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INTRODUÇÃO Cardiomiopatia (CMP) induzida por estresse, como a cardiomiopatia de Takotsubo, pode ter características clínicas semelhantes à isquemia miocárdica, como elevação de troponinas, alterações no Eletrocardiograma (ECG), mas sem obstrução coronariana ou lesões isquêmicas. Semelhante, a CMP induzida por Feocromocitoma possui sintomas também semelhantes a CMP hipertrófica, hipertensão e edema pulmonar devido a fatores cardiogênicos ou não cardiogênicos. Ambas supracitadas podem ter associação com excesso de catecolaminas, mas raramente estão associadas. RELATO DO CASO Paciente masculino, 46 anos, diabético, com história de estresse por situações familiares importantes, recentemente. Chega no serviço de emergência, com queixas de dispnéia, náuseas e êmese, iniciados há 1 dia, associado a retenção urinária e parestesia em mãos e paraparesia de membros inferiores. Refere também tratamento com Amoxicilina + Clavulanato há um mês por Colecistite Aguda. Na chegada, paciente se encontrava taquicárdico, taquipneico e saturando 98% em uso de óculos nasal a 2l/min, além de acidose metabólica. Realizou-se uma tomografia computadorizada de abdome, que evidenciou uma massa em Adrenal, sugestivo de Feocromocitoma, bem como metanefrinas urinárias e catecolaminas positivas. Ainda na emergência, evoluiu com insuficiência respiratória aguda por edema agudo de pulmão, necessitando de manejo com Nitroglicerina e 03 ampolas de Furosemida e uso de máscara não reinalante a 10l/min. Foi encaminhado para Unidade de Terapia Intensiva, onde foi realizado um ECG com alterações primárias da repolarização, seguido de alterações nos valores de Troponina e alterações no Ecocardiograma (ECO) de acinesia apical, hipocinesia de todos os segmentos médios e contratilidade preservada em segmentos basais. Cateterismo cardíaco com achados semelhantes ao ECO e presença de balonamento na ventriculografia, além de ausência de lesões obstrutivas em coronárias. CONCLUSÃO A excepcionalidade desse caso diz respeito ao quadro de síndrome coronariana aguda com dois motivos plausíveis e evidenciados na condução do caso, sendo eles: CMP de Takotsubo e a induzida por Feocromocitoma. Fica evidente, pela evolução do quadro, a gravidade do mesmo e a importância de considerar diagnósticos diferenciais, inclusive os menos comuns.

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Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by autoimmune destruction of the myelin sheath, leading to irreversible and progressive functional deficits in patients. Pre-clinical studies involving the use of neural stem cells (NSCs) have already demonstrated their potential in neuronal regeneration and remyelination. However, the exclusive application of cell therapy has not proved sufficient to achieve satisfactory therapeutic levels. Recognizing these limitations, there is a need to combine cell therapy with other adjuvant protocols. In this context, extracellular vesicles (EVs) can contribute to intercellular communication, stimulating the production of proteins and lipids associated with remyelination and providing trophic support to axons. This study aimed to evaluate the therapeutic efficacy of the combination of NSCs and EVs derived from oligodendrocyte precursor cells (OPCs) in an animal model of multiple sclerosis. OPCs were differentiated from NSCs and had their identity confirmed by gene expression analysis and immunocytochemistry. Exosomes were isolated by differential ultracentrifugation and characterized by Western, transmission electron microscopy and nanoparticle tracking analysis. Experimental therapy of C57BL/6 mice induced with experimental autoimmune encephalomyelitis (EAE) were grouped in control, treated with NSCs, treated with OPC-derived EVs and treated with a combination of both. The treatments were evaluated clinically using scores and body weight, microscopically using immunohistochemistry and immunological profile by flow cytometry. The animals showed significant clinical improvement and weight gain with the treatments. However, only the treatments involving EVs led to immune modulation, changing the profile from Th1 to Th2 lymphocytes. Fifteen days after treatment revealed a reduction in reactive microgliosis and astrogliosis in the groups treated with EVs. However, there was no reduction in demyelination. The results indicate the potential therapeutic use of OPC-derived EVs to attenuate inflammation and promote recovery in EAE, especially when combined with cell therapy.

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This paper reports the case of a female patient who underwent minimally invasive repair of pectus excavatum (MIRPE) in another service that evolved with bar rotation and cardiac perforation caused by the left stabilizer. The unique and frightening aspect of the case is that despite having the stabilizer inside the ventricle, the patient was oligosymptomatic: occasional chest pain and respiratory discomfort. Preoperative imaging showed rotation of the bar with stabilizers within the thoracic cavity. During surgery, intense ossification was observed around the prosthesis and it was noted that the left stabilizer had perforated the patient's left ventricle. Cardiac repair required a Clamshell incision and cardiopulmonary bypass. This case reinforces the validity of late radiological follow-up after MIRPE in an attempt to avoid this type of event, and the need to reevaluate the use of stabilizers perpendicular to the bar since they are not safe to prevent rotation of these implants.

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BACKGROUND: Increased costs in the health sector have put considerable strain on the public budgets allocated to pharmaceutical purchases. Faced with such pressures amplified by financial crises and pandemics, national purchasing authorities are presented with a puzzle: how to procure pharmaceuticals of the highest quality for the lowest price. The literature explored a range of impactful factors using data on producer and reference prices, but largely foregone the use of data on individual purchases by diverse public buyers. METHODS: Leveraging the availability of open data in public procurement from official government portals, the article examines the relationship between unit prices and a host of predictors that account for policies that can be amended nationally or locally. The study uses traditional linear regression (OLS) and a machine learning model, random forest, to identify the best models for predicting pharmaceutical unit prices. To explore the association between a wide variety of predictors and unit prices, the study relies on more than 200,000 purchases in more than 800 standardized pharmaceutical product categories from 10 countries and territories. RESULTS: The results show significant price variation of standardized products between and within countries. Although both models present substantial potential for predicting unit prices, the random forest model, which can incorporate non-linear relationships, leads to higher explained variance (R2 = 0.85) and lower prediction error (RMSE = 0.81). CONCLUSIONS: The results demonstrate the potential of i) tapping into large quantities of purchase-level data in the health care sector and ii) using machine learning models for explaining and predicting pharmaceutical prices. The explanatory models identify data-driven policy interventions for decision-makers seeking to improve value for money.

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This article maps the structural, nonstructural and functional vulnerabilities of healthcare facilities to the COVID-19 pandemic. It reports on a scoping review guided by JBI recommendations and structured by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. The PubMed, CINAHL, LILACS, EMBASE, SciELO, Scopus and Web of Science Repositories and databases were consulted, as was the grey literature. The protocol was registered in the Open Science Framework. The 54 studies included summarised 36 vulnerabilities in three categories in 29 countries. Functional and non-structural vulnerabilities were the most recurrent. Limited material and human resources, service disruption, non-COVID procedures and inadequate training were the items with most impact. COVID-19 exposed nations to the need to strengthen health systems to ensure their resilience in future health crises. Prospective risk management and systematic analysis of health facility vulnerabilities are necessary to ensure greater safety, sustainability and improved standards of preparedness and response to events of this nature.

O objetivo do artigo é mapear as vulnerabilidades estruturais, não-estruturais e funcionais de estabelecimentos de saúde frente à pandemia de COVID-19. Revisão de escopo conduzida mediante recomendações do JBI e estruturada pelos Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Foram consultados repositórios e bases de dados: PubMed, CINAHL, LILACS, EMBASE, SciELO, Scopus e Web of Science, além de literatura cinzenta. O protocolo foi registrado em Open Science Framework, 54 estudos foram incluídos, sumarizando 36 vulnerabilidades entre as três categorias, em 29 países. As vulnerabilidades funcionais e não-estruturais foram as mais recorrentes. Recursos materiais e humanos limitados, interrupção dos serviços e procedimentos não-COVID, além de capacitação profissional insuficiente foram os itens que mais impactaram. A COVID-19 expôs às nações a necessidade de fortalecer os sistemas de saúde para garantir sua resiliência em futuras crises sanitárias. Ações de gestão de risco prospectivas e análise sistematizada de vulnerabilidades dos estabelecimentos de saúde são necessárias para garantir maior segurança, sustentabilidade e melhor padrão de preparação e resposta a futuros eventos dessa natureza.

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BACKGROUND: Inflammatory bowel disease (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC), is a chronic condition that affects all age groups, predominantly in young individuals. Currently, an increase in the prevalence of IBD has been documented, in parallel with the increase in the elderly population. The scarce number of studies that better characterize the impact of IBD on Quality of Life (QoL) in the elderly motivated the present study. OBJECTIVE: To evaluate the impact of IBD on the QoL of elderly people treated at a Tertiary IBD Center. METHODS: Prospective cross-sectional study that included elderly patients (age ≥60 years) with quiescent or mildly active IBD treated at the HU-UFJF IBD Center between March 2019 and December 2022. Elderly companions without severe comorbidities who attended the consultation with the patients were included as a control group. Sociodemographic and IBD-related characteristics were recorded. QoL was assessed using previously validated questionnaires (WHOQOL-BREF and IBDQ). Patients with IBD with moderate to severe activity, history of recent or imminent hospitalization, serious or opportunistic infections in the last 6 months, previous neoplasia, dementia, and difficulty understanding/fulfilling the questionnaires were excluded. RESULTS: A total of 123 patients were included (74 with IBD and 49 in the control group), with a mean age of 67±6.2 years, 52.7% with CD, and 47.3% with UC. Mild disease activity was observed in 31.1%. Both groups (IBD patients and control) were comparable based on age, sex, BMI, and the Charlson Comorbidity Index. Patients with IBD and controls had similar QoL scores in the different domains assessed by the WHOQOL-BREF. On the other hand, when evaluating the general facet of QoL, IBD patients had significantly lower scores in General QoL (3.71±0.87 versus 4.02±0.62, respectively; P=0.021) and General Health (3.32±1.05 versus 3.69±0.94, respectively; P=0.035). The presence of mildly active IBD negatively impacted the general health score (2.91±0.99 versus 3.47±1.04, respectively; P=0.035) and the physical domain of the WHOQOL-BREF (12.27±2.63 versus 13.86±2.61, respectively; P=0.019) when compared to patients in remission. Conversely, no impact on QoL was observed with the Application of the IBDQ questionnaire regarding the type of the disease (161±38.5 versus 163.1±42.6 for CD and UC, respectively; P=0.84) or the presence of activity (152.5±38.8 versus 166.4±40.5, respectively; P=0.17). CONCLUSION: No statistically significant differences were found between elderly patients with mildly active or quiescent IBD and elderly patients without IBD when observing global QoL scores. However, IBD negatively impacted the general facet of QoL, just as mild activity was associated with lower scores in general health and the physical domain assessed by the WHOQOL-BREF. Patients with IBD treated with biological therapy had better Qol than those on conventional therapy. Future studies are needed to choose the most appropriate tool for assessing QoL in this population.

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BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer with poor 5-year survival rates. Surgery and radiation are the current first-line treatments for local and nodal disease. OBJECTIVES: The Brazilian Society of Surgical Oncology developed this document aiming to guide the surgical oncology role in multimodal MCC management. METHODS: The consensus was established in three rounds of online discussion, achieving consensus on specific topics including diagnosis, staging, treatment, and follow-up. RESULTS: Patients suspected of having MCC should undergo immunohistochemical examination and preferably undergo pathology review by a dermatopathologist. Initial staging should be performed with dermatologic and nodal physical examination, combined with complementary imaging. Whole-body imaging, preferably with positron emission tomography (PET) or computed tomography (CT) scans, are recommended. Due to the need for multidisciplinary approaches, we recommend that all cases should be discussed in tumor boards and referred to other specialties as soon as possible, reducing potential treatment delays. We recommend that all patients with clinical stage I or II may undergo local excision associated with sentinel lymph node biopsy. The decision on margin size should consider time to recovery, patient's comorbidities, and risk factors. Patients with positive sentinel lymph nodes or the presence of risk factors should undergo postoperative radiation therapy at the primary site. Exclusive radiation is a viable option for patients with low performance. Patients with positive sentinel lymph node biopsy should undergo nodal radiation therapy or lymphadenectomy. In patients with nodal clinical disease, in addition to primary tumor treatment, nodal radiation therapy and/or lymphadenectomy are recommended. Patients with advanced disease should preferably be enrolled in clinical trials and discussed in multidisciplinary meetings. The role of surgery and radiation therapy in the metastatic/advanced setting should be discussed individually and always in tumor boards. CONCLUSION: This document aims to standardize a protocol for initial assessment and treatment for Merkel cell carcinoma, optimizing oncologic outcomes in middle-income countries such as Brazil.

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OBJECTIVE: In the emergency care of cancer patients, in addition to cancer-related factors, two aspects influence the outcome: (1) where the patient is treated and (2) who will perform the surgery. In Brazil, a significant proportion of patients with surgical oncological emergencies will be operated on in general hospitals by surgeons without training in oncological surgery. OBJECTIVE: The objective was to discuss quality indicators and propose the creation of an urgent oncological surgery advanced life support course. METHODS: Review of articles on the topic. RESULTS: Generally, nonelective resections are associated with higher rates of morbidity and mortality, as well as lower rates of cancer-specific survival. In comparison to elective procedures, the reduced number of harvested lymph nodes and the higher rate of positive margins suggest a compromised degree of radicality in the emergency scenario. CONCLUSION: Among modifiable factors is the training of the emergency surgeon. Enhancing the practice of oncological surgery in emergency settings constitutes a formidable undertaking that entails collaboration across various medical specialties and warrants endorsement and support from medical societies and educational institutions. It is time to establish a national registry encompassing oncological emergencies, develop quality indicators tailored to the national context, and foster the establishment of specialized training programs aimed at enhancing the proficiency of physicians serving in emergency services catering to cancer patients.

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Abstract Introduction: Chronic kidney disease is usually asymptomatic, and its diagnosis depends on laboratory tests, with emphasis on serum creatinine and proteinuria. Objective: To assess knowledge on the role of serum creatinine as a biomarker of kidney function in a sample of the Brazilian population. Method: Cross-sectional observational study conducted in São Paulo (SP, Brazil), in which a random adult population was interviewed. Results: A total of 1138 subjects were interviewed, with a median age of 36 years old (27-52); 55.1% were female. Regarding the "creatinine" biomarker, 40.6% stated they had never performed such a test. When asked about their knowledge on the usefulness of this exam, only 19.6% knew its function. The other responses were "I don't know" (71.6%), evaluating heart function (0.9%) and liver function (7.8%). Of those who reported they had already taken a creatinine test, only 29.4% correctly identified the role of creatinine. When dividing the groups into "knows" and "does not know" the function of creatinine, a statistically significant difference (p < 0.05) was observed regarding level of education, female sex, being a healthcare student/worker, having ever measured creatinine, knowing someone with kidney disease and older age. In the multivariate analysis, the main variable related to knowing the creatinine role was having previously taken the test (OR 5.16; 95% CI 3.16-8.43, p < 0.001). Conclusion: There is a significant lack of knowledge about creatinine and its use in checkups. The results indicate that greater efforts are needed from healthcare professionals to raise awareness on the role of serum creatinine.

Resumo Introdução: A doença renal crônica costuma ser assintomática e seu diagnóstico depende da realização de exames laboratoriais, com destaque para a creatinina sérica e pesquisa de proteinúria. Objetivo: Avaliar em uma amostra da população brasileira o conhecimento sobre o papel da creatinina sérica como marcador de função renal. Método: Estudo observacional transversal realizado na cidade de São Paulo (SP, Brasil), em que foi entrevistada uma população adulta aleatória. Resultados: Foram entrevistados 1138 indivíduos, com idade mediana de 36 anos (27-52); 55,1% do sexo feminino. Com relação ao marcador "creatinina", 40,6% afirmaram que nunca realizaram tal dosagem. Quando questionados quanto ao conhecimento sobre a utilidade desse exame, somente 19,6% sabiam a sua função. As outras respostas foram "não sei" (71,6%), avaliar o funcionamento do coração (0,9%) e fígado (7,8%). Dos que afirmaram já terem realizado o exame de creatinina, somente 29,4% acertaram a função da creatinina. Ao dividir os grupos em "sabe" e "não sabe" a função da creatinina, percebeu-se diferença estatisticamente significante (p < 0,05) em relação ao grau de escolaridade, sexo feminino, ser aluno/trabalhador da saúde, ter dosado creatinina alguma vez, conhecer alguém com doença renal e maior idade. Na análise multivariada, a principal variável relacionada com conhecer a função da creatinina foi ter realizado o exame anteriormente (OR 5,16; IC 95% 3,16-8,43, p < 0,001). Conclusão: Há grande desconhecimento sobre a creatinina e seu uso em check-ups. Os resultados indicam que é necessário maior esforço por parte dos profissionais de saúde para divulgar o papel da creatinina sérica.

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The article discusses the evolution of the Brazilian College of Surgeons (CBC) specialist title exam, highlighting the importance of evaluating not only theoretical knowledge, but also the practical skills and ethical behavior of candidates. The test was instituted in 1971, initially with only the written phase, and later included the oral practical test, starting with the 13th edition in 1988. In 2022, the assessment process was improved by including the use of simulated stations in the practical test, with the aim of assessing practical and communication skills, as well as clinical reasoning, in order to guarantee excellence in the assessment of surgeons training. The aim of this study is to demonstrate the performance of candidates in the last five years of the Specialist Title Test and to compare the performance results between the different surgical training groups of the candidates. The results obtained by candidates from the various categories enrolled in the test in the 2018 to 2022 editions were analyzed. There was a clear and statistically significant difference between doctors who had completed three years of residency recognized by the Ministry of Education in relation to the other categories of candidates for the Specialist Title..

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Epilepsy is one of the most common chronical neurological conditions affecting over 50 million people worldwide. In addition to the stigma and discrimination, individuals with epilepsy suffer from a nearly three-fold increased risk of premature death compared to the general population. Although these premature deaths occur due to multiple causes, sudden unexpected death in epilepsy (SUDEP) still challenges neurologists and clinicians dealing with individuals with epilepsy. Recently, an increased interest in cardiac outcomes related to acute seizures and chronic epilepsy resulted in the groundbreaking development of the "epileptic heart" concept, and sudden cardiac death in individuals with epilepsy, which is 4.5 times as frequent as SUDEP according to some observational data, has gained more attention. As we gather information and learn about possible comorbidities and consequences of seizures and/or chronic epilepsy, we present a clinical case of a young patient with an unusual association of epilepsy, the Gorlin Goltz syndrome, and a cardiac fibroma with Wolf-Parkinson-White (WPW), who had multiple aborted cardiac arrests. Diagnostic challenges and multiple possible causes of sudden cardiac death in this single patient report are discussed.

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Background: Spinal ventral root injuries generate significant motoneuron degeneration, which hinders full functional recovery. The poor prognosis of functional recovery can be attributed to the use or combination of different therapeutic approaches. Several molecules have been screened as potential treatments in combination with surgical reimplantation of the avulsed roots, the gold standard approach for such injuries. Among the studied molecules, human natural killer-1 (HNK-1) stands out as it is related to the stimulation of motor axon outgrowth. Therefore, we aimed to comparatively investigate the effects of local administration of an HNK-1 mimetic peptide (mp-HNK-1) and systemic treatment with ursolic acid (UA), another HNK-1 mimetic, after ventral root avulsion and reimplantation with heterologous fibrin biopolymer (HFB). Methods: Female mice of the isogenic strain C57BL/6JUnib were divided into five experimental groups: Avulsion, Reimplantation, mp-HNK-1 (in situ), and UA (systemic treatment). Mice were evaluated 2 and 12 weeks after surgery. Functional assessment was performed every four days using the Catwalk platform. Neuronal survival was analyzed by cytochemistry, and glial reactions and synaptic coverage were evaluated by immunofluorescence. Results: Treatment with UA elicited long-term neuroprotection, accompanied by a decrease in microglial reactions, and reactive astrogliosis. The neuroprotective effects of UA were preceded by increased glutamatergic and GABAergic inputs in the ventral spinal cord two weeks after injury. However, a single application of mp-HNK-1 had no significant effects. Functional analysis showed that UA treatment led to an improvement in motor and sensory recovery. Conclusion: Overall, the results indicate that UA is neuroprotective, acting on glial cells and synaptic maintenance, and the combination of these findings led to a better functional recovery.

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Contrast agents are important imaging probes in clinical MRI, allowing the identification of anatomic changes that otherwise would not be possible. Intensive research on the development of new contrast agents is being made to image specific pathological markers or sense local biochemical changes. The most widely used MRI contrast agents are based on gadolinium(III) complexes. Due to their very high charge density, they have low permeability through tight biological barriers such as the blood-brain barrier, hampering their application in the diagnosis of neurological disorders. In this study, we explore the interaction between the widely used contrast agent [Gd(DOTA)]- (Dotarem) and POPC lipid bilayers by means of molecular dynamics simulations. This metal complex is a standard reference where several chemical modifications have been introduced to improve key properties such as bioavailability and targeting. The simulations unveil detailed insights into the agent's interaction with the lipid bilayer, offering perspectives beyond experimental methods. Various properties, including the impact on global and local bilayer properties, were analyzed. As expected, the results indicate a low partition coefficient (KP) and high permeation barrier for this reference compound. Nevertheless, favorable interactions are established with the membrane leading to moderately long residence times. While coordination of one inner-sphere water molecule is maintained for the membrane-associated chelate, the physical-chemical attributes of [Gd(DOTA)]- as a MRI contrast agent are affected. Namely, increases in the rotational correlation times and in the residence time of the inner-sphere water are observed, with the former expected to significantly increase the water proton relaxivity. This work establishes a reference framework for the use of simulations to guide the rational design of new contrast agents with improved relaxivity and bioavailability and for the development of liposome-based formulations for use as imaging probes or theranostic agents.

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OBJECTIVE: To map the ethical-legal dilemmas related to nursing practice in emergency and disaster situations. METHOD: A scoping review developed in accordance with the JBI method, whose information sources were accessed in databases, in addition to gray literature. The selection was made by reading the titles, abstracts and descriptors, observing eligibility criteria, including two reviewers and a third in case of discrepancies. After reading, data extraction and content analysis of 17 selected studies were carried out. RESULTS: Thirteen ethical-legal dilemmas were mapped related to professional/functional duty towards the family, lack of personal protective equipment and unsafe conditions at work, preparation and availability for action, skills, limits imposed by victims' religion, obligation to provide care. CONCLUSION: Professionals, researchers and representatives of the category need to resolve demands that involve acting in emergencies and disasters, (re)cognizing the ethical-legal dilemma, and seeking (re)legal frameworks and observance of the fundamental/ethical principles that govern the profession, in the sense to support decision-making and the development of legally safe practices.

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Vector control is one of the principal strategies used for reducing malaria transmission. Long-lasting insecticidal bed nets (LLINs) are a key tool used to protect populations at risk of malaria, since they provide both physical and chemical barriers to prevent human-vector contact. This study aimed to assess the physical durability and insecticidal efficacy of LLINs distributed in Cruzeiro do Sul (CZS), Brazil, after 4 years of use. A total of 3000 LLINs (PermaNet 2.0) were distributed in high malaria risk areas of CZS in 2007. After 4 years of use, 27 'rectangular' LLINs and 28 'conical' LLINs were randomly selected for analysis. The evaluation of physical integrity was based on counting the number of holes and measuring their size and location on the nets. Insecticidal efficacy was evaluated by cone bioassays, and the amount of residual insecticide remaining on the surface of the LLINs was estimated using a colorimetric method. After 4 years of use, physical damage was highly prevalent on the rectangular LLINs, with a total of 473 holes detected across the 27 nets. The upper portion of the side panels sustained the greatest damage in rectangular LLINs. The overall mosquito mortality by cone bioassay was < 80% in 25/27 rectangular LLINs, with panel A (at the end of the rectangular bednet) presenting the highest mortality (54%). The overall mean insecticide concentration was 0.5 µg/sample, with the bednet roof containing the highest average concentration (0.61 µg/sample). On the conical LLINs, 547 holes were detected, with the bottom areas sustaining the greatest damage. The cone bioassay mortality was < 80% in 26/28 of the conical LLINs. The mean insecticide concentration was 0.3 µg/sample. After 4 years of use, the insecticidal efficacy of the LLINs was diminished to below acceptable thresholds.

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BACKGROUND: Spinal ventral root avulsion results in massive motoneuron degeneration with poor prognosis and high costs. In this study, we compared different isoforms of basic fibroblast growth factor 2 (FGF2), overexpressed in stably transfected Human embryonic stem cells (hESCs), following motor root avulsion and repair with a heterologous fibrin biopolymer (HFB). METHODS: In the present work, hESCs bioengineered to overexpress 18, 23, and 31 kD isoforms of FGF2, were used in combination with reimplantation of the avulsed roots using HFB. Statistical analysis was conducted using GraphPad Prism software with one-way or two-way ANOVA, followed by Tukey's or Dunnett's multiple comparison tests. Significance was set at *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. RESULTS: For the first set of experiments, rats underwent avulsion of the ventral roots with local administration of HFB and engraftment of hESCs expressing the above-mentioned FGF2 isoforms. Analysis of motoneuron survival, glial reaction, and synaptic coverage, two weeks after the lesion, indicated that therapy with hESCs overexpressing 31 kD FGF2 was the most effective. Consequently, the second set of experiments was performed with that isoform, so that ventral root avulsion was followed by direct spinal cord reimplantation. Motoneuron survival, glial reaction, synaptic coverage, and gene expression were analyzed 2 weeks post-lesion; while the functional recovery was evaluated by the walking track test and von Frey test for 12 weeks. We showed that engraftment of hESCs led to significant neuroprotection, coupled with immunomodulation, attenuation of astrogliosis, and preservation of inputs to the rescued motoneurons. Behaviorally, the 31 kD FGF2 - hESC therapy enhanced both motor and sensory recovery. CONCLUSION: Transgenic hESCs were an effective delivery platform for neurotrophic factors, rescuing axotomized motoneurons and modulating glial response after proximal spinal cord root injury, while the 31 kD isoform of FGF2 showed superior regenerative properties over other isoforms in addition to the significant functional recovery.

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BACKGROUND: Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF). RESULTS: DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats' joints on the seventh day (inflammatory phase). CONCLUSIONS: Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.

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Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.

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Biodiversity is declining globally, yet many biodiversity hotspots still lack comprehensive species conservation assessments. Using multiple International Union for Conservation of Nature (IUCN) Red List criteria to evaluate extinction risks and millions of herbarium and forest inventory records, we present automated conservation assessments for all tree species of the Atlantic Forest biodiversity hotspot, including ~1100 heretofore unassessed species. About 65% of all species and 82% of endemic species are classified as threatened. We rediscovered five species classified as Extinct on the IUCN Red List and identified 13 endemics as possibly extinct. Uncertainties in species information had little influence on the assessments, but using fewer Red List criteria severely underestimated threat levels. We suggest that the conservation status of tropical forests worldwide is worse than previously reported.

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