Reduction in hospitalizations and emergency psychiatric care due to social distancing measures during the COVID-19 pandemic / Redução nas hospitalizações e atendimentos psiquiátricos de emergência devido a medidas de distanciamento social durante a pandemia de COVID-19

ABSTRACT Objetivo: Assess the impact of the lockdown measures on hospitalizations and emergency psychiatric care in a capital of a Brazilian state. Methods: Psychiatric hospitalizations and emergency psychiatric attendances carried out between January 7th and May 28th, 2020, were evaluated, covering the periods before and after lockdown due to COVID-19 pandemic in the city of Fortaleza, capital of the state of Ceará, Brazil. The data in the two periods were described and presented in time series graphs. Attendances were also described according to the severity categories. Comparisons were performed using Mann-Whitney U test and test for proportions. Results: The daily average of hospitalizations and of attendances decreased in the evaluated periods from 16.0 to 10.8 (p < 0.001) and 67.9 to 35.0 (p < 0.001), respectively. This absolute reduction was observed in all categories of severity. No difference was observed in the proportion of severe attendances (2.3% vs. 2.8%; p = 0.207). The proportion of mild cases decreased from 18.6% to 10.7% (p < 0.001) and of intermediate severity cases increased from 79.1% to 86.5% (p < 0.001). Conclusion: The findings showed both a decrease in emergency psychiatric attendances and hospitalizations, which can lead to severe impacts in the absence of counterpart mitigation measures by the local mental health system.

RESUMO Objetivo: Avaliar o impacto das medidas de distanciamento social em hospitalizações e atendimentos psiquiátricos de urgência em uma capital de estado brasileiro. Métodos: Foram avaliadas as internações e atendimentos psiquiátricos de urgência realizados entre 7 de janeiro e 28 de maio de 2020, abrangendo os períodos antes e após o lockdown em razão da pandemia de COVID-19 na cidade de Fortaleza, capital do estado do Ceará, Brasil. Os dados nos dois períodos foram descritos e apresentados em gráficos de séries temporais. Os atendimentos também foram descritos de acordo com as categorias de gravidade. As comparações foram realizadas pelo teste U de Mann-Whitney e o teste de hipóteses para proporções. Resultados: A média diária de internações e de atendimentos diminuiu nos períodos avaliados, de 16,0 para 10,8 (p < 0,001) e de 67,9 para 35,0 (p < 0,001), respectivamente. Tal redução absoluta foi observada em todas as categorias de gravidade. Não foi observada diferença na proporção de atendimentos graves (2,3% vs. 2,8%; p = 0,207). A proporção de casos leves diminuiu de 18,6% para 10,7% (p < 0,001) e a de gravidade intermediária aumentou de 79,1% para 86,5% (p < 0,001). Conclusões: Os resultados mostraram uma diminuição nos atendimentos psiquiátricos de urgência e nas hospitalizações, o que pode levar a impactos severos na ausência em contrapartida de medidas de mitigação pelo sistema de saúde mental local.

Neonatal tactile stimulation reverses alterations in fine structure of small, but not large myelinated fibers, from the optic nerve of iron-deficient rats: A size-based selectivity.

Iron is the most common micronutrient deficiency in the world and it is most prevalent in young children, exposing their developing brain to inadequate iron levels. The damage related to neuroanatomical parameters is not reversed after iron treatment. However, evidence suggest that tactile stimulation (TS) may offer great therapeutic efficacy in cases of nutritional disorders postnatally, since the brain is remarkably responsive to its interaction with the environment. Recently, we shown that neonatal iron deficient rats achieved some remedial effect by exposing them to TS treatment early in life, reinforcing the fact that the TS approach is a positive enriching experience, therefore, here we ask whether exposure to TS treatment, could also be employed to prevent fine structural changes in the fibers from optic nerve of rats maintained on an iron-deficient diet during brain development. To elucidate the protective effect of tactile stimulation, our methods resulted in 10,859 analyzed fibers, divided into small and large fibers. We found that iron deficiency led to a decreased axon, fiber and myelin size of small fibers, however, TS completely reversed the iron-decifiency-induced alteration on those fiber measurements. Large fibers were disproportionately affected by iron deficiency and there was no remediating effect due to tactile stimulation treatment. The present study adds new information regarding different alterations between small and large fibers due to diet and TS, which suggest a size-based selectivity. These results emphasize the concept that compromised brain development can be mitigated at an early age by environmental factors, such as tactile stimulation.

Insights into the full-length SRPK2 structure and its hydrodynamic behavior.

The serine/arginine-rich protein kinase 2 (SRPK2) has been reported as upregulated in several cancer types, with roles in hallmarks such as cell migration, growth, and apoptosis. These findings have indicated that SRPK2 is a promising emerging target in drug discovery initiatives. Although high-resolution models are available for SRPK2 (PDB 2X7G), they have been obtained with a heavily truncated recombinant protein version (~50% of the primary structure), due to the presence of long intrinsically unstructured regions. In the present work, we sought to characterize the structure of a full-length recombinant version of SRPK2 in solution. Low-resolution Small-Angle X-ray Scattering data were obtained for both versions of SRPK2. The truncated ΔNΔS-SRPK2 presented a propensity to dimerize at higher concentrations whereas the full-length SRPK2 was mainly found as dimers. The hydrodynamic behavior of the full-length SRPK2 was further investigated by analytical size exclusion chromatography and sedimentation velocity analytical ultracentrifugation experiments. SRPK2 behaved as a monomer-dimer equilibrium and both forms have an elongated shape in solution, pointing to a stretched-to-closed tendency among the conformational plasticity observed. Taken together, these findings allowed us to define unique structural features of the SRPK2 within SRPK family, characterized by its flexible regions outside the bipartite kinase domain.

Antimetastatic effect of the pharmacological inhibition of serine/arginine-rich protein kinases (SRPK) in murine melanoma.

The Serine/arginine-rich protein kinases (SRPK) are involved in pre-mRNA splicing control through the phosphorylation of the SR protein family of splicing factors. Over the last years, several studies have shown the relevance of SRPK for human cancers and their potential as promising drug targets. In this context, we have previously selected three trifluoromethyl arylamides (named here as SRVIC24, SRVIC30 and SRVIC36) with improved in vitro antileukemia effect and ability of impairing the cellular activity of SRPK. Given the increasing amount of reports on the implication of these kinases in metastatic cancers, in this study, we have evaluated the antimetastatic effect of these compounds and the known SRPK inhibitor (SRPIN340) on a murine model of metastatic melanoma. The compounds were able to impact the melanoma cell metastatic behavior by decreasing migration, invasion, adhesion, and colony formation in in vitro assays. Also, they presented antimetastatic in vivo activity, without apparent signs of systemic toxicity after treatments, as revealed by the histology of organs and analysis of key serum biochemical markers. Moreover, the effect of the treatments on SRPK1 nuclear translocation and SR protein phosphorylation was observed. Finally, molecular docking studies were carried out to gain structural information on the SRPK-compound complexes. Together, these data suggest that SRPK pharmacological inhibition should be considered as an interesting therapeutic strategy against metastatic cancers.

Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs).

The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC50 values ranging between 6.0 and 35.7 µM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.

Tactile stimulation partially prevents neurodevelopmental changes in visual tract caused by early iron deficiency.

Iron deficiency has a critical impact on maturational mechanisms of the brain and the damage related to neuroanatomical parameters is not satisfactorily reversed after iron replacement. However, emerging evidence suggest that enriched early experience may offer great therapeutic efficacy in cases of nutritional disorders postnatally, since the brain is remarkably responsive to its interaction with the environment. Given the fact that tactile stimulation (TS) treatment has been previously shown to be an effective therapeutic approach and with potential application to humans, here we ask whether exposure to TS treatment, from postnatal day (P) 1 to P32 for 3min/day, could also be employed to prevent neuroanatomical changes in the optic nerve of rats maintained on an iron-deficient diet during brain development. We found that iron deficiency changed astrocyte, oligodendrocyte, damaged fiber, and myelinated fiber density, however, TS reversed the iron-deficiency-induced alteration in oligodendrocyte, damaged fiber and myelinated fiber density, but failed to reverse astrocyte density. Our results suggest that early iron deficiency may act by disrupting the timing of key steps in visual system development thereby modifying the normal progression of optic nerve maturation. However, optic nerve development is sensitive to enriching experiences, and in the current study we show that this sensitivity can be used to prevent damage from postnatal iron deficiency during the critical period.

Splicing Regulators and Their Roles in Cancer Biology and Therapy.

Alternative splicing allows cells to expand the encoding potential of their genomes. In this elegant mechanism, a single gene can yield protein isoforms with even antagonistic functions depending on the cellular physiological context. Alterations in splicing regulatory factors activity in cancer cells, however, can generate an abnormal protein expression pattern that promotes growth, survival, and other processes, which are relevant to tumor biology. In this review, we discuss dysregulated alternative splicing events and regulatory factors that impact pathways related to cancer. The SR proteins and their regulatory kinases SRPKs and CLKs have been frequently found altered in tumors and are examined in more detail. Finally, perspectives that support splicing machinery as target for the development of novel anticancer therapies are discussed.

Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340).

Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates.

Neurocisticercose em tronco cerebral: relato de caso e revisão da literatura / Brainstem cysticercosis: case report and literature review

Descrever patologia rara em que há poucos relatos sobre a incidência em tronco cerebral (em torno de 8% dos casos), cujo tratamento adequado resulta em prognóstico favorável. Descrição de tratamento cirúrgico de paciente com neurocisticercose em tronco cerebral. Paciente evoluiu com regressão completa dos sintomas prévios após cirurgia. Na neurocisticercose, a definição do tratamento clínico ou cirúrgico está diretamente relacionada à localização, ao tamanho e ao número de lesões, diminuindo, assim, a mortalidade e a morbidade nessa patologia.

To describe a rare pathology, where there are few reports on the incidence of brain stem (about 8% of cases), whose proper treatment results in favorable prognosis. Description of surgical treatment of patients with neurocysticercosis in the brainstem. Following the surgery all previous symptoms resolved. In the definition of neurocysticercosis clinical or surgical treatment is directly related to location, size and number of lesions, thus decreasing mortality and morbidity in this disease.

Efeito da cinesioterapia na lesão isquêmica e reperfusão em ratos / Effects of kinesiotherapy in ischemic lesion and reperfusion in rats

OBJETIVO: Verificar o efeito da cinesioterapia na funcionalidade do membro pélvico de ratos após lesão isquêmica e reperfusão. MÉTODOS: Foram utilizados 10 ratos, divididos em dois grupos, GI (controle) e GII (cinesioterapia). Todos os animais foram submetidos à isquemia por um período de três horas, seguido de reperfusão tecidual. No Grupo GII foi realizado cinesioterapia sistêmica (natação) não resistida em três sessões semanais de 50 minutos durante quatro semanas, enquanto que no grupo GI os animais permaneceram em repouso. A análise funcional do comportamento motor foi realizada semanalmente. Posteriormente, os animais foram mortos e retirados os músculos sóleo, gastrocnêmio e nervo ciático para análise histopatológica. RESULTADOS: Houve uma recuperação significativa do comportamento motor com o tratamento cinesioterapêutico ao longo das quatro semanas de tratamento. No entanto, na avaliação histológica os tecidos não mostraram alterações morfológicas de lesão e reparação celular. CONCLUSÃO: Não foi possível afirmar que o exercício mostrou-se eficiente na reparação celular, pois, tanto no grupo controle como no experimental, não apresentou diferença histológica. Por outro lado, a cinesioterapia sistêmica apresentou um efeito benéfico na reabilitação funcional após isquemia e reperfusão. Nível de Evidência III, Estudo Caso-Controle.

OBJECTIVE: To investigate the effect of kinesiotherapy on the functionality of the pelvic limb of rats after ischemic and reperfusion injury. METHODS: 10 rats were divided into two groups, GI (control) and GII (kinesiotherapy). All the animals underwent ischemia for a period of three hours, followed by tissue reperfusion. In Group GII, non-resistive systemic kinesiotherapy was performed (swimming) in three weekly sessions of 50 minutes, over a period of four weeks, while the GI animals remained at rest. Functional analysis of motor behavior was evaluated weekly. The animals were then sacrificed, and the soleus, gastrocnemius and sciatic nerve removed for histopathological analysis. RESULTS: There was a significant recovery of motor behavior with kinesiotherapeutic treatment during the four weeks of treatment. However, the histological tissues showed no morphological changes of cell injury and repair. CONCLUSION: It was not possible to affirm that the exercise was effective in cell repair, because neither of the groups (control and experimental) showed any histological difference. On the other hand, systemic kinesiotherapy showed a beneficial effect on functional rehabilitation after ischemia and reperfusion. Level of evidence III, Case-Control Study.