Impact of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular and Renal Outcomes in Heart Failure Patients With Type 2 Diabetes: A Literature Review.

The management of heart failure (HF) in patients with type 2 diabetes has significantly evolved with the introduction of sodium-glucose cotransporter 2 (SGLT2) inhibitors. This article aims to consolidate existing knowledge on the efficacy of these inhibitors in managing HF in this patient population. Major medical databases, including PubMed, Scopus, and Web of Science, were reviewed, prioritizing research from the last decade. The results of this review highlight the mechanisms of action of SGLT2 inhibitors, their clinical benefits, challenges in patient management, and outcomes associated with their use. These medications were found to not only improve glycemic control but also offer significant cardiovascular and renal benefits, reducing cardiovascular mortality and major adverse cardiovascular events. However, challenges and knowledge gaps persist, particularly regarding long-term effects and safety in diverse populations. The conclusions of this review underscore the importance of updating clinical guidelines to incorporate these findings and propose the need for future research to address existing gaps and optimize the use of SGLT2 inhibitors in clinical practice.

Optimization of Hypothermic Protocols for Neurocognitive Preservation in Aortic Arch Surgery: A Literature Review.

Shifts from deep to moderate hypothermic circulatory arrest (HCA) in aortic arch surgery necessitate an examination of their differential impacts on neurocognitive functions, especially structured verbal memory, given its significance for patient recovery and quality of life. This study evaluates and synthesizes evidence on the effects of deep (≤20.0 °C), low-moderate (20.1-24.0 °C), and high-moderate (24.1-28.0 °C) hypothermic temperatures on structured verbal memory preservation and overall cognitive health in patients undergoing aortic arch surgery. We evaluated the latest literature from major medical databases such as PubMed and Scopus, focusing on research from 2020 to 2024, to gather comprehensive insights into the current landscape of temperature management during HCA. This comparative analysis highlights the viability of moderate hypothermia (20.1-28.0 °C), supported by recent trials and observational studies, as a method to achieve comparable neuroprotection with fewer complications than traditional deep hypothermia. Notably, low-moderate and high-moderate temperatures have been shown to support substantial survival rates, with impacts on structured verbal memory preservation that necessitate careful selection based on individual surgical risks and patient profiles. The findings advocate for a nuanced approach to selecting hypothermic protocols in aortic arch surgeries, emphasizing the importance of tailoring temperature management to optimize neurocognitive outcomes and patient recovery. This study fills a critical gap in the literature by providing evidence-based recommendations for temperature ranges during HCA, calling for ongoing updates to clinical guidelines and further research to refine these recommendations. The implications of temperature on survival rates, complications, and success rates underpin the necessity for evolving cardiopulmonary bypass techniques and cerebral perfusion strategies to enhance patient outcomes in complex cardiovascular procedures.

Comparative Efficacy of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in the Treatment of Ischemic Heart Disease: A Systematic Review and Meta-Analysis of Recent Randomized Controlled Trials.

Background: Ischemic heart disease (IHD) is a major global health issue and a leading cause of death. This study compares the effectiveness of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in the management of IHD, focusing on their impact on revascularization, myocardial infarction (MI), and post-procedural stroke. This study aimed to evaluate and compare the effectiveness of PCI and CABG in treating IHD based on an exhaustive literature review of the past 5 years, emphasizing recent advancements and outcomes in IHD management. Methods: A comprehensive literature review analyzed 32 randomized controlled trials (RCTs) retrieved from databases such as PubMed, Cochrane Library, and Google Scholar. The study specifically assessed the incidences of revascularization, stroke, and MI in patients treated with either PCI or CABG. The comparison between CABG and PCI exclusively focused on lesions with a SYNTAX score exceeding 32. Results: Our findings highlight CABG's significant efficacy over PCI in reducing revascularization and MI. The aggregated Mantel-Haenszel (M-H) value for revascularization was 1.85 (95% confidence interval (CI): 1.65 - 2.07), signifying CABG's advantage. Additionally, CABG demonstrated superior performance in diminishing MI occurrences (M-H = 2.71, 95% CI: 1.13 - 6.53). In contrast, PCI was more effective in reducing stroke (M-H = 0.80, 95% CI: 0.60 - 1.10). Conclusion: The study confirms CABG's superiority in reducing revascularization and MI in IHD patients, highlighting PCI's effectiveness in reducing stroke risk. These findings underscore the importance of personalized treatment strategies in IHD management and emphasize the need for ongoing research and evidence-based guidelines to aid in treatment selection for IHD patients.

Cannabidiol protects mouse hippocampal neurons from neurotoxicity induced by amyloid ß-peptide25-35.

Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is a significant health concern, according to the World Health Organization (WHO). The neuropathological diagnostic criteria for AD are based on the deposition of amyloid-ß peptide (Aß) and the formation of intracellular tau protein tangles. These proteins are associated with several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, lipid peroxidation, reduced neuronal viability, and cell death. In this context, our study focuses on the potential therapeutic use of cannabidiol (CBD), a non-psychotropic cannabinoid with antioxidant and anti-inflammatory effects. We aim to evaluate CBD's neuroprotective role, particularly in protecting hippocampal neurons from Aß25-35-induced toxicity. Our findings indicate that CBD significantly improves cell viability and decreases levels of lipid peroxidation and oxidative stress. The results demonstrate that CBD possesses a robust potential to rescue cells from induced neurotoxicity through its antioxidant properties. Additionally, the neuroprotective effect of CBD may be associated with the modulation of the endocannabinoid system. These findings suggest that CBD could be a promising compound for adjuvant treatments in neurodegenerative processes triggered by amyloid-ß peptide.

ATP-P2X7 signaling mediates brain pathology while contributing to viral control in perinatal Zika virus infection.

Zika virus (ZIKV), the causative agent of Zika fever, is a flavivirus transmitted by mosquitoes of the Aedes genus. Zika virus infection has become an international concern due to its association with severe neurological complications such as fetal microcephaly. Viral infection can induce the release of ATP in the extracellular environment, activating receptors sensitized by extracellular nucleotides, such as the P2X7 receptor. This receptor is the primary purinergic receptor involved in neuroinflammation, neurodegeneration, and immunity. In this work, we investigated the role of ATP-P2X7 receptor signaling in Zika-related brain abnormalities. Wild-type mice (WT) and P2X7 receptor-deficient (P2X7-/-) C57BL/6 newborn mice were subcutaneously inoculated with 5 × 106plaque-forming units of ZIKV or mock solution. P2X7 receptor expression increased in the brain of Zika virus-infected mice compared to the mock group. Comparative analyses of the hippocampi from WT and P2X7-/-mice revealed that the P2X7 receptor increased hippocampal damage in CA1/CA2 and CA3 regions. Doublecortin expression decreased significantly in the brains of ZIKV-infected mice. WT ZIKV-infected mice showed impaired motor performance compared to P2X7-/- infected mice. WT ZIKV-infected animals showed increased expression of glial markers GFAP (astrocytes) and IBA-1 (microglia) compared to P2X7-/- infected mice. Although the P2X7 receptor contributes to neuronal loss and neuroinflammation, WT mice were more efficient in controlling the viral load in the brain than P2X7 receptor-deficient mice. This result was associated with higher induction of TNF-α, IFN-ß, and increased interferon-stimulated gene expression in WT mice than P2X7-/-ZIKV-infected. Finally, we found that the P2X7 receptor contributes to inhibiting the neuroprotective signaling pathway AKT/mTOR while stimulating the caspase-3 activation, possibly two distinct pathways contributing to neurodegeneration. These findings suggest that ATP-P2X7 receptor signaling contributes to the antiviral response in the brain of ZIKV-infected mice while increasing neuronal loss, neuroinflammation, and related brain abnormalities.

Long-term recruitment of peripheral immune cells to brain scars after a neonatal insult.

Although brain scars in adults have been extensively studied, there is less data available regarding scar formation during the neonatal period, and the involvement of peripheral immune cells in this process remains unexplored in neonates. Using a murine model of neonatal hypoxic-ischemic encephalopathy (HIE) and confocal microscopy, we characterized the scarring process and examined the recruitment of peripheral immune cells to cortical and hippocampal scars for up to 1 year post-insult. Regional differences in scar formation were observed, including the presence of reticular fibrotic networks in the cortex and perivascular fibrosis in the hippocampus. We identified chemokines with chronically elevated levels in both regions and demonstrated, through a parabiosis-based strategy, the recruitment of lymphocytes, neutrophils, and monocyte-derived macrophages to the scars several weeks after the neonatal insult. After 1 year, however, neutrophils and lymphocytes were absent from the scars. Our data indicate that peripheral immune cells are transient components of HIE-induced brain scars, opening up new possibilities for late therapeutic interventions.

A Combination of Ex Vivo and In Vivo Strategies for Evaluating How Much New Oral Anticoagulants Exacerbate Experimental Intracerebral Bleeding.

Background Intracerebral hemorrhage is the most serious complication of anticoagulant therapy but the effects of different types of oral anticoagulants on the expansion of these hemorrhages are still unclear. Clinical studies have revealed controversial results; more robust and long-term clinical evaluations are necessary to define their outcomes. An alternative is to test the effect of these drugs in experimental models of intracerebral bleeding induced in animals. Aims To test new oral anticoagulants (dabigatran etexilate, rivaroxaban, and apixaban) in an experimental model of intracerebral hemorrhage induced by collagenase injection into the brain striatum of rats. Warfarin was used for comparison. Methods Ex vivo anticoagulant assays and an experimental model of venous thrombosis were employed to determine the doses and periods of time required for the anticoagulants to achieve their maximum effects. Subsequently, volumes of brain hematoma were evaluated after administration of the anticoagulants, using these same parameters. Volumes of brain hematoma were evaluated by magnetic resonance imaging, H&E (hematoxylin and eosin) staining, and Evans blue extravasation. Neuromotor function was assessed by the elevated body swing test. Results and Conclusions The new oral anticoagulants did not increase intracranial bleeding compared with control animals, while warfarin markedly favored expansion of the hematomas, as revealed by magnetic resonance imaging and H&E staining. Dabigatran etexilate caused a modest but statistically significant increase in Evans blue extravasation. We did not observe significant differences in elevated body swing tests among the experimental groups. The new oral anticoagulants may provide a better control over a brain hemorrhage than warfarin.

Randomized trial of the efficacy of trial-based cognitive therapy for obsessive-compulsive disorder: preliminary findings.

INTRODUCTION: Obsessive-compulsive disorder (OCD) is the fourth most prevalent mental disorder and is a disabling condition. OCD is associated with anatomical and functional changes in the brain, in addition to dysfunctional cognitions. The treatments of choice are selective serotonin reuptake inhibitors, cognitive-behavioral therapy (CBT), and exposure and response prevention (ERP). Trial-based cognitive therapy (TBCT) is a recent and empirically validated psychotherapy with a focus on restructuring dysfunctional negative core beliefs (CBs). The objective of this study was to evaluate the efficacy of TBCT relative to ERP for treatment of OCD. METHOD: A randomized, single-blind clinical trial was conducted, randomizing 26 patients for individual treatment with TBCT (n = 12) or ERP (n = 14). The groups were evaluated at baseline, at the end of 3 months (12 sessions), and at 3, 6, and 12-month follow-ups. RESULTS: Both approaches reduced the severity of symptoms with large effect sizes. These results were maintained at the 12-month follow-up assessment. CONCLUSION: TBCT may be a valid and promising treatment for this disorder.

Psiquiatras e psicotrópicos: o uso de substâncias psicoativas pela terapêutica psiquiátrica na década de 1950 em São Paulo / Psychiatrists and psychotropic drugs: the use of psychoactive substances in psychiatric therapy in the 1950s in São Paulo

Considerando o campo de estudos incipiente sobre história das drogas, a presente pesquisa busca compreender qual a formação social e histórica da dinâmica prescritiva de psicofármacos em contraposição a intensificação da restrição de outras drogas no processo de incorporação de substâncias psicoativas na terapêutica psiquiátrica entre os anos 1950 e 1964 em São Paulo. A proposta investigativa aborda a complexa relação entre o uso de drogas na psiquiatria paulista e a historiografia sobre o tema, destacando a necessidade de uma abordagem multidisciplinar e crítica e que considera como fundamentais os contextos sociais, econômicos, políticos e culturais. Articulando uma história das drogas com a história da psiquiatria, buscou-se entender de que forma foram assimiladas e incorporadas as primeiras drogas psiquiátricas e quais foram seus impactos na classe médica e no tecido social. Partindo do materialismo histórico e da história "vista de baixo", a ideia é romper com uma historiografia acritica e linear e construir uma história para além da oficialidade, que considera as relações e contextos em suas multideterminações e busca identificar rupturas, continuidades, diálogos, resistências e negociações entre os distintos atores sociais. Nesse sentido, as fontes documentais e clínicas são ferramentas potentes na promoção de uma perspectiva crítica e multidisciplinar nos estudos históricos e sociais sobre o uso de drogas e psicofármacos e sua regulação na psiquiatria e na sociedade em geral.

Considering the incipient field of studies on the history of drugs, this research aims to understand the social and historical formation of the prescriptive dynamics of psychotropic drugs as opposed to the intensification of restrictions on other drugs in the process of incorporating psychoactive substances into psychiatric therapy between the 1950s and 1964 in São Paulo. The investigative proposal addresses the complex relationship between drug use in psychiatry in São Paulo and the historiography about this topic, highlighting the need for a multidisciplinary and critical approach that considers social, economic, political and cultural contexts as fundamental. Articulating a history of drugs with the history of psychiatry, this study seeks to understand how the first psychiatric drugs were assimilated and incorporated such as their impacts on the medical profession and the social context. Starting from historical materialism and the history itself "seen from below", the idea is to break with an uncritical and linear historiography and build a history beyond officialdom, considering relationships and contexts in their multiple determinations and seeks to identify ruptures, continuities, dialogues, resistance and negotiations between different social players. In this sense, documentary and clinical sources are powerful tools in promoting a critical and multidisciplinary perspective in historical and social studies on the use of drugs and psychotropic drugs and their regulation in psychiatry and society in general.

Influence of Alpha-Actinin-3 R577X Polymorphism on Muscle Damage and the Inflammatory Response after an Acute Strength Training Session.

The objective of this study was to verify the influence of the ACTN3 R577X polymorphism on muscle damage and the inflammatory response after an acute strength training (ST) session. Twenty-seven healthy male individuals (age: 25 ± 4.3 years) participated in the study, including 18 RR/RX and 9 XX individuals. The participants were divided into two groups (RR/RX and XX groups) and subjected to an acute ST session, which consisted of a series of leg press, leg extension machine, and seated leg curl machine. The volunteers were instructed to perform the greatest volume of work until concentric muscle failure. Each volunteer's performance was analyzed as the load and total volume of training, and the blood concentrations of C-C motif chemokine ligand 2 (CCL2), interleukin-8 (IL-8), creatine kinase (CK), lactate dehydrogenase (LDH), myoglobin, testosterone, and cortisol were measured before the ST session and 30 min and 24 h postsession. The ACTN3 R577X polymorphism effect was observed, with increased concentrations of CCL2 (p < 0.01), IL-8 (p < 0.01), and LDH (p < 0.001) in XX individuals. There was an increase in the concentration of CK in the RR/RX group compared to XX at 24 h after training (p > 0.01). The testosterone/cortisol ratio increased more markedly in the XX group (p < 0.001). Regarding performance, the RR/RX group presented higher load and total volume values in the training exercises when compared to the XX group (p < 0.05). However, the XX group presented higher values of delayed onset muscle soreness (DOMS) than the RR/RX group (p < 0.05). The influence of ACTN3 R577X polymorphism on muscle damage and the inflammatory response was observed after an acute ST session, indicating that the RR/RX genotype shows more muscle damage and a catabolic profile due to a better performance in this activity, while the XX genotype shows more DOMS.

Burnout e a segurança do paciente na Atenção Primária à Saúde: aspectos jurídico-sanitários em tempos de pandemia de COVID-19 / Burnout and patient safety in Primary Health Care: legal-sanitary aspects in times of the COVID-19 pandemic / Burnout y seguridad del paciente en la Atención Primaria de Salud: aspectos jurídico-sanitarios en tiempos de la pandemia del COVID-19

Objetivo: discutir os desafios para a construção de uma política pública de segurança do paciente na Atenção Primária à Saúde (APS) brasileira frente ao crescimento da síndrome de burnout entre seus profissionais. Metodologia: pesquisa bibliográfica e documental sobre a segurança do paciente e o burnout entre trabalhadores da APS utilizando o referencial dos direitos humanos e a matriz teórica de Maslach e Jackson. Resultados: o burnout possui implicações sanitárias severas nos profissionais da APS e repercute sobre o processo de trabalho das equipes, gerando prejuízos nas ações e estratégias de segurança do paciente. As políticas de segurança do paciente e de saúde do trabalhador no Brasil são dialógicas e complementares, mas mostram-se insuficientes para impactar o cenário do burnout na APS frente à estagnação e retrocessos vivenciados recentemente nesse nível de atenção. Considerações finais: a resposta institucional para a abordagem da síndrome de burnout na APS tem sido insatisfatória. Para além do arcabouço das políticas preexistentes, mostra-se urgente a realização de mudanças no financiamento da APS e no aporte de equipes multiprofissionais para a melhoria das condições de trabalho que, em última instância, refletem na segurança do paciente na rede primária.

Objective: to discuss the challenges of building public policy on patient safety in Brazilian primary health care (PHC) considering the increase in burnout syndrome among health professionals. Methods: bibliographic and documentary research on patient safety and burnout among PHC staff using Maslach and Jackson's human rights framework and theoretical matrix. Results: burnout has serious health consequences for PHC professionals and affects the work process of teams, damaging patient safety policies and strategies.Patient safety and worker health policies in Brazil are dialogic and complementary, but they are not sufficient to affect the burnout scenario in PHC, given the stagnation and setbacks that have recently been experienced at this level of care. Conclusion: the institutional response to dealing with burnout syndrome in PHC is unsatisfactory. In addition to the policy framework already in place, urgent changes are needed in PHC funding and in the contribution of multidisciplinary teams to improve working conditions, which will ultimately impact patient safety in the primary network.

Objetivo: discutir los desafíos para la construcción de una política pública sobre seguridad del paciente en la Atención Primaria de Salud (APS) brasileña frente al crecimiento del síndrome de burnout entre sus profesionales. Metodología: investigación bibliográfica y documental sobre seguridad del paciente y burnout en trabajadores de la APS utilizando el marco de los derechos humanos y la matriz teórica de Maslach y Jackson. Resultados: el burnout tiene graves implicaciones para la salud de los profesionales de la APS y afecta el proceso de trabajo de los equipos, perjudicando las acciones y estrategias de seguridad del paciente. Las políticas de seguridad del paciente y salud del trabajador en Brasil son dialógicas y complementarias, pero insuficientes para impactar el escenario de burnout en la APS frente al estancamiento y retroceso experimentado recientemente en ese nivel de atención. Consideraciones finales: la respuesta institucional al abordaje del síndrome de burnout en APS ha sido insatisfactoria. Además del marco de política preexistente, es urgente realizar cambios en el financiamiento de la APS y en la contribución de los equipos multidisciplinarios para mejorar las condiciones de trabajo y que, en última instancia, reflejen la seguridad del paciente en la red primaria.

Hyperacute transplantation of umbilical cord mesenchymal stromal cells in a model of severe intracerebral hemorrhage.

Aim: Intracerebral hemorrhage (ICH) has limited therapeutic options. We have shown that an intravenous injection of human umbilical cord-derived mesenchymal stromal cells (hUC-MSC) 24 h after an ICH in rats reduced the residual hematoma volume after a moderate hemorrhage but was inefficient in severe ICH. Here, we investigated whether a treatment in the hyperacute phase would be more effective in severe ICH. Materials & methods: Wistar rats were randomly selected to receive an intravenous injection of hUC-MSC or the vehicle 1 h after a severe ICH. Results: The hyperacute treatment with hUC-MSC did not affect the 22-day survival rate, the motor function or the residual hematoma volume. Conclusion: These results indicate the need for optimization of hUC-MSC-based therapies for severe ICH.

IL-10 and IL-12 (P70) Levels Predict the Risk of Covid-19 Progression in Hypertensive Patients: Insights From the BRACE-CORONA Trial.

Background: Cardiovascular comorbidities such as hypertension and inflammatory response dysregulation are associated with worse COVID-19 prognoses. Different cytokines have been proposed to play vital pathophysiological roles in COVID-19 progression, but appropriate prognostic biomarkers remain lacking. We hypothesized that the combination of immunological and clinical variables at admission could predict the clinical progression of COVID-19 in hypertensive patients. Methods: The levels of biomarkers, including C-reactive protein, lymphocytes, monocytes, and a panel of 29 cytokines, were measured in blood samples from 167 hypertensive patients included in the BRACE-CORONA trial. The primary outcome was the highest score during hospitalization on the modified WHO Ordinal Scale for Clinical Improvement. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and biomarkers associated significantly with the primary outcome. Results: During hospitalization, 13 (7.8%) patients showed progression to more severe forms of COVID-19, including three deaths. Obesity, diabetes, oxygen saturation, lung involvement on computed tomography examination, the C-reactive protein level, levels of 15 cytokines, and lymphopenia on admission were associated with progression to severe COVID-19. Elevated levels of interleukin-10 and interleukin-12 (p70) combined with two or three of the abovementioned clinical comorbidities were associated strongly with progression to severe COVID-19. The risk of progression to severe disease reached 97.5% in the presence of the five variables included in our model. Conclusions: This study demonstrated that interleukin-10 and interleukin-12 (p70) levels, in combination with clinical variables, at hospital admission are key biomarkers associated with an increased risk of disease progression in hypertensive patients with COVID-19.

GD3 synthase deletion alters retinal structure and impairs visual function in mice.

Gangliosides are glycosphingolipids abundantly expressed in the vertebrate nervous system, and are classified into a-, b-, or c-series according to the number of sialic acid residues. The enzyme GD3 synthase converts GM3 (an a-series ganglioside) into GD3, a b-series ganglioside highly expressed in the developing and adult retina. The present study evaluated the visual system of GD3 synthase knockout mice (GD3s-/- ), morphologically and functionally. The absence of b- series gangliosides in the retinas of knockout animals was confirmed by mass spectrometry imaging, which also indicated an accumulation of a-series gangliosides, such as GM3. Retinal ganglion cell (RGC) density was significantly reduced in GD3s-/- mice, with a similar reduction in the number of axons in the optic nerve. Knockout animals also showed a 15% reduction in the number of photoreceptor nuclei, but no difference in the bipolar cells. The area occupied by GFAP-positive glial cells was smaller in GD3s-/- retinas, but the number of microglial cells/macrophages did not change. In addition to the morphological alterations, a 30% reduction in light responsiveness was detected through quantification of pS6-expressing RGC, an indicator of neural activity. Furthermore, electroretinography (ERG) indicated a significant reduction in RGC and photoreceptor electrical activity in GD3s-/- mice, as indicated by scotopic ERG and pattern ERG (PERG) amplitudes. Finally, evaluation of the optomotor response demonstrated that GD3s-/- mice have reduced visual acuity and contrast sensitivity. These results suggest that b-series gangliosides play a critical role in regulating the structure and function of the mouse visual system.

Intracerebral Injection of Heme Induces Lipid Peroxidation, Neuroinflammation, and Sensorimotor Deficits.

Background and Purpose: Heme is a red blood cell component released in the brain parenchyma following intracerebral hemorrhage. However, the study of the pathophysiological mechanisms triggered by heme in the brain is hampered by the lack of well-established in vivo models of intracerebral heme injection. This study aims to optimize and characterize a protocol of intrastriatal heme injection in mice, with a focus on the induction of lipid peroxidation, neuroinflammation and, ultimately, sensorimotor deficits. We also evaluated the involvement of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome sensor, in the behavior deficits induced by heme in this model. Methods: Mice were injected with heme in the striatum for the evaluation of neuroinflammation and brain damage through histological and biochemical techniques. Immunoblot was used to evaluate the expression of proteins involved in heme/iron metabolism and antioxidant responses and the activation of the MAPK (mitogen-activated protein kinase) signaling pathway. For the assessment of neurological function, we followed-up heme-injected mice for 2 weeks using the rotarod, elevated body swing, and cylinder tests. Mice injected with the vehicle (sham), or autologous blood were used as controls. Results: Heme induced lipid peroxidation and inflammation in the brain. Moreover, heme increased the expression of HO-1 (heme oxygenase-1), ferritin, p62, and superoxide dismutase 2, and activated the MAPK signaling pathway promoting pro-IL (interleukin)-1ß production and its cleavage to the active form. Heme-injected mice exhibited signs of brain damage and reactive astrogliosis around the injection site. Behavior deficits were observed after heme or autologous blood injection in comparison to sham-operated controls. In addition, behavior deficits and IL-1ß production were reduced in Nlrp3 knockout mice in comparison to wild-type mice. Conclusions: Our results show that intracerebral heme injection induces neuroinflammation, and neurological deficits, in an NLRP3-dependent manner, suggesting that this is a feasible model to evaluate the role of heme in neurological disorders.

Successful treatment and management of canine ehrlichiosis-leishmaniosis-heartworm comorbidity

Background: Canine vector borne diseases (CVBD) are common in tropical countries where the climate favors arthropods abundance. Comorbidity with one or more CVBD are reported as clinical complication and worsen prognostic. Canine visceral leishmaniosis (CanL) is an endemic zoonotic disease in Brazil caused by Leishmania infantum, with several restrictions to canine treatment and suggestion of reservoirs euthanasia for disease control. Heartworm (HW) is a helminthic disease caused by Dirofilaria immitis infection in dogs. It is a chronic heart disease, which can lead to death by congestive heart failure. Canine ehrlichiosis (CE) is caused by Ehrlichia canis bacterial infection with a zoonotic potential and fatal to dogs in acute and chronic presentations. Exposed the above, this study aims to describe a successful treatment and management of a dog with CanL, CE, and HW comorbidity. Case: A 3-year-old male uncastrated black Labrador dog, weighing 35 kg, was admitted to the veterinary clinic due to immunochromatographic CanL positive test performed by municipal zoonosis control center active surveillance. Clinical exam showed a mild shedding, intermittent eye white/yellow discharge and popliteal lymph nodes enlargement. After positive for CanL, veterinary requested more laboratorial exams. IFAT and ELISA were positive for CanL, blood smear showed presence of microfilaria, and bone marrow cytology showed Ehrlichia spp. morulae and microfilaria. Initial treatment prescribed was oral doxycycline, omeprazole, ranitidine, and domperidone for 30 days, and allopurinol and ivermectin until further recommendation. Additionally, repellent collar, repellent spray and vitamin supplement was indicated. After first month, marbofloxacin for 30 days and three doses of immunostimulant drug were administrated. After three months of treatment, dog still positive for heartworm, ehrlichiosis, and CanL. Doxycycline protocol was repeated. Dog became consistently negative for all pathogens one year later with persistent thrombocytopenia but without clinical signs, ergo allopurinol and ivermectin were discontinued. After 4 years of follow up, the animal had an acute pancreatitis and died, with unremarkable total blood count and negative for all pathogens. Discussion: CVBD coinfections are commonly reported as worsen prognostic in endemic regions. The pathogens reported here share a host immunomodulation competence. L. infantum and Ehrlichia spp. downregulates Th1 response, whereas D. immitis increase as Th2 profile. The therapeutic protocol was iniciated by staging CanL. Since the patient had clinical signs, allopurinol was prescribed as a well-established drug for CanL. Marbofloxacin was added due to its high safety drug in clinical improvement of infected dogs with and without renal disease and in vitro effectiveness against L. infantum. Domperidone was used to promote Th1 cytokine profile as INF-γ, IL-2, IL-12, and TNF-α. We used an immunostimulant protocol to favor polarization to the Th1 profile comprised by 30 days of domperidone protocol followed by a vaccine and an immunomodulator. Doxycycline was used successfully for Ehrlichia spp. and HE clearance after 2 treatment courses and 1 year of ivermectin every 15 days. The animal presented intermittent coughing episodes on the first treatment course, but no medical intervention was needed besides exercise restriction. Our report shows the successful management of one dog with CanL, CE and HE comorbidity. This success was possible due to early detection and good therapeutic choice.(AU)

Human Wharton's jelly mesenchymal stem cells protect neural cells from oxidative stress through paracrine mechanisms.

AIM: Mesenchymal stem cells (MSCs) have neuroprotective and immunomodulatory properties, which are partly mediated by extracellular vesicles (EVs) secretion. We aimed to evaluate the effects of human Wharton's jelly-derived MSCs (WJ-MSCs) and their EVs on rat hippocampal cultures subjected to hydrogen peroxide (H2O2). MATERIALS & METHODS: Hippocampal dissociated cultures were either co-cultured with WJ-MSCs or treated with their EVs prior to H2O2 exposure and reactive oxygen species levels and cell viability were evaluated. RESULTS: Coculture with WJ-MSCs or pre-incubation with EVs prior to the insult reduced reactive oxygen species after H2O2 exposure. Cell viability was improved only when coculture was maintained following the insult, while EVs did not significantly improve cell viability. CONCLUSION: WJ-MSCs have potential antioxidant and neuroprotective effects on hippocampal cultures which might be partially mediated by EVs.

INTER- AND INTRA-OBSERVER RELIABILITY OF SCHATZKER, AO, AND LUO CLASSIFICATIONS FOR TIBIAL PLATEAU FRACTURES.

OBJECTIVE: To verify inter- and intra-observer agreement of three classification systems for tibial plateau fractures - Schatzker, AO/ASIF, and Luo's - among orthopedic surgery residents. METHODS: This cross-sectional study was conducted with 29 observers. Radiographic and tomographic imaging of the knee of 15 patients presenting with fractures were evaluated. After six weeks, the test was reapplied. The level of agreement was calculated by the Kappa index. RESULTS: In test 1, inter-observer agreement of all residents, according to the Kappa index, for Schatzker classification was 0.226, for AO 0.431, and Luo's 0.319. In test 2, values were 0.316, 0.333, and 0.347, respectively (p < 0.001). Regarding intra-observer analysis, the mean Kappa indexes of 1st-year residents were: Schatzker, 0.20; AO, 0.32; and Luo's, 0.3. For 2nd-year residents, means were: 0.51, 0.58, and 0.38, respectively. As for 3rd-year, results were 0.42, 0.42, and 0.41, respectively (p < 0.001). CONCLUSION: AO/ASIF showed a better reproducibility than other classifications, with substantial inter- and intra-observer agreement. We also found a stronger agreement among 2nd- and 3rd-year residents. Level of Evidence III, Diagnostic Studies - Investigating a Diagnostic Test.

OBJETIVO: Verificar a concordância interobservador e intraobservador de três classificações utilizadas nas fraturas do platô tibial: Schatzker, AO/ASIF e a de Luo entre residentes de ortopedia. MÉTODOS: estudo transversal, por conveniência, com 29 observadores. Foram avaliadas imagens radiográficas de joelho e tomografia computadorizada em 15 pacientes com fraturas de platô tibial, submetidos a tratamento cirúrgico, sendo reaplicado o teste após seis semanas. O nível de concordância foi calculado através do índice Kappa. O estudo foi submetido ao Comitê de Ética em Pesquisa em humanos da instituição. RESULTADOS: A concordância interobservador dos residentes dos três anos juntos de acordo com o índice Kappa para a classificação Schatzker, AO e tomográfica no teste 1 foi 0,226, 0,431 e 0,319 respectivamente e no teste 2 0,316, 0,333, 0,347 respectivamente. Na análise intraobservador, foi calculada a média dos índices Kappa dos residentes do 1º ano: classificação Schatzker, 0,20; AO 0,32; e tomográfica 0,3. Já a média para os residentes do 2º ano Schatzker foi 0,51, 0,58 e 0,38, respectivamente. Os resultados para os residentes do 3º ano foram 0,42, 0,42 e 0,41 respectivamente. CONCLUSÃO: A classificação AO/ASIF mostrou-se ter uma melhor reprodutibilidade em relação as outras com uma concordância substancial na análise interobservador e intraobservador. Evidenciou-se também que os residentes do 2º e 3º ano tem uma concordância maior. Nível de Evidência III, Estudos diagnósticos - Investigação de um exame para diagnóstico.

Iso-Oncotic Albumin Mitigates Brain and Kidney Injury in Experimental Focal Ischemic Stroke.

Background: There is widespread debate regarding the use of albumin in ischemic stroke. We tested the hypothesis that an iso-oncotic solution of albumin (5%), administered earlier after acute ischemic stroke (3 h), could provide neuroprotection without causing kidney damage, compared to a hyper-oncotic albumin (20%) and saline. Objective: To compare the effects of saline, iso-oncotic albumin, and hyper-oncotic albumin, all titrated to similar hemodynamic targets, on the brain and kidney. Methods: Ischemic stroke was induced in anesthetized male Wistar rats (n = 30; weight 437 ± 68 g) by thermocoagulation of pial blood vessels of the primary somatosensory, motor, and sensorimotor cortices. After 3 h, animals were anesthetized and randomly assigned (n = 8) to receive 0.9% NaCl (Saline), iso-oncotic albumin (5% ALB), and hyper-oncotic albumin (20% ALB), aiming to maintain hemodynamic stability (defined as distensibility index of inferior vena cava <25%, mean arterial pressure >80 mmHg). Rats were then ventilated using protective strategies for 2 h. Of these 30 animals, 6 were used as controls (focal ischemic stroke/no fluid). Results: The total fluid volume infused was higher in the Saline group than in the 5% ALB and 20% ALB groups (mean ± SD, 4.3 ± 1.6 vs. 2.7 ± 0.6 and 2.6 ± 0.5 mL, p = 0.03 and p = 0.02, respectively). The total albumin volume infused (g/kg) was higher in the 20% ALB group than in the 5% ALB group (1.4 ± 0.6 vs. 0.4 ± 0.2, p < 0.001). Saline increased neurodegeneration (Fluoro-Jade C staining), brain inflammation in the penumbra (higher tumor necrosis factor-alpha expression), and blood-brain barrier damage (lower gene expressions of claudin-1 and zona occludens-1) compared to both iso-oncotic and hyper-oncotic albumins, whereas it reduced the expression of brain-derived neurotrophic factor (a marker of neuroregeneration) compared only to iso-oncotic albumin. In the kidney, hyper-oncotic albumin led to greater damage as well as higher gene expressions of kidney injury molecule-1 and interleukin-6 than 5% ALB (p < 0.001). Conclusions: In this model of focal ischemic stroke, only iso-oncotic albumin had a protective effect against brain and kidney damage. Fluid therapy thus requires careful analysis of impact not only on the brain but also on the kidney.