MGRN1 depletion promotes intercellular adhesion in melanoma by upregulation of E-cadherin and inhibition of CDC42.

Mahogunin Ring Finger 1 is an E3-ubiquitin ligase encoded by the color gene MGRN1. Our previous in vitro and in vivo studies demonstrated that Mgrn1 deletion in mouse melanoma cells induced cell differentiation and adhesion, and decreased cell motility and invasion on collagen I, and lung colonization in an in vivo model. Here, we investigated the role of MGRN1 on human melanoma cell morphology, adhesion and expression of genes/proteins involved in an EMT-like transition. We demonstrated that wild-type BRAF human melanoma cells adopted a clustering-like morphology on collagen I, with permanent MGRN1 abrogation resulting in bigger cell clusters. Enhanced intercellular adhesion was mostly mediated by induction of E-cadherin and higher co-localization with ß-catenin. Transcriptional upregulation of E-cadherin likely occurred through downregulation of the ZEB1 repressor. Finally, pulldown assays showed reduced activation of CDC42 in the absence of MGRN1, which was reverted after E-cadherin silencing. Overall, these findings highlight a new MGRN1-dependent pathway regulating melanoma cell shape, motility, and invasion potential.

Guías de prevención cardiovascular de sociedades científicas y administraciones sanitarias: la necesidad de convergencia / Cardiovascular prevention guidelines of the scientific societies and healthcare administrations: the need for convergence

No disponible

[Telemedicine, prison and illness associated with HIV]. / Telemedicina, centros penitenciarios y enfermedad por VIH.

OBJECTIVE: Communicate the activity of telemedicine, from its opening, between a hospital consultation of infectious diseases and a penitentiary center. METHODS: Descriptive study of the tele-consultation of infectious diseases of the Alcorcón Foundation University Hospital with the Navalcarnero penitentiary center from 2013 to 2017, which is carried out by videoconference. The reason and number of consultations, diagnosis of HIV, antiretroviral treatment (ART), immunovirological situation, diagnosis of hepatitis C virus (HCV= and intervention performed by the infectious expert were analyzed. RESULTS: A total of 75 patients were evaluated in a total of 168 consultations (in the first year 11 consultations and in the fifth year 62). The index of successive / new consultations was 1.24 and 85% of the patients required less than 1 year of follow-up. 84% of patients did not move to the hospital. 99% of patients accepted this modality. 96% were HIV positive, 94% of them took ART and 85% had undetectable viral load with 532 CD4/mL of medium. 90% had positive serology for HCV. 72% of the consultations were for the assessment of HCV treatment, which was sofosbuvir/ledipasvir by 63%. 40% changed their ART (70% to avoid interactions). CONCLUSIONS: Most of the evaluated patients have HIV infection. This type of consultation has a growing demand, is efficient (avoids transfers and is decisive) and has high acceptance. The most frequent reason for consultation was the treatment of HCV and more than a third of patients required ART change.

The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination.

Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboid transition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highly metastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or three-dimensional complex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficient amoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated with invasive features. NOX4 is necessary to maintain parenchymal structures, increase cell-cell and cell-to-matrix adhesion, and impair actomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating with higher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPase expression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42 levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worse prognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing to tumour aggressiveness.

¿Hay evidencias de que la elevación del colesterol unido a lipoproteínas de alta densidad obtiene beneficio clínico? / Is there evidence that increasing high-density lipoprotein cholesterol has clinical benefits?

La relación entre valores reducidos de colesterol unido a lipoproteínas de alta densidad (cHDL) y un aumento de riesgo de desarrollo de aterosclerosis es incuestionable desde el punto de vista epidemiológico. La mayoría de los ensayos clínicos ha valorado elevaciones del cHDL sin estudiar los cambios en la funcionalidad de las HDL. Adicionalmente, los fármacos que se han empleado para elevar el cHDL tienen una eficacia limitada, así como efectos secundarios no deseados, pertenecen a grupos farmacológicos heterogéneos con efectos metabólicos variados y, en algunas ocasiones, han mostrado efectos cardiovasculares contraproducentes. Globalmente, puede considerarse que la elevación farmacológica de los valores de cHDL ha producido, hasta ahora, efectos protectores cardiovasculares escasos, muy inferiores a los esperables a partir de los datos epidemiológicos. La importante diana del cHDL necesita nuevas aproximaciones terapéuticas que consigan de modo efectivo una reducción significativa del riesgo vascular (AU)

The association between reduced levels of high-density lipoprotein cholesterol (HDL-c) and an increased risk of the development of atherosclerosis is unquestionable from an epidemiological point of view. Most clinical trials have evaluated HDL-c elevations without studying changes in the functionality of high-density lipoproteins. Additionally, the drugs used to increase HDL-c have limited efficacy as well as unwanted side effects, belong to heterogeneous pharmacological groups with varied metabolic effects, and have sometimes shown deleterious cardiovascular effects. Overall, pharmacological elevation of HDL-c has produced scarce protective cardiovascular effects to date, much lower than those expected from the epidemiological data. HDL-c, a major and elusive target, requires new therapeutic approaches to significantly reduce vascular risk (AU)

Development of a short olfactory test based on the Connecticut Test (CCCRC).

OBJECTIVE: To create a short olfactory test, Connecticut Smell Test (CST), based on the CCCRC (Connecticut Chemosensor and Clinical Research Center). DESIGN: A prospective patient-based study. SETTINGS: Smell and Taste Outpatient Clinic at the Fundación Hospital Alcorcón, Madrid, Spain. MATERIAL AND METHODS: We compared a short test based on the CCCRC with the Pocket Smell Test (PST) based on the University of Pennsylvania Smell Identification Test) UPSIT in 40 patients with nasal polyposis, in order to determine the specificity, sensitivity, positive predictive and negative predictive values. The validity index was 95% with an accuracy rate of 10%. We determined unit cost, the time required to perform the test in the outpatient office and the difficulty to perform the test. RESULTS: The sensibility was 93.3% and the specificity was 76% with a positive predictive value of 70% and a negative predictive value of 95%. The unitary cost of CST was euro0.65 when it is performed by a doctor. The unitary cost of PST is euro1.76. Our short test took 34 seconds to perform. More than 96% of the patients thought the test was easy to do. CONCLUSION: Our test is a valid, easy and quick test to be used in patients with nasal polyposis.

Cortical reorganisation and tinnitus: principles of auditory discrimination training for tinnitus management.

Scientific evidence has proved reorganisation processes in the auditory cortex after sensorineural hearing loss and overstimulation of certain tonotopic cortical areas, as we see in auditory conditioning techniques. Acoustic rehabilitation reduces the impact of these reorganisation changes. Recent theories explain tinnitus mechanisms as a negative consequence of neural plasticity in the central nervous system after a peripheral aggression. Auditory discrimination training (ADT) could partially reverse the wrong changes in tonotopic representation and improve tinnitus. We discuss different studies and their efficacy on tinnitus perception and annoyance. Indications, method, dose and sound strategy need to be implemented.

Assessing the cause of tinnitus for therapeutic options.

BACKGROUND: The important development of tinnitus research in the last few years has improved the knowledge of tinnitus mechanisms, its diagnosis and its treatment. From a peripheral point of view, tinnitus is considered today as a brain reaction to erroneous input activity from the auditory or somatosensorial systems. METHOD: An accurate diagnosis is crucial to design the best therapeutic options. Treatment should be based on tinnitus aetiology as a first step. Medical counselling is a very effective tool, and it should be mandatory for all patients. Drug treatment experiments could take a step forward in the next few years. NMDA-antagonists or GABA-agonists are some of the targets of the research. The transtympanic delivery path is a good option for cochlear fluctuant diseases and gives us the possibility of higher dosages and fewer systemic side effects. Stimulation of the somatosensory pathways can help us to control somatic modulated tinnitus and it could be done through muscular training, electro-stimulation or pharmaceutical approaches. Auditory management is based in the fact that acoustic deprivation is the most powerful engine for tinnitus generation. Patients can be treated through passive training therapies as hearing aids, retraining therapies or filtered music approaches. Active acoustic training through auditory discrimination is a new promising approach and so is the repetitive transcranial magnetic stimulation over the auditory cortex. CONCLUSION: The combination of different approaches simultaneously will bring the best results for tinnitus relief and efforts should be made towards finding the best combination for each patient.

Trans-electrical nerve stimulation (TENS) for somatic tinnitus.

The somatic tinnitus syndrome includes those forms of tinnitus that are associated with a somatic disorder involving the head and upper neck. It has been suggested that physiological mechanisms where interactions occur between the somatosensory and auditory systems are the etiology for that kind of tinnitus. Trans-electrical nerve stimulation (TENS) of areas of skin close to the ear increases the activation of the dorsal cochlear nucleus through the somatosensory pathway and may augment the inhibitory role of this nucleus on the CNS and thereby ameliorate tinnitus. In a prospective descriptive study of 26 patients with the probable diagnosis of somatic tinnitus we found that TENS could improve the tinnitus in 46% of the participants (23% did not hear it anymore, and in 23% its intensity was reduced). VAS scores improved from 6.5 to 6.0 after 2 weeks of treatment (p<0.01). Patients used TENS at home for 2h, once per day during 2 weeks (alternating ramped burst, 150 pps, with pulse duration of 100 micro s, amplitude 0-60 mA; average TENS intensity was 27 mA). Intermittent "typewriter" type of tinnitus was the most responsive. Somatic tinnitus without otologic disease had better response than tinnitus associated to otological causes (p=0.047).

Auditory discrimination therapy (ADT) for tinnitus management.

Auditory discrimination training (ADT) designs a procedure to increase cortical areas responding to trained frequencies (damaged cochlear areas with cortical misrepresentation) and to shrink the neighboring over-represented ones (tinnitus pitch). In a prospective descriptive study of 27 patients with high frequency tinnitus, the severity of the tinnitus was measured using a visual analog scale (VAS) and the tinnitus handicap inventory (THI). Patients performed a 10-min auditory discrimination task twice a day during one month. Discontinuous 4 kHz pure tones were mixed randomly with short broadband noise sounds through an MP3 system. After the treatment mean VAS scores were reduced from 5.2 to 4.5 (p=0.000) and the THI decreased from 26.2% to 21.3% (p=0.000). Forty percent of the patients had improvement in tinnitus perception (RESP). Comparing the ADT group with a control group showed statistically significant improvement of their tinnitus as assessed by RESP, VAS, and THI.

Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

[The use of Quality of Life Questionnaire in patients with nasal polyposis]. / Utilidad del cuestionario RSDI para la valoración de la calidad de vida en pacientes con poliposis nasal.

OBJECTIVES: Polyposis handicap evaluation through Spanish validation of the Rhinosinusitis Disability Index. MATERIAL AND METHODS: Spanish validation of the Polyposis Disability Index (PDI). One hundred and fifty one patients referred to our Nose Unit in Fundación Hospital Alcorcón. The Spanish version of the PDI was administered after translation and retrotranslation. Internal consistency and reliability were established. RESULTS: Spanish adaptation of the PDI and ists subscales (functional, emotional and physical) showed a high reliability and internal consistency (Cronbach's alfa: 0,90). CONCLUSIONS: Spanish adaptation of the PDI is valid, reliable and can be used in a clinical setting to quantify the impact of polyposis on patient's quality of life.

[Mechanisms and management of hyperacusis (decreased sound tolerance)]. / Fisiopatología y tratamiento de la hiperacusia (hipersensibilidad al sonido).

Hyperacusis is a decreased sound tolerance. Prevalence of the disease is described in 9-15% of the population, but this percentage increases among the tinnitus patients. Pathophysiological mechanisms involve some disruptions in the amplification and regulation processes of the external hair cells or affect the central sound processing at the subcortical level. The role of the serotonin, also involved in other diseases related with hyperacusis (migraine, depression), can be crucial in this disorder. Other theories confirm the effect of the endorphins that activate the excitatory function of the glutamate, the auditory neurotransmitter, increasing its toxicity. The activation of the limbic and autonomic nervous systems produces the emotional reaction of the hyperacusis (anxiety, fear and depression). Proposed treatments are based on acoustic stimulation by a progressive introduction of sound (tinnitus retraining therapy TRT). Noise generators and hearing aids can be fitted in severe cases. The role of some drugs involved in the metabolism of the serotonin open new approaches for the management of hyperacusis.

Auditory discrimination therapy (ADT) for tinnitus managment: preliminary results.

CONCLUSION: This clinical assay has demonstrated the efficacy of auditory discrimination therapy (ADT) in tinnitus management compared with a waiting-list group. In all, 43% of the ADT patients improved their tinnitus, and its intensity together with its handicap were statistically decreased (EMB rating: B-2). OBJECTIVE: To describe the effect of sound discrimination training on tinnitus. ADT designs a procedure to increase the cortical representation of trained frequencies (damaged cochlear areas with a secondary reduction of cortical stimulation) and to shrink the neighbouring over-represented ones (corresponding to tinnitus pitch). STUDY DESIGN: This prospective descriptive study included 14 patients with high frequency matched tinnitus. Tinnitus severity was measured according to a visual analogue scale (VAS) and the Tinnitus Handicap Inventory (THI). Patients performed a 10-min auditory discrimination task twice a day for 1 month. Discontinuous 8 kHz pure tones were randomly mixed with 500 ms 'white noise' sounds through a MP3 system. ADT group results were compared with a waiting-list group (n=21). RESULTS: In all, 43% of our patients had improvement in their tinnitus. A significant improvement in VAS (p=0.004) and THI mean scores was achieved (p=0.038). Statistical differences between ADT and the waiting-list group have been proved, considering patients' self-evaluations (p=0.043) and VAS scores (p=0.004). A non-significant reduction of THI was achieved (p=0.113).

Utilidad del cuestionario RSDI para la valoración de la calidad de vida en pacientes con poliposis nasal / Quality of life in nasal polyposis

Objetivo: Presentar una adaptación al español del RSDI (Rinosinusitis Disability Index) denominada PDI (Rinosinusitis Disability Index) para valorar calidad de vida de pacientes con poliposis nasosinusal. Material y método: Estudio descriptivo en 151 enfermos con poliposis. Este test está compuesto de 30 preguntas agrupadas en 3 dominios: físico (9 preguntas), funcional (11 preguntas) y emocional (10 preguntas). El test presenta al final una valoración global de la calidad de vida que va de 1 a 10. Estudiamos la fiabilidad del cuestionario mediante el modelo alfa de Cronbach. Resultados: Para el 96% de los enfermos, el PDI era fácil de cumplimentar. El índice global de consistencia interna fue de 0,9. Para la subescala emocional fue de 0,82, para la subescala funcional fue de 0,84 y para la subescala física fue de 0,8. Conclusión: El PDI es un instrumento válido para el estudio de la calidad de vida en la poliposis nasosinusal

Objectives: Polyposis handicap evaluation through Spanish validation of the Rhinosinusitis Disability Index. Material and Methods: Spanish validation of the Polyposis Disability Index (PDI). One hundred and fifty one patients referred to our Nose Unit in Fundación Hospital Alcorcón. The Spanish version of the PDI was administered after tran-slation and retrotranslation. Internal consistency and reliability were established. Results: Spanish adaptation of the PDI and ists subscales (functional, emotional and physical) showed a high reliability and internal consistency (Cronbach´s alfa: 0,90). Conclusions: Spanish adaptation of the PDI is valid, reliable and can be used in a clinical setting to quantify the impact of polyposis on patient´s quality of life

[Assessment of hyperacusis: the self-rating questionnaire on hypersensitivity to sound]. / Evaluación de la hiperacusia: test de hipersensibilidad al sonido.

BACKGROUND: Hyperacusis is a decreased sound tolerance. The audiological examination includes the loudness discomfort level measurement and the handicap evaluation, so we introduce the Spanish validation of the german sound intolerance questionnaire. OBJECTIVES: To update the concept of hyperacusis and to evaluate its handicap through a Spanish validation of the Geräuschüberempfindlichkeit (GUF). PATIENTS: Forty patients referred to our Tinnitus and Hyperacusis Clinic in the University Hospital, between October 2004 and February 2005. OUTCOME MEASURES: The Spanish version of the GUF was performed after transla-tion and retro-translation. Internal consistency and reliability were established. RESULTS: Spanish adaptation of the GUF and its subscales (cognitive, somatic behaviour and emotional reaction) showed a high reliability and internal consistency (Cronbach's alfa: 0.9007). Higher GUF scores were statistically demonstrated in hyperacusis patients with hearing loss (p < 0.05) or tinnitus (p < 0.05). CONCLUSIONS: Spanish adaptation of the GUF is valid, reliable and can be used in a clinical setting to quantify the impact of hyperacusis on patient's quality of life.

Fisiopatología y tratamiento de la hiperacusia (hipersensibilidad al sonido) / Mechanisms and management of hyperacusis (decreased sound tolerance)

La hiperacusia es la reducción del umbral de tolerancia a los sonidos ambientales. Afecta a un 9-15% de la población, siendo su prevalencia mucho mayor entre los pacientes con acúfenos. Los mecanismos implicados abarcan alteraciones en la amplificación y regulación de las células ciliadas externas cocleares o bien se extienden hacia desórdenes en el procesamiento central del sonido, implicando niveles subcorticales. El papel de la serotonina, descrito en entidades clínicas relacionadas con la hiperacusia (migraña, depresión), y su relación con la vía auditiva, puede ser relevante en estos procesos. Otras teorías confirman un exceso de endorfinas como potenciador del efecto excitatorio del glutamato, neurotransmisor del sistema auditivo, y por tanto su toxicidad en la hiperacusia. La activación secundaria del sistema límbico y el sistema nervioso autónomo justifican la reacción psicoemocional de la hiperacusia (ansiedad, miedo, depresión). Los tratamientos descritos están basados en la desensibilización acústica a través de terapias de reintroducción progresiva de sonido (terapia de reentrenamiento TRT). La aplicación de generadores de ruido blanco o de prótesis auditivas de adaptación progresiva puede ser necesaria en los casos más severos. El papel de ciertos fármacos sobre el mecanismo de la serotonina abre otras vías en el manejo de esta entidad

Hyperacusis is a decreased sound tolerance. Prevalence of the disease is described in 9-15% of the population, but this percentage increases among the tinnitus patients. Pathophysiological mechanisms involve some disruptions in the amplification and regulation processes of the external hair cells or affect the central sound processing at the subcortical level. The role of the serotonin, also involved in other diseases related with hyperacusis (migraine, depression), can be crucial in this disorder. Other theories confirm the effect of the endorphins that activate the excitatory function of the glutamate, the auditory neurotransmitter, increasing its toxicity. The activation of the limbic and autonomic nervous systems produces the emotional reaction of the hyperacusis (anxiety, fear and depression). Proposed treatments are based on acoustic stimulation by a progressive introduction of sound (tinnitus retraining therapy TRT). Noise generators and hearing aids can be fitted in severe cases. The role of some drugs involved in the metabolism of the serotonin open new approaches for the management of hyperacusis

Evaluación de la hiperacusia: test de hipersensibilidad al sonido / Assessment of Hyperacusis: the self-rating questionnaire on hypersensitivity to sound

Introducción: La hiperacusia es la reducción anormal de la tolerancia a los sonidos ambientales. La exploración audiológica debe incluir la medida de los niveles de disconfort al sonido así como su incapacidad, para lo cual procedemos a la adaptación española del test aleman de hipersensibilidad al sonido. Objetivo: Exposición del protocolo de evaluación de la hiperacusia y adaptación al español del Test de Hipersensibilidad al sonido (THS) / Geräuschüberempfindlichkeit (G-ÜF). Muestra: Cuarenta pacientes remitidos a la Unidad de Acúfenos e Hiperacusia de un Hospital Universitario, entre los meses octubre 2004 y febrero de 2005. Medidas de evaluación: Administración de la versión española del THS-GÜF tras traducción y retrotraducción, y establecimiento de su fiabilidad y consistencia interna. Resultados: La adaptación española del THS-GÜF y sus subescalas (cognitiva, comportamiento somático y reacción emocional) muestran una fiabilidad y consistencia interna elevada (alfa de Cronbach de 0,9007). Se obtuvieron valores más elevados del GÜF en los pacientes que además presentaban hipoacusia (p<0,05) o acúfenos (p<0,05). Conclusión: La adaptación del THS-GÜF al idioma español es válida, fiable y puede ser utilizada en la evaluación clínica para cuantificar el impacto de la hiperacusia en la calidad de vida del paciente

BACKGROUND: Hyperacusis is a decreased sound tolerance. The audiological examination includes the loudness discomfort level measurement and the handicap evaluation, so we introduce the Spanish validation of the german sound intolerance questionnaire. OBJECTIVES: To update the concept of hyperacusis and to evaluate its handicap through a Spanish validation of the Gerauschuberempfindlichkeit (GUF). PATIENTS: Forty patients referred to our Tinnitus and Hyperacusis Clinic in the University Hospital, between October 2004 and February 2005. Outcome Measures: The Spanish version of the GUF was performed after transla-tion and retro-translation. Internal consistency and reliability were established. RESULTS: Spanish adaptation of the GUF and its subscales (cognitive, somatic behaviour and emotional reaction) showed a high reliability and internal consistency (Cronbach's alfa: 0.9007). Higher GUF scores were statistically demonstrated in hyperacusis patients with hearing loss (p < 0.05) or tinnitus (p < 0.05). CONCLUSIONS: Spanish adaptation of the GUF is valid, reliable and can be used in a clinical setting to quantify the impact of hyperacusis on patient's quality of life