Differential Effects of Pancreatic Cancer-Derived Extracellular Vesicles Driving a Suppressive Environment.

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs with or depleted of HA. Exposure of monocytes to sEVs resulted in unique phenotypic changes in HLA-DR, PD-L1, CD86 and CD64 expression, and cytokine secretion that was HA-independent except for IL-1ß and MIP1ß. In contrast, monocyte suppression of autologous T cell proliferation was reduced following exposure to HA-low sEVs. In addition, exposure of stellate cells to sEVs upregulated the secretion of various cytokines, including MMP-9, while removal of HA from PDAC-derived sEVs attenuated the secretion of MMP-9, demonstrating the role of sEV-associated HA in regulating expression of this pro-tumorigenic cytokine from stellate cells. This observation lends credence to the findings from the TCGA database that PDAC patients with high levels of enzymes in the HA synthesis pathway had worse survival rates compared with patients having low expression of these enzymes. PDAC-derived sEVs have an immune modulatory role affecting the activation state of monocyte subtypes. However, sEV-associated HA does not affect monocyte phenotype but alters cytokine secretion and suppression of autologous T cell proliferation and induces secretion of pro-tumorigenic factors by pancreatic stellate cells (PSC), as has been seen following the conversion of PSCs to cancer-associated fibroblasts (CAFs). Interruption of the hexosamine biosynthetic pathway, activated in PDAC producing the key substrate (UDP-GlcNAc) for HA synthesis, thus, represents a potential clinical interception strategy for PDAC patients. Findings warrant further investigations of underlying mechanisms involving larger sample cohorts.

Bone mineral density and its relationship with ground reaction force characteristics during gait in young adults with Prader-Willi Syndrome.

Introduction: The incidence of osteopenia and osteoporosis is of concern in adults with Prader-Willi syndrome (PWS). Walking generates reaction forces that could stimulate bone mineralization and is popular in people with PWS. This study compared bone parameters and ground reaction forces (GRF) during gait between young adults with PWS and without PWS and explored associations between bone and GRFs during gait. Methods: 10 adults with PWS, 10 controls with obesity (OB) and 10 with normal weight (NW) matched on sex participated. Segmental and full body dual-energy x-ray absorptiometry scans provided femoral neck, spine, total body minus the head bone mineral density (BMD), bone mineral content (BMC). Vertical GRF, vertical impulse, posterior force and negative impulse were measured during 5 walking trials at a self-selected speed along a 10 m runway. Results: Multivariate analyses of variance showed that adults with PWS (n = 7-8) had hip and body BMD and BMC comparable (p > .050) to NW and lower (p < .050) than OB. Adults with PWS showed slower speed than NW (p < .050) but similar to OB (p > .050). Adults with PWS presented lower absolute vertical GRF, vertical impulse and negative impulse than OB (p < .050). Pearson r correlations (p < .050) in those with PWS (n = 7-8) indicated that femoral neck BMC was associated with vertical GRF (r = 0.716), vertical impulse (r = 0.780), posterior force (r = -0.805), and negative impulse (r = -0.748). Spine BMC was associated with speed (r = 0.829) and body BMD was associated with speed (r = 0.893), and posterior force (r = -0.780). Conclusions: Increased BMC in the femoral neck and body were associated with larger breaking forces during walking, a phenomenon normally observed at greater gait speeds. Faster walking speed was associated with greater BMC in the spine and body. Our preliminary results suggest that young adults with PWS could potentially benefit from faster walking for bone health; however, larger prospective studies are needed to confirm this.

A descriptive study of the clinical impacts on COVID-19 survivors using telemonitoring (The TeleCOVID Study).

Background: There is increasing evidence that COVID-19 survivors are at increased risk of experiencing a wide range of cardiovascular complications post infection; however, there are no validated models or clear guidelines for remotely monitoring the cardiac health of COVID-19 survivors. Objective: This study aims to test a virtual, in-home healthcare monitoring model of care for detection of clinical symptoms and impacts on COVID-19 survivors. It also aims to demonstrate system usability and feasibility. Methods: This open label, prospective, descriptive study was conducted in South Western Sydney. Included in the study were patients admitted to the hospital with the diagnosis of COVID-19 between June 2021 and November 2021. Eligible participants after consent were provided with a pulse oximeter to measure oxygen saturation and a S-Patch EX to monitor their electrocardiogram (ECG) for a duration of 3 months. Data was transmitted in real-time to a mobile phone via Bluetooth technology and results were sent to the study team via a cloud-based platform. All the data was reviewed in a timely manner by the investigator team, for post COVID-19 related symptoms, such as reduction in oxygen saturation and arrhythmia. Outcome measure: This study was designed for feasibility in real clinical setting implementation, enabling the study team to develop and utilise a virtual, in-home healthcare monitoring model of care to detect post COVID-19 clinical symptoms and impacts on COVID-19 survivors. Results: During the study period, 23 patients provided consent for participation. Out of which 19 patients commenced monitoring. Sixteen patients with 81 (73.6%) valid tests were included in the analysis and amongst them seven patients were detected by artificial intelligence to have cardiac arrhythmias but not clinically symptomatic. The patients with arrhythmias had a higher occurrence of supraventricular ectopy, and most of them took at least 2 tests before detection. Notably, patients with arrhythmia had significantly more tests than those without [t-test, t (13) = 2.29, p < 0.05]. Conclusions: Preliminary observations have identified cardiac arrhythmias on prolonged cardiac monitoring in 7 out of the first 16 participants who completed their 3 months follow-up. This has allowed early escalation to their treating doctors for further investigations and early interventions.

The use of arts-based methodologies and methods with young people with complex psychosocial needs: A systematic narrative review.

BACKGROUND: Arts-based methodologies and methods (ABM) can elicit rich and meaningful data with seldom-heard groups and empower participants in research. Young people with complex psychosocial needs could be better engaged in research using arts-based approaches to overcome communication and literacy issues as well as distrust of those with power, including researchers. A critical review of the use and impact of ABM among this population is timely. The purpose of this review is to synthesize and examine the experience and use of ABM with young people with complex psychosocial needs. METHODS: A systematic narrative literature review was conducted with a search of the literature from 2009 to 2021. All abstracts were reviewed independently by two authors and full papers were screened for eligibility against inclusion and exclusion criteria. Data synthesis focused on a descriptive numerical summary and a thematic analysis focused on key patterns across papers relating to the review objectives. RESULTS AND DISCUSSION: A total of 25 papers were included. The most common issues of focus were mental health (n = 10) and homelessness (n = 11) and methods using Photovoice (n = 12) and Body Mapping (n = 5). Individual interview data (n = 20) were the most commonly analysed, followed by created works (n = 19). Less than half the studies involved young people in the interpretation of the data collected. Knowledge translation was not described in almost half the studies, with public exhibits (n = 7) and forums with service providers (n = 4) being the most common activities. Key themes across the studies were valued over traditional methods in eliciting data, ABM as an approach to engage these young people in research and the impact of the use of ABM on participants and on key stakeholders through knowledge translation. CONCLUSIONS: The growing field of ABM presents opportunities to enhance research with young people with complex psychosocial needs by promoting meaningful exploration of experiences, engaging participants in research and strengthening knowledge translation. The involvement of young people in the interpretation of data and ensuring that knowledge translation occurs are key areas for future attention. PATIENT OR PUBLIC CONTRIBUTION: The findings of this review will inform future research to improve the engagement of young people with complex psychosocial needs in research and promote power sharing between researchers and research participants.

Dendritic Cells: The Long and Evolving Road towards Successful Targetability in Cancer.

Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with many studies proving inconclusive or of no benefit in a clinical trial setting. In this review, we highlight the known and unknown about this rare but powerful immune cell. As technologies have expanded our understanding of the complexity of DC development, subsets and response features, we are now left to apply this knowledge to the design of new therapeutic strategies in cancer. We propose that utilization of these technologies through a multiomics approach will allow for an improved directed targeting of DCs in a clinical trial setting. In addition, the DC research community should consider a consensus on subset nomenclature to distinguish new subsets from functional or phenotypic changes in response to their environment.

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach.

5-Lipoxygenase (5-LOX) converts arachidonic acid to lipidic inflammatory mediators such as leukotrienes (LTs). In diseases such as asthma, LTs contribute to a physiopathology that could be reverted by blocking 5-LOX. Natural products with anti-inflammatory potential such as ginger have been used as nutraceuticals since ancient times. 6-Gingerol and 6-shogaol are the most abundant compounds in the ginger rhizome; they possess anti-inflammatory, antioxidant, and chemopreventive properties. In the present study, 6-gingerol and 6-shogaol structures were analyzed and compared with two commercial 5-LOX inhibitors (zileuton and atreleuton) and with other inhibitor candidates (3f, NDGA, CP 209, caffeic acid, and caffeic acid phenethyl ester (CAPE)). The pharmacokinetics and toxicological properties of 6-gingerol, 6-shogaol, and the other compounds were evaluated. Targeted molecular coupling was performed to identify the optimal catalytic pocket for 5-LOX inhibition. The results showed that 6-gingerol and 6-shogaol follow all of the recommended pharmacokinetic parameters. These compounds could be inhibitors of 5-LOX because they present specific interactions with the residues involved in molecular inhibition. The current study demonstrated the potential of 6-gingerol and 6-shogaol as anti-inflammatory agents that inhibit 5-LOX, as they present a high level of performance in the toxicological analysis and could be catabolized by the cytochrome p450 enzymatic complex; however, 6-gingerol was superior in safety compared to 6-shogaol.

Influence of N-acetyltransferase 2 gene polymorphisms on the in vitro metabolism of the epidermal growth factor receptor inhibitor rociletinib.

AIMS: Rociletinib showed activity in T790M-positive non-small cell lung cancer patients. It undergoes amide hydrolysis to form M502, followed by N-acetylation to M544 or amide hydrolysis to M460. We identified the enzymes responsible for rociletinib metabolism, and investigated the relationship between M544 formation and N-acetyltransferase 2 (NAT2) polymorphisms. METHODS: Rociletinib and metabolites were incubated with carboxylesterase (CES)1b, CES1c, CES2, NAT1, NAT2, arylacetamide deacetylase, inhibitors, pooled human liver microsomes (HLM) and cytosols (HLC). Cytosols (n = 107) were genotyped for NAT2 polymorphisms (rs1041983 and rs1801280) and incubated with M502. Human hepatocytes from intermediate (NAT2*6/*12A) and slow (NAT2*5B/*5B) acetylators were incubated with 10 µM rociletinib and metabolites for 24 hours. Metabolites were measured by high-performance liquid chromatography. RESULTS: M502 was formed from rociletinib and M544 by CES2 and HLM; M544 and N-acetyl-M460 were formed by NAT2 and HLC; M460 was not formed by CES or arylacetamide deacetylase. M502 formation by HLM was inhibited by bis-(4-nitrophenyl)phosphate and eserine (10 µM). M544 formation in HLC was inhibited by 100 µM quercetin and was associated with NAT2 genotype (P < .0001). M460 formation in HLM was inhibited by eserine, and M460 was N-acetylated in HLC. Hepatocytes formed M502, M544 and M460. The intermediate acetylator showed higher production (range: 3.4-5.1-fold) of N-acetylated metabolites than the slow acetylator. CONCLUSIONS: Results indicate that NAT2 and CES2 are involved in rociletinib metabolism, and polymorphic NAT2 could alter drug exposure in patients. Slow NAT2 acetylators would have higher exposure to M502 and M460 and consequently, be at increased risk of experiencing hyperglycaemia and QTc prolongation.

A bioinformatic prediction of antigen presentation from SARS-CoV-2 spike protein revealed a theoretical correlation of HLA-DRB1*01 with COVID-19 fatality in Mexican population: An ecological approach.

SARS-CoV-2 infection is causing a pandemic disease that is reflected in challenging public health problems worldwide. Human leukocyte antigen (HLA)-based epitope prediction and its association with disease outcomes provide an important base for treatment design. A bioinformatic prediction of T cell epitopes and their restricted HLA Class I and II alleles was performed to obtain immunogenic epitopes and HLA alleles from the spike protein of the severe acute respiratory syndrome coronavirus 2 virus. Also, a correlation with the predicted fatality rate of hospitalized patients in 28 states of Mexico was done. Here, we describe a set of 10 highly immunogenic epitopes, together with different HLA alleles that can efficiently present these epitopes to T cells. Most of these epitopes are located within the S1 subunit of the spike protein, suggesting that this area is highly immunogenic. A statistical negative correlation was found between the frequency of HLA-DRB1*01 and the fatality rate in hospitalized patients in Mexico.

Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients.

Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-FU/LV plus bevacizumab were significant covariates (p < 0.01) for volumes of the central compartment of CPT-11 and SN-38, and clearance of CPT-11. Pre-treatment total bilirubin and co-administration with 5-FU/LV and bevacizumab were significant covariates (p < 0.01) for clearance of SN-38. Accurate and precise predictive performance (r2 > 0.99, -2 < bias (%ME) < 0, precision (% RMSE) < 12) of both CPT-11 and SN-38 was achieved using: (i) 6 fixed sampling times collected at 1.5, 3.5, 4, 5.75, 22, 23.5 hours post-infusion; or (ii) 1 fixed time and 2 sampling windows collected at 1.5, [3-5.75], [22-23.5] hours post-infusion. The present study demonstrates that an optimal sampling design with three blood samples achieves accurate and precise pharmacokinetic parameter estimates for both CPT-11 and SN-38.

Latest Updates in Dengue Fever Therapeutics: Natural, Marine and Synthetic Drugs.

In this paper, we review the history of Dengue, the mechanism of infection, the molecular characteristics and components of Dengue, the mechanism of entry to the target cells, cyclization of the genome and replication process, as well as translation of the proteins for virus assembly. The major emphasis of this work is on natural products and plant extracts, which were used for as palliative or adjuvant treatment of Dengue. This review article also summarizes the latest findings in regards to the marine products as effective drugs to target different symptoms of Dengue. Furthermore, an update on synthetic drugs for treating Dengue is provided in this review. As a novel alternative, we describe monoclonal antibody therapy for Dengue management and treatment.

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib.

This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug-drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady-state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04-1.49), 1.30 (1.11-1.53) and 1.28 (1.11-1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration-time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16-1.66), minimum plasma concentration (1.53; 1.10-2.12) and area under the concentration-time curve from time zero to 8 hours (1.41; 1.19-1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients.

LprG and PE_PGRS33 Mycobacterium tuberculosis virulence factors induce differential mitochondrial dynamics in macrophages.

The interaction of a pathogen with its host cell takes place at different levels, including the bioenergetics adaptation of both the pathogen and the host cell in the course of an infection. In this regard, Mycobacterium tuberculosis infection of macrophages induces mitochondrial membrane potential (Δψm) changes and cytochrome c release, depending on the bacteria strain's virulence, and the mitochondrial dynamics is modified by pathogens, such as Listeria monocytogenes. Here, we investigated whether two M. tuberculosis virulence factors are able to induce distinguishable bioenergetics traits in human monocyte-derived macrophages (MDMs). Results showed that Rv1411c (LprG, p27) induced mitochondrial fission, lowered the cell respiratory rate and modified the kinetics of mitochondrial Ca2+ uptake in response to agonist stimulation. In contrast, Rv1818c (PE_PGRS33) induced mitochondrial fusion, but failed to induce any appreciable effect on cell respiratory rate or mitochondrial Ca2+ uptake. Overall, these results suggest that two different virulence factors from the same pathogen (M. tuberculosis) induce differential effects on mitochondrial dynamics, cell respiration and mitochondrial Ca2+ uptake in MDMs. The timing of differential mitochondrial activity could ultimately determine the outcome of host-pathogen interactions.

Multilingual Diversity in the Field of Applied Behavior Analysis and Autism: A Brief Review and Discussion of Future Directions.

This review addresses multilingual diversity within the field of Applied Behavior Analysis (ABA) as it relates to treatment for autism spectrum disorders (ASD). The United States was founded as a diverse, multicultural "melting pot" and migration patterns continue to increase cultural and linguistic diversity, making it increasingly important to address these issues within the field of ABA. The role of multilingualism in ABA treatment for autism has scarcely been addressed in practice or in research and yet these factors likely impact the ABA treatment process significantly. The purpose of this review is to discuss how multilingualism might be better addressed within the field of ABA. We briefly review the very small amount of existing research on multilingual approaches when using ABA and discuss directions for future research. In addition, we discuss potential future directions for the field, in terms of increasing the number of international students in graduate programs, enhancing diversity curricula within graduate programs and continuing education, and efforts by professional organizations to address diversity.

Comparación del rendimiento diagnóstico clínico versus la prueba rápida durante dos temporadas de influenza / Comparison of clinical diagnostic performance versus the rapid test during two seasons of influenza

Resumen Introducción Una reflexión de la pandemia de influenza en 2009 es la prioridad de la prescripción temprana de los antivirales, previniendo el uso injustificado de antibióticos. Objetivo: Describir la sintomatología que se asocia más al diagnóstico definitivo de influenza y comparar el rendimiento del diagnóstico clínico contra el diagnóstico arrojado por la prueba rápida. Material y métodos Estudio retrospectivo, transversal, descriptivo y analítico. Se incluyeron pacientes con diagnóstico presuntivo de influenza admitidos en el Servicio de Urgencias del Hospital Español de México en dos temporadas consecutivas que van de octubre de 2016 a marzo de 2017 y de octubre de 2017 a marzo de 2018. Se formaron dos grupos: pacientes con PCR positiva (grupo A) y pacientes con PCR negativa (grupo B). Resultados Se obtuvo un total de 857 pacientes con diagnóstico presuntivo clínico de influenza, de los cuales 537 se confirmaron con influenza por PCR (grupo A) y 320 fueron negativos para dicha prueba (grupo B). El síndrome conformado por tos, fiebre, rinorrea y artralgias tiene una especificidad de 92.2% en comparación con la prueba rápida de 99.1%. Conclusiones El síndrome caracterizado por tos, fiebre, rinorrea, artralgias presentes durante los meses invernales tiene una alta especificidad para infección por el virus de la influenza.

Abstract Introduction One of the reflections of the influenza pandemic in 2009 is the priority of the early prescription of antivirals, preventing the unjustified use of antibiotics. Objective: To describe the symptomatology that is associated more with the definitive diagnosis of Influenza and to compare the performance of the clinical diagnosis against the diagnosis thrown by the rapid test. Material and methods A retrospective, cross-sectional, descriptive and analytical study. All patients with presumptive diagnosis of Influenza admitted to the Emergency Service of the Hospital Español de Mexico were included in two consecutive seasons from October 2016 to March 2017 and October 2017 to March 2018. Two groups were formed of the included patients: patients with positive PCR (group A) and patients with negative PCR (group B). Results A total of 857 patients with presumptive clinical diagnosis of influenza were obtained, of whom 537 were confirmed with Influenza by PCR (group A) and 320 were negative for the test (group B). The syndrome consisting of cough, fever, rhinorrhea and arthralgia has a specificity of 92.2% compared to the rapid test of 99.1%. Conclusions The syndrome characterized by cough, fever, rhinorrhea, arthralgia present during winter months has a high specificity for an infection by the Influenza virus.

Dengue Fever: A Worldwide Threat An Overview of the Infection Process, Environmental Factors for a Global Outbreak, Diagnostic Platforms and Vaccine Developments.

Current review article focuses on dengue, which is one of the most fatal infectious illnesses and is considered to be a worldwide threat. The paper covers essential topics including an overview on neglected tropical diseases with specific emphasis on Dengue fever, mosquito's cycle of life and mechanism of infection, adaptive response, and different stages in dengue immunopathogenesis. The current work is also dedicated to the thorough study of dengue outbreak across the globe with a narrowed study to tropical and subtropical regions. Moreover, this review article demonstrates the correlation between climate factors and dengue incidence. Furthermore, we present an overview of the detection strategies of dengue including the latest developments in commercial and non-commercial platforms. Several attempts in developing an effective vaccine to protect individuals from dengue infection and the stage of clinical trials are gathered in the present work as well. Future directions including bio-control are also discussed in this review article. In an overall view, effective management of Dengue is a multidisciplinary task that requires international involvement from different backgrounds and expertise to address this global concern. This review article briefly portrays some of these connecting areas across the disciplines while many other perspectives remain uncovered.

Clipaje endoscópico de la arteria esfenopalatina para el tratamiento de la epistaxis posterior / Endoscopic sphenopalatine artery ligation for posterior epistaxis

Resumen Antecedentes Los casos de epistaxis posterior representan alrededor del 10 al 20% de las epistaxis. El tratamiento convencional para este tipo de padecimientos son los taponamientos nasales. El abordaje quirúrgico (cauterización y/o clipaje) está indicado cuando existe falla del tratamiento médico convencional; sin embargo, en la actualidad, se considera como primera opción. Material y métodos Se revisaron todos los casos de epistaxis posterior tratados en el Hospital Español de México de enero de 2007 a enero de 2017. Se realizó estadística descriptiva e inferencial para comparar al grupo conservador (taponamiento nasal) versus el grupo quirúrgico (clipaje). Resultados Se revisaron 242 expedientes; de ellos, se excluyeron 108. Se incluyeron 134 pacientes: 96 correspondieron al grupo quirúrgico y 38 al conservador. El 60.20% perteneció al género masculino y el 39.80% al femenino. La media para la edad fue de 60 años. El grupo quirúrgico (3.4 ± 1.9 días) requirió menos días de estancia hospitalaria en comparación con el conservador (4.8 ± 3.0 días), p < 0.01. Los pacientes con una epistaxis del lado derecho en el grupo quirúrgico tuvieron un mayor tiempo quirúrgico (p = 0.001) y más días de estancia hospitalaria (p = 0.006). Conclusiones La epistaxis sucede en la mayoría de los casos de forma idiopática; es frecuente en hombres mayores de 60 años con enfermedades cardiopulmonares, sin conocerse de forma precisa su fisiopatología. La epistaxis derecha tratada quirúrgicamente resulta tener más morbilidad. El abordaje quirúrgico es seguro, eficaz y acorta los días de estancia hospitalaria en comparación con el tratamiento conservador.

Abstract Background The cases of posterior epistaxis represent approximately 10 to 20% of all epistaxis. The conventional treatment for this type of ailment is nasal packing. A surgical approach (cauterization and/ or clipping) is indicated when there is a failure of the conventional medical treatment; however, it is currently considered as the first option. Material and methods All the epistaxis cases treated at the Hospital Español de México from January 2007 to January 2017 were reviewed. Descriptive and inferential statistics were used to compare the conservative group (nasal packing) versus the surgical one (clipping). Results 242 dossiers were reviewed, of which 108 were excluded. 134 patients were included: 96 belonged to the surgical group and 38 to the conservative one. 60.20% were male and 39.80% were female. The mean age was 60 years. The surgical group (3.4 ± 1.9 days) required fewer days of hospital stay compared to the conservative group (4.8 ± 3.0 days), p < 0.01. Patients with right-sided epistaxis in the surgical group had a longer surgical time (p = 0.001) and more days of hospital stay (p = 0.006). Conclusions Epistaxis occurs in most cases idiopathically, often in men over 60 years with cardiopulmonary diseases, without a precise knowledge of its physiopathology. Right epistaxis treated surgically results in more morbidity. The surgical approach is safe, effective and shortens the days of hospital stay compared to the conservative treatment.

Dexamethasone implant in silicone oil: in vitro behavior.

BACKGROUND: To determine the effect of the silicone on the dexamethasone intravitreal implant. METHODS: Basic, experimental, prospective and transversal study performed at the hospital "Nuestra Señora de la Luz" in Mexico City. One dexamethasone implant was placed in a test tube with 4 mL of each tamponade medium: 1000cS, 5000cS and heavy silicone oil; basic saline solution was used as the control medium. Photographs were taken weekly for 12 months. 200 µL samples were taken from each medium at 24 h, 1, 2 weeks and monthly for 12 months. ELISA test was performed to quantify dexamethasone release in every sample. An inflammatory stimulus was created and later exposed it to every sample in order to test their anti-inflammatory capacity by cytokine analysis using cytometric bead array. Statistically significant results were obtained with p < 0.05. RESULTS: Photographic follow-up showed disintegration of the implant in control medium. Implants in silicone oil suffered no changes during follow-up. Dexamethasone levels in control medium showed stability from month 2 to 12. Silicone oil mediums showed irregular dexamethasone release during the 1 year period. Dexamethasone in control medium had inhibitory effects on TNF-α starting at 24 h (p < 0.001) and remained stable. Dexamethasone in 1000cS silicone oil showed inhibitory effects from month 2 (p < 0.001) until month 6 (p < 0.001). Implants in denser silicone oils showed no inhibitory effects in any of the samples. CONCLUSIONS: Denser mediums altered the implant pharmacokinetics and showed no anti-inflammatory effects even when concentrations were quantified at levels similar to control medium in vitro.

Metabolism of megestrol acetate in vitro and the role of oxidative metabolites.

1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively). 2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62 µM (HLM Km for metabolite 1; M1) and 28 µM (HLM Km for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62 µM MA. 3. At 28 µM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR.

Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children.

UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this relationship. Using previously generated data, we investigated age-dependent mRNA expression levels of 11 hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) and 16 transcription factors (AHR, AR, CAR, ESR2, FXR, GCCR, HNF1a, HNF3a, HNF3b, HNF4a, PPARA, PPARG, PPARGC, PXR, SP1, and STAT3) in liver tissue of donors (n = 38) ranging from 0 to 25 years of age. We also examined the correlation between age and microsomal activities using 14 known UGT drug substrates in the liver samples (n = 19) of children donors. We found a statistically significant increase (nominal p < 0.05) in the expression of UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT2B7, and UGT2B17, as well as glucuronidation activities of serotonin, testosterone, and vorinostat during the first 25 years of life. Expression of estrogen receptor 1 and pregnane X receptor, two strong UGT transcriptional regulators, were significantly correlated with both age and UGT mRNA expression (p ≤ 0.05). These results suggest that both UGT expression and activity increase during childhood and adolescence, possibly driven in part by hormonal signaling. Our findings may help explain inter-patient variability in response to medications among children.

In vitro glucuronidation of aprepitant: a moderate inhibitor of UGT2B7.

1. Aprepitant, an oral antiemetic, commonly used in the prevention of chemotherapy-induced nausea and vomiting, is primarily metabolized by CYP3A4. Aprepitant glucuronidation has yet to be evaluated in humans. The contribution of human UDP-glucuronosyltransferase (UGT) isoforms to the metabolism of aprepitant was investigated by performing kinetic studies, inhibition studies and correlation analyses. In addition, aprepitant was evaluated as an inhibitor of UGTs. 2. Glucuronidation of aprepitant was catalyzed by UGT1A4 (82%), UGT1A3 (12%) and UGT1A8 (6%) and Kms were 161.6 ± 15.6, 69.4 ± 1.9 and 197.1 ± 28.2 µM, respectively. Aprepitant glucuronidation was significantly correlated with both UGT1A4 substrates anastrazole and imipramine (rs = 0.77, p < 0.0001 for both substrates; n = 44), and with the UGT1A3 substrate thyroxine (rs = 0.58, p < 0.0001; n = 44). 3. We found aprepitant to be a moderate inhibitor of UGT2B7 with a Ki of ∼10 µM for 4-MU, morphine and zidovudine. Our results suggest that aprepitant can alter clearance of drugs primarily eliminated by UGT2B7. Given the likelihood for first-pass metabolism by intestinal UGT2B7, this is of particular concern for oral aprepitant co-administered with oral substrates of UGT2B7, such as zidovudine and morphine.