Hyperthermia-induced doxorubicin delivery from thermosensitive liposomes via MR-HIFU in a pig model.

PURPOSE: Encapsulation of cytotoxic drugs for a localized release is an effective way to increase the therapeutic window of such agents. In this article we present the localized release of doxorubicin (DOX) from phosphatidyldiglycerol (DPPG2) based thermosensitive liposomes using MR-HIFU mediated hyperthermia in a swine model. MATERIALS AND METHODS: German landrace pigs of weights between 37.5 and 53.5 kg received a 30-min infusion of DOX containing thermosensitive liposomes (50 mg DOX/m2). The pigs' biceps femoris was treated locally in two separate target areas with mild hyperthermia using magnetic resonance guided high intensity focused ultrasound, starting 10 min and 60 min after initiation of the infusion, respectively. The pharmacokinetics and biodistribution of DOX were determined and an analysis of the treatment parameters' influence was performed. RESULTS: Compared to untreated tissue, we found a 15-fold and a 7-fold increase in DOX concentration in the muscle volumes that had undergone hyperthermia starting 10 min and 60 min after the beginning of the infusion, respectively. The pharmacokinetic analysis showed a prolonged circulation time of DOX and a correlation between the AUC of extra-liposomal DOX in the bloodstream and the amount of DOX accumulated in the target tissue. CONCLUSIONS: We have demonstrated a workflow for MR-HIFU hyperthermia drug delivery that can be adapted to a clinical setting, showing that HIFU-hyperthermia is a suitable method for local drug release of DOX using DPPG2 based thermosensitive liposomes in stationary targets. Using the developed pharmacokinetic model, an optimization of the drug quantity deposited in the target via the timing of infusion and hyperthermia should be possible.

Visualization of thermal washout due to spatiotemporally heterogenous perfusion in the application of a model-based control algorithm for MR-HIFU mediated hyperthermia.

PURPOSE: This article will report results from the in-vivo application of a previously published model-predictive control algorithm for MR-HIFU hyperthermia. The purpose of the investigation was to test the controller's in-vivo performance and behavior in the presence of heterogeneous perfusion. MATERIALS AND METHODS: Hyperthermia at 42°C was induced and maintained for up to 30 min in a circular section of a thermometry slice in the biceps femoris of German landrace pigs (n=5) using a commercial MR-HIFU system and a recently developed MPC algorithm. The heating power allocation was correlated with heat sink maps and contrast-enhanced MRI images. The temporal change in perfusion was estimated based on the power required to maintain hyperthermia. RESULTS: The controller performed well throughout the treatments with an absolute average tracking error of 0.27 ± 0.15 °C and an average difference of 1.25 ± 0.22 °C between T10 and T90. The MPC algorithm allocates additional heating power to sub-volumes with elevated heat sink effects, which are colocalized with blood vessels visible on contrast-enhanced MRI. The perfusion appeared to have increased by at least a factor of ∼1.86 on average. CONCLUSIONS: The MPC controller generates temperature distributions with a narrow spectrum of voxel temperatures inside the target ROI despite the presence of spatiotemporally heterogeneous perfusion due to the rapid thermometry feedback available with MR-HIFU and the flexible allocation of heating power. The visualization of spatiotemporally heterogeneous perfusion presents new research opportunities for the investigation of stimulated perfusion in hypoxic tumor regions.

Feasibility study of MR-guided pancreas ablation using high-intensity focused ultrasound in a healthy swine model.

Purpose: Pancreatic cancer is typically diagnosed in a late stage with limited therapeutic options. For those patients, ultrasound-guided high-intensity focused ultrasound (US-HIFU) can improve local control and alleviate pain. However, MRI-guided HIFU (MR-HIFU) has not yet been studied extensively in this context. To facilitate related research and accelerate clinical translation, we report a workflow for the in vivo HIFU ablation of the porcine pancreas under MRI guidance.Materials and methods: The pancreases of five healthy German landrace pigs (35-58 kg) were sonicated using a clinical MR-HIFU system. Acoustic access to the pancreas was supported by a specialized diet and a hydrogel compression device for bowel displacement. Organ motion was suspended using periods of apnea. The size of the resulting thermal lesions was assessed using the thermal threshold- and dose profiles, non-perfused volume, and gross examination. The effect of the compression device on beam path length was assessed using MRI imaging.Results: Eight of ten treatments resulted in clearly visible damage in the target tissue upon gross examination. Five treatments resulted in coagulative necrosis. Good agreement between the four metrics for lesion size and a clear correlation between the delivered energy dose and the resulting lesion size were found. The compression device notably shortened the intra-abdominal beam path.Conclusions: We demonstrated a workflow for HIFU treatment of the porcine pancreas in-vivo under MRI-guidance. This development bears significance for the development of MR-guided HIFU interventions on the pancreas as the pig is the preferred animal model for the translation of pre-clinical research into clinical application.

Predictors of Early Reading Acquisition in Children of Low Socioeconomic Status / Preditores da Leitura Inicial em Crianças de Baixa Condição Socioeconômica / Predictores de la Lectura Inicial en Niños de Condiciones Socioeconómicas Bajas

Abstract The aim of the present study was to identify the predictors of early-grade reading acquisition in monolingual speakers of a transparent language. Eighty students attending preschool (M = 5 years, SD = 0.40), first grade (M = 6 years, SD = 0.59) and second grade (M = 7 years, SD = 0.55) in a public institution participated in the study. All were evaluated with the Early Grade Reading Acquisition test, an ad hoc sociodemographic questionnaire and the language domain of the Child Neuropsychological Assessment battery. Multiple regression analysis showed that phonological awareness and years of education are the factors that explain reading performance of children in their early years of school. These findings highlight the importance of improving oral skills prior to early reading acquisition and contribute to enhancing the early reading skills of monolingual children with limited socioeconomic opportunities.

Resumo O presente estudo teve como objetivo identificar os preditores da leitura inicial de uma linguagem transparente em crianças monolíngues. Oitenta alunos pertencentes à educação infantil N3 (M = 5 anos, DE = 0.40), 1ª série (M = 6 anos, DE = 0.59) e 2ª série (M = 7 anos, DE = 0.55) do ensino fundamental participaram do estudo. As crianças foram avaliadas por meio do teste Early Grade Reading Acquisition, por um questionário sociodemográfico ad hoc e apenas pelo Domínio da Linguagem do teste Evaluación Neuropsicológica Infantil. A análise de regressão múltipla mostrou que a consciência fonológica e o nível de escolaridade são os fatores que explicam o desempenho na leitura em crianças nas primeiras séries. Os resultados deste estudo sugerem a importância de promover habilidades orais antes da aquisição da leitura inicial, para melhorar o aprendizado da leitura de crianças monolíngues com limitadas oportunidades socioeconômicas.

Resumen El presente estudio tuvo por objetivo identificar los predictores de la lectura inicial en niños monolingües de un lenguaje transparente. Ochenta estudiantes que cursaban los grados de transición (M = 5 años, DE = 0.40), primero (M = 6 años, DE = 0.59) y segundo de primaria (M = 7 años, DE = 0.55) en una institución pública, participaron en el estudio. Todos fueron evaluados con la prueba Early Grade Reading Acquisition, un cuestionario sociodemográfico ad hoc y el dominio de Lenguaje de la batería Evaluación Neuropsicológica Infantil. Los análisis de regresión múltiple mostraron que la conciencia fonológica y el grado de escolaridad son los factores que explican el desempeño lector de niños de los primeros grados escolares. Estos hallazgos destacan la importancia de promover habilidades orales previas a la adquisición de la lectura inicial, para mejorar el aprendizaje lector de niños monolingües, con limitadas oportunidades socio-económicas.

CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer.

Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conjugates for chemokine-like receptor 1 (CMKLR1) targeting in a breast cancer xenograft model. Methods: By conjugation with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of five highly specific, high-affinity tracers for hybrid positron emission tomography/magnetic resonance (PET/MR) imaging. A xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging in vivo. We acquired small animal PET/MR images, assessed biodistribution by ex vivo measurements and investigated the tracer specificity by blocking experiments. Results: Five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinity in vitro with EC50 and IC50 values below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be validated by ex vivo analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers [68Ga]Ga-DOTA-AHX-CG34, [68Ga]Ga-DOTA-KCap-CG34 and [68Ga]Ga-DOTA-ADX-CG34 with best tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 3.3% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. In addition, tumor uptake was blocked by excess of unlabeled peptide (6.4-fold, 5.5-fold and 3.4-fold 1 h post-injection), further confirming CMKLR1 specificity. Out of five tracers, we identified these three tracers with moderate, balanced hydrophilicity to be the most potent in receptor-mediated tumor targeting. Conclusion: We demonstrated the applicability of 68Ga-labeled peptide tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging, paving the way for developing them into theranostics for tumor treatment.

El costo social para la salud pública a causa de la regularización de las drogas ilícitas / The social cost to public health of the regularization of illicit drugs

El más reciente estudio epidemiológico sobre consumo de drogas en estudiantes universitarios efectuado por la Comisión Interamericana para el Control del Abuso de Drogas (CICAD) de la OEA, con el apoyo de diferentes instituciones educativas en Latinoamérica, arrojó, en términos de significación estadística en comparación con estudios anteriores, un resultado completamente nuevo y sorprendente en el que se ve un aumento en el consumo de marihuana y una disminución de la percepción del riesgo entre consumidores y no consumidores. Hipotéticamente, resulta plausible proponer que dichos resultados se deben en gran medida a la regularización o legalización del uso del cannabis con fines medicinales o recreativos en países como Colombia y Uruguay, así como en países de las Américas tales como Canadá y Estados Unidos, donde de alguna forma se ha naturalizado entre la población del común la idea de que la marihuana, con todos sus componentes, es una sustancia medicinal práctica-mente inocua para la salud física y mental. El negocio transnacional más próspero y lucrativo de toda la economía subterránea es el de las drogas ilegales. Sus ventas minoristas probablemente alcanzan un 0.9 % del PIB mundial, estimando adicionalmente el tamaño del mercado al menudeo de drogas sintéticas y de diseño, el cual puede representar cerca del 30 % del mercado de las otras drogas.

The most recent epidemiological study on drug use among university students conducted by the Inter-American Drug Abuse Control Commission (CICAD) of the OAS, with the support of different educational institutions in Latin America, yielded, in terms of statistical significance compared to previous studies, a completely new and surprising result showing an increase in marijuana use and a decrease in the perception of risk among users and non-users. Hypothetically, it is plausible to propose that these results are largely due to the regularization or legalization of the use of cannabis for medicinal or recreational purposes in countries such as Colombia and Uruguay, as well as in countries of the Americas such as Canada and the United States, where the idea that marijuana, with all its components, is a medicinal substance that is practically harmless to physical and mental health has somehow become naturalized among the common population. The most prosperous and lucrative transnational business in the entire subway economy is that of illegal drugs. Its retail sales probably amount to 0.9 % of the world GDP, estimating additionally the size of the retail market for synthetic and designer drugs, which may represent about 30 % of the market for other drugs.

Psychological distress, family dysfunction, maltreatment during childhood of students at a private university, Bogota Colombia / Distress psicológico, disfunção familiar, maus-tratos na infância de estudantes de uma universidade privada, Bogotá, Colombia / Malestar psicológico, disfunción familiar, maltrato de estudiantes durante la niñez en una universidad privada de Bogotá, Colombia

Estudio derivado de una investigación exploratoria, correlacional-descriptiva, que estudió retrospectivamente el maltrato durante la infancia y su posible relación con el uso de sustancias psicoactivantes entre estudiantes universitarios. El maltrato infantil auto-reportado se evaluó mediante el Cuestionario de Experiencias Adversas Durante la Niñez, y para evaluar la disfunción familiar y el malestar psicológico (distress) se aplicó la Escala de Kessler (K10) a 302 estudiantes. Los principales indicadores de maltrato infantil fueron: negligencia =18,2%; maltrato emocional =17.9%; maltrato físico =13.6%; abuso sexual =2.0%. Otros indicadores relevantes fueron: madre/cuidadora agredida, 9.3%; madre/cuidadora golpeada repetidamente por al menos algunos minutos, 5.3%; y madre/cuidadora herida con arma blanca o de fuego, 3.6%. Se concluye que existe relación entre el "abuso emocional y el "abuso físico", y entre el "abuso emocional" y la "disfunción familiar" así como la detección de violencia de género en familias según estrato socioeconómico.

Este é um estudo exploratório-descritivo, retrospectivo, com o objetivo de avaliar a potencial relação entre maus-tratos na infância e o uso de substâncias psicoactivas entre os estudantes universitários. Os maus-tratos na infância foram avaliados por meio do questionário "Experiências Adversas na Infância", e para avaliar a disfunção familiar e os fatores de sofrimento psíquico foi aplicado a Scale Kessler (K10) a 302 estudantes. Os principais indicadores de maus-tratos na infância foram: negligência =18,2%; abuso emocional =17,9%, abuso físico =13,6%; abuso sexual =2,0%. Outros indicadores relevantes foram: abuso à mãe/cuidador (9,3%), a mãe/cuidador repetidamente espancado por pelo menos alguns minutos (5,3%) e mãe/cuidador ferido por arma branca ou arma de fogo (3,6%). Conclui-se que há relação significativa entre maus-tratos físico e emocional e entre maus-tratos emocional e "disfunção familiar", bem como, a detecção de violência de gênero nas famílias de acordo com os estratos socioeconômicos.

This article is an exploratory, correlational, descriptive and retrospective research aimed to study the potential relationship between maltreatment during childhood and the use of psychoactive drugs among university students. Self-reported child maltreatment was assessed through the Adverse Childhood Experiences Questionnaire, and to evaluate family dysfunction and distress factors the Kessler Scale (K10) was applied to 302 students. The main indicators of childhood maltreatment were; negligence 18.2%, emotional abuse 17.9%, physical abuse 13.6%, sexual abuse 2.0%. Other relevant indicators were: mother/caregiver assaulted 9.3%, mother/caregiver repeatedly assaulted for at least a few minutes 5.3% and mother/caregiver wounded by knife or gunshot 3.6%. We conclude that there is a significant relationship between "emotional abuse" and "physical abuse"; and between "emotional abuse" and "family dysfunction"; and the detection of gender violence in families by socio-economic statuses.

Estudio exploratorio sobre conocimientos y actitudes frente algunas intervenciones neurocientíficas en Colombia / Exploratory study about the knowledge and attitudes towards neuroscientific interventions in Colombia

El objetivo del estudio fue evaluar las actitudes y conocimientos de 40 participantes pertenecientes a diferentes esferas sociales frente a las intervenciones neurocientíficas en ensanchamiento o mejoramiento cognitivo. Esto, con el fin de explorar en qué medida encuentran moralmente aceptable los desarrollos biotecnológicos en las neurociencias del comportamiento. Se realizó un análisis cuantitativo y cualitativo. No se encontraron diferencias en la actitud hacia las intervenciones según el nivel de conocimiento. Por último, se observó una tendencia central en lo que respecta a las percepciones éticas sobre estas intervenciones, a pesar de encontrar diferencias de aceptabilidad moral en los diferentes grupos.

This study was aimed to assess attitudes and knowledge of 40 people from different social status toward the scientific interventions in cognitive neuroenhancement. It is in order to inquire about the moral acceptance of the biotechnologically viable in behavioral neuroscience. Both, quantitative and qualitative analyses were performed. No differences in attitude towards interventions according to the level of knowledge were presented. Finally a central tendency was observed toward the ethical perceptions about the mentioned interventions, in spite of having found moral differences in moral acceptability among the different groups.