BUPROPION MISUSE BY NASAL INSUFFLATION WITH A FATAL OUTCOME: CASE REPORT AND REVIEW.

Bupropion is the only FDA - approved synthetic cathinone, with increasing popularity in clinical practice due to its wide range of action, and lack of sexual side effects. However, its stimulant effect similar to amphetamines has growing the concern regarding its recreational use.

Overlaid Transcriptional and Proteome Analyses Identify Mitotic Kinesins as Important Targets of Arylsulfonamide-Mediated RBM39 Degradation.

Certain arylsulfonamides (ArSulf) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. However, degradation of a splicing factor introduces complex pleiotropic effects that are difficult to untangle, since, aside from direct protein degradation, downstream transcriptional effects also influence the proteome. By overlaying transcriptional data and proteome datasets, we distinguish transcriptional from direct degradation effects, pinpointing those proteins most impacted by splicing changes. Using our workflow, we identify and validate the upregulation of the arginine-and-serine rich protein (RSRP1) and the downregulation of the key kinesin motor proteins KIF20A and KIF20B due to altered splicing in the absence of RBM39. We further show that kinesin downregulation is connected to the multinucleation phenotype observed upon RBM39 depletion by ArSulfs. Our approach should be helpful in the assessment of potential cancer drug candidates which target splicing factors. IMPLICATIONS: Our approach provides a workflow for identifying and studying the most strongly modulated proteins when splicing is altered. The work also uncovers a splicing-based approach toward pharmacologic targeting of mitotic kinesins.

Overlaid transcriptome and proteome analyses identify mitotic kinesins as important targets of arylsulfonamide-mediated RBM39 degradation.

Certain arylsulfonamides (ArSulfs) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. However, degradation of a splicing factor introduces complex pleiotropic effects that are difficult to untangle, since, aside from direct protein degradation, downstream transcriptional effects also influence the proteome. By overlaying transcriptional data and proteome datasets, we distinguish transcriptional from direct degradation effects, pinpointing those proteins most impacted by splicing changes. Using our workflow, we identify and validate the upregulation of the argininie-and-serine rich protein (RSRP1) and the downregulation of the key kinesin motor proteins KIF20A and KIF20B due to altered splicing in the absence of RBM39. We further show that kinesin downregulation is connected to the multinucleation phenotype observed upon RBM39 depletion by ArSulfs. Our approach should be helpful in the assessment of potential cancer drug candidates which target splicing factors. Implications: Our approach provides a workflow for identifying and studying the most strongly modulated proteins when splicing is altered; the work also uncovers a splicing-based approach toward pharmacological targeting of mitotic kinesins.

Uso indebido de bupropión por insuflación nasal con desenlace fatal: reporte de un caso y revisión / Abuse of bupropion by nasal insufflation with fatal outcome: report of a case and review

Introducción. El bupropión es la única catinona sintética aprobada por la FDA, con una creciente popularidad en la práctica clínica debido a su amplio rango de acción y la falta de efectos secundarios sexuales. Sin embargo, su efecto estimulante similar al de las anfetaminas ha hecho crecer la preocupación respecto a su uso recreativo. Objetivos y métodos. En este manuscrito informamos un caso de uso indebido de bupropión mediante insuflación nasal con desenlace fatal y realizamos una breve revisión deluso recreativo de bupropión. Resultados. Presentamos el caso de un hombre de unos50 años, con abuso prolongado de bupropión principalmente por insuflación nasal, que falleció súbitamente unas dos semanas después de ser dado de alta por un infarto agudo de miocardio tipo 2 secundario a sobredosis de bupropión. A lo largo de las últimas décadas, varios estudios han informado un uso indebido cada vez mayor de bupropión por vías no orales, especialmente a través de la insuflación nasal, y el uso intravenoso, particularmente en pacientes con antecedentes de abuso de sustancias, adolescentes o en entornos penitenciarios. A pesar de que la mayoría de los pacientes tienen efectos secundarios de leves a moderados, consecuencias devastadoras, tales como convulsiones refractarias o shock cardiogénico refractario, pueden ocurrir en caso de sobredosis, lo que exige un reconocimiento oportuno y un enfoque rápido para prevenir estos resultados importantes. En caso de sobredosis, no existe un antídoto específico disponible ni un tratamiento curativo aprobado, su manejo se centra en el tratamiento de los síntomas. Conclusiones. El bupropión es un antidepresivo eficaz, sin embargo, tiene potencial para uso recreativo, especialmente en grupos de alto riesgo. Este documento alerta a todos los médicos sobre el problema emergente relacionado con el uso indebido de bupropión y agrega algunas ideas sobre su reconocimiento y manejo oportunos. (AU)

Impact of Height Estimation on Tidal Volume Calculation for Protective Ventilation-A Prospective Observational Study.

OBJECTIVES: The current standard of care to deliver invasive mechanical ventilation support is the protective ventilation approach. One pillar of this approach is the limitation of tidal volume to less than 6 mL/Kg of predicted body weight. Predicted body weight is calculated from patient's height. Yet, little is known about the potential impact of errors arising from visual height estimation, a common practice, to calculate tidal volumes. The aim of this study was to evaluate that impact on tidal volume calculation to use during protective ventilation. DESIGN: Prospective observational study. SETTING: An eight-bed polyvalent ICU. PATIENTS: Adult patients (≥ 18 yr). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tidal volumes were calculated from visual height estimates made by physicians, nurses, and patients themselves and compared with tidal volumes calculated from measured heights. Comparisons were made using the paired t test. Modified Bland-Altman plots were used to assess agreement between height estimates and measurements. One-hundred patients were recruited. Regardless of the height estimator, all the mean tidal volumes would be greater than 6 mL/Kg predicted body weight (all p < 0.001). Additionally, tidal volumes would be greater than or equal to 6.5 mL/Kg predicted body weight in 18% of patients' estimates, 25% of physicians' estimates, and 30% of nurses' estimates. Patients with lower stature (< 165 cm), older age, and surgical typology of admission were at increased risk of being ventilated with tidal volumes above protective threshold. CONCLUSIONS: The clinical benefit of the protective ventilation strategy can be offset by using visual height estimates to calculate tidal volumes. Additionally, this approach can be harmful and potentially increase mortality by exposing patients to tidal volumes greater than or equal to 6.5 mL/Kg predicted body weight. In the interest of patient safety, every ICU patient should have his or her height accurately measured.

Electroconvulsive Therapy Use in Psychiatric Hospitalizations in Portugal: A Nationwide Descriptive Study.

OBJECTIVES: The primary aim of this study was to describe a Portuguese nationwide epidemiological perspective on the use of electroconvulsive therapy (ECT) in hospitalized psychiatric patients. The secondary aims of the study were to characterize clinical and sociodemographic trends of hospitalized patients treated with ECT. METHODS: A retrospective-observational study was conducted using an administrative database gathering every registered Portuguese public hospital hospitalizations from 2008 to 2015. We selected all hospitalizations with a procedure code 94.27 (Other electroshock therapy) defined by the International Classification of Diseases version 9, Clinical Modification. Variables included birth date, sex, address, primary and secondary diagnoses, admission/discharge date, length of stay, and discharge status from each single hospitalization episode. We also calculated Portugal's inpatient ECT prevalence rate (iP%). RESULTS: There were a total of 879 registered hospitalizations with ECT within the 8-year period of this study. Most occurred in female patients (53.4%), belonging to the age group of 51 to 70 years old, with a mean age of 50.5 years. The median length of stay was 43.0 days with an interquartile range of 27.0 to 68.0. The most frequent primary diagnosis was major depressive disorder, recurrent episode, representing 19.6% of all hospitalizations. The iP% for the study period was 0.71%. CONCLUSIONS: In Portugal, most of the patients who received ECT were women above middle age, and depressive disorders were the most common indication. Portugal's iP% represents a low rate when compared with other European countries, which might indicate an underutilization of ECT in Portuguese psychiatric hospitals.

The Impact of COVID-19 Pandemic on Psychiatric Emergency Department Visits - A Descriptive Study.

The coronavirus disease 2019 pandemic (COVID-19) has an important direct and indirect impact on both physical and mental health. We aim to describe the impact of an emergency state period due to COVID-19 on psychiatric emergency department (ED) visits. We conducted a retrospective observational study analysing all emergency visits occurring at a metropolitan psychiatric ED between March 19th and May 2nd 2019 and 2020 (the beginning/end date of the emergency state which Portugal was under due to COVID-19). Data regarding age, sex, diagnoses, admission date, discharge destiny and status were collected. Diagnoses were classified using the International Classification of Diseases version 9, Clinical Modification (ICD-9-CM). There was a 52·2% decrease on the number of psychiatric emergency visits during the emergency state period (n2020 = 780 vs n2019 = 1633 episodes). The decrease on psychiatric ED visits was greater in the female sex and in the younger age groups. Episodes with a primary diagnosis of Mood disorders lead the decrease on psychiatric ED visits with 68·3% less episodes. Schizophrenia and other psychotic disorders was the diagnosis group with the smaller decline (9·8% decrease). COVID-19 emergency state period had an important impact on the number and characteristics of psychiatric ED visits, reinforcing the great indirect effects of COVID-19 on mental health.

Tibialis Posterior Tendon Dislocation: A Case Report.

CASE: A 37-year-old man presented after a sudden snap followed by pain in the medial side of the ankle while playing football. Physical examination showed edema and pain posteriorly to the medial malleolus, and a longitudinal structure was palpable anteriorly. Ultrasound confirmed a dislocated tibialis posterior tendon (TPT). The patient underwent surgery, and the flexor retinaculum was repaired. Six months after the surgery, he was asymptomatic and had resumed his usual physical activity, with an AOFAS score of 100. CONCLUSION: TPT dislocation is rare and orthopaedic surgeons should be aware of this condition in patients with a sudden traumatic medial ankle pain.

High discrimination of Mycobacterium bovis isolates in Brazilian herds by spoligotyping.

Bovine tuberculosis is an infectious disease caused by Mycobacterium bovis (M. bovis), that leads to economic losses in infected herds and it is also considered an important zoonosis. The molecular typing methods of M. bovis isolates are fundamental for the bovine tuberculosis surveillance system, and spoligotyping is the standard genotyping technique for this species. Thus, the aim of the present study is to analyze the spatial and cluster distribution of M. bovis strains from several regions of Brazil through molecular typing. Spoligotyping technique was applied on 422 isolates identified as M. bovis, and Ripley's K function was used to perform the spatial and cluster analysis of each identified profile. Forty-three (43) different profiles were identified and spoligotype SB0121 was the most frequent and showed a uniform pattern in the spatial distribution while spoligotypes SB0295, SB1380 and SB1050 formed clusters. In addition, three novel spoligotype profiles (SB2361, SB2362, SB2364) were identified in different herds. In this perspective, it is believed that molecular identification and typing can significantly improve the performance of surveillance systems for bovine tuberculosis in Brazil.

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance.

: Ovarian cancer is a highly lethal disease, mainly due to chemoresistance. Our previous studies on metabolic remodeling in ovarian cancer have supported that the reliance on glutathione (GSH) bioavailability is a main adaptive metabolic mechanism, also accounting for chemoresistance to conventional therapy based on platinum salts. In this study, we tested the effects of the in vitro inhibition of GSH synthesis on the restoration of ovarian cancer cells sensitivity to carboplatin. GSH synthesis was inhibited by exposing cells to l-buthionine sulfoximine (l-BSO), an inhibitor of -glutamylcysteine ligase (GCL). Given the systemic toxicity of l-BSO, we developed a new formulation using polyurea (PURE) dendrimers nanoparticles (l-BSO@PUREG4-FA2), targeting l-BSO delivery in a folate functionalized nanoparticle.

Institutional strategies as a mechanism to rationalize the negative effects of the judicialization of access to medicine in Brazil.

BACKGROUND: Recently, the Executive Branch and Judiciary in Brazil increased spending due to larger numbers of lawsuits that forced the State to provide health goods and services. This phenomenon, known as health judicialization, has created challenges and required the Executive Branch and Judiciary to create institutional strategies such as technical chambers and departments to reduce the social, economic and political distortions caused by this phenomenon. This study aims to evaluate the effects of two institutional strategies deployed by a Brazilian municipality in order to cope with the economic, social and political distortions caused by the phenomenon of health judicialization regarding access to medicines. METHODS: A longitudinal study was carried out in a capital in the Central-West Region of Brazil. A sample of 511 lawsuits was analyzed. The variables were placed into three groups: the sociodemographic characteristics and the plaintiffs' disease, the characteristics of the claimed medical products and the institutional strategies. To analyze the effect of the interventions on the total cost of the medicines in the lawsuits, bivariate and multivariate linear regressions with variance were performed. For the categorical outcomes, Poisson regressions were performed with robust variance, using a significance level of 5%. RESULTS: A reduction in the costs of medicines in the lawsuits and of the requests for medicines within the SUS formulary was verified after the deployment of the Department of Assessment of Nonstandardized Medicines (DAMNP) and the Technical Chamber of Health Assessment (CATS); an increase in processed prescriptions from the Brazilian Universal Health System was observed after the deployment of the CATS; and an increase in medicines outside the SUS formulary without a therapeutic alternative was verified after the CATS. CONCLUSION: The institutional strategies deployed were important tools to reduce the high costs of the medicines in the lawsuits. In addition, they represented a step forward for the State, provided a benefit to society and indicated a potential path for the health and justice systems of other countries that also face problems caused by the judicialization of health.

Development of a natural molluscicide prototype kit (MoluSchall) for the control of schistosomiasis mansoni transmission.

INTRODUCTION: In Brazil, Biomphalaria glabrata, B. tenagophila, and B. straminea are intermediate hosts of Schistosoma mansoni, the etiological agent of schistosomiasis mansoni. Molluscicide use is recommended by the WHO for controlling the transmission of this parasite. Euphorbia milii latex has shown promising results as an alternative molluscicide. Thus, a natural molluscicide prototype kit based on freeze-dried E. milii latex was developed and evaluated against Biomphalaria spp. METHODS: E. milii latex was collected, processed, and lyophilized. Two diluents were defined for freeze-dried latex rehydration, and a prototype kit, called MoluSchall, was produced. A stability test was conducted using prototype kits stored at different temperatures, and a toxicity assay was performed using Danio rerio. Additionally, MoluSchall was tested against B. glabrata under semi-natural conditions according to defined conditions in the laboratory. RESULTS: MoluSchall was lethal to three Brazilian snail species while exhibiting low toxicity to D. rerio. Regardless of storage temperature, MoluSchall was stable for 24 months and was effective against B. glabrata under semi-natural conditions, with the same LD100 as observed under laboratory conditions. CONCLUSIONS: MoluSchall is a natural, effective, and inexpensive molluscicide with lower environmental toxicity than existing molluscicides. Its production offers a possible alternative strategy for controlling S. mansoni transmission.

Targeting Glutathione and Cystathionine ß-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation.

Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H2S-synthesizing enzyme cystathionine ß-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H2S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PUREG4-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PUREG4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.

l-Buthionine Sulfoximine Detection and Quantification in Polyurea Dendrimer Nanoformulations.

l-Buthionine sulfoximine (l-BSO) is an adjuvant drug that is reported to increase the sensitivity of cancer cells to neoplastic agents. Dendrimers are exceptional drug delivery systems and l-BSO nanoformulations are envisaged as potential chemotherapeutics. The absorption of l-BSO at a low wavelength limits its detection by conventional analytical tools. A simple and sensitive method for l-BSO detection and quantification is now reported. In this study, l-BSO was encapsulated in a folate-targeted generation four polyurea dendrimer (PUREG4-FA2) and its release profile was followed for 24 h at pH 7.4 and 37 °C. The protocol uses in situ l-BSO derivatization, by the formation of a catechol-derived orto-quinone, followed by visible detection of the derivative at 503 nm. The structure of the studied l-BSO derivative was assessed by NMR spectroscopy.

Evaluation of post-mortem diagnostic tests' sensitivity and specificity for bovine tuberculosis using Bayesian latent class analysis.

This study aimed to evaluate the performance of real-time PCR (qPCR), ELISA IDEXX™, and bacterial isolation as post-mortem diagnostic tests in animals with lesions compatible with bovine tuberculosis detected by Brazilian Federal Inspection Service as part of the bovine tuberculosis active surveillance. Bayesian latent class models were used to estimate diagnostic tests' sensitivity, specificity, correlations, predictive values and frequency of infected animals. Samples of tuberculosis-suggestive lesions collected by FIS sanitary inspection routine in slaughterhouses from 11 Brazilian states were analyzed. Isolation was the most sensitive technique, 94.54% (95% Credible Interval (CrI) 90.09%-97.65%), qPCR was 64.69% (95% CrI 54.41%-74.15%) sensitive and ELISA IDEXX™ 26.74% (95% CrI 22.82%-30.97%). Tests' specificities were 98.19% (95% CrI 95.75%-99.45%), 93.49% (95% CrI 79.28%-99.66%), 95.53% (95% CrI 91.71%-98.02%) respectively. Despite its low sensitivity, ELISA IDEXX™ was able to identify positive samples that were not detected by the other techniques. These samples had high probability to be true positives given ELISA's positive predictive value. The correlations between qPCR and isolation were neither biologically nor statistically significant. The low sensitivity of the qPCR is a limiting factor to its use as a post-mortem diagnosis in bovine tuberculosis suggestive lesions. Its use could be recommended in situations of high prevalence, or in parallel association with other tests, such as ELISA IDEXX™. ELISA IDDEX™ should not be used as a unique test, or in substitution of the other tests, for the post-mortem diagnosis of bovine tuberculosis due to its sensitivity.