Exposure to endogenous and exogenous sex hormones and reproductive history influence prognosis in women with ALS.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a higher incidence in men suggesting an influence of sex steroids. Our objective was to investigate past exposure to endogenous and synthetic steroids in female ALS patients and controls. METHODS: We administered a questionnaire to 158 postmenopausal women (75 ALS patients and 83 controls). We calculated reproductive time span (RTS), lifetime endogenous estrogen (LEE) and progesterone exposures (LPE), oral contraceptive pill (OCP) use, and reproductive history. RESULTS: ALS patients showed shorter LEE and LPE, a lower proportion of breast cancer, and 11% showed no history of pregnancies vs. 4% of controls. Odds ratios (ORs) showed that <17 y of LEE and a delayed menarche (>13 y) constitute risk factors for ALS [OR = 2.1 (95% confidence interval {CI}, 1.08-4.2); and OR = 2.4 (95% CI, 1.1-5.1) respectively]. According to Cox survival analysis, for each year the LEE increased over 17 y, it was independently associated with longer survival [hazard ratio (HR) = 0.37 (95% CI, 0.16-0.85)] after adjusting for smoking, age and site of onset. Multivariate regression analysis demonstrated that for each month using OCP for longer than 40 mo increased the risk of ALS [adjusted OR = 4.1 (95% CI, 1.2-13.8)]. DISCUSSION: Thus, longer exposure to endogenous female sex steroids increased survival and reduced ALS susceptibility. In contrast, longer exposure to synthetic sex steroids showed a negative impact by reducing the production of endogenous female sex steroids or due to crossover with other steroid receptors. Given the neuroprotective effects of sex steroids, we suggest that abnormalities of neuroendocrine components may alter motor function in women with ALS.

Effect of age on human ACE2 and ACE2-expressing alveolar type II cells levels.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19. Viral entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). Transcriptomic studies showed that children display lower ACE2 than adults, though gene expression levels do not always correlate with protein levels. We investigated the effect of age on ACE2 and TMPRSS2 protein expression in alveolar type II (AT2) cells in the lungs of children compared to adults. We also analysed the ratio of Ang-(1-7) to Ang II as a surrogate marker of ACE2 activity in the subjects' lung parenchyma. METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. RESULTS: The amount of ACE2-expressing AT2 cells and ACE2 protein content were lower in children than in adults. Ang II levels were higher in children compared to adults and inversely correlated with the amount of ACE2-expressing AT2 cells. Children presented lower Ang-(1-7)/Ang II ratio than adult suggesting lower ACE2 activity in children. TMPRSS2 protein expression was not influenced by age. CONCLUSIONS: These results expand on previous transcriptomic studies and may partially explain the low susceptibility of children to SARS-CoV-2 infection. CATEGORY OF STUDY: Clinical original research IMPACT: Children display lower ACE2 protein content and activity compared to adults. Ang II levels were higher in children compared to adults and inversely correlated with the amount of ACE2-expressing AT2 cells TMPRSS2 protein expression was not influenced by age. These results expand on previous transcriptomic studies and may partially explain the low susceptibility of children to SARS-CoV-2 infection.

Cognitive Deficits Found in a Pro-inflammatory State are Independent of ERK1/2 Signaling in the Murine Brain Hippocampus Treated with Shiga Toxin 2 from Enterohemorrhagic Escherichia coli.

Shiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS), and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. The purpose of this work is to elucidate the signaling pathways that may activate the inflammatory processes triggered by Stx2, which produces cognitive alterations at the level of the hippocampus. Results demonstrate that Stx2 produced depression-like behavior, pro-inflammatory cytokine release, and NF-kB activation independent of the ERK1/2 signaling pathway, while co-administration of Stx2 and LPS reduced memory index. On the other hand, LPS activated NF-kB dependent on ERK1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.

Plasmatic renin-angiotensin system in normotensive and hypertensive patients hospitalized with COVID-19.

BACKGROUND: Besides its counterbalancing role of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) 2 is the receptor for the type 2 coronavirus that causes severe acute respiratory syndrome, the etiological agent of COVID-19. COVID-19 is associated with increased plasmatic ACE2 levels, although conflicting results have been reported regarding angiotensin (Ang) II and Ang-(1-7) levels. We investigated plasmatic ACE2 protein levels and enzymatic activity and Ang II and Ang-(1-7) levels in normotensive and hypertensive patients hospitalized with COVID-19 compared to healthy subjects. METHODS: Ang II and Ang-(1-7), and ACE2 activity and protein levels were measured in 93 adults (58 % (n = 54) normotensive and 42 % (n = 39) hypertensive) hospitalized with COVID-19. Healthy, normotensive (n = 33) and hypertensive (n = 7) outpatient adults comprised the control group. RESULTS: COVID-19 patients displayed higher ACE2 enzymatic activity and protein levels than healthy subjects. Within the COVID-19 group, ACE2 activity and protein levels were not different between normotensive and hypertensive-treated patients, not even between COVID-19 hypertensive patients under RAS blockade treatment and those treated with other antihypertensive medications. Ang II and Ang-(1-7) levels significantly decreased in COVID-19 patients. When COVID-19 patients under RAS blockade treatment were excluded from the analysis, ACE2 activity and protein levels remained higher and Ang II and Ang-(1-7) levels lower in COVID-19 patients compared to healthy people. CONCLUSIONS: Our results support the involvement of RAS in COVID-19, even when patients under RAS blockade treatment were excluded. The increased circulating ACE2 suggest higher ACE2 expression and shedding.

Renin-angiotensin system blockade on angiotensin-converting enzyme 2 and TMPRSS2 in human type II pneumocytes.

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.

Difluprednate 0.05% twice a day vs prednisolone acetate 1% 4 times a day for cataract postsurgical inflammation treatment: noninferiority trial.

PURPOSE: To establish whether difluprednate 0.05% nanoemulsion (DIFL) twice a day is as effective as prednisolone acetate 1% + phenylephrine hydrochloride 0.12% suspension (PRED) 4 times a day for postsurgical inflammation treatment. SETTING: 4 private Argentine ophthalmological centers. DESIGN: Noninferiority, prospective, multicenter, double-blind, randomized, parallel-group, comparative trial. METHODS: A total of 259 patients who underwent phacoemulsification randomly received DIFL or PRED, starting the day before surgery and continuing for 28 days. The primary endpoint was central corneal thickness. Noninferior anti-inflammatory efficacy was considered if the difference of corneal thickness between baseline and day 4 did not differ beyond 17 µm between treatments. Secondary endpoints were cell and flare, corrected distance visual acuity (CDVA), endothelial cell count, optical coherence tomography (OCT) central macular thickness, and intraocular pressure. All outcomes were evaluated at baseline and day 1, 4, and 28 postoperatively. RESULTS: 225 patients finished the study. The difference in corneal thickness at baseline and day 4 did not differ beyond 17 µm between treatments (95% CI -2.78 µm to 14.84 µm), with no statistically significant difference ( P = .523). No statistically significant differences were found between groups in total anterior chamber clearance at any study timepoint ( P > .05). Moreover, no statistically significant differences were reported between treatments in CDVA ( P = .455), endothelial cell count ( P = .811), OCT central macular thickness ( P = .869), and intraocular pressure outcome ( P = .316). CONCLUSIONS: Difluprednate administered twice a day was at least as effective as prednisolone acetate administered 4 times a day for inflammatory treatment after cataract surgery.

A poor and delayed anti-SARS-CoV2 IgG response is associated to severe COVID-19 in children.

BACKGROUND: Most children and youth develop mild or asymptomatic disease during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, a very small number of patients suffer severe Coronavirus induced disease 2019 (COVID-19). The reasons underlying these different outcomes remain unknown. METHODS: We analyzed three different cohorts: children with acute infection (n=550), convalescent children (n=138), and MIS-C (multisystem inflammatory syndrome in children, n=42). IgG and IgM antibodies to the spike protein of SARS-CoV-2, serum-neutralizing activity, plasma cytokine levels, and the frequency of circulating Follicular T helper cells (cTfh) and plasmablasts were analyzed by conventional methods. FINDINGS: Fifty-eight percent of the children in the acute phase of infection had no detectable antibodies at the time of sampling while a seronegative status was found in 25% and 12% of convalescent and MIS-C children, respectively. When children in the acute phase of the infection were stratified according disease severity, we found that contrasting with the response of children with asymptomatic, mild and moderate disease, children with severe COVID-19 did not develop any detectable response. A defective antibody response was also observed in the convalescent cohort for children with severe disease at the time of admission. This poor antibody response was associated to both, a low frequency of cTfh and a high plasma concentration of inflammatory cytokines. INTERPRETATION: A weak and delayed kinetic of antibody response to SARS-CoV-2 together with a systemic pro-inflammatory profile characterize pediatric severe COVID-19. Because comorbidities are highly prevalent in children with severe COVID-19, further studies are needed to clarify their contribution in the weak antibody response observed in severe disease. FUNDING: National Agency for Scientific and Technological Promotion from Argentina (IP-COVID-19-0277 and PMO-BID-PICT2018-2548).

Reduced Trypanosoma cruzi-specific humoral response and enhanced T cell immunity after treatment interruption with benznidazole in chronic Chagas disease.

BACKGROUND: Interruption of benznidazole therapy due to the appearance of adverse effects, which is presumed to lead to treatment failure, is a major drawback in the treatment of chronic Chagas disease. METHODS: Trypanosoma cruzi-specific humoral and T cell responses, T cell phenotype and parasite load were measured to compare the outcome in 33 subjects with chronic Chagas disease treated with an incomplete benznidazole regimen and 58 subjects treated with the complete regimen, during a median follow-up period of 48 months. RESULTS: Both treatment regimens induced a reduction in the T. cruzi-specific antibody levels and similar rates of treatment failure when evaluated using quantitative PCR. Regardless of the regimen, polyfunctional CD4+ T cells increased in the subjects, with successful treatment outcome defined as a decrease of T. cruzi-specific antibodies. Regardless of the serological outcome, naive and central memory T cells increased after both regimens. A decrease in CD4+ HLA-DR+ T cells was associated with successful treatment in both regimens. The cytokine profiles of subjects with successful treatment showed fewer inflammatory mediators than those of the untreated T. cruzi-infected subjects. High levels of T cells expressing IL-7 receptor and low levels of CD8+ T cells expressing the programmed cell death protein 1 at baseline were associated with successful treatment following benznidazole interruption. CONCLUSIONS: These findings challenge the notion that treatment failure is the sole potential outcome of an incomplete benznidazole regimen and support the need for further assessment of the treatment protocols for chronic Chagas disease.

Communicating bad news in the context of COVID-19 / Comunicación de malas noticias en el contexto de la COVID-19

Abstract Communicating bad news is one of the most frequent activities in hospitals, for which some recommendations have been adapted to the needs within the coronavirus-2 disease (COVID-19) context. This document presents nine steps to deliver bad news (face to face or remotely) adapted to the COVID-19 context from two international protocols (SPIKES and GRIEV_ING). The importance of promoting physical and emotional self-care skills in health personnel is also described, as well as psychological first aid strategies to address the emotional response of the family member who receives the news. Finally, the limitations and advantages of the proposal should be considered.

Resumen La comunicación de malas noticias es una de las actividades más frecuentes en los hospitales dentro del contexto de la COVID-19. A pesar de su alta frecuencia, existen pocas recomendaciones adaptadas a las necesidades que el contexto de la COVID-19 demanda. Debido a lo anterior, en el presente escrito se presentan nueve pasos para dar malas noticias (cara a cara o por vía remota) de dos protocolos internacionales (SPIKES y GRIEV_ING) adaptados a las necesidades de transmisión de información de la COVID-19. Se describe también la importancia de promover habilidades de autocuidado físico y emocional en el personal de salud, así como estrategias de primeros auxilios psicológicos para el abordaje de la respuesta emocional del familiar que recibe la noticia. Finalmente, se deben considerar las limitaciones y ventajas de la propuesta.

Apoptotic regulator BCL-2 blockade as a potential therapy in classical Hodgkin Lymphoma.

The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases. AIMS: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax. MAIN METHODS: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively. KEY FINDINGS: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated. SIGNIFICANCE: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines.

Psychological support during COVID-19 death notifications: Clinical experiences from a hospital in Mexico.

It is estimated that more than 300,000 people have died because of COVID-19 globally. The vast majority of documented deaths have occurred within hospitals, leading to psychological impacts on both family members and health care workers. This paper describes the actions (online death notification education, remote crisis intervention, and support for health care professionals) taken at a hospital in Mexico to address the psychological impacts of the notification of a COVID-19-related death on both the deceased's relatives and the health care personnel involved. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Thyroid hormones in ovarian follicular fluid: Association with oocyte retrieval in women undergoing assisted fertilization procedures.

OBJECTIVE: Our aim was to analyze the role of thyroid hormones in follicular fluid (FF) in relation to the number of oocytes retrieved in women recruited for an assisted fertilization procedure. METHODS: Retrospective cohort study of 51 women 37.5±3.3 years, range 29-42, evaluated after a controlled ovarian stimulation protocol in a University Hospital. FF was sampled by transvaginal ultrasound-guided aspiration after ovarian hyperstimulation and we measured T3 (T3f), T4 (T4f), TSH (TSHf) and free T4 (T4ff). The oocyte maturation rate was calculated as: Number of metaphase II oocytes/Number of oocytes retrieved x 100. Statistical analysis was performed using the SPSS-19 software. RESULTS: Hormone levels in FF were: TSHf 1.3µIU/ml (0.4 - 2.7), T3f: 1.52±0.46 nmol/L, T4f 88.8±30.9nmol/L and T4ff: 15.44±2.57pmol/L. The number of oocytes recovered was dependent onT4f following the equation: Log (oocyte) = 0.379+0.042*T4f (r:0.352, p=0.012). After a logistic regression model analysis, T3f showed a tendency to be associated with the OMR: OR (95 % CI)= 0.977 (0.954 to 1.001), p=0.057. CONCLUSIONS: The correlation found between thyroid hormones and the number of oocytes retrieved suggests an interaction between thyroid and gonadal axes in relation to follicular development.

Communicating bad news in the context of COVID-19.

Communicating bad news is one of the most frequent activities in hospitals, for which some recommendations have been adapted to the needs within the coronavirus-2 disease (COVID-19) context. This document presents nine steps to deliver bad news (face to face or remotely) adapted to the COVID-19 context from two international protocols (SPIKES and GRIEV_ING). The importance of promoting physical and emotional self-care skills in health personnel is also described, as well as psychological first aid strategies to address the emotional response of the family member who receives the news. Finally, the limitations and advantages of the proposal should be considered.

La comunicación de malas noticias es una de las actividades más frecuentes en los hospitales dentro del contexto de la COVID-19. A pesar de su alta frecuencia, existen pocas recomendaciones adaptadas a las necesidades que el contexto de la COVID-19 demanda. Debido a lo anterior, en el presente escrito se presentan nueve pasos para dar malas noticias (cara a cara o por vía remota) de dos protocolos internacionales (SPIKES y GRIEV_ING) adaptados a las necesidades de transmisión de información de la COVID-19. Se describe también la importancia de promover habilidades de autocuidado físico y emocional en el personal de salud, así como estrategias de primeros auxilios psicológicos para el abordaje de la respuesta emocional del familiar que recibe la noticia. Finalmente, se deben considerar las limitaciones y ventajas de la propuesta.

Impaired frequencies and function of platelets and tissue remodeling in chronic Chagas disease.

Chronic inflammation, as a consequence of the persistent infection with Trypanosoma cruzi, leads to continuous activation of the immune system in patients with chronic Chagas disease. We have previously shown that increased sera levels of soluble P-selectin are associated with the severity of the cardiomyopathy distinctive of chronic Chagas disease. In this study, we explored the expression of biomarkers of platelet and endothelial activation, tissue remodeling, and mediators of the coagulation cascade in patients at different clinical stages of chronic Chagas heart disease. The frequencies of activated platelets, measured by the expression of CD41a and CD62P were decreased in patients with chronic Chagas disease compared with those in uninfected subjects, with an inverse association with disease severity. Platelet activation in response to adenosine diphosphate was also decreased in T. cruzi-infected subjects. A major proportion of T. cruzi infected subjects showed increased serum levels of fibrinogen. Patients with severe cardiac dysfunction showed increased levels of endothelin-1 and normal values of procollagen I. In conclusion, chronic infection with T. cruzi induced hemostatic alterations, even in those patients who do not yet present cardiac symptoms.

Frecuencia de la afección auditiva y los factores asociados en pacientes con artritis idiopática juvenil / Frequency of auditory involvement and of associated factors in patients with juvenile idiopathic arthritis

Introducción: La artritis idiopática juvenil (AIJ) es una enfermedad autoinmune de curso crónico, caracterizada por la presencia de artritis en menores de 16 años, por más de 6 semanas en ausencia de otra causa conocida. La expresión extra articular en el sistema audiovestibular se relaciona con la afección de las articulaciones de la cadena oscicular, como consecuencia del proceso inflamatorio de la membrana sinovial. Estudios previos realizados en población infantil han reportado que la pérdida auditiva puede ser de tipo neurosensorial y/o conductiva. Objetivo: Determinar la frecuencia de la afección auditiva y los factores asociados en los pacientes con AIJ. Metodología: Estudio prospectivo y analítico. Se incluyó a 62 pacientes con AIJ con edades comprendidas entre 5 y 15 años, a partir de agosto del 2013 a enero del 2014. El estudio fue aprobado por el comité de ética local y los padres firmaron el consentimiento bajo información. Se realizó otoscopia microscópica, audiometría tonal, timpanometría, reflejo estapedial y emisiones otoacústicas transitorias (EOT); la evaluación reumatológica incluyó exploración articular y aplicación de cuestionario para la evaluación del estado de salud en la infancia (CHAQ). Se utilizaron medidas de tendencia y de dispersión; asociación χ2 con una p<0,05 para la significación estadística. Resultados: Se incluyó a 62 pacientes; 56 niñas y 6 niños, edad media 11,9 años, duración media de la enfermedad de 3,4 años; el 46% presentó AIJ poliarticular factor reumatoide (FR) positivo; el 40%, AIJ poliarticular FR negativo; el 15% AIJ sistémica y el 3% oligoarticular. Se encontró enfermedad activa en 29 pacientes y 33 en remisión con medicamentos. Se evaluaron en total 124 oídos; en 78 se encontró curva tipo As de la clasificación de Jerger, curva tipo A en 45 y en uno se reportó curva tipo AD. En la audiometría tonal no se encontró hipoacusia en ningún paciente y esta estuvo acorde con la logoaudiometría. Las EOT se encontraron ausentes en el 4% de los evaluados y sin reflejo estapedial en menos del 10%. Los factores que presentaron una asociación con la afección auditiva fueron la variedad poliarticular FR positivo, el tiempo de evolución, el índice de discapacidad y los niveles de VSG (p<0,001). Conclusión: Se encontró en más de la mitad de los pacientes estudiados alteraciones auditivas presentes en el timpanograma, asociadas con la variedad poliarticular FR positivo, tiempo de evolución, actividad de la enfermedad y la elevación de la VSG

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease characterized by the presence of arthritis in children under 16 years of age for more than 6 weeks in the absence of any other known cause. The extra-articular manifestations, especially in the audiovestibular system, are related to the involvement of the joints of the ossicular chain as a result of the inflammatory process in the synovium. Previous clinical studies in pediatric patients have shown conductive or sensorineural hearing loss. Objective: The aim of this study was to assess the frequency of hearing impairment and of associated factors in patients with JIA. Methodology: A prospective, analytical study was conducted from January 2013 to August 2014 in 62 patients with JIA aged between 5 and 15 years. The study was approved by the local ethics committee and parents signed their informed consent. All subjects underwent audiological examination involving otomicroscopy, audiometry, tympanometry, stapedius reflex and test for transient otoacoustic emissions (TOAE); rheumatologic evaluation included joint examination and the application of a measure of functional ability (disability) using the Childhood Health Assessment Questionnaire (CHAQ). Measures of central tendency and of dispersion were used (chi-square for associations and P<.05 for statistical significance). Results: Sixty-two patients were included: 56 girls and 6 boys, mean age 11.9 years and mean disease duration of 3.4 years; 46% had rheumatoid factor (RF)- positive polyarticular JIA, 40% had RF-negative polyarticular JIA, 15% had disease of systemic onset and 3% had oligoarthritis. Active disease was found in 29 patients and 33 were in remission with medication. Of the total of 124 ears evaluated according to the Jerger classification for tympanometry, abnormal findings were observed in 78 that were type As and in 1 that was type Ad, whereas there were 45 type A ears. Hearing loss was disclosed by speech audiometry, rather than by pure tone audiometry. The TOAE were absent in 4% of those assessed and the stapedius reflex was absent in less than 10%. Factors that had a positive correlation with hearing impairment were RF-positive polyarticular JIA, disease duration, degree of disability and the erythrocyte sedimentation rate level (P<.000). Conclusion: The presence of an abnormal tympanogram suggested early involvement in the structure of the tympanic-ossicular complex; however, 3.4 years later, no hearing loss had been reported

Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer.

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

Heme Oxygenase-1 Has an Antitumor Role in Breast Cancer.

Aims: Heme oxygenase-1 (HO-1) is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, which is also true for breast cancer (BC). In this work, we address this discrepancy regarding the role of HO-1 in BC. Results: HO-1 was detected in human BC tissues, and its protein levels correlated with reduced tumor size and longer overall survival time of patients, thus suggesting the clinical importance of HO-1 in this type of cancer. Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade suggesting that the effect of HO-1 is dependent on its cellular localization. In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduce the tumor burden in two different animal models of BC. Furthermore, the pharmacological and genetic activation of HO-1 in several BC cell lines reduce the cellular viability by inducing apoptosis and cell cycle arrest and decrease the cellular migration and invasion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination. Innovation and Conclusion: By using various BC cell lines and animal models as well as human tumor samples, we demonstrated that total HO-1 displays antitumor activities in BC. Furthermore, our study suggests that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types.

Frequency of auditory involvement and of associated factors in patients with juvenile idiopathic arthritis. / Frecuencia de la afección auditiva y los factores asociados en pacientes con artritis idiopática juvenil.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease characterized by the presence of arthritis in children under 16 years of age for more than 6 weeks in the absence of any other known cause. The extra-articular manifestations, especially in the audiovestibular system, are related to the involvement of the joints of the ossicular chain as a result of the inflammatory process in the synovium. Previous clinical studies in pediatric patients have shown conductive or sensorineural hearing loss. OBJECTIVE: The aim of this study was to assess the frequency of hearing impairment and of associated factors in patients with JIA. METHODOLOGY: A prospective, analytical study was conducted from January 2013 to August 2014 in 62 patients with JIA aged between 5 and 15 years. The study was approved by the local ethics committee and parents signed their informed consent. All subjects underwent audiological examination involving otomicroscopy, audiometry, tympanometry, stapedius reflex and test for transient otoacoustic emissions (TOAE); rheumatologic evaluation included joint examination and the application of a measure of functional ability (disability) using the Childhood Health Assessment Questionnaire (CHAQ). Measures of central tendency and of dispersion were used (chi-square for associations and P<.05 for statistical significance). RESULTS: Sixty-two patients were included: 56 girls and 6 boys, mean age 11.9 years and mean disease duration of 3.4 years; 46% had rheumatoid factor (RF)- positive polyarticular JIA, 40% had RF-negative polyarticular JIA, 15% had disease of systemic onset and 3% had oligoarthritis. Active disease was found in 29 patients and 33 were in remission with medication. Of the total of 124 ears evaluated according to the Jerger classification for tympanometry, abnormal findings were observed in 78 that were type As and in 1 that was type Ad, whereas there were 45 type A ears. Hearing loss was disclosed by speech audiometry, rather than by pure tone audiometry. The TOAE were absent in 4% of those assessed and the stapedius reflex was absent in less than 10%. Factors that had a positive correlation with hearing impairment were RF-positive polyarticular JIA, disease duration, degree of disability and the erythrocyte sedimentation rate level (P<.000). CONCLUSION: The presence of an abnormal tympanogram suggested early involvement in the structure of the tympanic-ossicular complex; however, 3.4 years later, no hearing loss had been reported.