Furoxan-piplartine hybrids as effective NO donors and ROS inducers in PC3 cancer cells: design, synthesis, and biological evaluation.

Conjugation of the naturally occurring product piplartine (PPT, 1), which is a potent cytotoxic compound and ROS inducer, with a diphenyl sulfonyl-substituted furoxan moiety (namely, 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide), an important type of NO donor, via an ether linker of different chain lengths is described, characterized and screened for the anticancer potential. The cytotoxicity of the new hybrids was evaluated on a panel of human cancer cell lines (MCF-7, PC3 and OVCAR-3) and two non-cancer human cells (MCF10A and PNT2). In general, the synthesized hybrids were more cytotoxic and selective compared to their furoxan precursors 4-6 and PPT in the above cancer cells. Particularly, PC3 cells are the most sensitive to hybrids 7 and 9 (IC50 values of 240 nM and 50 nM, respectively), while a lower potency was found for the prostate normal cells (IC50 = 17.8 µM and 14.1 µM, respectively), corresponding to selectivity indices of ca. 75 and 280, respectively. NO generation by the PPT-furoxan compounds in PC3 cells was confirmed using the Griess reaction. Furthermore, the cell growth inhibitory effect of 9 was significantly attenuated by the NO scavenger carboxy-PTIO. The intracellular ROS generation by 7 and 9 was also verified, and different assays showed that co-treatment with the antioxidant N-acetyl-l-cysteine (NAC) provided protection against PPT-induced ROS generation. Further mechanistic studies revealed that 7 and 9 had strong cytotoxicity to induce apoptosis in PC3 cells, being mediated, at least in part, by the NO-release and increase in ROS production. Notably, the ability of 9 to induce apoptosis was stronger than that of 7, which may be attributed to higher levels of NO released by 9. Compounds 7 and 9 modulated the expression profiles of critical regulators of cell cycle, such as CDKN1A (p21), c-MYC, and CCND1 (cyclin D1), as well as induced DNA damage. Overall, tethering the furoxan NO-releasing moiety to the cytotoxic natural product PPT had significant impact on the potential anticancer activity and selectivity of the novel hybrid drug candidates, especially 9, as a result of synergistic effects of both furoxan and PPT's ability to release NO, generate ROS, induce DNA damage, and trigger apoptosis.

Heterogenous relapse and efficacy endpoint definitions for neuromyelitis optica spectrum disorder studies: A systematic review.

BACKGROUND: Over the last years, multiple studies have been dedicated to evaluate the efficacy of different treatment options for Neuromyelitis Optica Spectrum Disorder (NMOSD). However, there is a wide variety of endpoints employed across these studies. Our goal is to conduct a systematic review describing the endpoints utilized in studies related to NMOSD. METHODS: Medline, Embase, and Cochrane were searched from inception to May 2023, to identify studies analyzing treatment options in patients with NMOSD. We collected data on baseline study characteristics and all efficacy outcomes available. RESULTS: We included 127 studies and identified approximately 40 different efficacy endpoints, categorized into 1) relapse, 2) disability, 3) visual acuity, and 4) surrogate outcomes. Most studies were retrospective (54.3 %) and aimed at attack prevention (81.4 %). The most common relapse-related outcomes were annualized relapse rate (73.2 %), followed by relapse rate (50.4 %), and relapse-free rate (36.2 %). The relapse definition also varied widely among studies, with only 73 (57.4 %) studies explicitly addressing the definition used. The most common disability outcome was the Expanded Disability Scale (97.6 %), followed by the Modified Rankin Scale (7.9 %). Visual Acuity Score was employed in 14.2 % of studies, followed by Visual Evoked Potentials (6.3 %). Imaging was the most common surrogate (20.5 %), followed by the fraction of B cells (18.1 %). CONCLUSION: Publications were heterogeneous in measuring efficacy, with different use of endpoints and relapse definitions. Standardization across studies would improve data analysis and application in clinical practice.

Spinal cord compression by cystic IgG4-related spinal pachymeningitis mimicking neurocysticercosis: a case report.

BACKGROUND: To report a case of IgG4-related pachymeningitis presenting with cystic lesions mimicking neurocysticercosis. CASE PRESENTATION: A 40-year-old female patient with tetraparesis, dysphagia and dysphonia was evaluated with clinical examination, magnetic resonance imaging, and meningeal biopsy. Magnetic resonance imaging (MRI) revealed diffuse pachymeningeal enhancement involving the cranial, cervical, thoracic, and lumbar segments with spinal cord compression and cystic lesions. CSF immunology was initially positive for cysticercus cellulosae. After disease progression a meningeal biopsy was compatible with IgG4 related disease. The patient had partial response to rituximab and needed multiple surgical procedures for spinal cord decompression and CSF shunting. CONCLUSIONS: This case highlights the possibility of IgG4-related disease in patients with diffuse pachymeningitis causing spinal cord compression, even with cystic lesions on MRI. Diagnosis of IgG4-related pachymeningitis is paramount due to the possibility of treatment response to immunotherapy, particularly to anti-CD20 agents.

Nematodes of concern to public and animal health associated with the invasive snail Achatina fulica, in Sergipe, Northeastern Brazil.

The giant African land snail Achatina fulica is known to be the intermediate host of a number of nematode species that are prejudicial to human and veterinary health, being also an agricultural and urban pest. The present study investigated the presence of nematodes in A. fulica and other terrestrial mollusks in 24 municipalities of Sergipe State, northeastern of Brazil, in the dry and rainy seasons. In 2019 and 2020, the specimens were collected in standard 20 m × 10 m plots (10 min/01 collector), while in 2021, they were collected by convenience sampling. The nematode species were identified based on sequencing of the mitochondrial Cytochrome C Oxidase Subunit I (COI) gene and the ribosomal nuclear Internal Transcribed Spacer (ITS 2). Specimens of A. fulica infected with Angiostrongylus cantonensis, a nematode that causes eosinophilic meningitis (EM) in humans and animals, were collected in four municipalities. Two nematodes of veterinary importance were also identified, Aelurostrongylus abstrusus and Cruzia tentaculata in seven municipalities. This is the first record of Cruzia tentaculata in Sergipe. Free-living nematodes were also found in 18 municipalities. One of these species - Caenorhabditis briggsae - was identified in the municipality of Itabaiana. Specimens of other mollusks species were also collected. Only one of these mollusks, C. fasciata from Japaratuba, was found infected with free-living nematodes. A. fulica showed greater positivity for nematodes in the dry season, especially in the regions of Lower São Francisco River, Greater Aracaju and South Central Sergipe. The probability of infection increased when mollusks were larger and more recurrent in plots. Given that A. cantonensis is the etiological agent of EM and was found associated to A. fulica in four municipalities, it will be important to implement programs of continuous monitoring of the mollusk's fauna, combined with educational programs that provide information necessary to control A. fulica.

Executive functions and functioning in women with fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a chronic condition characterized by widespread pain that is associated with sleep, emotional, and cognitive disturbances, including in executive functions (EFs). OBJECTIVE: To investigate the relationship between EFs and functionality in women with FM. METHODS: The study included 17 women with FM, aged between 30 and 59 years, with no history of neurological disease. The EFs were assessed using the Digit Span Subtest (DS), Five Digit Test, Trail Making Test (TMT), Corsi Block-Tapping Task, Hayling Test (HT), and Verbal Fluency Task. Functionality was evaluated through the Fibromyalgia Impact Questionnaire. The Beck Depression Inventory, Hamilton Anxiety Rating Scale, and Brief Pain Inventory were used to measure depression, anxiety, and pain, which were controlled in the statistical analyses. RESULTS: The FM patients showed longer response latency on the HT and TMT. They made fewer errors on part B of the HT, and they performed worse on the DS backward and on the Corsi Block-Tapping Task forward and backward. There were moderate correlations in the expected direction between performance on the Corsi Block-Tapping Task backward and interference at work, as well as between the time to complete part B of the Trail Making Test - B (TMT-B) and fatigue. An unexpected relationship was found between errors on part B of the HT and interference at work. CONCLUSION: The results suggest lower efficiency in processes such as inhibitory control and cognitive flexibility, difficulties in working memory and non-executive processes such as processing speed. Even with pain, anxiety, and depression controlled, some relationships between EFs and functionality were observed, indicating that these symptoms do not fully explain this relationship. We suggest that cognition, particularly EFs, and broader measures of functionality be considered in the evaluation of FM.

ANTECEDENTES: A fibromialgia (FM) é uma condição crônica caracterizada por dor generalizada, associada a distúrbios do sono, emocionais e cognitivos, entre os quais os das funções executivas (FEs). OBJETIVO: Investigar a relação entre FEs e funcionalidade em mulheres com FM. MéTODOS: O estudo incluiu 17 mulheres com FM, com idades entre 30 e 59 anos, sem histórico de doença neurológica. Para a avaliação das FEs, utilizou-se Subteste de Span de Dígitos (SD), o Teste dos Cinco dígitos, o Teste de Trilhas (TT), Tarefa dos Cubos de Corsi, O Teste de Hayling (TH), e a Tarefa de Fluência Verbal. A funcionalidade foi avaliada pelo Questionário de Impacto da Fibromialgia. O Inventário de Depressão de Beck, a Escala de Ansiedade Hamilton e o Inventário Breve de Dor foram usados para mensurar depressão, ansiedade e dor, que foram controladas nas análises estatísticas. RESULTADOS: Pacientes com FM apresentaram maior latência de resposta na TH e no TT. Elas cometeram menos erros na parte B da TH, e tiveram pior desempenho no SD em ordem inversa e na Tarefa dos Cubos de Corsi nas ordens direta e inversa. Houve relações moderadas, na direção esperada, entre a Tarefa dos Cubos de Corsi na ordem inversa e interferência no trabalho, assim como entre tempo até completar a parte B do Teste de Trilhas (TT) e fadiga. Encontrou-se uma relação inesperada entre erros na parte B da TH e interferência no trabalho. CONCLUSãO: Os resultados sugerem menor eficiência em processos como controle inibitório e flexibilidade cognitiva, dificuldades na memória de trabalho e em processos não executivos, como velocidade de processamento. Mesmo com controle da dor, da ansiedade e da depressão, houve algumas relações entre FEs e funcionalidade, o que indica que esses sintomas não explicam completamente essa relação. Sugere-se considerar a cognição, particularmente as FEs, e medidas mais abrangentes de funcionalidade na avaliação da FM.

Ecotoxicological study of seven pharmaceutically active compounds: Mixture effects and environmental risk assessment.

Pharmaceutically active compounds (PhACs) have been detected in several aquatic compartments, which has been of environmental concern since PhACs can cause adverse effects on the aquatic ecosystem at low concentrations. Despite the variety of PhACs detected in surface water, ecotoxicological studies are non-existent for many of them, mainly regarding their mixture. In addition, water bodies can continuously receive the discharge of raw or treated wastewater with micropollutants. Thus, PhACs are subject to mixture and interactions, potentiating or reducing their toxicity. Therefore, the present study evaluated the toxicity on Aliivibrio fischeri of seven PhACs, which still needs to be explored in the literature. The effects were evaluated for the PhACs individually and for their binary and tertiary mixture. Also, the experimental effects were compared with the concentration addition (CA) and independent action (IA) models. Finally, an environmental risk assessment was carried out. Fenofibrate (FEN), loratadine (LOR), and ketoprofen (KET) were the most toxic, with EC50 of 0.32 mg L-1, 6.15 mg L-1 and 36.8 mg L-1, respectively. Synergistic effects were observed for FEN + LOR, KET + LOR, and KET + FEN + LOR, showing that the CA and IA may underestimate the toxicity. Environmental risks for KET concerning algae, and LOR e 17α-ethynylestradiol (EE2) for crustaceans and fish were high for several locations. Besides, high removals by wastewater treatment technologies are required to achieve the concentrations necessary for reducing KET and LOR risk quotients. Thus, this study contributed to a better understanding of the toxic interactions and environmental risks of PhACs.

Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations.

BACKGROUND: Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis. OBJECTIVE: With the support of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, ABN) and the Brazilian Society of Child Neurology (Sociedade Brasileira de Neurologia Infantil, SBNI), a consensus on the diagnosis and treatment of AIE in Brazil was developed using the Delphi method. METHODS: A total of 25 panelists, including adult and child neurologists, participated in the study. RESULTS: The panelists agreed that patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques. Children should also be screened for anti-myelin oligodendrocyte glucoprotein antibodies (anti-MOG). Treatment should be started within the first 4 weeks of symptoms. The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis, the second-line includes rituximab and/or cyclophosphamide, while third-line treatment options are bortezomib and tocilizumab. Most seizures in AIE are symptomatic, and antiseizure medications may be weaned after the acute stage. In anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the panelists have agreed that oral immunosuppressant agents should not be used. Patients should be evaluated at the acute and postacute stages using functional and cognitive scales, such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Modified Rankin Scale (mRS), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSION: The present study provides tangible evidence for the effective management of AIE patients within the Brazilian healthcare system.

ANTECEDENTES: Encefalites autoimunes (EAIs) são um grupo de doenças inflamatórias caracterizadas pela presença de anticorpos contra antígenos neuronais e gliais, que ocasionam sintomas psiquiátricos subagudos, queixas de memória e distúrbios anormais do movimento. A maioria dos pacientes é jovem, e o atraso no tratamento está associado a pior prognóstico. OBJETIVO: Com o apoio da Academia Brasileira de Neurologia (ABN) e da Sociedade Brasileira de Neurologia Infantil (SBNI), desenvolvemos um consenso sobre o diagnóstico e o tratamento da EAIs no Brasil utilizando a metodologia Delphi. MéTODOS: Um total de 25 especialistas, incluindo neurologistas e neurologistas infantis, foram convidados a participar. RESULTADOS: Os especialistas concordaram que os pacientes com critérios de possíveis EAIs devem ser submetidos ao rastreio de anticorpos antineuronais no soro e no líquido cefalorraquidiano (LCR) por meio das técnicas de ensaio baseado em tecidos (tissue-based assay, TBA, em inglês) e ensaio baseado em células (cell-based assay, CBA, em inglês). As crianças também devem ser submetidas ao rastreio de de anticorpo contra a glicoproteína da mielina de oligodendrócitos (anti-myelin oligodendrocyte glycoprotein, anti-MOG, em inglês). O tratamento deve ser iniciado dentro das primeiras 4 semanas dos sintomas, sendo as opções de primeira linha metilprednisolona combinada com imunoglobulina intravenosa (IGIV) ou plasmaférese. O tratamento de segunda linha inclui rituximabe e ciclofosfamida. Bortezomib e tocilizumab são opções de tratamento de terceira linha. A maioria das crises epilépticas nas EAIs são sintomáticas, e os fármacos anticrise podem ser desmamadas após a fase aguda. Em relação à encefalite antirreceptor de N-metil-D-aspartato (anti-N-methyl-D-aspartate receptor, anti-NMDAR, em inglês), os especialistas concordaram que agentes imunossupressores orais não devem ser usados. Os pacientes devem ser avaliados na fase aguda e pós-aguda mediante escalas funcionais e cognitivas, como Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Modified Rankin Scale (mRS), e Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSãO: Esta pesquisa oferece evidências tangíveis do manejo efetivo de pacientes com EAIs no sistema de saúde Brasileiro.

A combined treatment for self-traumatic chronic skin lesions associated with post-surgical neuropathic pain in a domestic cat: a pharmacological and cold atmospheric plasma approach.

Cold atmospheric plasma (CAP) has been employed as a therapy against both acute and chronic skin lesions, contaminated or not, and has effects on angiogenesis and reepithelialization promoting healing. In this context, the present study aimed to evaluate the effects of a CAP jet associated with pharmacological treatment described by the 2015 AAHA/AAFP pain management guidelines and the 2022 WSAVA guidelines for the recognition, assessment, and treatment of pain, on the healing of chronic skin lesions caused by a pruritic reaction resulting from post-surgical neuropathic pain. To this end, a single CAP application was performed on a feline patient with a 6 months old recurrent contaminated cervical skin lesions along with administration of ketamine (10 µg/kg/min) following the prescription of prednisone (1 mg/kg, SID, 6 days), gabapentin (8 mg/kg, BID, 60 days) and amitriptyline (0.5 mg /kg, SID, 60 days). A single application of plasma associated with an NMDA antagonist, anti-inflammatory steroid, tricyclic antidepressant and gabapentinoid thus provided a significant improvement in the macroscopic appearance of the lesion within 10 days, and the owner reported the cessation of intense itching within the first four hours after treatment and a consequent improvement in the animal's quality of life. The medical treatment was finished almost a year since the writing of this paper, without clinical or reported recurrent signs of the condition. Therefore, we observed that single dose CAP application associated with ketamine, gabapentin, amitriptyline and prednisone leads to significant healing of chronically infected skin lesions resulting from post-surgical neuropathic pain.

Spinal Cord Stimulation Modulates Rat Cortico-Basal Ganglia Locomotor Circuit.

OBJECTIVE: The cortico-basal ganglia circuit is crucial to understanding locomotor behavior and movement disorders. Spinal cord stimulation modulates that circuit, which is a promising approach to restoring motor functions. However, the effects of electrical spinal cord stimulation in the healthy brain motor circuit in pre- and postgait are poorly understood. Thus, this report aims to evaluate, through electrophysiological analyses, the dynamic spectral features of motor networks underlying locomotor initiation with spinal cord stimulation. MATERIALS AND METHODS: Wistar male rats underwent spinal cord stimulation (current 30-150 µA, frequency 100, 333, and 500 Hz) with the electrophysiological recording of the caudate and putamen nuclei, primary and secondary motor cortices, and primary somatosensory cortex. Video tracking recorded treadmill locomotion and extracted the motor planning and gait initiation. RESULTS: Spectral analysis of segments of gait initiation (pre- and postgait), with stimulation off, showed increased low-frequency activity. Postgait initiation showed increased alpha and beta rhythms and decreased delta rhythm with the stimulation off. Overall, the stimulation frequencies reduced alpha and beta rhythms in all brain areas during movement initiation. Regarding movement planning, such an effect was observed in the sensorimotor area, comprising the delta and alpha rhythms. CONCLUSION: This study showed a short-term effect of spinal cord stimulation on the brain areas of the motor circuit, suggesting possible facilitation of movement planning and starting through neuromodulation. Thus, the electrophysiological characterization of this study may contribute to understanding basal ganglia networks and developing new approaches to treat movement disorders in the gait initiation phase.

A Pilot Study of Functional Brain Magnetic Resonance Imaging in BPS/IC Patients: Evidence of Central Sensitization.

Bladder pain syndrome/Interstitial cystitis (BPS/IC) is characterized by increased activity in bladder afferent pathways, recruitment of silent nociceptive neurons, and sensitization of the brain areas responsible for pain amplification. Default mode network (DMN) is a set of regions activated during the resting state, which reflect the brain's intrinsic activity. Conversely, the sensorimotor network (SMN) plays a key role in structural neuroplasticity. This study aimed to evaluate DMN and SMN activity in BPS/IC patients, both with and without bladder noxious stimulus, using functional brain magnetic resonance imaging (MRI). Six BPS/IC female patients underwent 3 Tesla fMRI brain scanners. Acquisitions consisted of 10-minute blood oxygen level-dependent echo-planar imaging. The first acquisition was with an empty bladder, painless, and the second was with suprapubic pain. Data were processed using the independent component analysis method with the MELODIC tool from the functional brain MRI of the Brain Software Library (FSL). A semi-quantitative analysis was performed afterward. The patients' age was 42.6 ± 5 years, pain intensity was 7 ± 0.7 (0-10), day and night frequency were 9.2 ± 2.2 and 2.8 ± 1.0, and maximal bladder capacity was 260 ± 54 mL. One patient was unable to complete the study. All patients showed a comparable DMN activation in both empty and full bladder states, and all presented high SMN activation whether the bladder was empty or full. The activation of DMN at both bladder states, empty and full, and constant SMN activation without and with pain supports the role of these networks in BPS/IC. Similar findings have been reported in other chronic pain syndromes.

Carbohydrate storage in cells: a laboratory activity for the assessment of glycogen stores in biological tissues.

Carbohydrates and fats constitute our primary energy sources. The importance of each of these energy substrates varies across cell types and physiological conditions. For example, the brain normally relies almost exclusively on glucose oxidation, whereas skeletal muscle shifts from lipids toward higher carbohydrate oxidation rates as exercise intensity increases. Understanding how carbohydrates are stored in our cells and which tissues contain significant carbohydrate stores is crucial for health professionals, especially given the role of carbohydrate metabolism in various pathophysiological conditions. This laboratory activity uses a simple and low-cost iodine binding method to quantify glycogen in mouse skeletal muscle and liver samples. By integrating the results of this activity with literature data, students can determine overall glycogen storage in the human body. The primary goal of the activity is to enhance students' understanding of the importance and limitations of glycogen stores in energy metabolism.NEW & NOTEWORTHY Carbohydrates are one of the primary energy sources utilized by our cells. Liver and skeletal muscle glycogen, which are the main carbohydrate reserves in the body, play a central role in energy metabolism, especially during periods of fasting and exercise. In this laboratory activity, students measure glycogen levels in tissues to gain insights into how carbohydrates are stored in our cells and understand the role and limitations of liver and muscle carbohydrate stores.

Structural analysis and shape-based identification of novel inhibitors targeting the Trypanosoma cruzi proteasome.

There is an urgent need to develop new, safer, and more effective drugs against Chagas disease (CD) as well as related kinetoplastid diseases. Targeting and inhibiting the Trypanosoma cruzi proteasome has emerged as a promising therapeutic approach in this context. To expand the chemical space for this class of inhibitors, we performed virtual screening campaigns with emphasis on shape-based similarity and ADMET prioritization. We describe the ideation and application of robustly validated shape queries for these campaigns, which furnished 44 compounds for biological evaluation. Five hit compounds demonstrated in vitro antitrypanosomal activity by potential inhibition of T. cruzi proteasome and notable chemical diversities, particularly, LCQFTC11. Structural insights were achieved by homology modeling, sequence/structure alignment, proteasome-species comparison, docking, molecular dynamics, and MMGBSA binding affinity estimations. These methods confirmed key interactions as well as the stability of LCQFTC11 at the ß4/ß5 subunits' binding site of the T. cruzi proteasome, consistent with known inhibitors. Our results warrant future assay confirmation of our hit as a T. cruzi proteasome inhibitor. Importantly, we also shed light into dynamic details for a proteasome inhibition mechanism that shall be further investigated. We expect to contribute to the development of viable CD drug candidates through such a relevant approach.

Galactose-1-phosphate inhibits cytochrome c oxidase and causes mitochondrial dysfunction in classic galactosemia.

Classic galactosemia is an inborn error of metabolism caused by mutations in the GALT gene resulting in the diminished activity of the galactose-1-phosphate uridyltransferase enzyme. This reduced GALT activity leads to the buildup of the toxic intermediate galactose-1-phosphate and a decrease in ATP levels upon exposure to galactose. In this work, we focused our attention on mitochondrial oxidative phosphorylation in the context of this metabolic disorder. We observed that galactose-1-phosphate accumulation reduced respiratory rates in vivo and changed mitochondrial function and morphology in yeast models of galactosemia. These alterations are harmful to yeast cells since the mitochondrial retrograde response is activated as part of the cellular adaptation to galactose toxicity. In addition, we found that galactose-1-phosphate directly impairs cytochrome c oxidase activity of mitochondrial preparations derived from yeast, rat liver, and human cell lines. These results highlight the evolutionary conservation of this biochemical effect. Finally, we discovered that two compounds - oleic acid and dihydrolipoic acid - that can improve the growth of cell models of mitochondrial diseases, were also able to improve galactose tolerance in this model of galactosemia. These results reveal a new molecular mechanism relevant to the pathophysiology of classic galactosemia - galactose-1-phosphate-dependent mitochondrial dysfunction - and suggest that therapies designed to treat mitochondrial diseases may be repurposed to treat galactosemia.

Association between neuroimaging and clinical outcomes in individuals with central nervous system cryptococcosis.

BACKGROUND: The radiological manifestations of central nervous system (CNS) cryptococcosis are diverse and often subtle. There is heterogeneity on how different neuroimaging patterns impact prognosis. This study aims to assess the association between the neuroimaging and clinical outcomes of CNS cryptococcosis. METHODS: All patients with CNS cryptococcosis between July 2017 and April 2023 who underwent brain magnetic resonance imaging (MRI) were included. The primary outcome was mortality during hospitalisation. Secondary outcomes were readmission, ventricular shunting, duration of hospitalisation and time to the first negative cerebrospinal fluid culture. We compared the outcomes for each of the five main radiological findings on the brain MRI scan. RESULTS: We included 46 proven CNS cryptococcosis cases. The two main comorbidity groups were HIV infection (20, 43%) and solid organ transplantation (10, 22%), respectively. Thirty-nine patients exhibited at least one radiological abnormality (85%), with the most common being meningeal enhancement (34, 74%). The mortality rates occurred at 11% (5/46) during hospitalisation. We found no significant disparities in mortality related to distinct radiological patterns. The presence of pseudocysts was significantly associated with the need for readmission (p = .027). The ventricular shunting was significantly associated with the presence of pseudocysts (p = .005) and hydrocephalus (p = .044). CONCLUSION: In this study, there is no association between brain MRI findings and mortality. Larger studies are needed to evaluate this important issue.

Comparing open and closed cell stents in idiopathic intracranial hypertension: A comprehensive meta-analysis of clinical outcomes.

Background: Open cell stents (OC) and closed cell stents (CC) each offer unique advantages and potential drawbacks in the context of idiopathic intracranial hypertension (IIH) treatment. We aim to investigate the safety and efficacy of using OC and CC for IIH.Methods: We conducted a systematic review in PubMed, Embase, and Cochrane Library databases following the PRISMA guidelines. Eligible studies included ≥4 patients with IIH treated by OC or CC. Primary outcomes were headache, visual acuity, and papilledema status before and after the procedure. Additionally, failure rate, minor complications, major complications, and total complications were assessed. Pooled analysis of the OC group and CC group were done separately and then compared.Results: Twenty-four studies were included. Of these, 20 reported on OC and 6 reported on CC. Pooled analysis of failure rate was 8% (4%-12%) in OC and 5% (0%-11%) in CC. For headache improvement rate: 78% (70%-86%) in OC and 81% (66%-69%) in CC. For visual acuity improvement: 78% (65%-92%) in OC and 76% (29%-100%) in CC. For papilledema improvement: 88% (77%-98%) in OC and 82% (67%-98%) in CC. For minor complications: 0% (0%-1%) in OC and 0% (0%-2%) in CC. For major complications: 0% (0%-1%) in OC and 2% (0%-6%) in CC. Total complications: 0% (0%-1%) in OC and 2% (0%-6%) in CC.Conclusion: Low failure and complication rates were found in both OC and CC, with no significant difference between them in effectiveness. The CC showed a slight but significant increase in major and total complications compared to the OC. Additionally, a subtle yet significantly lower failure rate was identified in the CC.

Biocompatibility, bioactivity, porosity, and sealer/dentin interface of bioceramic ready-to-use sealers using a dentin-tube model.

This study evaluated the biocompatibility, bioactivity, porosity, and sealer/dentin interface of Sealer Plus BC (SP), Bio-C Sealer (BIOC), TotalFill BC Sealer (TF), and AH Plus (AHP). Dentin tubes filled with the sealers and empty tubes (control group) were implanted in the subcutaneous tissue of rats for different periods (n = 6 per group/period). Number of inflammatory cells (ICs), capsule thickness, von Kossa reaction, interleukin-6 (IL-6) and osteocalcin (OCN) were evaluated. Porosity and voids in the interface dentin/sealers were assessed by micro-computed tomography. The data were submitted to ANOVA/Tukey's tests (α = 0.05). Greater capsule thickness, ICs and IL-6 immunolabeling cells were observed in AHP. No significant difference in thickness of capsule, ICs, and IL-6- immunolabeling cells was detected between SP and TF, in all periods, and after 30 and 60 days between all groups. At 60 days all groups had reduction in capsule thickness, ICs and IL-6 immunolabeling cells. Von Kossa-positive and birefringent structures were observed in the capsules around the sealers. BIOC, SP, and TF exhibited OCN-immunolabeling cells. All sealers had porosity values below 5%, besides low and similar interface voids. BIOC, SP and TF are biocompatible, bioactive, and have low porosity and voids. The dentin-tube model used is an alternative for evaluating bioceramic materials.

Young-Onset Alzheimer Dementia Due to a Novel Pathogenic Presenilin 1 Variant Initially Misdiagnosed as Autoimmune Encephalitis.

OBJECTIVES: Pathogenic variants in presenilin 1 (PSEN1) are related to early-onset Alzheimer disease (AD) and may occur as de novo variants. In comparison with sporadic forms, it can present with psychiatric manifestations, seizures, myoclonus, and focal presentation. Because PSEN1 can occur in young patients who lack a family history of neurologic disorders and because these symptoms are also frequent in autoimmune encephalitis (AE), diagnosis may be overlooked. Our aim was to demonstrate the challenge in diagnosing young patients with neurodegenerative diseases that simulate AE. METHODS: We describe a case of a young patient with insidious progressive dementia, myoclonus, seizures, and aphasia, with no family history of dementia, along with signs suggestive of neuroinflammation on brain MRI and CSF examination. RESULTS: She was initially misdiagnosed as having AE. Further investigation was performed, leading to the discovery of a novel and de novo pathogenic variant in PSEN1. DISCUSSION: This case demonstrates the importance of considering PSEN1 in young patients with insidious progressive dementia with atypical clinical and neuroimaging features, even in patients without a family history of neurologic disorders. Not adhering to published criteria of possible and probable AE and overinterpretation of subtle inflammatory findings in CSF and MRI contribute to misdiagnosis.

Histoplasmosis in a fingolimod-treated patient: case report and scoping review.

Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat multiple sclerosis. While fingolimod has been associated with an increased risk of cryptococcal meningitis, its correlation with other deep mycoses remains unclear. In this study, we conducted a scoping review of fingolimod associated with histoplasmosis, based on a case report, a literature review, and data from the FDA Adverse Events Reporting System (FAERS) as of January 24th, 2023. A 30-year-old Brazilian woman diagnosed with relapsing-remitting multiple sclerosis, receiving a daily dose of 0.5 mg of fingolimod, presented with a two-month history of fever and unintended weight loss, accompanied by lymphadenopathy, splenomegaly, and lung involvement was investigated. Biopsy of a lung nodule revealed fungal structures suggestive of Histoplasma sp. Additionally, serological testing yielded positive for Histoplasma capsulatum. Disseminated histoplasmosis should be considered in the differential diagnosis of febrile syndromes in patients undergoing fingolimod therapy for multiple sclerosis, particularly in the Americas, where this mycosis is endemic. Treatment with itraconazole and modification of immunotherapy can achieve excellent clinical outcomes.

Luteoma da gravidez: um pseudotumor ovariano / Luteoma of pregnancy: an ovarian pseudotumor

Contexto: Luteoma é neoplasia rara e benigna do ovário, específica da gravidez. Considera-se que seja causada por efeitos hormonais, principalmente da gonadotrofina coriônica. Objetivo: Analisar artigos selecionados sobre luteoma da gravidez e realizar revisão bibliográfica a partir dessas publicações. Desenho: A busca dos artigos foi realizada por meio da plataforma PubMed. Procedeu-se uma busca aos descritores da doença e seu correspondente em inglês (luteoma) no portal da BVSalud. Métodos: Consistiu em revisão bibliográfica, onde foram utilizados artigos publicados de 1972 até 2022. Resultados: A origem celular dos luteomas ainda é desconhecida, mas considera-se que tal processo ocorra devido a uma reação hiperplásica à gravidez, visto que o efeito de virilização regride após o parto. Discussão: Sendo pouco diagnosticado, tendo menos de 200 casos reportados, são geralmente achados durante parto cesáreo ou durante ligadura tubária no pós-parto. Seu aparecimento está relacionado a fatores hormonais da gravidez e hiperplasia ocasionada pela luteinização das células estromais. Os efeitos do luteoma gravídico no organismo estão relacionados, além da virilização da paciente e do feto, com o surgimento da síndrome do ovário policístico e diabetes. Conclusões: Tendo baixa incidência, o luteoma gravídico pode se apresentar como desafio para seu diagnóstico adequado. O diagnóstico precoce permitirá o tratamento adequado, evitando-se efeitos indesejáveis, virilizantes, para a gestante e para o nascituro. É fundamental o preparo dos profissionais de saúde para o diagnóstico e tratamento do luteoma gravídico.