Genetically modified ZIKA virus as a microRNA-sensitive oncolytic virus against central nervous system tumors

Here we introduce a first-in-class microRNA-sensitive oncolytic Zika virus (ZIKV) for virotherapy application against central nervous system (CNS) tumors. The described methodology produced two synthetic modified ZIKV strains that are safe in normal cells, including neural stem cells, while preserving brain tropism and oncolytic effects in tumor cells. The microRNA-sensitive ZIKV introduces genetic modifications in two different virus sites: first, in the established 3′UTR region, and secondly, in the ZIKV protein coding sequence, demonstrating for the first time that the miRNA inhibition systems can be functional outside the UTR RNA sites. The total tumor remission in mice bearing human CNS tumors, including metastatic tumor growth, after intraventricular and systemic modified ZIKV administration, confirms the promise of this virotherapy as a novel agent against brain tumors—highly deadly diseases in urgent need of effective advanced therapies.

Human Fallopian Tube - Derived Mesenchymal Stem Cells Inhibit Experimental Autoimmune Encephalomyelitis by Suppressing Th1/Th17 Activation and Migration to Central Nervous System.

Mesenchymal stem cells comprise a natural reservoir of undifferentiated cells within adult tissues. Given their self-renewal, multipotency, regenerative potential and immunomodulatory properties, MSCs have been reported as a promising cell therapy for the treatment of different diseases, including neurodegenerative and autoimmune diseases. In this study, we investigated the immunomodulatory properties of human tubal mesenchymal stem cells (htMSCs) using the EAE model. htMSCs were able to suppress dendritic cells activation downregulating antigen presentation-related molecules, such as MHCII, CD80 and CD86, while impairing IFN-γ and IL-17 and increasing IL-10 and IL-4 secretion. It further correlated with milder disease scores when compared to the control group due to fewer leukocytes infiltrating the CNS, specially Th1 and Th17 lymphocytes, associated with increased IL-10 secreting Tr1 cells. Conversely, microglia were less activated and infiltrating mononuclear cells secreted higher levels of IL-4 and IL-10 and expressed reduced chemokine receptors as CCR4, CCR6 and CCR8. qPCR of the spinal cords revealed upregulation of indoleamine-2,3-dioxygenase (IDO) and brain derived neurotrophic factor (BDNF). Taken together, here evidenced the potential of htMSCs as an alternative for the treatment of inflammatory, autoimmune or neurodegenerative diseases.

Placental magnetic resonance imaging: normal appearance, anatomical variations, and pathological findings.

Placental magnetic resonance imaging (MRI) has been increasingly requested, especially for the evaluation of suspected cases of placental adhesive disorders, generally known as placenta accreta. Abdominal radiologists need to become familiar with normal placental anatomy, anatomical variations, the current terminology, and major placental diseases that, although rare, are important causes of maternal and fetal morbidity and mortality. The aim of this didactic pictorial essay is to illustrate various findings on placental MRI, as well as to emphasize the importance of communication between radiologists and obstetricians in the search for best practices in the management of the affected patients.

A ressonância magnética placentária tem sido cada vez mais solicitada, sobretudo na avaliação de casos suspeitos de acretismo. Os radiologistas abdominais precisam se familiarizar com a anatomia placentária normal, variações anatômicas, terminologias atuais e principais doenças placentárias que, embora raras, são causas importantes de morbimortalidade materno-fetal. O objetivo deste ensaio é ilustrar, de maneira didática, diferentes achados placentários e enfatizar a importância da comunicação entre radiologistas e obstetras na busca da melhor conduta para as pacientes.

Placental magnetic resonance imaging: normal appearance, anatomical variations, and pathological findings / Ressonância magnética placentária: aspecto normal, variações anatômicas e achados patológicos

Abstract Placental magnetic resonance imaging (MRI) has been increasingly requested, especially for the evaluation of suspected cases of placental adhesive disorders, generally known as placenta accreta. Abdominal radiologists need to become familiar with normal placental anatomy, anatomical variations, the current terminology, and major placental diseases that, although rare, are important causes of maternal and fetal morbidity and mortality. The aim of this didactic pictorial essay is to illustrate various findings on placental MRI, as well as to emphasize the importance of communication between radiologists and obstetricians in the search for best practices in the management of the affected patients.

Resumo A ressonância magnética placentária tem sido cada vez mais solicitada, sobretudo na avaliação de casos suspeitos de acretismo. Os radiologistas abdominais precisam se familiarizar com a anatomia placentária normal, variações anatômicas, terminologias atuais e principais doenças placentárias que, embora raras, são causas importantes de morbimortalidade materno-fetal. O objetivo deste ensaio é ilustrar, de maneira didática, diferentes achados placentários e enfatizar a importância da comunicação entre radiologistas e obstetras na busca da melhor conduta para as pacientes.

Transcutaneous Administration of Dengue Vaccines.

In the present study, we evaluated the immunological responses induced by dengue vaccines under experimental conditions after delivery via a transcutaneous (TC) route. Vaccines against type 2 Dengue virus particles (DENV2 New Guinea C (NGC) strain) combined with enterotoxigenic Escherichia coli (ETEC) heat-labile toxin (LT) were administered to BALB/c mice in a three-dose immunization regimen via the TC route. As a control for the parenteral administration route, other mouse groups were immunized with the same vaccine formulation via the intradermic (ID) route. Our results showed that mice vaccinated either via the TC or ID routes developed similar protective immunity, as measured after lethal challenges with the DENV2 NGC strain. Notably, the vaccine delivered through the TC route induced lower serum antibody (IgG) responses with regard to ID-immunized mice, particularly after the third dose. The protective immunity elicited in TC-immunized mice was attributed to different antigen-specific antibody properties, such as epitope specificity and IgG subclass responses, and cellular immune responses, as determined by cytokine secretion profiles. Altogether, the results of the present study demonstrate the immunogenicity and protective properties of a dengue vaccine delivered through the TC route and offer perspectives for future clinical applications.

Protective Immunity to Dengue Virus Induced by DNA Vaccines Encoding Nonstructural Proteins in a Lethal Challenge Immunocompetent Mouse Model.

Dengue virus represents the main arbovirus affecting humans, but there are no effective drugs or available worldwide licensed vaccine formulations capable of conferring full protection against the infection. Experimental studies and results generated after the release of the licensed anti-DENV vaccine demonstrated that induction of high-titer neutralizing antibodies does not represent the sole protection correlate and that, indeed, T cell-based immune responses plays a relevant role in the establishment of an immune protective state. In this context, this study aimed to further demonstrate protective features of immune responses elicited in immunocompetent C57BL/6 mice immunized with three plasmids encoding DENV2 nonstructural proteins (NS1, NS3, and NS5), which were subsequently challenged with a DENV2 strain naturally capable of inducing lethal encephalitis in immunocompetent mouse strains. The animals were immunized intramuscularly with the DNA vaccine mix and complete protection was observed among vaccinated mice. Vaccine induced protection correlated with the cytokine profiles expressed by spleen cells and brain-infiltrating mononuclear cells. The results confirm the pivotal role of cellular immune responses targeting nonstructural DENV proteins and validate the experimental model based on a DENV2 strain capable of infecting and killing immunocompetent mice as a tool for the evaluation of protective immunity induced by anti-DENV vaccines.

Corrigendum: Protective Immunity to Dengue Virus Induced by DNA Vaccines Encoding Nonstructural Proteins in a Lethal Challenge Immunocompetent Mouse Model.

[This corrects the article DOI: 10.3389/fmedt.2020.558984.].

Zika virus congenital syndrome: experimental models and clinical aspects.

Viral infections have long been the cause of severe diseases to humans, increasing morbidity and mortality rates worldwide, either in rich or poor countries. Yellow fever virus, H1N1 virus, HIV, dengue virus, hepatitis B and C are well known threats to human health, being responsible for many million deaths annually, associated to a huge economic and social cost. In this context, a recently introduced flavivirus in South America, called Zika virus (ZIKV), led the WHO to declare in February 1st 2016 a warning on Public Health Emergency of International Concern (PHEIC). ZIKV is an arbovirus of the Flaviviridae family firstly isolated from sentinels Rhesus sp. monkeys at the Ziika forest in Uganda, Africa, in 1947. Lately, the virus has well adapted to the worldwide spread Aedes aegypti mosquito, the vector for DENV, CHIKV, YFV and many others. At first, it was not considered a threat to human health, but everything changed when a skyrocketing number of babies born with microcephaly and adults with Guillain-Barré syndrome were reported, mainly in northeastern Brazil. It is now well established that the virus is responsible for the so called congenital Zika syndrome (CZS), whose most dramatic features are microcephaly, arthrogryposis and ocular damage. Thus, in this review, we provide a brief discussion of these main clinical aspects of the CZS, correlating them with the experimental animal models described so far.

Zika virus congenital syndrome: experimental models and clinical aspects

Viral infections have long been the cause of severe diseases to humans, increasing morbidity and mortality rates worldwide, either in rich or poor countries. Yellow fever virus, H1N1 virus, HIV, dengue virus, hepatitis B and C are well known threats to human health, being responsible for many million deaths annually, associated to a huge economic and social cost. In this context, a recently introduced flavivirus in South America, called Zika virus (ZIKV), led the WHO to declare in February 1st 2016 a warning on Public Health Emergency of International Concern (PHEIC). ZIKV is an arbovirus of the Flaviviridae family firstly isolated from sentinels Rhesus sp. monkeys at the Ziika forest in Uganda, Africa, in 1947. Lately, the virus has well adapted to the worldwide spread Aedes aegypti mosquito, the vector for DENV, CHIKV, YFV and many others. At first, it was not considered a threat to human health, but everything changed when a skyrocketing number of babies born with microcephaly and adults with Guillain-Barré syndrome were reported, mainly in northeastern Brazil. It is now well established that the virus is responsible for the so called congenital Zika syndrome (CZS), whose most dramatic features are microcephaly, arthrogryposis and ocular damage. Thus, in this review, we provide a brief discussion of these main clinical aspects of the CZS, correlating them with the experimental animal models described so far.(AU)

Zika virus congenital syndrome: experimental models and clinical aspects

Abstract Viral infections have long been the cause of severe diseases to humans, increasing morbidity and mortality rates worldwide, either in rich or poor countries. Yellow fever virus, H1N1 virus, HIV, dengue virus, hepatitis B and C are well known threats to human health, being responsible for many million deaths annually, associated to a huge economic and social cost. In this context, a recently introduced flavivirus in South America, called Zika virus (ZIKV), led the WHO to declare in February 1st 2016 a warning on Public Health Emergency of International Concern (PHEIC). ZIKV is an arbovirus of the Flaviviridae family firstly isolated from sentinels Rhesus sp. monkeys at the Ziika forest in Uganda, Africa, in 1947. Lately, the virus has well adapted to the worldwide spread Aedes aegypti mosquito, the vector for DENV, CHIKV, YFV and many others. At first, it was not considered a threat to human health, but everything changed when a skyrocketing number of babies born with microcephaly and adults with Guillain-Barré syndrome were reported, mainly in northeastern Brazil. It is now well established that the virus is responsible for the so called congenital Zika syndrome (CZS), whose most dramatic features are microcephaly, arthrogryposis and ocular damage. Thus, in this review, we provide a brief discussion of these main clinical aspects of the CZS, correlating them with the experimental animal models described so far.

Effects of pelvic floor muscle training during pregnancy.

OBJECTIVE: The objective of the present study was to evaluate the effect of pelvic floor muscle training in 46 nulliparous pregnant women. METHODS: The women were divided into 2 groups: an exercise group and a control group. Functional evaluation of the pelvic floor muscle was performed by digital vaginal palpation using the strength scale described by Ortiz and by a perineometer (with and without biofeedback). RESULTS: The functional evaluation of the pelvic floor muscles showed a significant increase in pelvic floor muscle strength during pregnancy in both groups (P < .001). However, the magnitude of the change was greater in the exercise group than in the control group (47.4% vs. 17.3%, P < .001). The study also showed a significant positive correlation (Spearman's test, r = 0.643; P < .001) between perineometry and digital assessment in the strength of pelvic floor muscles. CONCLUSIONS: Pelvic floor muscle training resulted in a significant increase in pelvic floor muscle pressure and strength during pregnancy. A significant positive correlation between functional evaluation of the pelvic floor muscle and perineometry was observed during pregnancy.

Ciclo único de betametasona para maturação pulmonar fetal em gestações com diástole zero ou reversa: impacto em resultados pós-natais / Single course of antenatal betamethasone therapy for the acceleration of fetal lung maturation in absent or reversed end-diastolic velocity in the umbilical arteries: impact on postnatal outcomes

Para investigar o impacto em resultados pós-natais do uso de ciclo único de betametasona para maturação pulmonar em gestações (únicas, sem malformações fetais ou neonatais) com diástole zero ou diástole reversa à dopplervelocimetria das artérias umbilicais, foi conduzido estudo de coorte histórico com 62 recém-nascidos entre 26 e 34 semanas. Desses, 31 tinham uso antenatal do corticóide (nascidos entre maio de 2004 e julho de 2006) e 31 controles sem o uso da droga (nascidos entre janeiro de 2000 a março de 2004), pareados individualmente segundo índice de pulsatilidade para veias do ducto venoso (até 1,0 ou entre 1,01 e 1,50), idade gestacional ao nascimento (variação máxima de seis dias) e peso ao nascimento (variação máxima de 10%). Avaliaram-se: índice de Apgar de primeiro e quinto minutos, internação em unidade de terapia intensiva, uso de suporte respiratório (intubação orotraqueal, pressão positiva contínua nas vias aéreas, suplemento de oxigênio), tempo de internação, sobrevida, ocorrência de óbito (e causa principal), além da ocorrência de complicações (doença das membranas hialinas, displasia broncopulmonar, hemorragia intracraniana, retinopatia da prematuridade, persistência de canal arterial, enterocolite necrosante, sepse precoce e tardia). Fez-se análise estatística para os pares de recém-nascidos dos dois grupos, baseada na razão de pares discordantes e utilizaram-se os testes: t de Student para amostras pareadas, qui-quadrado de McNemar, de simetria assintótica, de Wilcoxon, de log-rank. No caso dos desfechos em que o uso de betametasona apresentou associação com ocorrência significativamente menor de complicações, foi calculado o número necessário para tratar para evitar o desfecho em um recém-nascido. Adotou-se significância de 5%. A média de idade gestacional foi de 29,4 semanas e, de peso, 794,2gramas...

A retrospective cohort study of 62 pregnancies with absent or reversed end-diastolic flow in the umbilical arteries was conducted in order to investigate the impact on postnatal outcome of a single course of antenatal betamethasone therapy for the acceleration of fetal lung maturation. Sixty-two singleton pregnancies, without fetal or neonatal anomalies, delivered during the period of January 2000 and July 2006 with a gestational age ranging from 26 to 34 weeks were included. The study included 31 newborns with the antenatal corticosteroid therapy and 31 nontreated, matched individually according to gestational age (within about six days), birth weight (within about 10%) and value of pulsatility index for veins in the ductus venosus (maximum of 1,0 or between 1,01 and 1,50). The outcomes assessed were: 1- and 5-minute Apgar scores, referral to the neonatal intensive care unit, need of tracheal intubation, use of continuous positive airway pressure, use of oxygen therapy, length of hospital stay, survival, in-hospital mortality (and main cause), use of surfactant, number of surfactant doses, and the occurrence of hyaline membrane disease, bronchopulmonary dysplasia, intracranial hemorrhage, retinopathy of prematurity, patent ductus arteriosus, necrotizing enterocolitis, early-onset and late-onset neonatal sepsis. Data from each matched-pair of infants were analyzed in terms of its discordance by the use of these tests: Student's t test for matched-pairs, McNemar´s chi-square test, symmetry test, Wilcoxon matched-pairs signed-ranks test, log-hank test. Numbers needed to treat in the case of beneficial effect were calculated for each outcome. A significance level of 5% was adopted for all tests. Mean of gestational age and birth weight were 29,4 weeks and 794,4grams...

Effects of pelvic floor muscle training during pregnancy

OJETIVE: The objective of the present study was to evaluate the effect of pelvic floor muscle training in 46 nulliparous pregnant women. METHODS: The women were divided into 2 groups: an exercise group and a control group. Functional evaluation of the pelvic floor muscle was performed by digital vaginal palpation using the strength scale described by Ortiz and by a perineometer (with and without biofeedback). RESULTS: The functional evaluation of the pelvic floor muscles showed a significant increase in pelvic floor muscle strength during pregnancy in both groups (P < .001). However, the magnitude of the change was greater in the exercise group than in the control group (47.4 percent vs. 17.3 percent, P < .001). The study also showed a significant positive correlation (Spearman's test, r = 0.643; P < .001) between perineometry and digital assessment in the strength of pelvic floor muscles. CONCLUSIONS: Pelvic floor muscle training resulted in a significant increase in pelvic floor muscle pressure and strength during pregnancy. A significant positive correlation between functional evaluation of the pelvic floor muscle and perineometry was observed during pregnancy.

INTRODUÇÃO: A gravidez traz importantes modificações hormonais e anatômicas que têm efeito sobre a musculatura do assoalho pélvico. A cinesioterapia aplicada à musculatura do assoalho pélvico na gestação pode ser grande aliada no controle das alterações músculo-esqueléticas. OBJETIVOS: Avaliar efeitos da cinesioterapia no assoalho pélvico durante a gravidez, por meio da perineometria com e sem "biofeedback" e da avaliação funcional do assoalho pélvico, e correlacionar os valores da avaliação funcional com as perineometrias. MÉTODOS: Estudamos 46 gestantes nulíparas em seguimento pré-natal no Departamento de Obstetrícia do Hospital das Clínicas da Universidade de São Paulo, entre novembro de 2003 e dezembro de 2004, com até 20 semanas de gestação, atendidas no Setor de Baixo-Risco, divididas em dois grupos: Grupo exercício (23 casos): pacientes submetidas à cinesioterapia para a musculatura do assoalho pélvico; e grupo controle (23 casos): sem a prática da cinesioterapia. Por 12 semanas, até a 36ª semana, seguiu-se um protocolo, com treinamento de 60 minutos semanais, executando-se quatro séries de 10 contrações destes músculos com seis segundos de manutenção e 12 segundos de relaxamento, em decúbitos distintos. Realizaram-se 2 avaliações: 1ª (até 20 semanas) e 2ª (36 semanas gestacionais), por meio da avaliação funcional do assoalho pélvico e da perineometria. RESULTADOS: Na avaliação funcional do assoalho pélvico, tanto o grupo exercício como o grupo controle apresentaram aumento significativo da 1ª avaliação para a 2ª avaliação. Para a perineometria sem "biofeedback", na 2ª avaliação, somente o grupo exercício obteve aumento significativo, com p < 0,001. Quanto à perineometria com "biofeedback", tanto o grupo exercício como o controle tiveram aumento significativo nos valores, porém o delta porcentual foi maior no grupo exercício. Houve correlação significativa e positiva entre a avaliação funcional do assoalho pélvico e as perineometrias...