Searching for new antifungals for the treatment of cryptococcosis

ABSTRACT There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.

Low dosis of alteplase, for ischemic stroke after Enchanted and its determinants, a single center experience / Dosis reducida de alteplase en el accidente cerebrovascular isquémico después del estudio Enchanted y sus determinantes, una experiencia de un solo centro

Abstract Background: Low-dose alteplase (LrtPA) has been shown not to be inferior to the standard-dose (SrtPA) with respect to death/disability. Objective: We aim to evaluate the percentage of patients treated with LrtPA at our center after the ENCHANTED trial and the factors associated with the use of this dosage. Methods: Prospective study in consecutive patients with an acute stroke admitted between June 2016 and November 2018. Results: 160 patients were treated with intravenous thrombolysis, 50% female; mean age 65.4±18.5 years. Of these, 48 patients (30%) received LrtPA. In univariate analysis, LrtPA was associated with patient's age (p=0.000), previous modified Rankin scale scores (mRS) (p<0.000), hypertension (p=0.076), diabetes mellitus (p=0.021), hypercholesterolemia (p=0.19), smoking (p=0.06), atrial fibrillation (p=0.10), history of coronary artery disease (p=0.06), previous treatment with antiplatelet agents (p<0.000), admission International Normalized Ratio-INR (p=0.18), platelet count (p=0.045), leukoaraiosis on neuroimaging (p<0.003), contraindications for thrombolytic treatment (p=0.000) and endovascular treatment (p=0.027). Previous relevant bleedings were determinants for treatment with LrtPA. Final diagnosis on discharge of stroke mimic was significant (p=0.02) for treatment with SrtPA. In multivariate analysis, mRS (OR: 2.21; 95%CI 1.37‒14.19), previous antiplatelet therapy (OR: 11.41; 95%CI 3.98‒32.70), contraindications for thrombolysis (OR: 56.10; 95%CI 8.81‒357.80), leukoaraiosis (OR: 4.41; 95%CI 1.37‒14.10) and diagnosis of SM (OR: 0.22; 95%CI 0.10‒0.40) remained independently associated. Conclusions: Following the ENCHANTED trial, LrtPA was restricted to 30% of our patients. The criteria that clinicians apply are based mostly on clinical variables that may increase the risk of brain or systemic hemorrhage or exclude the patient from treatment with lytic drugs.

RESUMEN Introducción: Dosis reducidas de trombolitico (LrtPA) podrían no ser inferiores en muerte/discapacidad. Objetivo: Evaluar el porcentaje de pacientes tratados con LrtPA en nuestro centro después del ensayo ENCHANTED, y los factores asociados con el uso de esta dosis. Métodos: Estudio prospectivo de pacientes consecutivos con infarto cerebral ingresados ​entre junio de 2016 y noviembre de 2018. Resultados: 160 pacientes fueron tratados con trombólisis intravenosa, 50% mujeres; edad media 65,4±18,5 años. 48 casos (30%) recibieron LrtPA. En el análisis univariado, LrtPA se asoció con la edad del paciente (p=0,000), escala de Rankin modificadas (mRS) (p<0,000), hipertensión arterial (p=0,076), diabetes mellitus (p=0,021), hipercolesterolemia (p=0,19), tabaquismo (p=0,06), fibrilación auricular (p=0,10), antecedentes de enfermedad coronaria (p=0,06), tratamiento previo con antiplaquetarios (p<0,000), International Normalized Ratio-INR (p=0,18), recuento de plaquetario (p=0,045), leucoaraiosis en neuroimagen (p<0,003), contraindicaciones para el tratamiento trombolítico (p=0,000) y tratamiento endovascular (p=0,027). Las hemorragias previas relevantes fueron determinantes para el tratamiento con LrtPA. El diagnóstico al alta de imitador de accidente cerebrovascular fue significativo (p=0,02) para el tratamiento con dosis estándar. El análisis multivariado demostró que mRS (OR: 2,21; IC95% 1,37‒14,19), tratamiento antiplaquetario previo (OR: 11,41; IC95% 3,98‒32,7), contraindicaciones para trombólisis (OR: 56,1; IC95% 8,81‒357,8), leucoaraiosis (OR: 4,41; IC95% 1,37‒14,1) y un diagnóstico de imitador de accidente cerebrovascular (OR: 0,22; IC95% 0,1‒0,40) fueron asociados con la dosis recibida. Conclusiones: LrtPA está restringido al 30% de nuestros pacientes. Los criterios para tomar esta decisión se basan en variables que podrían aumentar el riesgo de hemorragia cerebral/sistémica o excluir al paciente del tratamiento con fármacos líticos.

De Sitter symmetries and inflationary scalar-vector models / Simetrías en el espacio de De Sitter y modelos inflacionarios escalar-vector / Simetrias de De Sitter e modelos inflacionarios escalar-vetors

Abstract In this paper, we study the correspondence between a field theory in de Sitter space in D-dimensions and a dual conformal field theory in a euclidean space in (D-1)-dimensions. In particular, we investigate the form in which this correspondence is established for a system of interacting scalar and a vector fields propagating in de Sitter space. We analyze some necessary (but not sufficient) conditions for which conformal symmetry is preserved in the dual theory in (D - 1)-dimensions, making possible the establishment of the correspondence. The discussion that we address in this paper is framed on the context of inflationary cosmology. Thusly, the results obtained here pose some relevant possibilities of application to the calculation of the fields's correlation functions and of the primordial curvature perturbation Z, in inflationary models including coupled scalar and vector fields.

Resumen En este artículo se estudia la correspondencia entre una teoría de campos en el espacio de De Sitter en D-dimensiones y una teoría dual conforme en un espacio euclidiano en (D - 1)-dimensiones. En particular, se investiga la forma en la que se establece esta correspondencia para un sistema compuesto por un campo escalar y un campo vectorial acoplados propagándose en el espacio de De Sitter. Se analizan algunas condiciones necesarias (pero no suficientes) en las cuales la simetría conforme se preserva en la teoría dual en (D - 1)-dimensiones y hace posible el establecimiento de la correspondencia. La discusión presentada aquí se enmarca en el contexto de la cosmología inflacionaria, así que los resultados obtenidos plantean algunas posibilidades relevantes de aplicación en el cálculo de funciones de correlación de los campos y de la perturbación de ¡a curvatura primordial Z en modelos inflacionarios que incluyen campos escalares y vectoriales acoplados.

Resumen Neste artigo, é estudada a correspondencia entre uma teoria de campos no espaço de De Sitter em D-dimensões e uma teoria dual conforme num espaço euclidiano em (D - 1)-dimensões. Em particular, é pesquisado o caminho no qual se estabelece esta correspondência para um sistema de interação composto dum campo escalar e um vetorial, propagando-se no espaço de De Sitter. São analisadas algumas condições necessárias (mas não suficientes) para as quais a simetria conforme é preservada na teoria dual em (D-l)-dimensões, fazendo viável o estabelecimento da correspondência. A discussão apresentada aqui, está situada no contexto da cosmologia inflacionária. Portanto, os resultados obtidos representam algumas possibilidades relevantes para sua aplicacão no cálculo de funções de correlação dos campos e da perturbação da curvatura primordial Ç em modelos inflacionários incluindo campos acoplados escalares e vetoriais.

Tumor fibroso solitario pleural como causa de disnea en un paciente de 53 años / Pleural fibrous solitary tumor as cause of dyspnea in a patient 53 years old

El tumor fbroso solitario pleural es una neoplasia infrecuente originada en las células mesoteliales de la superfcie pleural con una incidencia calculada en alrededor de 2.8 casos por 100.000 pacientes al año [1]; además, representa el 8% de las neoplasias benignas del tórax y 10% de los tumores pleurales [2]. El curso clínico de la mayoría de estos tumores es benigno, raramente pueden recurrir localmente o dar metástasis. Las recurrencias pueden ser tardías, con un período de latencia de hasta 30 años [3], la mayoría de los casos se localizan en la pleura visceral o parietal; además, pueden aparecer en otras áreas tales como peritoneo, mediastino, meninges, pulmón, tiroides, parótida, órbita, nariz y fosas nasales. Clínicamente este tumor es asintomático y suele diagnosticarse de manera casual en una radiografía de tórax. Los síntomas ocasionalmente descritos son tos, disnea, dolor torácico y derrame pleural, y entre las manifestaciones sistémicas fguran artralgias, acropaquias e hipoglicemia

The pleural solitary fibrous tumor is an infrequent neoplasm originated in the mesothelial cells of the pleural surface with an incidence calculated at around 2.8 cases per 100,000 patients per year [1]; In addition, it represents 8% of benign neoplasms of the thorax and 10% of pleural tumors [2]. The clinical course of most of these tumors It is benign, rarely they can recur locally or metastasize. The recurrences may be late, with a latency period of up to 30 years [3], most cases are located in the visceral pleura or parietal; In addition, they may appear in other areas such as peritoneum, mediastinum, meninges, lung, thyroid, parotid, orbit, nose and pits Nasal Clinically, this tumor is asymptomatic and is usually diagnosed casual way on a chest x-ray. The symptoms occasionally described are cough, dyspnea, chest pain and pleural effusion, and between Systemic manifestations include arthralgias, acropachias and hypoglycemia