Superior semicircular canal dehiscence in relation with the superior petrosal sinus: our experience, surgical management and systematic review of literature.

PURPOSE: Most of Superior Semicircular Canal Dehiscence (SSCD) are located in the apical region of the SSC. However, in a small number of cases, it may be situated in the medial wall, causing the SSC to contact with the superior petrosal sinus (SPS). The aim of this study is to describe four patients with SSCD involving the superior petrosal sinus (SSCD-SPS) and to perform a review of the literature. METHODS: Observational retrospective study of patients diagnosed of SSCD-SPS in a tertiary referral center. A systematic review was made, identifying 7 articles in the literature. Clinical presentation, complementary test (pure-tone audiometry, PTA; vestibular evoked myogenic potential, VEMP; computed tomography, CT), therapeutic management and outcomes were reported. RESULTS: Four new cases of SSCD-SPS are reported, in three of them a transmastoid plugging was performed. 54 patients with SSCD-SPS (57 dehiscences) were reported in the literature. The most frequent symptoms were aural pressure (57.41%) and vertigo provoked by pressure/Valsalva (55.55%). Conductive hearing loss was the most common finding in PTA (47.37%). Abnormally low thresholds were observed in 59.46% of reported VEMP. Transmastoid approach was used in ten cases, middle fossa approach in four, round window reinforcement in one, and occlusion of the SPS using coils in two. CONCLUSIONS: Within SSCD, we have encountered a rare subtype characterized by its medial wall location in close proximity to the SPS. This subgroup needs special consideration as it has shown its own distinct characteristics. Regarding therapeutic management, we advocate a transmastoid approach.

Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic ß-catenin.

Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a link between oncogenic APC, loss of plasma membrane homeostasis and CRC development.

Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk.

Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.

"The Triptan's Hangover": A Multicentric Cross-sectional Observational Study of the Adverse Events of Triptans in Patients With Migraine.

ABSTRACT: The emergence of triptans represented a breakthrough in the treatment of migraine, but in clinical practice, patients describe symptoms that resemble those of a hangover after taking them. We propose the use of the Hangover Symptoms Scale (HSS) to evaluate this syndrome in patients that take triptans, which may help identify patients at higher risk of presenting these adverse effects that may interfere with therapeutic compliance.A cross-sectional observational pilot study with prospective data collection through a clinical-demographic questionnaire and the HSS was carried out on patients with migraine treated in headache units in 3 tertiary hospitals in Madrid.Sixty-six patients were included in the study. The median HSS was 4 and all symptoms were present in at least 15% of the patients, with difficulty to concentrate being the most frequent (57.6%). No significant differences were found between the presence of a higher HSS score and the sociodemographic characteristics of the patient or his migraine. The presence of aura was associated with a higher percentage of trembling (P = 0.029) and fatigue (nonvisual, polymodal auras; P = 0.017).According to our study, triptans are responsible for a set of symptoms overlapping with those that occur during a hangover. Therefore, we propose that the HSS could be a useful tool for the evaluation and quantification of these effects in patients receiving triptans. In addition, we found that clinical features could be more frequently associated with the appearance of these adverse effects that, however, are not related to any particular patient profile.

Implementation of Advanced Methods for Reproductive Pharmacovigilance in Autism: A Meta-Analysis of the Effects of Prenatal Antidepressant Exposure.

OBJECTIVE: Observational studies of prenatal antidepressant safety are hindered by methodological concerns, including susceptibility to surveillance bias. Some studies address potential bias by using alternative strategies to operationalize study comparison groups. In a meta-analysis of the association between prenatal antidepressant exposure and autism risk, the authors examined the utility of comparison group operationalization in reducing surveillance bias. METHODS: A systematic search of multiple databases through August 2017 was conducted, selecting controlled observational studies of the association of prenatal antidepressant exposure with autism. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis produced summary effect measures with 95% confidence intervals stratified by comparator group composition, antidepressant class, and trimester of exposure. RESULTS: Fourteen studies were included, with 13 reporting results using a population-based comparison group, five using a psychiatric control group, and four using a discordant-sibling control group. Eight of the 14 studies were rated poor because of inadequate control for prenatal depression and maternal ethnicity. Autism risk estimates after prenatal exposure to any antidepressant were decidedly different for population-based designs (hazard ratio=1.42, 95% CI=1.18, 1.70; odds ratio=1.58, 95% CI=1.25, 1.99) compared with psychiatric control (hazard ratio=1.14, 95% CI=0.84, 1.53; odds ratio=1.24, 95% CI=0.93, 1.66) and discordant-sibling (hazard ratio=0.97, 95% CI=0.68, 1.37; odds ratio=0.85, 95% CI=0.54, 1.35) designs. Findings for prenatal exposure to selective serotonin reuptake inhibitors were similar. Meta-regression of population-based studies demonstrated that despite statistical adjustment, ethnicity differences remained a significant source of study heterogeneity. CONCLUSIONS: In this meta-analysis, neither psychiatric control nor discordant-sibling designs supported an association between prenatal antidepressant exposure and autism. Discordant-sibling designs effectively addressed surveillance bias in pharmacovigilance reports derived from national registries and other large databases.

Thrombin Promotes Macrophage Polarization into M1-Like Phenotype to Induce Inflammatory Responses.

Despite strong evidence supporting the cellular interplay between haemostasis and innate immunity, humoral connections between blood coagulation and the behavior of inflammatory macrophages are not well understood. In this study, we investigated changes in gene expression of selected cytokines and chemokines and their secretion profiles following thrombin stimulation of murine macrophages. Thrombin promoted differentiation of macrophages into an M1-like phenotype that was associated with the expression of classical pro-inflammatory markers. The cellular actions of thrombin on macrophages were mediated in part by protease-activated receptor-1 (PAR-1) and were dependent on phosphoinositide 3-kinase/AKT and nuclear factor-κB. Moreover, heat-denatured thrombin stimulated the secretion of some pro-inflammatory mediators to the same magnitude indicating that different receptors transmit cellular signals of enzymatically active thrombin and nonactive thrombin, the latter remaining so far undefined. Finally, pretreatment of macrophages with thrombin resulted in tolerance against secondary stimulation by lipopolysaccharide with regard to expression of tumor necrosis factor-α. These results provide new insights into the molecular link between the key enzyme of haemostasis and innate immunity responses.

The Impact of Anodal tDCS on the Attentional Networks as a Function of Trait Anxiety and Depressive Symptoms: A Preregistered Double-Blind Sham-Controlled Experiment.

OBJECTIVE: Attention is a multifaceted construct, including three distinct attentional networks: the alerting, orienting, and executive conflict networks. Recently, researchers have started to envision strategies to enhance the attentional networks, and transcranial Direct Current Stimulation (tDCS) has emerged as a promising tool to do so, especially regarding the executive conflict network. On the other hand, other research lines have suggested that anodal tDCS might yield more substantial impacts among depressive and anxious participants. METHOD: In this preregistered study, we thus examined two questions. First, we wanted to replicate previous observations and tested whether anodal tDCS does improve the executive conflict network's efficiency. Second, we set out to clarify the impact of anxiety and depressive symptoms on this effect. To do so, we adopted a double-blind within-subject protocol in an unselected sample (n = 50) and delivered a single session of anodal- applied over the dorsolateral part of the left prefrontal cortex-versus sham tDCS during the completion of a task assessing the attentional networks. We assessed anxiety and depressive symptoms at baseline. RESULTS AND CONCLUSIONS: Although there were no significant direct effects of tDCS on the attentional networks, we found that the higher the levels of depression and trait anxiety, the larger the executive conflict network's enhancement during tDCS. By highlighting the importance of trait anxiety and depression when considering the impact of tDCS on the attentional networks, this study fulfills a valuable niche in clinical neuroscience, wherein preclinical data provide critical clues for larger, more definitive future translational efforts.

Incidencia de Escherichia coli O157: H7 en heces de rumiantes lactantes con síndrome diarreico / Incidence of Escherichia coli 0157: H7 in feces of lactating ruminants with diarrheal syndrome

RESUMEN Objetivo. Identificar Escherichia coli O157:H7 presente en heces diarreicas de rumiantes lactantes con síndrome diarreico y seguridad de ingesta de calostro. Materiales y métodos. Se realizó un muestreo de 316 rumiantes durante el período de agosto 2015 a marzo 2016 en los municipios de Río Grande, General Enrique Estrada, Morelos y Calera de Víctor Rosales del estado de Zacatecas, 67 de bovinos, 183 de ovinos y 66 de caprinos. Resultados. Se identificaron en medio cromogénico CHROMagarTM: 260 coliformes, 78 Escherichia coli O157:H7, 16 Proteus spp., y 25 colonias de bacterias sin identificar con este medio, encontrándose una incidencia de Escherichia coli O157:H7 de 22.03% en los cuatro municipios. Conclusiones. Escherichia coli O157:H7 es la segunda bacteria encontrada en heces de rumiantes con un 22% de incidencia, la cual es un factor de riesgo de muerte en rumiantes lactantes (menos de 21 días de nacidos) causando pérdidas económicas y riesgo para la salud de la población del estado de Zacatecas.

ABSTRACT Objective. To identify Escherichia coli 0157:H7 present in diarrheal feces of lactating ruminants with diarrheal syndrome and safety of colostrum intake. Materials and methods. A feces sampling of 316 ruminants was carried out during the period of August 2015 to March 2016 in the municipalities of Río Grande, General Enrique Estrada, Morelos and Calera de Victor Rosales of the state of Zacatecas, obtained from 67 cattle, 183 sheep and 66 goats. Results. The following were identified in CHROMagarTM chromogenic medium: 260 coliforms, 78 Escherichia coli 0157:H7, 16 Proteus spp. and 25 colonies of unidentified bacteria, finding an incidence of Escherichia coli 0157:H7 of 22.03% in the four municipalities. Conclusions. Escherichia coli 0157:H7 is the second bacteria found in ruminant feces with an incidence of 22%, which is a mortality risk factor in lactating ruminants (less than 21 days old), causing economic loss and health risk for the population of the state of Zacatecas.

HDL-Mediated Lipid Influx to Endothelial Cells Contributes to Regulating Intercellular Adhesion Molecule (ICAM)-1 Expression and eNOS Phosphorylation.

Reverse cholesterol transport (RCT) is considered as the most important antiatherogenic role of high-density lipoproteins (HDL), but interventions based on RCT have failed to reduce the risk of coronary heart disease. In contrast to RCT, important evidence suggests that HDL deliver lipids to peripheral cells. Therefore, in this paper, we investigated whether HDL could improve endothelial function by delivering lipids to the cells. Internalization kinetics using cholesterol and apolipoprotein (apo) AI fluorescent double-labeled reconstituted HDL (rHDL), and human dermal microvascular endothelial cells-1 (HMEC-1) showed a fast cholesterol influx (10 min) and a slower HDL protein internalization as determined by confocal microscopy and flow cytometry. Sphingomyelin kinetics overlapped that of apo AI, indicating that only cholesterol became dissociated from rHDL during internalization. rHDL apo AI internalization was scavenger receptor class B type I (SR-BI)-dependent, whereas HDL cholesterol influx was independent of SR-BI and was not completely inhibited by the presence of low-density lipoproteins (LDL). HDL sphingomyelin was fundamental for intercellular adhesion molecule-1 (ICAM-1) downregulation in HMEC-1. However, vascular cell adhesion protein-1 (VCAM-1) was not inhibited by rHDL, suggesting that components such as apolipoproteins other than apo AI participate in HDL's regulation of this adhesion molecule. rHDL also induced endothelial nitric oxide synthase eNOS S1177 phosphorylation in HMEC-1 but only when the particle contained sphingomyelin. In conclusion, the internalization of HDL implies the dissociation of lipoprotein components and a SR-BI-independent fast delivery of cholesterol to endothelial cells. HDL internalization had functional implications that were mainly dependent on sphingomyelin. These results suggest a new role of HDL as lipid vectors to the cells, which could be congruent with the antiatherogenic properties of these lipoproteins.

Responses of Endothelial Cells Towards Ischemic Conditioning Following Acute Myocardial Infarction.

One of the primary therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial infarct size and optimizing cardiac function following acute myocardial infarction (AMI). Patients with AMI who underwent reperfusion therapy display dysfunction of the coronary endothelium. Consequently, ischemic endothelial cells become more permeable and weaken their natural anti-thrombotic and anti-inflammatory potential. Ischemia-reperfusion injury (IRI) is associated with activation of the humoral and cellular components of the hemostatic and innate immune system, and also with excessive production of reactive oxygen species (ROS), the inhibition of nitric oxide synthase, and with inflammatory processes. Given its essential role in the regulation of vascular homeostasis, involving platelets and leukocytes among others, dysfunctional endothelium can lead to increased risk of coronary vasospasm and thrombosis. Endothelial dysfunction can be prevented by ischemic conditioning with a protective intervention based on limited intermittent periods of ischemia and reperfusion. The molecular mechanisms and signal transduction pathways underlying conditioning phenomena in the coronary endothelium have been described as involving less ROS production, reduced adhesion of neutrophils to endothelial cells and diminished inflammatory reactions. This review summarizes our current understanding of the cellular and molecular mechanisms regulating IRI-affected and -damaged coronary endothelium, and how ischemic conditioning may preserve its function.

Characterization of immortalized human dermal microvascular endothelial cells (HMEC-1) for the study of HDL functionality.

BACKGROUND: Primary cultures endothelial cells have been used as models of endothelial related diseases such atherosclerosis. Biological behavior of primary cultures is donor-dependent and data could not be easily reproducible; endothelial cell lines are emerging options, particularly, human dermal microvascular endothelial cells (HMEC-1), that should be validated to substitute primary cultures for the study of HDL functions. METHODS: Morphology, size and granularity of cells were assessed by phase contrast microscopy and flow cytometry of HMEC-1. The adhesion molecules, ICAM-1and VCAM-1 after TNF-α stimulation, and endothelial markers CD105 endoglin, as well as HDL receptor SR-BI were determined by flow cytometry. Internalization of HDL protein was demonstrated by confocal microscopy using HDL labeled with Alexa Fluor 488. HUVECs were used as reference to compared the characteristics with HMEC-1. RESULTS: HMEC-1 and HUVEC had similar morphologies, size and granularity. HMEC-1 expressed endothelial markers as HUVECs, as well as functional SR-B1 receptor since the cell line was able to internalize HDL particles. HMEC-1 effectively increased ICAM-1 and VCAM-1 expression after TNF-α stimulation. HUVECs showed more sensibility to TNF-α stimulus but the range of ICAM-1 and VCAM-1 expression was less homogeneous than in HMEC-1, probably due to biological variation of the former. Finally, the expression of adhesion molecules in HMEC-1 was attenuated by co-incubation with HDL. CONCLUSION: HMEC-1 possess characteristics of endothelial cells, similar to HUVECs, being a cell line suitable to evaluate the functionality of HDL vis-à-vis the endothelium.

Increased HDL Size and Enhanced Apo A-I Catabolic Rates Are Associated With Doxorubicin-Induced Proteinuria in New Zealand White Rabbits.

The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I.

Pheochromocytoma in pregnancy: A case Report.

This is the case of a 38 year-old female patient with an intrauterine pregnancy, in which a previous incidentally identified adrenal mass proved to be a pheochromocytoma during the antenatal period. The patient was started on α-and ß-adrenergic blockade to maintain hemodynamic stability, and surgical removal of the lesion was performed during the second trimester without major complications. In view of the rarity of this disorder in pregnancy, it is imperative to have a high index of suspicion for a prompt and dedicated management, since this tumor, if unrecognized, is associated with high fetal and maternal mortality.

Inpatient Management of Diabetes Mellitus among Noncritically Ill Patients at University Hospital of Puerto Rico.

OBJECTIVE: To describe the state of glycemic control in noncritically ill diabetic patients admitted to the Puerto Rico University Hospital and adherence to current standard of care guidelines for the treatment of diabetes. METHODS: This was a retrospective study of patients admitted to a general medicine ward with diabetes mellitus as a secondary diagnosis. Clinical data for the first 5 days and the last 24 hours of hospitalization were analyzed. RESULTS: A total of 147 noncritically ill diabetic patients were evaluated. The rates of hyperglycemia (blood glucose ≥180 mg/dL) and hypoglycemia (blood glucose <70 mg/dL) were 56.7 and 2.8%, respectively. Nearly 60% of patients were hyperglycemic during the first 24 hours of hospitalization (mean random blood glucose, 226.5 mg/dL), and 54.2% were hyperglycemic during the last 24 hours of hospitalization (mean random blood glucose, 196.51 mg/dL). The mean random last glucose value before discharge was 189.6 mg/dL. Most patients were treated with subcutaneous insulin, with basal insulin alone (60%) used as the most common regimen. The proportion of patients classified as uncontrolled receiving basal-bolus therapy increased from 54.3% on day 1 to 60% on day 5, with 40% continuing to receive only basal insulin. Most of the uncontrolled patients had their insulin dose increased (70.1%); however, a substantial proportion had no change (23.7%) or even a decrease (6.2%) in their insulin dose. CONCLUSION: The management of hospitalized diabetic patients is suboptimal, probably due to clinical inertia, manifested by absence of appropriate modification of insulin regimen and intensification of dose in uncontrolled diabetic patients. A comprehensive educational diabetes management program, along with standardized insulin orders, should be implemented to improve the care of these patients.

Relaciones intergeneracionales: implicaciones en procesos de formación política en jóvenes / Intergenerational Relationships: Implications in processes of political formation of young people

Las relaciones intergeneracionales, en siete experiencias de acción política con vinculación de jóvenes en Colombia, permiten señalar algunas tendencias frente a los procesos de socialización y formación política, a partir de las narrativas biográficas y colectivas en contextos diversos. Para tal fin abordaremos algunas que amplían la noción de formación política, tales como las implicaciones en las dimensiones histórica, identitaria e intercultural, especialmente, a partir de los procesos de auto-formación. Es muy importante anotar que en este texto no pretendemos establecer comparaciones entre las experiencias para hallar las comunes; al contrario, buscamos reconocer las distinciones y las diversidades en sus procesos y sentidos de socialización y en sus prácticas de formación política, relacionados directamente con los contextos culturales donde habitan.