Cell Transplantation for Repair of the Spinal Cord and Prospects for Generating Region-Specific Exogenic Neuronal Cells.

Spinal cord injury (SCI) is associated with currently irreversible consequences in several functional components of the central nervous system. Despite the severity of injury, there remains no approved treatment to restore function. However, with a growing number of preclinical studies and clinical trials, cell transplantation has gained significant potential as a treatment for SCI. Researchers have identified several cell types as potential candidates for transplantation. To optimize successful functional outcomes after transplantation, one key factor concerns generating neuronal cells with regional and subtype specificity, thus calling on the developmental transcriptome patterning of spinal cord cells. A potential source of spinal cord cells for transplantation is the generation of exogenic neuronal progenitor cells via the emerging technologies of gene editing and blastocyst complementation. This review highlights the use of cell transplantation to treat SCI in the context of relevant developmental gene expression patterns useful for producing regionally specific exogenic spinal cells via in vitro differentiation and blastocyst complementation.

Comparison between 200 mg generic celecoxib hard capsules and Celebra®: bioequivalence study in healthy male and female subjects under fasting conditions after a single dose / Comparação entre celecoxibe genérico de 200 mg em cápsulas duras e Celebra®: estudo de bioequivalência em indivíduos saudáveis do sexo masculino e feminino, em jejum, após uma dose única

ABSTRACT BACKGROUND AND OBJECTIVES: The objective of this study was to assess the bioequivalence between two 200 mg celecoxib hard capsule formulations administered to healthy male and female participants under fasting conditions with the aim of providing an alternative pharmaceutical product to the reference drug, Celebra®. METHODS: A randomized, open label, single dose, 2x2 crossover trial was conducted with 60 adult healthy subjects under fasting conditions comparing single doses of two celecoxib hard capsules formulation. Pharmacokinetic parameters were calculated following the determination of drugs concentrations in human plasma using a validated liquid chromatography with a tandem mass spectrometer detector method (LC-MS/MS). RESULTS: Statistical analysis provided geometric mean of test/reference ratio, confidence intervals, intra-subject variation coefficient and power of the test to the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. Confidence intervals for the geometric mean (90% CI) of the test/reference drugs for celecoxib were 98.26 to 122.75% for Cmax, 100.27% to 110.78% for AUC0-t, and 96.87% to 110.29% for AUC0-∞. The power of the test found was 95.09% for Cmax, 100.00% for AUC0-t, and 99.99% for AUC0-∞. CONCLUSION: The formulations met the Brazilian standards for interchangeability, as the confidence intervals for Cmax and AUC0-t ratios are within the range of 80% to 125%, thus meeting the requirements of the legislation during market registration. The researched product was approved by the regulatory authorities and became a commercially competitive option to the reference product for the Brazilian population.

RESUMO JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi avaliar a bioequivalência entre duas formulações de cápsulas duras de celecoxibe de 200 mg administradas a participantes saudáveis do sexo masculino e feminino em condições de jejum com o objetivo de fornecer um produto farmacêutico alternativo ao fármaco de referência, Celebra®. MÉTODOS: Estudo randomizado, aberto, de dose única e cruzado 2x2. Foi conduzido com 60 indivíduos adultos saudáveis em condições de jejum, comparando doses únicas de duas formulações de cápsulas duras de celecoxibe. Os parâmetros farmacocinéticos foram calculados após a determinação das concentrações dos fármacos no plasma humano usando uma cromatografia líquida validada com um método detector de espectrômetro de massa em tandem (LC-MS/MS). RESULTADOS: A análise estatística forneceu a média geométrica da razão teste/referência, os intervalos de confiança, o coeficiente de variação intra-sujeito e o poder do teste para os parâmetros farmacocinéticos Cmáx, AUC0-t e AUC0-∞. Os intervalos de confiança para a média geométrica (IC 90%) dos fármacos teste/referência para o celecoxibe foram 98,26 a 122,75% para Cmáx, 100,27% a 110,78% para AUC0-t e 96,87% a 110,29% para AUC0-∞. O poder do teste encontrado foi de 95,09% para Cmáx, 100,00% para AUC0-t e 99,99% para AUC0-∞. CONCLUSÃO: As formulações atenderam aos padrões brasileiros de intercambialidade, pois os intervalos de confiança para as razões Cmáx e AUC0-t estão dentro da faixa de 80% a 125%, atendendo, assim, às exigências da legislação para o registro no mercado. O produto pesquisado foi aprovado pelas autoridades regulatórias e tornou-se uma opção comercialmente competitiva ao produto de referência para a população brasileira.

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury.

BACKGROUND: There are currently no effective clinical therapies to ameliorate the loss of function that occurs after spinal cord injury. Electrical stimulation of the rat spinal cord through the rat tail has previously been described by our laboratory. We propose combinatorial treatment with human induced pluripotent stem cell-derived spinal neural progenitor cells (sNPCs) along with tail nerve electrical stimulation (TANES). The purpose of this study was to examine the influence of TANES on the differentiation of sNPCs with the hypothesis that the addition of TANES would affect incorporation of sNPCs into the injured spinal cord, which is our ultimate goal. METHODS: Chronically injured athymic nude rats were allocated to one of three treatment groups: injury only, sNPC only, or sNPC + TANES. Rats were sacrificed at 16 weeks post-transplantation, and tissue was processed and analyzed utilizing standard histological and tissue clearing techniques. Functional testing was performed. All quantitative data were presented as mean ± standard error of the mean. Statistics were conducted using GraphPad Prism. RESULTS: We found that sNPCs were multi-potent and retained the ability to differentiate into mainly neurons or oligodendrocytes after this transplantation paradigm. The addition of TANES resulted in more transplanted cells differentiating into oligodendrocytes compared with no TANES treatment, and more myelin was found. TANES not only promoted significantly higher numbers of sNPCs migrating away from the site of injection but also influenced long-distance axonal/dendritic projections especially in the rostral direction. Further, we observed localization of synaptophysin on SC121-positive cells, suggesting integration with host or surrounding neurons, and this finding was enhanced when TANES was applied. Also, rats that were transplanted with sNPCs in combination with TANES resulted in an increase in serotonergic fibers in the lumbar region. This suggests that TANES contributes to integration of sNPCs, as well as activity-dependent oligodendrocyte and myelin remodeling of the chronically injured spinal cord. CONCLUSIONS: Together, the data suggest that the added electrical stimulation promoted cellular integration and influenced the fate of human induced pluripotent stem cell-derived sNPCs transplanted into the injured spinal cord.

Accelerated differentiation of human induced pluripotent stem cells into regionally specific dorsal and ventral spinal neural progenitor cells for application in spinal cord therapeutics.

Spinal cord injury can attenuate both motor and sensory function with minimal potential for full recovery. Research utilizing human induced pluripotent stem cell (hiPSC) -derived spinal cell types for in vivo remodeling and neuromodulation after spinal cord injury has grown substantially in recent years. However, the majority of protocols for the differentiation of spinal neurons are lengthy, lack the appropriate dorsoventral or rostrocaudal specification, and are not typically replicated in more than one cell line. Furthermore, most researchers currently utilize hiPSC-derived motor neurons for cell transplantation after injury, with very little exploration of spinal sensory neuron transplantation. The lack of studies that utilize sensory populations may be due in part to the relative scarcity of dorsal horn differentiation protocols. Building upon our previously published work that demonstrated the rapid establishment of a primitive ectoderm population from hiPSCs, we describe here the production of a diverse population of both ventral spinal and dorsal horn progenitor cells. Our work creates a novel system allowing dorsal and ventral spinal neurons to be differentiated from the same intermediate ectoderm population, making it possible to construct the dorsal and ventral domains of the spinal cord while decreasing variability. This technology can be used in tandem with biomaterials and pharmacology to improve cell transplantation for spinal cord injury, increasing the potential for neuroregeneration.

Eventos adversos associados às doses de fentanil utilizadas nos primeiros dez de vida em neonatos submetidos à correção de gastrosquise / Adverse events associated with doses of fentanyl used in the first ten days of life in neonates undergoing gastroschisis repair

Objetivo: Avaliar a associação entre as doses de fentanil utilizadas nos primeiros dez dias de vida de neonatos submetidos à correção cirúrgica de gastrosquise e as complicações respiratórias e gastrointestinais comumente associadas à essa faixa etária e defeito congênito. Métodos: O presente estudo avaliou de forma retrospectiva a coorte de recém-nascidos portadores de gastrosquise operados no IFF no período de janeiro de 2016 até junho de 2021. Dados demográficos dos neonatos e gestantes, das intervenções cirúrgicas, dos procedimentos anestésicos e dos cuidados perioperatórios em unidade de terapia intensiva neonatal foram coletados de prontuários. Os principais desfechos avaliados foram o tempo de intubação orotraqueal e de ventilação mecânica (IOT/VM), tempo de uso de NPT e data de início de dieta enteral. Foram descritos, tempo para dieta oral plena, tempo de internação em unidade de cuidados intensivos neonatais, diagnóstico de sepse, diagnóstico de apnéia, estridor, pneumonia e taxa de mortalidade. Nos primeiros dez dias de vida dos bebês, as doses de fentanil utilizadas no intraoperatório e periopratório, em bolus ou infusão contínua, foram quantificadas. Assim como, fez-se uma análise descritiva das abordagens cirúrgicas, das técnicas anestésicas e das complicações clínico-cirúrgicas apresentadas durante o período de internação na UTI. Por meio de modelagem estatística, o impacto do aumento das dose de fentanil sobre as complicações respiratórias e gastrointestinais foi avaliado. Resultados: No período do estudo 184 crianças receberam correção cirúrgica do defeito de parede no IFF e a taxa de mortalidade foi de 8,69%. Os dados de 176 neonatos foram coletados e 94% desses pacientes foram indentificadas como gastrosquise simples. Nossa coorte de 144 pacientes foi avaliada e os eventos mais frequentemente relacionados ao uso de maiores doses de fentanil foram aumento do tempo de ventilação mecânica, aumento do tempo total de uso de NPT e retardo para início da dieta enteral. Conclusão: O estudo mostrou piores desfechos respiratórios e gastrointestinais nos pacientes que receberam doses maiores de fentanil.

Objective: To evaluate the association between doses of fentanyl used in the first ten days of life in neonates undergoing surgical correction of gastroschisis and the respiratory and gastrointestinal complications commonly associated with this age group and congenital defect. Methods: This study evaluated retrospectively the cohort of newborns with gastroschisis operated at IFF between January 2016 and June 2021. Demographic data of newborns and pregnant women, surgical interventions, anesthetic procedures and perioperative care in the neonatal intensive care unit were collected from medical records. The main outcomes evaluated were time of orotracheal intubation and time on mechanical ventilation (TI/MV), time of use of PN, time to start enteral nutrition, time to full oral diet, length of stay in the neonatal intensive care unit, sepsis diagnosis, diagnosis of apnea,stridor, pneumonia and mortality rate. In the first ten days of the babies' lives, the doses of fentanyl used in the intraoperative and perioperative, in bolus or continuous infusion, were quantified. As well, a descriptive analysis of surgical approaches, anesthetic techniques and the clinical-surgical complications presented during the ICU stay was made. Through statistical modeling, the impact of increasing fentanyl doses on respiratory and gastrointestinal complications was evaluated. Results: During the study period, 184 children received surgical correction of the wall defect at IFF and the mortality rate was 8.69%. The data from 176 neonates were collected and 94% of these patients were identified as simple gastroschisis. Our cohort of 144 patients was evaluated and the most frequently related events to the use of fentanyl in higher doses were increased time on mechanical ventilation, increased total time of PN use, and delay in starting enteral feeding. Conclusion: The study demontrated worse respiratory and gastrointestinal outcomes in the neonates that received higher doses of fentanyl.

A construção do campo da Saúde Coletiva e as políticas de saúde - Contribuições da Revista Ciência & Saúde Coletiva / The building of Collective Health and health policies - Contributions from Journal Ciência & Saúde Coletiva

Resumo Com o objetivo de analisar a contribuição da Revista Ciência & Saúde Coletiva (C&SC) para a construção do campo da Saúde Coletiva, particularmente nas suas relações com a Política de Saúde, compreendida tanto como disciplina acadêmica como âmbito de práticas, foi realizada uma revisão dos artigos publicados na C&SC no período compreendido entre 1996 e 2019. Para dimensionar a magnitude e identificar as principais temáticas e abordagens teórico-metodológicas foram lidos títulos e resumos de 397 documentos sobre políticas de saúde. Já para investigar a contribuição da Revista para a construção do campo da Saúde Coletiva foram selecionados e lidos na íntegra 35 documentos dentre os 142 localizados. A análise apoiou-se na sociologia de Bourdieu. Revelou que a C&SC constituiu-se em um dos espaços de construção da Saúde Coletiva em múltiplos âmbitos, particularmente no que diz respeito à reflexividade sobre campo. Especificamente em relação à Política de Saúde, a despeito do pequeno percentual de documentos sobre essa problemática (6,8%), ela abarcou os diversos significados dessa temática para o campo. Os autores discutem as possíveis relações existentes entre as características identificadas e o processo histórico de incorporação desse objeto nos diversos âmbitos de constituição do campo da Saúde Coletiva.

Abstract This paper aimed to analyze the contribution of Journal Ciência & Saúde Coletiva (C&SC) to the construction of the CH field, particularly in its relationships with the Health Policy, understood both as an academic discipline and as a scope of practice. We reviewed papers published between 1996 and 2019 in the C&SC. Titles and abstracts of the 397 documents on health policies were read to measure the magnitude and identify the main themes and theoretical-methodological approaches. Thirty-five documents were selected and read in full among the 142 revised ones to investigate the Journal's contribution to CH's construction. The analysis was based on Bourdieu's sociology. It revealed that C&SC was established as a space for the construction of CH in multiple dimensions, particularly concerning the reflexivity on the field. Specifically, concerning the Health Policy, despite the small percentage of documents on the issue (6.8%), it encompassed the different meanings of this subject for the field. The authors discuss the possible relationships between the characteristics identified and the historical process of incorporating this subject in the various areas of CH.

Reviewing the prognostic factors in myelomeningocele.

OBJECTIVE: The goal of this study was to analyze the factors that have an impact on morbidity and mortality in patients with myelomeningocele (MMC). METHODS: A retrospective cohort study was conducted to analyze factors associated with MMC that influence the morbidity and mortality of the disease. Data were collected from medical records of children who underwent the primary repair of MMC at the Fernandes Figueira Institute-Oswaldo Cruz Foundation (IFF-Fiocruz) between January 1995 and January 2015, with a minimum follow-up of 1 year. The following variables were analyzed: demographic characteristics (gestational age, sex, and birth weight); clinical features (head circumference at birth, anatomical and functional levels of MMC, hydrocephalus, symptomatic Chiari malformation type II, neurogenic bladder, and urinary tract infection [UTI]); and surgical details such as timing of repair of MMC, age at first shunt placement, shunt surgery modality (elective or emergency), concurrent surgery (correction of MMC and shunt insertion in the same surgical procedure), incidence and cause of shunt dysfunction, use of external ventricular drain, transfontanelle puncture, surgical wound complications prior to shunting, and endoscopic treatment of hydrocephalus. RESULTS: A total of 231 patients with MMC were included in the analysis. Patients were followed for periods ranging from 1 to 20 years, with a mean of 6.9 years. The frequency of shunt placement was observed mainly among patients with MMC at the highest spinal levels (p < 0.01). The main causes of morbidity and mortality in patients with MMC were shunt failures, diagnosed in 91 of 193 cases (47.2%) of hydrocephalus, and repeated UTIs, in 129 of 231 cases (55.8%) of MMC; these were the main causes of hospitalization and death. Head circumference ≥ 38 cm at birth was found to be a significant risk factor for shunt revision (p < 0.001; 95% CI 1.092-1.354). Also, the lumbar functional level of MMC was associated with less revision than upper levels (p < 0.014; 95% CI 0.143-0.805). There was a significant association between recurrent UTI and thoracic functional level. CONCLUSIONS: Macrocephaly at birth and higher levels of the defect have an impact on worse outcome and, therefore, are a challenge to the daily practice of pediatric neurosurgery.

Mães adolescentes em situação de rua: uma revisão sistemática da literatura: [revisão] / Homeless adolescent mothers: a systematic review of the literature: [review]

Pouco se sabe sobre mães adolescentes que passam por gravidez ou maternidade fora de casa. Este estudo é uma revisão da literatura epidemiológica sobre esse fenômeno crescente. Os artigos foram identificados através de pesquisa nas seguintes bases de dados eletrônicas: MEDLINE, Lilacs, SciELO, PsychINFO, CINHAL, ERIC e Sociological Abstracts; 19 referências foram recuperadas. Os estudos mostram ampla heterogeneidade dos objetivos e dos métodos e revelam principalmente que as adolescentes têm elevadas taxas de abuso de substâncias, transtornos mentais, falta de apoio social, comportamento sexual, violência física e sexual; gravidez e interação mãe-criança problemáticas. Poucos artigos resultaram da revisão metodológica realizada sobre essa população. As mães adolescentes de rua têm grande exposição à violência, abuso de drogas e risco de problemas de saúde física e mental. Mais estudos centrados no estigma e em métodos de intervenção para esse grupo de mulheres são necessários nesta área, especialmente em populações culturalmente distintas.

Little is known about adolescent mothers who are homeless during pregnancy and motherhood. This study is a review of the epidemiological literature about this increasing phenomenon. Articles were identified by searching the following electronic databases: MEDLINE, Lilacs, SciELO, PsychINFO, CINHAL, ERIC and Sociological Abstracts; 19 studies were retrieved. The studies showed a wide heterogeneity of objectives and methods, and mainly revealed that the teenagers have high rates of substance abuse, mental disorders, lack of social support, sexual behavior, physical and sexual violence, and troublesome pregnancy and mother-child interaction. Our methodological review found few articles about this population. Homeless adolescent mothers are extensively exposed to violence, drug abuse, and risk of physical and mental health problems. Further studies are needed about this topic, mainly involving culturally different populations, focusing on stigma and intervention methods for this group of women.