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.

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, while skeletal muscle shifts from lipids towards higher carbohydrate oxidation rates as exercise intensity increases. Understanding how carbohydrate 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.

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.

Selective inhibition of HDAC6 by N-acylhydrazone derivative reduces the proliferation and induces senescence in carcinoma hepatocellular cells.

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths globally. Systemic therapy is the only treatment option for HCC at an advanced stage, with limited therapeutic response. In this study, we evaluated the antitumor potential of four N-acylhydrazone (NAH) derivatives, namely LASSBio-1909, 1911, 1935, and 1936, on HCC cell lines. We have previously demonstrated that the aforementioned NAH derivatives selectively inhibit histone deacetylase 6 (HDAC6) in lung cancer cells, but their effects on HCC cells have not been explored. Thus, the present study aimed to evaluate the effects of NAH derivatives on the proliferative behavior of HCC cells. LASSBio-1911 was the most cytotoxic compound against HCC cells, however its effects were minimal on normal cells. Our results showed that LASSBio-1911 inhibited HDAC6 in HCC cells leading to cell cycle arrest and decreased cell proliferation. There was also an increase in the frequency of cells in mitosis onset, which was associated with disturbing mitotic spindle formation. These events were accompanied by elevated levels of CDKN1A mRNA, accumulation of CCNB1 protein, and sustained ERK1 phosphorylation. Furthermore, LASSBio-1911 induced DNA damage, resulting in senescence and/or apoptosis. Our findings indicate that selective inhibition of HDAC6 may provide an effective therapeutic strategy for the treatment of advanced HCC, including tumor subtypes with integrated viral genome. Further, in vivo studies are required to validate the antitumor effect of LASSBio-1911 on liver cancer.

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.

Tongue pressure is a strong predictor of recommendation for gastrostomy in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Objective and practical biomarkers to determine the need for gastrostomy in patients with amyotrophic lateral sclerosis (ALS) are lacking. Tongue pressure (TP) is a promising biomarker because it is associated with bulbar dysfunction. The aims of this study were to evaluate the association of TP with the need for gastrostomy, and to determine its optimal cut-off value. METHODS: This prospective observational study included participants with ALS taking nutrition orally. TP was evaluated using the Iowa Oral Performance Instrument. Need for gastrostomy as determined by a multidisciplinary team during a 12-month follow up period was recorded. Associations between TP and need for gastrostomy placement were performed. ROC curve analysis determined the optimal cut-off value of TP to predict gastrostomy. RESULTS: Of 208 screened participants, 119 were included. Gastrostomy was indicated in 45% (53), in a 12-month follow up period. TP of ≤20 kPA was a strong predictor of gastrostomy indication (OR 11.8, CI 95% [4.61, 34.7], p < .001). The association persisted even after adjustment for weight loss, pneumonia, prolonged feeding duration, Revised ALS Functional Rating Scale score, and American Speech-Language-Hearing Association scale score (OR 4.51, CI 95% [1.50, 14.9], p = .009). By receiver operating characteristic curve analysis, 20 kPA represented the optimal cut-off value (sensitivity 0.75, specificity 0.89). DISCUSSION: TP is a strong independent predictor of gastrostomy indication in the subsequent 12 months in patients with ALS, with good sensitivity and specificity at a cutoff value of ≤20 kPA, suggesting that it may be a promising biomarker in clinical practice.

Advances in Legume Systematics 14. Classification of Caesalpinioideae. Part 2: Higher-level classification.

Caesalpinioideae is the second largest subfamily of legumes (Leguminosae) with ca. 4680 species and 163 genera. It is an ecologically and economically important group formed of mostly woody perennials that range from large canopy emergent trees to functionally herbaceous geoxyles, lianas and shrubs, and which has a global distribution, occurring on every continent except Antarctica. Following the recent re-circumscription of 15 Caesalpinioideae genera as presented in Advances in Legume Systematics 14, Part 1, and using as a basis a phylogenomic analysis of 997 nuclear gene sequences for 420 species and all but five of the genera currently recognised in the subfamily, we present a new higher-level classification for the subfamily. The new classification of Caesalpinioideae comprises eleven tribes, all of which are either new, reinstated or re-circumscribed at this rank: Caesalpinieae Rchb. (27 genera / ca. 223 species), Campsiandreae LPWG (2 / 5-22), Cassieae Bronn (7 / 695), Ceratonieae Rchb. (4 / 6), Dimorphandreae Benth. (4 / 35), Erythrophleeae LPWG (2 /13), Gleditsieae Nakai (3 / 20), Mimoseae Bronn (100 / ca. 3510), Pterogyneae LPWG (1 / 1), Schizolobieae Nakai (8 / 42-43), Sclerolobieae Benth. & Hook. f. (5 / ca. 113). Although many of these lineages have been recognised and named in the past, either as tribes or informal generic groups, their circumscriptions have varied widely and changed over the past decades, such that all the tribes described here differ in generic membership from those previously recognised. Importantly, the approximately 3500 species and 100 genera of the former subfamily Mimosoideae are now placed in the reinstated, but newly circumscribed, tribe Mimoseae. Because of the large size and ecological importance of the tribe, we also provide a clade-based classification system for Mimoseae that includes 17 named lower-level clades. Fourteen of the 100 Mimoseae genera remain unplaced in these lower-level clades: eight are resolved in two grades and six are phylogenetically isolated monogeneric lineages. In addition to the new classification, we provide a key to genera, morphological descriptions and notes for all 163 genera, all tribes, and all named clades. The diversity of growth forms, foliage, flowers and fruits are illustrated for all genera, and for each genus we also provide a distribution map, based on quality-controlled herbarium specimen localities. A glossary for specialised terms used in legume morphology is provided. This new phylogenetically based classification of Caesalpinioideae provides a solid system for communication and a framework for downstream analyses of biogeography, trait evolution and diversification, as well as for taxonomic revision of still understudied genera.

Temporal Trends in Transcatheter Aortic Valve Implantation: 10-Year Analysis of the TAVIDOR Registry. / Tendência Temporal no Implante Percutâneo de Bioprótese Aórtica: Análise de 10 Anos do Registro TAVIDOR.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has established itself as the preferential strategy to approach severe aortic stenosis. Information on procedural improvements and nationwide results obtained with the technique throughout the past decade are unknown. OBJECTIVES: To assess the temporal variation of the demographic profile, procedural characteristics, and in-hospital outcomes of patients undergoing TAVI procedures at the Rede D'Or São Luiz. METHODS: Observational registry comprising 29 national institutions, comparing the characteristics of the TAVI procedures performed from 2012 to 2017 (Group 1) to those performed from 2018 to 2023 (Group 2). The statistical significance level adopted was p < 0.05. RESULTS: This study assessed 661 patients, 95 in Group 1 and 566 in Group 2, with a mean age of 81.1 years. Group 1 patients had a higher prevalence of New York Heart Association functional class III or IV and STS risk score > 8%. In addition, they more often underwent general anesthesia, transesophageal echocardiographic monitoring, and access through femoral dissection. Group 2 patients had a higher success rate of the TAVI procedure (95.4% versus 89.5%; p = 0.018), lower mortality (3.9% versus 11.6%; p = 0.004), and less often needed permanent pacemaker implantation (8.5% versus 17.9%; p = 0.008). CONCLUSIONS: The 10-year temporal trends analysis of the TAVIDOR Registry shows a reduction in patients' clinical complexity over time. Furthermore, the advance to minimalistic implantation techniques, added to the technological evolution of the devices, may have contributed to the favorable outcomes observed among those whose implantation occurred in the last 5 years studied.

FUNDAMENTO: O implante percutâneo de bioprótese valvar aórtica (TAVI) consolidou-se como opção terapêutica da estenose aórtica de grau importante. Dados sobre as características evolutivas dos procedimentos e dos resultados obtidos com a técnica ao longo da última década, em escala nacional, são desconhecidos. OBJETIVOS: Analisar a tendência temporal referente ao perfil demográfico, características dos procedimentos e desfechos hospitalares de pacientes submetidos a TAVI na Rede D'Or São Luiz. MÉTODOS: Registro observacional envolvendo 29 instituições nacionais. Comparou-se características dos procedimentos realizados de 2012 a 2017 (Grupo 1) e de 2018 a 2023 (Grupo 2). Foram considerados significantes os resultados com valor de p < 0,05. RESULTADOS: Foram analisados 661 casos, 95 pertencentes ao Grupo 1 e 566 ao Grupo 2. A média de idade foi 81,1 anos. Observou-se no Grupo 1 maior prevalência de pacientes em classe funcional III ou IV e escore de risco > 8%. Foi mais frequente o emprego de anestesia geral, monitorização ecocardiográfica transesofágica e via de acesso por dissecção. Maior taxa de sucesso do procedimento (95,4% versus 89,5%; p = 0,018) foi aferida em implantes efetivados a partir de 2018, assim como menor mortalidade (3,9% versus 11,6%; p = 0,004) e necessidade de marcapasso definitivo (8,5% versus 17,9%; p = 0,008). CONCLUSÕES: A análise temporal de 10 anos do Registro TAVIDOR demonstra uma queda na complexidade clínica dos pacientes. Além disso, o avanço para técnicas de implante minimalistas, somadas à evolução tecnológica dos dispositivos, podem ter contribuído para desfechos favoráveis dentre aqueles cujo implante ocorreu no último quinquênio.

Avaliação das boas práticas de fabricação e da contaminação de preparações cárneas de restaurantes institucionais e comerciais na cidade de Americana, SP / Evaluation of good manufacturing practices and contamination in meat preparations from institutional and commercial restaurants in the city of Americana/SP

Diante do ritmo acelerado da vida contemporânea, observa-se um aumento na tendência dos indivíduos em optar por realizar suas refeições fora de casa. A carne, reconhecida como um componente essencial na alimentação dos brasileiros, está suscetível à contaminação pois apresenta ambiente favorável à proliferação de microrganismos patogênicos. Fazendo-se necessária uma análise de contaminação pós-produção afim de evitar Doenças Transmitidas por Alimentos. No presente estudo objetivouse avaliar as boas práticas de fabricação e contaminação de preparações de carne bovina assada, de restaurantes particulares e institucionalizados no município de Americana-SP. Amostras de carne prontas para o consumo foram obtidas de seis estabelecimentos comerciais e seis institucionais. Durante a coleta, foram verificadas as temperaturas e realizadas análises de conformidades com a RDC n° 275, de 2002. As amostras foram examinadas para detectar a presença ou ausência de E. coli e coliformes termotolerantes a 45° C. Para a análise foi realizada a técnica de tubos múltiplos para quantificar a totalidade dos coliformes. Observou-se que, conforme estipulado pela Resolução n°43 de 2015, nenhuma das amostras oriundas de restaurantes comerciais, e a maioria das provenientes de restaurantes institucionais, atingiram as temperaturas requeridas. No que concerne à identificação de E. coli através de testes microbiológicos, foi constatado que seis amostras de restaurantes comerciais e quatro de restaurantes institucionais testaram positivo para a presença deste microrganismo. Conclui-se que as amostras de restaurantes comerciais apresentaram níveis de contaminação superiores em comparação com as amostras de restaurantes institucionais.

Given the fast-paced rhythm of contemporary life, there is an increase in individuals choosing to have their meals outside the home. Meat, recognized as an essential component in the Brazilian diet, is susceptible to contamination as it provides a favorable environment for the proliferation of pathogenic microorganisms. It is necessary to conduct post-production contamination analysis to prevent Foodborne Diseases. This study aimed to evaluate the good manufacturing practices and contamination of roasted beef preparations from private and institutional restaurants in the city of Americana-SP. Samples of ready-to-eat meat were obtained from six commercial establishments and six institutional ones. During collection, temperatures were checked, and conformity analyses were conducted according to RDC No. 275, 2002. The samples were examined for the presence or absence of E. coli and thermotolerant coliforms at 45°C using the multiple tube technique to quantify the total coliforms. It was observed that, as stipulated by Resolution No. 43, 2015, none of the samples from commercial restaurants and the majority from institutional restaurants reached the required temperatures. Regarding the identification of E. coli through microbiological tests, it was found that six samples from commercial restaurants and four from institutional ones tested positive for the presence of this microorganism. It is concluded that samples from commercial restaurants showed higher contamination levels compared to institutional restaurant samples.

In silico structural features of the CgNR5A: CgDAX complex and its role in regulating gene expression of CYP target genes in Crassostrea gigas.

Contamination of aquatic environments has been steadily increasing due to human activities. The Pacific oyster Crassostrea gigas has been used as a key species in studies assessing the impacts of contaminants on human health and the aquatic biome. In this context, cytochrome P450 (CYPs) play a crucial role in xenobiotic metabolism. In vertebrates many of these CYPs are regulated by nuclear receptors (NRs) and little is known about the NRs role in C. gigas. Particularly, the CgNR5A represents a homologue of SF1 and LRH-1 found in vertebrates. Members of this group can regulate genes of CYPs involved in lipid/steroid metabolism, with their activity regulated by other NR, called as DAX-1, generating a NR complex on DNA response elements (REs). As C. gigas does not exhibit steroid biosynthesis pathways, CgNR5A may play other physiological roles. To clarify this issue, we conducted an in silico investigation of the interaction between CgNR5A and DNA to identify potential C. gigas CYP target genes. Using molecular docking and dynamics simulations of the CgNR5A on DNA molecules, we identified a monomeric interaction with extended REs. This RE was found in the promoter region of 30 CYP genes and also the NR CgDAX. When the upstream regulatory region was analyzed, CYP2C39, CYP3A11, CYP4C21, CYP7A1, CYP17A1, and CYP27C1 were mapped as the main genes regulated by CgNR5A. These identified CYPs belong to families known for their involvement in xenobiotic and lipid/steroid metabolism. Furthermore, we reconstructed a trimeric complex, previously proposed for vertebrates, with CgNR5A:CgDAX and subjected it to molecular dynamics simulations analysis. Heterotrimeric complex remained stable during the simulations, suggesting that CgDAX may modulate CgNR5A transcriptional activity. This study provides insights into the potential physiological processes involving these NRs in the regulation of CYPs associated with xenobiotic and steroid/lipid metabolism.

Effects of Intravenous Lidocaine on Quality of Recovery After Laparoscopic Bariatric Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis aimed to assess the effects of pre and intraoperative lidocaine infusion on short-term recovery quality after laparoscopic bariatric surgeries. In the search across MEDLINE, Embase, and Cochrane databases, we considered randomized controlled trials comparing intravenous lidocaine vs placebo (saline) for patients with obesity undergoing laparoscopic bariatric surgery. Seven studies (640 patients) were included. The lidocaine group had a significantly higher recovery quality score, a lower morphine consumption, and a notably reduced rate of nausea and vomiting compared with the placebo group. Additionally, Lidocaine infusion was associated with a shorter hospital stay, while no significant difference was observed in the time to bowel function recovery between both groups. In conclusion, lidocaine infusion before and during laparoscopic bariatric surgery contributes to an enhanced quality of recovery.

Efficacy and safety of microvascular decompression with or without partial sensory rhizotomy: a comprehensive meta-analysis and systematic review in treating trigeminal neuralgia.

Classical trigeminal neuralgia (TN), caused by vascular compression of the nerve root, is a severe cause of pain with a considerable impact on a patient's quality of life. While microvascular decompression (MVD) has lower recurrence rates when compared with partial sensory rhizotomy (PSR) alone, refractoriness can still be as high as 47%. We aimed to assess the efficacy and safety profile of MVD + PSR when compared to standalone MVD for TN. We searched Medline, Embase, and Web of Science following PRISMA guidelines. Eligible studies included those with ≥ 4 patients, in English, published between January 1980 and December 2023, comparing MVD vs. MVD + PSR for TN. Endpoints were pain cure, immediate post-operative pain improvement, long-term effectiveness, long-term recurrence, and complications (facial numbness, hearing loss, and intracranial bleeding). We pooled odds ratios (OR) with 95% confidence intervals with a random-effects model. I2 was used to assess heterogeneity, and sensitivity and Baujat analysis were conducted to address high heterogeneity. Eight studies were included, comprising a total of 1,338 patients, of whom 1,011 were treated with MVD and 327 with MVD + PSR. Pain cure analysis revealed a lower likelihood of pain cure in patients treated with MVD when compared to patients treated with MVD + PSR (OR = 0.30, 95% CI: 0.13 to 0.72). Immediate postoperative pain improvement assessment revealed a lower likelihood of improvement in the MVD group when compared with the MVD + PSR group (OR = 0.31, 95% CI: 0.10 to 0.95). Facial numbness assessment revealed a lower likelihood of occurrence in MVD alone when compared to MVD + PSR (OR = 0.08, 95% CI: 0.04 to 0.15). Long-term effectiveness, long-term recurrence, hearing loss, and intracranial bleeding analyses revealed no difference between both approaches. Our meta-analysis identified that MVD + PSR was superior to MVD for pain cure and immediate postoperative pain improvement for treating TN. However, MVD + PSR demonstrated a higher likelihood of facial numbness complications. Furthermore, identified that hearing loss and intracranial bleeding complications appear comparable between the two treatments, and no difference between long-term effectiveness and recurrence.

Impact of Elevated Gradients After Transcatheter Aortic Valve Implantation for Degenerated Surgical Aortic Valve Bioprostheses.

BACKGROUND: Elevated aortic valve gradients are common after transcatheter aortic valve implantation for degenerated surgical aortic valve replacement bioprostheses, but their clinical impact is uncertain. METHODS: A total of 12 122 patients who underwent transcatheter aortic valve implantation-in-surgical aortic valve replacement from November 2011 to December 2019 in the Society of Thoracic Surgery/American College of Cardiology Transvalvular Therapeutics Registry were included. The primary outcome was a composite of 1-year all-cause mortality, stroke, myocardial infarction, or valve reintervention. Secondary outcomes included 1-year all-cause mortality, readmission, and change from baseline 12-question self-administered Kansas City Cardiomyopathy Questionnaire-Overall Summary Score. Due to nonlinearity observed with restricted cubic splines analysis, a Cox regression analysis with aortic valve mean gradient modeled as a spline-continuous variable (with 20 mm Hg as a cutoff) was used to study the 1-year composite outcome and mortality. RESULTS: The composite outcome occurred most frequently in patients with aortic valve mean gradient ≥30 and <10 mm Hg, as compared with those with 10 to 20 and 20 to 30 mm Hg ranges (unadjusted rates, 13.9%, 12.1%, 7.5%, and 6.5%, respectively; P=0.002). When the mean aortic valve gradient was ≥20 mm Hg, higher gradients were associated with greater risk of the 1-year composite outcome (adjusted hazard ratio, 1.02 [1.02-1.03] per mm Hg; P<0.001) and 1-year mortality (adjusted hazard ratio, 1.02 [1.00-1.03] per mm Hg; P=0.007). Whereas when the mean aortic valve gradient was <20 mm Hg, higher gradients were not significantly associated with the composite outcome (adjusted hazard ratio, 0.99 [0.98-1.003] per mm Hg; P=0.12) but were associated with lower 1-year mortality (adjusted hazard ratio, 0.98 [0.97-0.99] per mm Hg; P=0.007). CONCLUSIONS: The relationship between postprocedural aortic valve mean gradient after transcatheter aortic valve implantation-in-surgical aortic valve replacement and clinical outcomes is complex and nonlinear, with relatively greater adverse events occurring at low and high gradient extremes. Further study of factors mediating the relationship between postprocedural gradients and clinical outcomes, including low-flow states, is necessary.

Hepatic transcriptome, transcriptional effects and antioxidant responses in Poecilia vivipara exposed to sanitary sewage.

Aquatic environments are subject to threats from multiple human activities, particularly through the release of untreated sanitary sewage into the coastal environments. These effluents contain a large group of natural or synthetic compounds referred to as emerging contaminants. Monitoring the types and quantities of toxic substances in the environment, especially complex mixtures, is an exhausting and challenging task. Integrative effect-based tools, such as biomarkers, are recommended for environmental quality monitoring programs. In this study, fish Poecilia vivipara were exposed for 24 and 96 h to raw untreated sewage diluted 33 % (v/v) in order to identify hepatic genes to be used as molecular biomarkers. Through a de novo hepatic transcriptome assembly, using Illumina MiSeq, 54,285 sequences were assembled creating a reference transcriptome for this guppy species. Transcripts involved in biotransformation systems, antioxidant defenses, ABC transporters, nuclear and xenobiotic receptors were identified and evaluated by qPCR. Sanitary sewage induced transcriptional changes in AhR, PXR, CYP2K1, CYP3A30, NQO1, UGT1A1, GSTa3, GSTmu, ST1C1, SOD, ABCC1 and SOX9 genes from liver of fish, particularly after 96 h of exposure. Changes in hepatic enzyme activities were also observed. The enzymes showed differences in fish exposed to both periods, while in the gills there was a prevalence of significant results after 96 h. The observed differences were associated to gender and/or to sewage exposure. The obtained results support the use of P. vivipara as sentinel and model organism for ecotoxicological studies and evidence the importance of understanding the differential responses associated to gender.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.

Analysis of COVID-19 Infection in Kidney Transplant Recipients.

BACKGROUND: COVID-19, caused by SARS-CoV-2, was responsible for higher morbidity and mortality in renal transplant recipients (RTx). The objective of the study was to evaluate the impact of COVID-19 infection on RTx in a single center in Brazil. METHODS: A cohort of 135 RTx was evaluated between December 2019 and June 202l, and demographics, clinical, and laboratory profiles were analyzed from deceased donors with COVID-19. RESULTS: Diabetic and RTx from extended criterion donors presented more frequently the severe form of the disease. Serum creatinine (sCr) after 3 months of diagnosis of COVID-19 varied according to the severity of infection. The lethality rate was higher in the group with severe symptoms (65%) compared with those with mild infection (1.5%). CONCLUSION: The increase in sCr was associated with disease severity. The lethality rate for COVID-19 was 26.6%. These rates are 10-20 times higher than those reported in the general population and suggest that rigorous observation, early diagnosis, and disease prevention measures are crucial in RTx.

Spinal tumor embolization with Onyx: A systematic review and meta-analysis.

INTRODUCTION: Onyx embolization has emerged as a promising technique for spinal tumor embolization due to its high devascularization rate and low incidence of complications. OBJECTIVE: Evaluate the safety and efficacy of Onyx embolization in spinal tumor procedures. METHODS: Following the PRISMA guidelines, we conducted a systematic review and meta-analysis. To be included, the articles had to report specific outcomes of Onyx embolization for spinal tumors (complications, mortality, blood loss, tumor devascularization, or reduction in tumor blush). RESULTS: We selected 11 out of 2941 articles, encompassing 127 patients. Among them, no major complications or persistent neurological deficits were reported, and no deaths occurred as a result of the embolization procedure. Of the 63 patients with available data, two complications were observed: one infarct leading to transient neurological deficit and one clinically silent vessel perforation related to the microcatheter. Thus, the complication rate was 1% (95% confidence interval (CI): 0% to 6%). Blood loss during surgery ranged from 100 to 1500 mL (four studies). Complete tumor blush reduction was achieved in 52% of the cases (95% CI: 16% to 88%) across 32 patients. Three studies reported a median percentage of tumor devascularization of 91% (86.1% to 97.5%). CONCLUSION: Onyx embolization for spinal tumor procedures appears to be a safe technique, as evidenced by the absence of major complications or deaths. However, the determination of its efficacy remains challenging due to limited data availability and substantial heterogeneity across studies. These findings highlight the need for future research to address this knowledge gap and further validate our results.

Obesity-dependent molecular alterations in fatal COVID-19: A retrospective postmortem study of metabolomic profile of adipose tissue.

We investigated the effects of obesity on metabolic, inflammatory, and oxidative stress parameters in the adipose tissue of patients with fatal COVID-19. Postmortem biopsies of subcutaneous adipose tissue were obtained from 25 unvaccinated inpatients who passed from COVID-19, stratified as nonobese (N-OB; body mass index [BMI], 26.5 ± 2.3 kg m-2) or obese (OB BMI 34.2 ± 5.1 kg m-2). Univariate and multivariate analyses revealed that body composition was responsible for most of the variations detected in the metabolome, with greater dispersion observed in the OB group. Fifteen metabolites were major segregation factors. Results from the OB group showed higher levels of creatinine, myo-inositol, O-acetylcholine, and succinate, and lower levels of sarcosine. The N-OB group showed lower levels of glutathione peroxidase activity, as well as higher content of IL-6 and adiponectin. We revealed significant changes in the metabolomic profile of the adipose tissue in fatal COVID-19 cases, with high adiposity playing a key role in these observed variations. These findings highlight the potential involvement of metabolic and inflammatory pathways, possibly dependent on hypoxia, shedding light on the impact of obesity on disease pathogenesis and suggesting avenues for further research and possible therapeutic targets.

Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Pharmacokinetics Profiler (PhaKinPro): Model Development, Validation, and Implementation as a Web Tool for Triaging Compounds with Undesired Pharmacokinetics Profiles.

Computational models that predict pharmacokinetic properties are critical to deprioritize drug candidates that emerge as hits in high-throughput screening campaigns. We collected, curated, and integrated a database of compounds tested in 12 major end points comprising over 10,000 unique molecules. We then employed these data to build and validate binary quantitative structure-activity relationship (QSAR) models. All trained models achieved a correct classification rate above 0.60 and a positive predictive value above 0.50. To illustrate their utility in drug discovery, we used these models to predict the pharmacokinetic properties for drugs in the NCATS Inxight Drugs database. In addition, we employed the developed models to predict the pharmacokinetic properties of all compounds in the DrugBank. All models described in this paper have been integrated and made publicly available via the PhaKinPro Web-portal that can be accessed at https://phakinpro.mml.unc.edu/.