17-ß-estradiol and phytoestrogens elicit NO production and vasodilatation through PI3K, PKA and EGF receptors pathways, evidencing functional selectivity.

Endothelial cells express multiple receptors mediating estrogen responses; including the G protein-coupled estrogen receptor (GPER). Past studies on nitric oxide (NO) production elicited by estrogens raised the question whether 17-ß-estradiol (E2) and natural phytoestrogens activate equivalent mechanisms. We hypothesized that E2 and phytoestrogens elicit NO production via coupling to distinct intracellular pathways signalling. To this aim, perfusion of E2 and phytoestrogens to the precontracted rat mesentery bed examined vasorelaxation, while fluorescence microscopy on primary endothelial cells cultures quantified single cell NO production determined following 4-amino-5-methylamino-2',7'-difluoroescein diacetate (DAF) incubation. Daidzein (DAI) and genistein (GEN) induced rapid vasodilatation associated to NO production. Multiple estrogen receptor activity was inferred based on the reduction of DAF-NO signals; G-36 (GPER antagonist) reduced 75 % of all estrogen responses, while fulvestrant (selective nuclear receptor antagonist) reduced significantly more the phytoestrogens responses than E2. The joint application of both antagonists abolished the E2 response but not the phytoestrogen-induced DAF-NO signals. Wortmannin or LY-294002 (PI3K inhibitors), reduced by 90% the E2-evoked signal while altering significantly less the DAI-induced response. In contrast, H-89 (PKA inhibitor), elicited a 23% reduction of the E2-induced signal while blocking 80% of the DAI-induced response. Desmethylxestospongin-B (IP3 receptor antagonist), decreased to equal extent the E2 or the DAI-induced signal. Epidermal growth factor (EGF) induced NO production, cell treatment with AG-1478, an EGF receptor kinase inhibitor reduced 90% DAI-induced response while only 53% the E2-induced signals; highlighting GPER induced EGF receptor trans-modulation. Receptor functional selectivity may explain distinct signalling pathways mediated by E2 and phytoestrogens.

Manejo de los pacientes con cáncer de próstata localizado y recurrencia bioquímica en España: encuesta médica / Management of patients with localized prostate cancer and biochemical recurrence in Spain: A medical survey

Introducción El tratamiento de los pacientes con cáncer de próstata (CaP) está establecido en las guías de práctica clínica, las cuales se basan en estudios aleatorizados según el nivel de evidencia. En España se desconoce el grado de cumplimiento de estas guías en la práctica clínica. Objetivos Describir los perfiles de los pacientes con CaP en el momento del diagnóstico y el manejo de los pacientes con CaP localizado y con recurrencia bioquímica (RBQ) en España. Materiales y métodos Se realizó una encuesta médica en 3 especialidades médicas (85 urólogos [URO], 64 oncólogos radioterápicos [OR] y 21 oncólogos médicos [OM]). Para este estudio se elaboraron 3 cuestionarios, 2 con 22 preguntas (URO y OR) y uno con 21 preguntas (OM). Resultados La incidencia anual de CaP en los hospitales participantes (N=131) fue de 24.057 casos. La incidencia anual extrapolada a España fue de 40.531 casos. La prevalencia estimada de CaP en España es de 221.689. Cabe destacar que el 79 y el 80% de los pacientes atendidos por URO y OR, respectivamente, presentaban CaP localizado en el momento del diagnóstico. La biopsia fue la prueba diagnóstica más utilizada en las 3 especialidades, seguida de la tomografía computarizada abdominopélvica. Más del 90% de los pacientes con RBQ se sometieron a pruebas estándar. Las técnicas de imagen de nueva generación y la PET con colina/PSMA se siguen utilizando en menor medida. Actualmente, la mayoría de los pacientes con CaP localizado reciben tratamiento con cirugía o radioterapia, pero en el caso de los pacientes con RBQ, los URO y OR prefieren la radioterapia y los OM la terapia de privación androgénica exclusiva o combinada. Conclusión Este estudio describe los perfiles de los pacientes en el momento del diagnóstico y proporciona una visión general del manejo terapéutico actual del CaP localizado y con RBQ en la práctica clínica en España. (AU)

Introduction The management of patients with prostate cancer (PCa) is established in clinical practice guidelines, which are based on randomized studies according to the level of evidence. In Spain, the degree of compliance with these guidelines in clinical practice is unknown. Objectives To describe the profiles of PCa patients at the time of diagnosis and the management of patients with localized PCa and those with biochemical recurrence (BCR) in Spain. Materials and methods A medical survey was conducted in specialized care (85 urologists [UROs], 64 radiation oncologists [ROs], and 21 medical oncologists [MOs]). Three questionnaires were developed for this study with 22 (UROs and ROs) or 21 questions (MOs). Results The annual incidence of PCa was 24,057 in participating hospitals (N=131). The extrapolated annual incidence in Spain is 40,531 cases. The estimated prevalence of PCa in Spain is 221,689. Of note, 79 and 80% of patients seen by UROs and ROs, respectively had localized PCa at diagnosis. Biopsy was the most used diagnostic test among the 3 specialties, followed by abdominopelvic computer tomography. More than 90% of patients with BCR underwent standard tests. Next generation imaging tests and PET-choline/PSMA are still used residually. Most patients with localized PCa are currently treated with either surgery or radiotherapy, while for BCR patients, UROs and ROs prefer radiotherapy and MOs androgen deprivation therapy alone or in combination. Conclusion This study describes patient profiles at the time of diagnosis and provides an overview of the current therapeutic management of localized PCa and BCR in clinical practice in Spain. (AU)

Management of patients with localized prostate cancer and biochemical recurrence in Spain: A medical survey.

INTRODUCTION: The management of patients with prostate cancer (PCa) is established in clinical practice guidelines, which are based on randomized studies according to the level of evidence. In Spain, the degree of compliance with these guidelines in clinical practice is unknown. OBJECTIVES: To describe the profiles of PCa patients at the time of diagnosis and the management of patients with localized PCa and those with BCR in Spain. MATERIALS & METHODS: A medical survey was conducted in specialized care (85 urologists [UROs], 64 radiation oncologists [ROs], and 21 medical oncologists [MOs]). Three questionnaires were developed for this study with 22 (UROs and ROs) or 21 questions (MOs). RESULTS: The annual incidence of PCa was 24,057 in participating hospitals (N = 131). The extrapolated annual incidence in Spain is 40,531 cases. The estimated prevalence of PCa in Spain is 221,689. Of note, 79% and 80% of patients seen by UROs and ROs, respectively had localized PCa at diagnosis. Biopsy was the most used diagnostic test among the three specialties, followed by abdominopelvic computer tomography. More than 90% of patients with BCR underwent standard tests. Next generation imaging tests and PET-choline/PSMA are still used residually. Most patients with localized PCa are currently treated with either surgery or radiotherapy, while for BCR patients, UROs and ROs prefer radiotherapy and MOs androgen deprivation therapy alone or in combination. CONCLUSION: This study describes patient profiles at the time of diagnosis and provides an overview of the current therapeutic management of localized PCa and BCR in clinical practice in Spain.

Comparison of single coronal thick-slab minimum intensity projection with flexible bronchoscopy for airway compression in children with lymphobronchial tuberculosis.

AIM: To generate standardised coronal minimum intensity projection (MinIP) computed tomography (CT) reconstructions, and compare these with flexible bronchoscopy in children with lymphobronchial tuberculosis (LBTB). MATERIALS AND METHODS: Standardised coronal MinIP reconstructions were performed from CT images in children with LBTB and the findings of three readers were compared with the reference standard, flexible bronchoscopy (FB), regarding airway narrowing. Intraluminal lesions, the site of the stenosis, and the degree of stenosis were also evaluated. The length of stenosis was evaluated by CT MinIP only. RESULTS: Sixty-five children (38 males; 58.5% and 27 females; 41.5%), with ages ranging from 2.5 to 144 months were evaluated. Coronal CT MinIP demonstrated a sensitivity of 96% and specificity of 89% against FB. The most common site of stenosis was the bronchus intermedius (91%), followed by the left main bronchus (85%), the right upper lobe bronchus RUL (66%), and the trachea (60%). CONCLUSION: Coronal CT MinIP reconstruction is useful in demonstrating airway stenosis in children with lymphobronchial TB, with high sensitivity and specificity. CT MinIP had additional advantages over FB in that it allowed objective measurement of the diameter of stenosis, measurement of the length of stenosis, and evaluation of post-stenotic segments of the airways and lung parenchymal abnormalities.

Predictive factors of six-week mortality in critically ill patients with SARS-CoV-2: A multicenter prospective study.

OBJECTIVE: The objective of the study is to identify the risk factors associated with mortality at six weeks, especially by analyzing the role of antivirals and munomodulators. DESIGN: Prospective descriptive multicenter cohort study. SETTING: 26 Intensive care units (ICU) from Andalusian region in Spain. PATIENTS OR PARTICIPANTS: Consecutive critically ill patients with confirmed SARS-CoV-2 infection were included from March 8 to May 30. INTERVENTIONS: None. VARIABLES: Variables analyzed were demographic, severity scores and clinical condition. Support therapy, drug and mortality were analyzed. An univariate followed by multivariate Cox regression with propensity score analysis was applied. RESULTS: 495 patients were enrolled, but 73 of them were excluded for incomplete data. Thus, 422 patients were included in the final analysis. Median age was 63 years and 305 (72.3%) were men. ICU mortality: 144/422 34%; 14 days mortality: 81/422 (19.2%); 28 days mortality: 121/422 (28.7%); 6-week mortality 152/422 36.5%. By multivariable Cox proportional analysis, factors independently associated with 42-day mortality were age, APACHE II score, SOFA score at ICU admission >6, Lactate dehydrogenase at ICU admission >470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission <6.5%, and thrombocytopenia whereas the use of lopinavir/ritonavir was a protective factor. CONCLUSION: Age, APACHE II, SOFA>value of 6 points, along with vasopressor requirements or renal replacement therapy have been identified as predictor factors of mortality at six weeks. Administration of corticosteroids showed no benefits in mortality, as did treatment with tocilizumab. Lopinavir/ritonavir administration is identified as a protective factor.

Nanomolar clodronate induces adenosine accumulation in the perfused rat mesenteric bed and mesentery-derived endothelial cells.

The vesicular nucleotide transporter (VNUT) is critical for sympathetic co-transmission and purinergic transmission maintenance. To examine this proposal, we assessed whether the bisphosphonate clodronate, claimed as a potent in vitro VNUT blocker, modified spontaneous and/or the electrically evoked overflow of ATP/metabolites and NA from mesentery sympathetic perivascular nerve terminals. Additionally, in primary endothelial cell cultures derived from this tissue, we also evaluated whether clodronate interfered with ATP/metabolite cell outflow and metabolism of N6-etheno adenosine 5'-triphosphate (eATP), N6-etheno adenosine (eADO), and adenosine deaminase enzyme activity. Rat mesenteries were perfused in the absence or presence of .01-1,000 nM clodronate, 1-1,000 nM Evans blue (EB), and 1-10 µM DIDS; tissue perfusates were collected to determine ATP/metabolites and NA before, during, and after perivascular electrical nerve terminal depolarization. An amount of 1-1,000 nM clodronate did not modify the time course of ATP or NA overflow elicited by nerve terminal depolarization, and only 10 nM clodronate significantly augmented perfusate adenosine. Electrical nerve terminal stimulation increased tissue perfusion pressure that was significantly reduced only by 10 nM clodronate [90.0 ± 18.6 (n = 8) to 35.0 ± 10.4 (n = 7), p = .0277]. As controls, EB, DIDS, or reserpine treatment reduced the overflow of ATP/metabolites and NA in a concentration-dependent manner elicited by nerve terminal depolarization. Moreover, mechanical stimulation of primary endothelial cell cultures from the rat mesentery added with 10 or 100 nM clodronate increased adenosine in the cell media. eATP was metabolized by endothelial cells to the same extent with and without 1-1,000 nM clodronate, suggesting the bisphosphonate did not interfere with nucleotide ectoenzyme metabolism. In contrast, extracellular eADO remained intact, indicating that this nucleoside is neither metabolized nor transported intracellularly. Furthermore, only 10 nM clodronate inhibited (15.5%) adenosine metabolism to inosine in endothelial cells as well as in a commercial crude adenosine deaminase enzyme preparation (12.7%), and both effects proved the significance (p < .05). Altogether, present data allow inferring that clodronate inhibits adenosine deaminase activity in isolated endothelial cells as in a crude extract preparation, a finding that may account for adenosine accumulation following clodronate mesentery perfusion.

Anthocyanins Activate Membrane Estrogen Receptors With Nanomolar Potencies to Elicit a Nongenomic Vascular Response Via NO Production.

Background The vascular pharmacodynamics of anthocyanins is only partially understood. To examine whether the anthocyanin-induced vasorelaxation is related to membrane estrogen receptor activity, the role of ERα or GPER antagonism was ascertained on anthocyanins or 17-ß estradiol-(E2) induced vasodilatations and NO production. Methods and Results The rat arterial mesenteric bed was perfused with either anthocyanins or corresponding 3-O-glycosides, or E2, to examine rapid concentration-dependent vasorelaxations. The luminally accessible fraction of NO in mesenteric perfusates before and after anthocyanins or E2 administration was quantified. Likewise, NO-DAF signal detected NO production in primary endothelial cells cultures incubated with anthocyanins or E2 in the absence and presence of ERα (ICI 182,780) or GPER (G-36) selective antagonists. Anthocyanins or corresponding glycosides elicited, within minutes, vasodilation with nanomolar potencies; half maximal anthocyanin response reached 50% to 60% efficacy, in contrast to acetylcholine. The vasorelaxation is of rapid onset and exclusively endothelium-dependent; NOS inhibition annulled the vasorelaxation. The delphinidin vascular response was not modified by 100 nmol/L atropine but significantly attenuated by joint application of ICI plus G-36 (52±4.6 versus 8.5±1.5%), revealing the role of membrane estrogen receptors. Moreover, the anthocyanin or E2-induced NO production was antagonized up to 70% by these antagonists. NO-DAF signal elicited by anthocyanins was annulled by NOS inhibition or by ICI plus G-36 addition. Conclusions The biomedical effect of anthocyanins or 3-O-glycosylates derivatives contained in naturally purple-colored foods or berries is due to increased NO production, and not to the phytochemical's antioxidant potential, highlighting the nutraceutical role of natural products in cardiovascular diseases.

Hybrid QM/MM Simulations Confirm Zn(II) Coordination Sphere That Includes Four Cysteines from the P2 × 4R Head Domain.

To ascertain the role of Zn(II) as an allosteric modulator on P2X4R, QM/MM molecular dynamic simulations were performed on the WT and two P2X4R mutants suggested by previous electrophysiological data to affect Zn(II) binding. The Gibbs free energy for the reduction of the putative P2X4R Zn(II) binding site by glutathione was estimated at -22 kcal/mol. Simulations of the WT P2X4R head domain revealed a flexible coordination sphere dominated by an octahedral geometry encompassing C126, N127, C132, C149, C159 and a water molecule. The C132A mutation disrupted the metal binding site, leading to a coordination sphere with a majority of water ligands, and a displacement of the metal ion towards the solvent. The C132A/C159A mutant exhibited a tendency towards WT-like stability by incorporating the R148 backbone to the coordination sphere. Thus, the computational findings agree with previous experimental data showing Zn(II) modulation for the WT and C132A/C159A variants, but not for the C132A mutant. The results provide molecular insights into the nature of the Zn(II) modulation in P2X4R, and the effect of the C132A and C132A/C159A mutations, accounting for an elusive modulation mechanism possibly occurring in other extracellular or membrane protein.

Predictive factors of six-week mortality in critically ill patients with SARS-CoV-2: A multicenter prospective study.

OBJECTIVE: The objective of the study is to identify the risk factors associated with mortality at six weeks, especially by analyzing the role of antivirals and munomodulators. DESIGN: Prospective descriptive multicenter cohort study. SETTING: 26 Intensive care units (ICU) from Andalusian region in Spain. PATIENTS OR PARTICIPANTS: Consecutive critically ill patients with confirmed SARS-CoV-2 infection were included from March 8 to May 30. INTERVENTIONS: None. VARIABLES: Variables analyzed were demographic, severity scores and clinical condition. Support therapy, drug and mortality were analyzed. An univariate followed by multivariate Cox regression with propensity score analysis was applied. RESULTS: 495 patients were enrolled, but 73 of them were excluded for incomplete data. Thus, 422 patients were included in the final analysis. Median age was 63 years and 305 (72.3%) were men. ICU mortality: 144/422 34%; 14 days mortality: 81/422 (19.2%); 28 days mortality: 121/422 (28.7%); 6-week mortality 152/422 36.5%. By multivariable Cox proportional analysis, factors independently associated with 42-day mortality were age, APACHE II score, SOFA score at ICU admission >6, Lactate dehydrogenase at ICU admission >470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission <6.5%, and thrombocytopenia whereas the use of lopinavir/ritonavir was a protective factor. CONCLUSION: Age, APACHE II, SOFA>value of 6 points, along with vasopressor requirements or renal replacement therapy have been identified as predictor factors of mortality at six weeks. Administration of corticosteroids showed no benefits in mortality, as did treatment with tocilizumab. Lopinavir/ritonavir administration is identified as a protective factor.

Factores clínicos determinantes para la realización de pruebas de imagen en cáncer de próstata resistente a la castración no metastásico en la práctica clínica: resultados del estudio IDENTIFICA / Clinical drivers for imaging testing in non-metastatic castration-resistant prostate cancer in clinical practice: Results of the IDENTIFICA study

Introducción: El objetivo del estudio consistió en describir los factores clínicos que llevan a los médicos a realizar pruebas de imagen para identificar metástasis en pacientes con cáncer de próstata (CP) resistente a la castración no metastásico (CPRCnm).MétodosEstudio observacional transversal realizado en los servicios de Urología de 38 hospitales españoles; 188 pacientes diagnosticados con CPRCnm sometidos una prueba de imagen para evaluar la presencia de metástasis fueron incluidos. Se solicitó a los médicos, en una única visita del estudio, que especificaran los factores clínicos que los llevaron a realizar estas pruebas. Se presentaron los resultados de las pruebas de imagen y las características clínicas de los pacientes desde el diagnóstico de CP. Se utilizaron análisis de regresión para determinar factores predictivos de los resultados de las pruebas de imagen.ResultadosEl valor del «prostate-specific antigen» (por sus siglas en inglés, PSA), fue el factor más importante que determinó la solicitud de pruebas de imagen (57,1%), seguido de un seguimiento habitual (16,5%) y del tiempo de duplicación del PSA (TDPSA) (12,0%). Aunque estos factores no guardaron relación con la detección de metástasis, los pacientes con una concentración de PSA ≥ 20 ng/ml tuvieron un mayor riesgo de metástasis que aquellos con una concentración <4 ng/ml (p=0,004), mientras que los pacientes con CPRC diagnosticados de metástasis (CPRCm) tuvieron una mayor mediana de concentración de PSA (20,9; intervalo intercuartílico [IIC]: 6,7-38,6) que aquellos con CPRCnm (9,1; IIC: 5,0-18,0) (p=0,005). Un 66% no se sometió a ninguna prueba de imagen entre el diagnóstico de CPRC y la visita del estudio (10,6, IIC: 4,0-19,5 meses). El tratamiento con intención curativa en el momento del diagnóstico de CP y la puntuación de Gleason predijeron un mayor tiempo transcurrido entre los diagnósticos de CP y CPRC. (AU)

Introduction: The aim of the study was to describe the clinical drivers that lead physicians to perform imaging tests in search of metastasis in non-metastasic castration prostate resistant cancer (nmCRPC) patients.MethodsObservational, cross-sectional study conducted at the Departments of Urology of 38 Spanish hospitals. The study included 188 patients diagnosed with nmCRPC who underwent an imaging test for the assessment of metástasis. In one study visit, physicians were requested to specify the clinical factors that led them to perform these tests. The results of the imaging tests and the clinical characteristics of the patients since the time of prostate cancer (PC) diagnosis, were reported. Regression analyses were used to determine predictors of imaging test results.ResultsProstate-specific antigen (PSA) level was the most important driver to order imaging tests (57.1%), followed by regular follow-up (16.5%) and PSA doubling time (PSADT) (12.0%). Although these drivers were not associated to detection of metastasis, patients with PSA levels ≥20 ng/mL had a greater risk of metastasis than patients with PSA levels <4ng/mL (P=.004) and CRPC patients diagnosed with metastasis (mCRPC) had higher median PSA levels (20.9; interquartile range [IQR]: 6.7-38.6) than nmCRPC (9.1; IQR: 5.0-18.0) (P=.005). Sixty-six percent of the patients did not undergo any imaging test after CRPC diagnosis until the study visit (10.6, IQR: 4.0-19.5 months). Curative-intent treatment at PC diagnosis and Gleason score predicted longer time from PC to CRPC diagnosis.ConclusionsPhysicians based their decisions to order imaging tests for metastasis detection in nmCRPC patients mainly on PSA and PSA kinetics, including the regular follow-up stated by guideline recommendations. (AU)

A Stacked Generalization of 3D Orthogonal Deep Learning Convolutional Neural Networks for Improved Detection of White Matter Hyperintensities in 3D FLAIR Images.

BACKGROUND AND PURPOSE: Accurate and reliable detection of white matter hyperintensities and their volume quantification can provide valuable clinical information to assess neurologic disease progression. In this work, a stacked generalization ensemble of orthogonal 3D convolutional neural networks, StackGen-Net, is explored for improving automated detection of white matter hyperintensities in 3D T2-FLAIR images. MATERIALS AND METHODS: Individual convolutional neural networks in StackGen-Net were trained on 2.5D patches from orthogonal reformatting of 3D-FLAIR (n = 21) to yield white matter hyperintensity posteriors. A meta convolutional neural network was trained to learn the functional mapping from orthogonal white matter hyperintensity posteriors to the final white matter hyperintensity prediction. The impact of training data and architecture choices on white matter hyperintensity segmentation performance was systematically evaluated on a test cohort (n = 9). The segmentation performance of StackGen-Net was compared with state-of-the-art convolutional neural network techniques on an independent test cohort from the Alzheimer's Disease Neuroimaging Initiative-3 (n = 20). RESULTS: StackGen-Net outperformed individual convolutional neural networks in the ensemble and their combination using averaging or majority voting. In a comparison with state-of-the-art white matter hyperintensity segmentation techniques, StackGen-Net achieved a significantly higher Dice score (0.76 [SD, 0.08], F1-lesion (0.74 [SD, 0.13]), and area under precision-recall curve (0.84 [SD, 0.09]), and the lowest absolute volume difference (13.3% [SD, 9.1%]). StackGen-Net performance in Dice scores (median = 0.74) did not significantly differ (P = .22) from interobserver (median = 0.73) variability between 2 experienced neuroradiologists. We found no significant difference (P = .15) in white matter hyperintensity lesion volumes from StackGen-Net predictions and ground truth annotations. CONCLUSIONS: A stacked generalization of convolutional neural networks, utilizing multiplanar lesion information using 2.5D spatial context, greatly improved the segmentation performance of StackGen-Net compared with traditional ensemble techniques and some state-of-the-art deep learning models for 3D-FLAIR.

Normal head and neck lymph nodes in the paediatric population.

AIM: To determine the normal range of head and neck lymph nodes in a paediatric population. MATERIALS AND METHODS: A retrospective review was undertaken of 200 brain magnetic resonance imaging (MRI) examinations in patients aged between 5 months to 16 years. Exclusion criteria included possible causes for lymphadenopathy. Studies were reported previously as normal. Eight regions were assessed for the presence of nodes, short and long axis of the largest node measured, and the ratio was calculated. RESULTS: Most commonly identifiable nodes were the deep cervical, submandibular, and posterior cervical in 100%, 99.5%, and 92.5% of studies. In the long axis, the three largest were the submandibular, deep, and posterior cervical with mean values of 19.7, 18.1, and 15.4 mm, respectively. For the S/L ratio, the three with the most oval shape were the pre-auricular, occipital, and submental with ratios of 0.64, 0.63, and 0.6, respectively. A positive correlation between the occipital and deep cervical lymph node groups with age was found to be stronger than the rest of localisations. CONCLUSION: This study characterises the normal distribution, size, and shape of head and neck lymph nodes in a healthy paediatric population, demonstrating that rounder and larger lymph nodes may be a normal finding, depending on their location and patient age.

Clinical drivers for imaging testing in non-metastatic castration-resistant prostate cancer in clinical practice: Results of the IDENTIFICA study. / Factores clínicos determinantes para la realización de pruebas de imagen en cáncer de próstata resistente a la castración no metastásico en la práctica clínica: resultados del estudio IDENTIFICA.

INTRODUCTION: The aim of the study was to describe the clinical drivers that lead physicians to perform imaging tests in search of metastasis in non-metastasic castration prostate resistant cancer (nmCRPC) patients. METHODS: Observational, cross-sectional study conducted at the Departments of Urology of 38 Spanish hospitals. The study included 188 patients diagnosed with nmCRPC who underwent an imaging test for the assessment of metástasis. In one study visit, physicians were requested to specify the clinical factors that led them to perform these tests. The results of the imaging tests and the clinical characteristics of the patients since the time of prostate cancer (PC) diagnosis, were reported. Regression analyses were used to determine predictors of imaging test results. RESULTS: Prostate-specific antigen (PSA) level was the most important driver to order imaging tests (57.1%), followed by regular follow-up (16.5%) and PSA doubling time (PSADT) (12.0%). Although these drivers were not associated to detection of metastasis, patients with PSA levels ≥20 ng/mL had a greater risk of metastasis than patients with PSA levels <4ng/mL (P=.004) and CRPC patients diagnosed with metastasis (mCRPC) had higher median PSA levels (20.9; interquartile range [IQR]: 6.7-38.6) than nmCRPC (9.1; IQR: 5.0-18.0) (P=.005). Sixty-six percent of the patients did not undergo any imaging test after CRPC diagnosis until the study visit (10.6, IQR: 4.0-19.5 months). Curative-intent treatment at PC diagnosis and Gleason score predicted longer time from PC to CRPC diagnosis. CONCLUSIONS: Physicians based their decisions to order imaging tests for metastasis detection in nmCRPC patients mainly on PSA and PSA kinetics, including the regular follow-up stated by guideline recommendations.

On the detection of surface spin freezing in iron oxide nanoparticles and its long-term evolution under ambient oxidation.

Exchange bias (EB) effects linked to surface spin freezing (SSF) are commonly found in iron oxide nanoparticles, while signatures of SSF in low-field temperature-dependent magnetization curves have been much less frequently reported. Here, we present magnetic properties of dense assemblies of similar-sized (∼8 nm diameter) particles synthesized by a magnetite (sample S1) and a maghemite (sample S2) method, and the influence of long-term (4 year) sample aging under ambient conditions on these properties. The size of the EB field of the different sample (fresh or aged) states is found to correlate with (a) whether a low-temperature hump feature signaling the SSF transition is detected in out-of-phase ac susceptibility or zero-field-cooled (ZFC) dc magnetization recorded at low field and with (b) the prominence of irreversibility between FC and ZFC curves recorded at high field. Sample S1 displays a lower magnetization than S2, and it is in S1 where the largest SSF effects are found. These effects are significantly weakened by aging but remain larger than the SSF effects in S2, where the influence of aging is considerably smaller. A non-saturating component due to spin disorder in S1 also weakens with aging, accompanied by, we infer, an increase in the superspin and the radius of the ordered nanoparticle cores. X-ray diffraction and Mössbauer spectroscopy provide indication of maghemite-like stoichiometry in both aged samples as well as thicker disordered particle shells in aged-S1 relative to aged-S2 (crystallographically-disordered and spin-disordered according to diffraction and Mössbauer, respectively). The pronounced diminution in SSF effects with aging in S1 is attributed to a (long-term) transition, caused by ambient oxidation, from magnetite-like to maghemite-like stoichiometry, and a concomitant softening of the spin-disordered shell anisotropy. We assess the impact of this anisotropy on the nature of the blocking of the nanoparticle superspins.

Diagnostic decision-making tool for imaging term neonatal bowel obstruction.

Term neonatal bowel obstruction is common, and absence of treatment is potentially catastrophic. There is a relatively narrow differential diagnosis, with causes categorised as either low or high bowel obstruction. The commonest causes of low bowel obstruction include anorectal malformations (ARM), Hirschsprung's disease, ileal atresia, meconium ileus, meconium plug, and colonic atresia. The commonest causes of high bowel obstruction include duodenal atresia, duodenal stenosis/web, jejunal atresia, and malrotation with volvulus (and hypertrophic pyloric stenosis usually presenting in slightly older infants). Diagnosis can be decided using a step-wise binary decision tool that includes the appropriate imaging steps and evaluation of bowel calibre. This paper presents the decision-making tool from the presenting features, through plain radiographic findings and, where necessary, the additional radiological investigations to assist the general radiologist, novice paediatric radiologist and paediatric surgeon. The tool is pictorial, with the radiological findings accompanied by eight schematics, serving as a simplified visual aid for memorizing the imaging patterns of the differential diagnosis. The imaging and decision-making steps allow for a rapid, simplified diagnosis that can benefit patients by recommending when to perform surgery, when to perform further imaging, and when imaging can act in a therapeutic manner.

New Insights of the Zn(II)-Induced P2 × 4R Positive Allosteric Modulation: Role of Head Receptor Domain SS2/SS3, E160 and D170.

P2 × 4R is allosterically modulated by Zn(II), and despite the efforts to understand the mechanism, there is not a consensus proposal; C132 is a critical amino acid for the Zn(II) modulation, and this residue is located in the receptor head domain, forming disulfide SS3. To ascertain the role of the SS2/SS3 microenvironment on the rP2 × 4R Zn(II)-induced allosteric modulation, we investigated the contribution of each individual SS2/SS3 cysteine plus carboxylic acid residues E118, E160, and D170, located in the immediate vicinity of the SS2/SS3 disulfide bonds. To this aim, we combined electrophysiological recordings with protein chemical alkylation using thiol reagents such as N-ethylmaleimide or iodoacetamide, and a mutation of key amino acid residues together with P2 × 4 receptor bioinformatics. P2 × 4R alkylation in the presence of the metal obliterated the allosteric modulation, a finding supported by the site-directed mutagenesis of C132 and C149 by a corresponding alanine. In addition, while E118Q was sensitive to Zn(II) modulation, the wild type receptor, mutants E160Q and D170N, were not, suggesting that these acid residues participate in the modulatory mechanism. Poisson-Boltzmann analysis indicated that the E160Q and D170N mutants showed a shift towards more positive electrostatic potential in the SS2/SS3 microenvironment. Present results highlight the role of C132 and C149 as putative Zn(II) ligands; in addition, we infer that acid residues E160 and D170 play a role attracting Zn(II) to the head receptor domain.

Pioneros de un siglo de enseñanza anatómica en la ciudad de Concepción, Chile / Pioneers of a century of anatomical teaching in the city of Concepción, Chile

Revisando un siglo de historia, el desarrollo de las actividades anatómicas en la ciudad de Concepción, en el sur de Chile, no estuvieron ajenas a dificultades. El presente trabajo reunió los antecedentes históricos que relatan los inicios y desarrollo de la enseñanza de la anatomía en la naciente Universidad de Concepción. Se realizó una búsqueda que incluyó la revisión de libros históricos, revistas, archivos digitales y registros institucionales como actas y archivos fotográficos. La fundación de la Universidad, los inicios de las actividades anatómicas en 1919 y el aporte de sus principales pioneros, evidencian las dificultades de la enseñanza de esta disciplina en Chile. Desde una perspectiva histórica, conocer dentro de este siglo de enseñanza los recursos físicos utilizados para la disección cadavérica, el detalle de las metodologías pedagógicas utilizadas y los recursos anatómicos disponibles, resultan ser un aporte al conocimiento del desarrollo de la anatomía en Chile.

Reviewing a century of history, the development of anatomical activities in the city of Concepción, in the south of Chile, did not occur without difficulties. The present work gathered the historical background related with the beginnings and development of Anatomy teaching at the Universidad de Concepcion. Research was carried out including the review of historical books, magazines, digital archives and institutional records such as files or photographic archives. The foundation of the university, the beginnings of anatomical activities in 1919 and the contribution of its highlighted pioneers, show the difficulties of teaching this discipline in Chile. From a historical perspective, having knowledge during this century of teaching, the physical resources used in cadaveric dissection, the detail of teaching methodologies applied, and the anatomical resources available, contribute the anatomy´s development knowledge in Chile.

Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts.

Knowledge and research results about hand osteoarthritis (hOA) are limited due to the lack of samples and animal models of the disease. Here, we report the generation of two induced pluripotent stem cell (iPSC)-lines from patients with radiographic hOA. Furthermore, we wondered whether these iPSC-lines carried single nucleotide polymorphisms (SNPs) within genes that have been associated with hOA. Finally, we performed chondrogenic differentiation of the iPSCs in order to prove their usefulness as cellular models of the disease. We performed a non-integrative reprogramming of dermal fibroblasts obtained from two patients with radiographic rhizarthrosis and non-erosive hOA by introducing the transcriptional factors Oct4, Sox2, Klf4 and c-Myc using Sendai virus. After reprogramming, embryonic stem cell-like colonies emerged in culture, which fulfilled all the criteria to be considered iPSCs. Both iPSC-lines carried variants associated with hOA in the four studied genes and showed differences in their chondrogenic capacity when compared with a healthy control iPSC-line. To our knowledge this is the first time that the generation of iPSC-lines from patients with rhizarthrosis and non-erosive hOA is reported. The obtained iPSC-lines might enable us to model the disease in vitro, and to deeper study both the molecular and cellular mechanisms underlying hOA.

La adherencia a los medicamentos en pacientes hipertensos y en muestra de la población general / Characterization of medication adherence in a sample of the general population and another of hypertensive patients in Panama

OBJETIVO: Caracterizar la adherencia al tratamiento farmacológico en la población adulta, y en pacientes hipertensos atendidos en dos centros de atención primaria de la Caja de Seguro Social en Panamá. MÉTODOS: Aplicación de encuesta poblacional sobre la adherencia medicamentosa a 1.200 personas en las 4 ciudades de mayor población y crecimiento económico en Panamá y otra encuesta a pacientes hipertensos atendidos en centros de atención primaria de la Seguridad Social, durante los meses de septiembre a octubre del 2016. RESULTADOS: De 1.200 personas que participaron en la encuesta, 671 tomaban medicamentos, 54% eran mujeres y 54% con estudios universitarios. El 91% manifestaron padecer algún tipo de enfermedad y uso de diversos medicamentos. El 55% contestó que alguna vez había olvidado tomar el medicamento. Fueron 176 pacientes encuestados en los centros de atención primaria, 67% mujeres, 42% con grado universitario. El 97% eran hipertensos, 48% diabéticos. El 80% de los hipertensos tomaban diversos medicamentos. Al aplicarse el test de Morisky-Green a los pacientes, el 40% indicó haber dejado de tomar los medicamentos por lo tanto no cumplían con la farmacoterapia ordenada. De acuerdo al test de Batalla, los pacientes mostraron tener un gran conocimiento sobre su enfermedad. CONCLUSIONES: La mayoría de la población encuestada sufría HTA y habían olvidado tomar los medicamentos. Los pacientes reconocieron padecer y conocer la hipertensión, sin embargo, no fueron adherentes al tratamiento medicamentoso. Se hace necesario una toma de conciencia y participación en el control de su enfermedad e impulsar campañas nacionales sobre la adherencia medicamentosa

OBJECTIVE: To characterize adherence to pharmacological treatment in the adult population, and in hypertensive patients treated in two primary care centers of the Social Security in Panama. METHODS: A survey on drug adherence was applied to 1,200 study participants in 4 major cities in Panama. The survey for hypertensive patients was applied in primary health care centers. RESULTS: Of 1,200 study participants, 671 were taking medications, 54% were women and 54% university degrees. 91% reported suffering from some type of illness and use of various medications. 55% replied that they had once forgotten to take the medication whereas 80% of the participants said they forget medication intake frequently. There were 176 hypertensive patients survey in primary care centers, 67% women, and 42% with university degree. 97% were hypertensive and 48% diabetic. 80% of patients with hypertension took various medications. When the Morisky-Green test was applied to patients, 40% indicated that they stopped taking the medications; therefore, they did not comply with the ordered pharmacotherapy. According to the Batalla test, patients showed great knowledge about their disease. CONCLUSIONS: The majority of the population surveyed suffered from hypertension and had forgotten to take the medications. The patients recognized suffering and knowing the hypertension, however, they were not adherent to the drug treatment. Awareness and participation in the control of your disease is necessary and to promote national campaigns on drug adherence

PREVALENCE OF FATIGUE AND IMPACT ON QUALITY OF LIFE IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS: the VITAL study.

BACKGROUND: Fatigue is one of the most prevalent symptoms among cancer patients. Specifically, in metastatic castration-resistant prostate cancer (mCRPC) patients, fatigue is the most common adverse event associated with current treatments. The purpose of this study is to describe the prevalence of fatigue and its impact on quality of life (QoL) in patients with CRPC in routine clinical practice. METHODS: This was a cross-sectional, multicentre study. Male chemo-naïve adults with high-risk non-metastatic (M0) CRPC and metastatic (M1) CRPC (mCRPC) were eligible. Fatigue was measured using the Brief Fatigue Inventory (BFI) and QoL was assessed using the Functional Assessment of Cancer Therapy questionnaire for patients with prostate cancer (FACT-P) and the FACT-General (FACT-G) questionnaire. Data were analysed using Mann-Whitney or Kruskal-Wallis tests (non-parametric distribution), a T-test or an ANOVA (parametric distribution) and the Fisher or chi-squared tests (categorical variables). RESULTS: A total of 235 eligible patients were included in the study (74 [31.5%] with M0; and 161 [68.5%] with M1). Fatigue was present in 74%, with 38.5% of patients reporting moderate-to-severe fatigue. Mean FACT-G and FACT-P overall scores were 77.6 ± 16.3 and 108.7 ± 21.4, respectively, with no differences between the CRPC M0 and CRPC M1 subgroups. Fatigue intensity was associated with decreased FACT-G/P scores, with no differences between groups. Among 151 mCRPC patients with available treatment data, those treated with abiraterone-prednisone ≥3 months showed a significant reduction in fatigue intensity (p = 0.043) and interference (p = 0.04) compared to those on traditional hormone therapy (HT). Patients on abiraterone-prednisone ≥3 months showed significantly better FACT-G/P scores than patients on HT (p = 0.046 and 0.018, respectively). CONCLUSION: Our data show a high prevalence and intensity of fatigue and its impact on QoL in chemo-naïve CRPC patients. There is an association between greater fatigue and less QoL, irrespective of the presence or absence of metastasis. Chemo-naïve mCRPC patients receiving more than 3 months of abiraterone acetate plus prednisone showed an improvement of fatigue and QoL when compared to those on traditional HT. TRIAL REGISTRATION: Not applicable since it is not an interventional study.