days. When comparing the change in scores from baseline after each condition, subjects showed a significant improvement in scores on the visual-spatial task after the music listening (p = 0.02) but not the silence (p = 0.51) condition. This finding provides further support that a short-term improvement on a visual-spatial task can be observed in subjects with AD and may reflect underlying behavioral plasticity. [ABSTRACT FROM AUTHOR]

Abstract Cyanobacteria can produce groups of structurally and functionally unrelated but highly potent toxins. Cyanotoxins are used in multiple research endeavours, either for direct investigation of their toxicologic properties, or as functional analogues for various biochemical and physiological processes. This paper presents occupational safety guidelines and recommendations for personnel working in field, laboratory or industrial settings to produce and use purified cyanotoxins and toxic cyanobacteria, from bulk harvesting of bloom material, mass culture of laboratory isolates, through routine extraction, isolation and purification. Oral, inhalational, dermal and parenteral routes are all potential occupational exposure pathways during the various stages of cyanotoxin production and application. Investigation of toxicologic or pharmacologic properties using in vivo models may present specific risks if radiolabelled cyanotoxins are employed, and the potential for occupational exposure via the dermal route is heightened with the use of organic solvents as vehicles. Inter- and intra-national transport of living cyanobacteria for research purposes risks establishing feral microalgal populations, so disinfection of culture equipment and destruction of cells by autoclaving, incineration and/or chlorination is recommended in order to prevent viable cyanobacteria from escaping research or production facilities.

Abstract Background Case studies and anecdotal reports have documented a range of acute illnesses associated with exposure to cyanobacteria and their toxins in recreational waters. The epidemiological data to date are limited; we sought to improve on the design of some previously conducted studies in order to facilitate revision and refinement of guidelines for exposure to cyanobacteria in recreational waters. Methods A prospective cohort study was conducted to investigate the incidence of acute symptoms in individuals exposed, through recreational activities, to low (cell surface area 2/mL), medium (2.4–12.0 mm2/mL) and high (>12.0 mm2/mL) levels of cyanobacteria in lakes and rivers in southeast Queensland, the central coast area of New South Wales, and northeast and central Florida. Multivariable logistic regression analyses were employed; models adjusted for region, age, smoking, prior history of asthma, hay fever or skin disease (eczema or dermatitis) and clustering by household. Results Of individuals approached, 3,595 met the eligibility criteria, 3,193 (89%) agreed to participate and 1,331 (37%) completed both the questionnaire and follow-up interview. Respiratory symptoms were 2.1 (95%CI: 1.1–4.0) times more likely to be reported by subjects exposed to high levels of cyanobacteria than by those exposed to low levels. Similarly, when grouping all reported symptoms, individuals exposed to high levels of cyanobacteria were 1.7 (95%CI: 1.0–2.8) times more likely to report symptoms than their low-level cyanobacteria-exposed counterparts. Conclusion A significant increase in reporting of minor self-limiting symptoms, particularly respiratory symptoms, was associated with exposure to higher levels of cyanobacteria of mixed genera. We suggest that exposure to cyanobacteria based on total cell surface area above 12 mm2/mL could result in increased incidence of symptoms. The potential for severe, life-threatening cyanobacteria-related illness is likely to be greater in recreational waters that have significant levels of cyanobacterial toxins, so future epidemiological investigations should be directed towards recreational exposure to cyanotoxins.

Abstract Cyanobacteria are common inhabitants of freshwater lakes and reservoirs throughout the world. Under favourable conditions, certain cyanobacteria can dominate the phytoplankton within a waterbody and form nuisance blooms. Case reports and anecdotal references dating from 1949 describe a range of illnesses associated with recreational exposure to cyanobacteria: hay fever-like symptoms, pruritic skin rashes and gastro-intestinal symptoms are most frequently reported. Some papers give convincing descriptions of allergic reactions while others describe more serious acute illnesses, with symptoms such as severe headache, pneumonia, fever, myalgia, vertigo and blistering in the mouth. A coroner in the United States found that a teenage boy died as a result of accidentally ingesting a neurotoxic cyanotoxin from a golf course pond. This death is the first recorded human fatality attributed to recreational exposure to cyanobacteria, although uncertainties surround the forensic identification of the suspected cyanotoxin in this case. We systematically reviewed the literature on recreational exposure to freshwater cyanobacteria. Epidemiological data are limited, with six studies conducted since 1990. Statistically significant increases in symptoms were reported in individuals exposed to cyanobacteria compared to unexposed counterparts in two Australian cohort studies, though minor morbidity appeared to be the main finding. The four other small studies (three from the UK, one Australian) did not report any significant association. However, the potential for serious injury or death remains, as freshwater cyanobacteria under bloom conditions are capable of producing potent toxins that cause specific and severe dysfunction to hepatic or central nervous systems. The exposure route for these toxins is oral, from ingestion of recreational water, and possibly by inhalation. A range of freshwater microbial agents may cause acute conditions that present with features that resemble illnesses attributed to contact with cyanobacteria and, conversely, acute illness resulting from exposure to cyanobacteria or cyanotoxins in recreational waters could be misdiagnosed. Accurately assessing exposure to cyanobacteria in recreational waters is difficult and unreliable at present, as specific biomarkers are unavailable. However, diagnosis of cyanobacteria-related illness should be considered for individuals presenting with acute illness following freshwater contact if a description is given of a waterbody visibly affected by planktonic mass development.

Abstract Cyanobacterial lipopolysaccharide/s (LPS) are frequently cited in the cyanobacteria literature as toxins responsible for a variety of heath effects in humans, from skin rashes to gastrointestinal, respiratory and allergic reactions. The attribution of toxic properties to cyanobacterial LPS dates from the 1970s, when it was thought that lipid A, the toxic moiety of LPS, was structurally and functionally conserved across all Gram-negative bacteria. However, more recent research has shown that this is not the case, and lipid A structures are now known to be very different, expressing properties ranging from LPS agonists, through weak endotoxicity to LPS antagonists. Although cyanobacterial LPS is widely cited as a putative toxin, most of the small number of formal research reports describe cyanobacterial LPS as weakly toxic compared to LPS from the Enterobacteriaceae. We systematically reviewed the literature on cyanobacterial LPS, and also examined the much lager body of literature relating to heterotrophic bacterial LPS and the atypical lipid A structures of some photosynthetic bacteria. While the literature on the biological activity of heterotrophic bacterial LPS is overwhelmingly large and therefore difficult to review for the purposes of exclusion, we were unable to find a convincing body of evidence to suggest that heterotrophic bacterial LPS, in the absence of other virulence factors, is responsible for acute gastrointestinal, dermatological or allergic reactions via natural exposure routes in humans. There is a danger that initial speculation about cyanobacterial LPS may evolve into orthodoxy without basis in research findings. No cyanobacterial lipid A structures have been described and published to date, so a recommendation is made that cyanobacteriologists should not continue to attribute such a diverse range of clinical symptoms to cyanobacterial LPS without research confirmation.

Objectives: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing., Patients and Methods: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length., Results: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms., Conclusion: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers., Competing Interests: Jack Cuzick receives royalties from and is on the advisory board of Myriad Genetics., (© 2022 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Objective: The purpose of this study was to determine if university students understood the differences between first responders and emergency management as awareness of the differences informs the individual's decision-making processes., Design: Convenience sampling, mixed methods data collection with descriptive analysis and means testing., Setting: US, Southeastern Conference University, during summer semester., Participants: 500 convenience sampled student volunteers., Intervention: Convenience sampled, mixed-mode survey administered May to July 2017., Main Outcome Measures: Population sampling of a minimum of n = 372 (actual n = 500 obtained) surveys to achieve a 95 percent confidence level of p ≤ 0.05 ± 4.29 percent., Results: 19.6 percent of the participants were able to associate response and recovery with emergency management. Word association with "Emergency Management" as the trigger word produced a 35.8 percent association with disasters and emergencies. 70.4 percent of the participants attended a university sponsored emergency preparedness course, but only 44.2 percent indicated they had received emergency preparedness training., Conclusions: There was a derivation of three issues: A lack of understanding in the differences between first responders and emergency management, a non-association of emergencies and disasters with emergency management, and a lack of understanding in what emergency preparedness training is. Results point to a need for further education on the duties and responsibilities of the emergency management profession. A form of information transfer that may be productive would be to administer an awareness campaign via social marketing. Further study is indicated, using a more rigorous sampling and analysis methodology.

The VERDICT framework for modelling diffusion MRI data aims to relate parameters from a biophysical model to histological features used for tumour grading in prostate cancer. Validation of the VERDICT model is necessary for clinical use. This study compared VERDICT parameters obtained ex vivo with histology in five specimens from radical prostatectomy. A patient-specific 3D-printed mould was used to investigate the effects of fixation on VERDICT parameters and to aid registration to histology. A rich diffusion data set was acquired in each ex vivo prostate before and after fixation. At both time points, data were best described by a two-compartment model: the model assumes that an anisotropic tensor compartment represents the extracellular space and a restricted sphere compartment models the intracellular space. The effect of fixation on model parameters associated with tissue microstructure was small. The patient-specific mould minimized tissue deformations and co-localized slices, so that rigid registration of MRI to histology images allowed region-based comparison with histology. The VERDICT estimate of the intracellular volume fraction corresponded to histological indicators of cellular fraction, including high values in tumour regions. The average sphere radius from VERDICT, representing the average cell size, was relatively uniform across samples. The primary diffusion direction from the extracellular compartment of the VERDICT model aligned with collagen fibre patterns in the stroma obtained by structure tensor analysis. This confirmed the biophysical relationship between ex vivo VERDICT parameters and tissue microstructure from histology., (© 2019 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

Background: Active surveillance is recommended for insignificant prostate cancer (PCa). Tools exist to identify suitable candidates using clinical variables. We aimed to develop and validate a novel risk score (NRS) predicting which patients are harbouring insignificant PCa., Methods: We used prospectively collected data from 8040 consecutive unscreened patients who underwent radical prostatectomy between 2006 and 2016. Of these, data from 2799 patients with Gleason 3 + 3 on biopsy were used to develop a multivariate model predicting the presence of insignificant PC at radical prostatectomy (ERSPC updated definition 3 : Gleason 3 + 3 only, index tumour volume < 1.3 cm 3 and total tumour volume < 2.5 cm 3 ). This was used to develop a novel risk score (NRS) which was validated in an equivalent independent cohort (n = 441). We compared the accuracy of existing predictive tools and the NRS in these cohorts., Results: The NRS (incorporating PSA, prostate volume, age, clinical T Stage, percent and number of positive biopsy cores) outperformed pre-existing predictive tools in derivation and validation cohorts (AUC 0.755 and 0.76, respectively). Selection bias due to analysis of a surgical cohort is acknowledged., Conclusions: The advantage of the NRS is that it can be tailored to patient characteristics and may prove to be valuable tool in clinical decision-making.

This article describes apparatus to aid histological validation of magnetic resonance imaging studies of the human prostate. The apparatus includes a 3D-printed patient-specific mold that facilitates aligned in vivo and ex vivo imaging, in situ tissue fixation, and tissue sectioning with minimal organ deformation. The mold and a dedicated container include MRI-visible landmarks to enable consistent tissue positioning and minimize image registration complexity. The inclusion of high spatial resolution ex vivo imaging aids in registration of in vivo MRI and histopathology data.

Background: Early detection and treatment of asymptomatic men with advanced and high-risk prostate cancer (PCa) may improve survival rates., Objective: To determine outcomes for men diagnosed with advanced PCa following prostate-specific antigen (PSA) testing who were excluded from the ProtecT randomised trial., Design, Setting, and Participants: Mortality was compared for 492 men followed up for a median of 7.4 yr to a contemporaneous cohort of men from the UK Anglia Cancer Network (ACN) and with a matched subset from the ACN., Outcome Measurements and Statistical Analysis: PCa-specific and all-cause mortality were compared using Kaplan-Meier analysis and Cox's proportional hazards regression., Results and Limitations: Of the 492 men excluded from the ProtecT cohort, 37 (8%) had metastases (N1, M0=5, M1=32) and 305 had locally advanced disease (62%). The median PSA was 17μg/l. Treatments included radical prostatectomy (RP; n=54; 11%), radiotherapy (RT; n=245; 50%), androgen deprivation therapy (ADT; n=122; 25%), other treatments (n=11; 2%), and unknown (n=60; 12%). There were 49 PCa-specific deaths (10%), of whom 14 men had received radical treatment (5%); and 129 all-cause deaths (26%). In matched ProtecT and ACN cohorts, 37 (9%) and 64 (16%), respectively, died of PCa, while 89 (22%) and 103 (26%) died of all causes. ProtecT men had a 45% lower risk of death from PCa compared to matched cases (hazard ratio 0.55, 95% confidence interval 0.38-0.83; p=0.0037), but mortality was similar in those treated radically. The nonrandomised design is a limitation., Conclusions: Men with PSA-detected advanced PCa excluded from ProtecT and treated radically had low rates of PCa death at 7.4-yr follow-up. Among men who underwent nonradical treatment, the ProtecT group had a lower rate of PCa death. Early detection through PSA testing, leadtime bias, and group heterogeneity are possible factors in this finding., Patient Summary: Prostate cancer that has spread outside the prostate gland without causing symptoms can be detected via prostate-specific antigen testing and treated, leading to low rates of death from this disease., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Due to increased sensitivity, the expression of circulating nucleotides is rapidly gaining popularity in cancer diagnosis. Whole blood mRNA has been used in studies on a number of cancers, most notably two separate studies that used whole blood mRNA to define non-overlapping signatures of prostate cancer that has become castration independent. Prostate cancer is known to rely on androgens for initial growth, and there is increasing evidence on the importance of the androgen axis in advanced disease. Using whole blood mRNA samples from patients with prostate cancer, we have identified the four-gene panel of FAM129A, MME, KRT7 and SOD2 in circulating mRNA that are differentially expressed in a discovery cohort of metastatic samples. Validation of these genes at the mRNA and protein level was undertaken in additional cohorts defined by risk of relapse following surgery and hormone status. All the four genes were downregulated at the mRNA level in the circulation and in primary tissue, but this was not always reflected in tissue protein expression. MME demonstrated significant differences in the hormone cohorts, whereas FAM129A is downregulated at the mRNA level but is raised at the protein level in tumours. Using published ChIP-seq data, we have demonstrated that this may be due to AR binding at the FAM129A and MME loci in multiple cell lines. These data suggest that whole blood mRNA of androgen-regulated genes has the potential to be used for diagnosis and monitoring of prostate cancer., (© 2016 Society for Endocrinology.)

Unlabelled: The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression)., Patient Summary: This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: The androgen receptor (AR) is the master regulator of prostate cancer cell metabolism. Degarelix is a novel gonadotrophin-releasing hormone blocker, used to decrease serum androgen levels in order to treat advanced human prostate cancer. Little is known of the rapid metabolic response of the human prostate cancer tissue samples to the decreased androgen levels., Objectives: To investigate the metabolic responses in benign and cancerous tissue samples from patients after treatment with Degarelix by using HRMAS 1 H NMR spectroscopy., Methods: Using non-destructive HR-MAS 1 H NMR spectroscopy we analysed the metabolic changes induced by decreased AR signalling in human prostate cancer tissue samples. Absolute concentrations of the metabolites alanine, lactate, glutamine, glutamate, citrate, choline compounds [t-choline = choline + phosphocholine (PC) + glycerophosphocholine (GPC)], creatine compounds [t-creatine = creatine (Cr) + phosphocreatine (PCr)], taurine, myo-inositol and polyamines were measured in benign prostate tissue samples (n = 10), in prostate cancer specimens from untreated patients (n = 7) and prostate cancer specimens from patients treated with Degarelix (n = 6)., Results: Lactate, alanine and t-choline concentrations were significantly elevated in high-grade prostate cancer samples when compared to benign samples in untreated patients. Decreased androgen levels resulted in significant decreases of lactate and t-choline concentrations in human prostate cancer biopsies., Conclusions: The reduced concentrations of lactate and t-choline metabolites due to Degarelix could in principle be monitored by in vivo 1 H MRS, which suggests that it would be possible to monitor the effects of physical or chemical castration in patients by that non-invasive method.

Unlabelled: Tumors are often characterized by high levels of de novo fatty acid synthesis. The kinetics of acetate incorporation into tricarboxylic acid cycle intermediates and into lipids suggest that detection of tumors with [1-(11)C]acetate PET could be improved by imaging at later time points., Methods: The uptake and metabolism of [1-(11)C], [1-(13)C], and [1-(14)C]acetate were measured in mouse prostate and lung cancer models to investigate the time course of (11)C label incorporation into tumor metabolites., Results: Radioactivity in the lipid fraction, as compared with the aqueous fraction, in extracts of C4-2B human prostate xenografts peaked at 90 min after [1-(14)C]acetate injection, which coincided with peak (13)C label incorporation into the fatty acids palmitate and stearate. Contrast between the tumor and tissues, such as blood and muscle, increased in PET images acquired over a period of 120 min after [1-(11)C]acetate injection, and Patlak plots were linear from 17.5 min after injection. Similar results were obtained in a genetically engineered K-ras(G12D); p53(null) lung cancer model, in which the mean tumor-to-lung ratio at 90 min after [1-(14)C]acetate injection was 4.4-fold higher than at 15 min., Conclusion: These findings suggest that when imaging de novo fatty acid synthesis with [1-(11)C]acetate it is preferable to measure uptake at later time points, when the effects of perfusion and (11)C incorporation into tricarboxylic acid cycle intermediates and bicarbonate are declining. The data presented here suggest that future clinical PET scans of tumors should be acquired later than 30 min, when tracer accumulation due to de novo fatty acid synthesis prevails., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Identification of men harbouring insignificant prostate cancer (PC) is important in selecting patients for active surveillance. Tools have been developed in PSA-screened populations to identify such men based on clinical and biopsy parameters., Methods: Prospectively collected case series of 848 patients was treated with radical prostatectomy between July 2007 and October 2011 at an English tertiary care centre. Tumour volume was assessed by pathological examination. For each tool, receiver operator characteristics were calculated for predicting insignificant disease by three different criteria and the area under each curve compared. Comparison of accuracy in screened and unscreened populations was performed., Results: Of 848 patients, 415 had Gleason 3+3 disease on biopsy. Of these, 32.0% had extra-prostatic extension and 50.2% were upgraded. One had positive lymph nodes. Two hundred and six (24% of cohort) were D'Amico low risk. Of these, 143 had more than two biopsy cores involved. None of the tools evaluated has adequate discriminative power in predicting insignificant tumour burden. Accuracy is low in PSA-screened and -unscreened populations., Conclusions: In our unscreened population, tools designed to identify insignificant PC are inaccurate. Detection of a wider size range of prostate tumours in the unscreened may contribute to relative inaccuracy.

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

• The optimal management of high-risk localised prostate cancer is a major challenge for urologists and oncologists. It is clear that multimodal therapy including radical local treatment is needed in these men to achieve the best outcomes. • External beam radiotherapy (EBRT) is an essential component of therapy either as a primary or adjuvant treatment. However, the role of radical prostatectomy (RP) is more controversial. Both methods are currently valid therapy options. • There have been many individual studies of EBRT and RP in high-risk disease, but no good quality large prospective randomized trials. • In EBRT, combination with neoadjuvant plus long-term adjuvant androgen-deprivation therapy (ADT) has been conclusively shown to improve outcomes and is widely considered the standard of care. • However, the role of RP has achieved recent prominence with several important studies. Published data from prospective randomized trials in patients after RP have shown that in men with adverse pathological features at surgery, the addition of adjuvant RT improves biochemical-free and progression-free survival. • More recently, studies from large-volume centres comparing EBRT and RP have provided intriguing suggestions of better outcomes with RP as the primary treatment. • An important question therefore, is which of the two methods provides the best outcome in men with localised high-risk disease. Crucially, does the combination of RP and selective adjuvant EBRT provide clinically significant better outcomes compared with EBRT alone? • In this review we discuss the current evidence for the role of RP for high-risk localised prostate cancer and define the parameters and urgent need for a prospective trial to test the role of surgery for this group of patients., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Objective: To describe for surgeons contemplating performing cytoreductive nephrectomy (CRN) on patients after neoadjuvant sunitinib compared to a benchmark of open radical nephrectomy, describing technical difficulties, safety and feasibility., Patients and Methods: We compared measurable surgical parameters and perioperative complications in 22 patients with metastatic renal cell carcinoma (mRCC) undergoing CRN after neoadjuvant sunitinib, with 28 patients who underwent open radical nephrectomy for non-metastatic disease (nmRCC)., Results: Median blood loss (320 vs. 775 ml), median operative time (128 vs. 195 min) and median length of stay (5 vs. 7 days) were greater in the mRCC group. Surgery after sunitinib was technically challenging due to fibrosis, loss of the tissue planes that usually facilitate radical nephrectomy and abnormal blood vessel formation. Side effects of sunitinib resulted in predictable complications., Conclusion: CRN after treatment with sunitinib is safe and feasible in our hands, although the surgery is more time-consuming and technically demanding. A multidisciplinary approach is mandatory., (Copyright © 2012 S. Karger AG, Basel.)

Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer (PCa). We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia (BPH) samples using the pyrosequencing (PSQ) method to identify genes with diagnostic and prognostic potential. RARB, HIN1, BCL2, GSTP1, CCND2, EGFR5, APC, RASSF1A, MDR1, NKX2-5, CDH13, DPYS, PTGS2, EDNRB, MAL, PDLIM4, HLAa, ESR1 and TIG1 were highly methylated in PCa compared to BPH (p < 0.001), while SERPINB5, CDH1, TWIST1, DAPK1, THRB, MCAM, SLIT2, CDKN2a and SFN were not. RARB methylation above 21% completely distinguished PCa Separation based on methylation level of SFN, SLIT2 and SERPINB5 distinguished low and high Gleason score cancers, e.g. SFN and SERPINB5 together correctly classified 81% and 77% of high and low Gleason score cancers respectively. Several genes including CDH1 previously reported as methylation markers in PCa were not confirmed in our study. Increasing age was positively associated with gene methylation (p < 0.0001).Accurate quantitative measurement of gene methylation in PCa appears promising and further validation of genes like RARB, HIN1, BCL2, APC and GSTP1 is warranted for diagnostic potential and SFN, SLIT2 and SERPINB5 for prognostic potential.

Hexylaminolevulinate (hexa ALA) "blue light" fluorescence for detecting cellular changes in mucosal epithelium is used in urology to detect transitional-cell carcinoma and carcinoma in situ in the bladder. It is is also being studied for the detection of precancerous/cancerous lesions in the colon. We present a case in which hexa ALA fluorescence cystoscopy was used in the evaluation of cecal mucosa that was incorporated into the bladder as an augmentation cystoplasty. To our knowledge, this is the first time the imaging appearance of an augmented bladder under Hexa ALA fluorescence cystoscopy is described.

Flourescence cystoscopy is a new development which is gaining credence in the treatment of bladder cancer. It has been shown to decrease recurrence rates compared with white light cystoscopy. Analysis has demonstrated the cost effectiveness of this approach. It is a technique which is easy to learn for those experienced in white light cystoscopy. Here we describe how it works and exactly how to perform this examination.

Overactive bladder is a common and disabling problem. The mainstay of pharmacological treatment is with oral anticholinergic drugs. Anticholinergic side effects are common and include dry mouth and constipation. Compliance is limited by these side effects. Transdermal administration of oxybutynin has been shown to be as effective as oral treatment while minimising the anticholinergic side effects. Skin reactions occur frequently, necessitating changes of application site. Despite this, the preparation is a useful element in the armamentarium to treat overactive bladder. It is likely to be particularly useful in those in whom side effects of oral medication are intolerable or in whom oral administration of drug is not possible. Here, the pharmacokinetics, pharmacodynamics, efficacy and safety of transdermal oxybutynin are reviewed.

Objective: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment., Methods: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed., Results: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome., Conclusions: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.

Objectives: An animal model of the 'generalized Mozart effect' (GME) - enhanced/normalized higher brain function in response to music exposure - has been established. We extend those results in two studies using another species (mice). Study 1: (1) maze testing after music exposure was extended to a minimum of 6 hours; (2) no exposure to music in utero. Study 2: (1) music exposure time further reduced; (2) maze testing extended to 24 hours., Methods: Study 1: two mouse groups were exposed to music continuously for 10 hours per day for 10 weeks (Group I: Mozart's Sonata K.448, Group II: Beethoven's Fur Elise). After 10 weeks, the ability to negotiate a T-maze was assessed (recording working time in maze, number of errors). Maze ability was tested 6 hours following the last music exposure. Study 2: two mouse groups were exposed periodically to music (58% silence) 10 hours per day for 10 weeks. Experiments after 10 weeks examined the groups' abilities to run the maze (recording working time/errors). Experiments were conducted 24 hours following the last music exposure., Results: The Mozart group exhibited significant enhancements compared with the control mice in both studies, i.e. significantly lower working time (p<0.05) and committed fewer errors., Discussion: Observation of GME in another species supports its generality for the mammalian cortex. The absence of a GME in fMRI studies for the control music also indicates a neurophysiological basis. With extended exposure, GME is a long-term effect, indicating potential clinical importance. It has been demonstrated that GME reduces neuropathological spiking significantly in epileptics. We discuss the relevance of this study for epilepsy treatment.

This review considers the problem of the encrustation of biomaterials used for urinary prostheses. After a general discussion of the problem it deals with exciting new developments which may prove to be clinically applicable in preventing this costly and resource consuming complication. The widespread use of use of in vitro models which accurately simulate the conditions found in the human urinary tract will allow appropriate preliminary studies. Perhaps then clinical evaluation will be warranted.

The teaching of mathematics is invariably language-based, but spatial-temporal (ST) reasoning (making a mental image and thinking ahead in space and time) is crucial to the understanding of math. Here we report that Big Seed, a demanding ST video game, based upon the mathematics of knot theory and previously applied to understanding DNA structure and function, can be used to reveal innate ST reasoning. Big Seed studies with middle and elementary school children provide strong evidence that ST reasoning ability is not only innate but far exceeds optimistic expectations based on age, the percentage of children achieving exceptional ST performance in less than 7 h of training, and retention of ability. A third grader has been identified as a genius (functionally defined) in ST performance. Big Seed may be used for training and assessing 'creativity' (functionally defined) and ST reasoning as well as discovering genius.