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Purpose: Methylene blue (MB) has been used to increase blood pressure in patients with septic shock by acting on guanylate cyclase and nitric oxide synthase., Objective: To determine whether the administration of MB to patients in the initial phase of septic shock leads to a reduction in the use of vasopressors compared to the Control group., Methods: This was a 1:1 randomized clinical trial of two groups (MB and Control). Forty-two patients were included in the present study; 23 patients were allocated to the Control group, and 19 were randomized to the MB group. Both groups had access to standard treatment, consisting of fluid replacement, vasopressors, and antibiotic therapy. Patients received a loading dose of MB (3 mg/kg) and maintenance (0.5 mg/kg/h) for 48 h. Vasopressor doses, laboratory test results, inflammatory and anti-inflammatory cytokine levels, and hemodynamic monitoring were recorded before the infusion of MB (T1) and after 20 min (T2), 2 h (T3), 24 h (T4), 48 h after the infusion started (T5) and 24 h after weaning (T6)., Results: MB therapy was started together with the indication of vasopressin (VAS) as a second vasopressor. The MB group showed an immediate reduction in NOR dosage, an earlier reduction in VAS dosage, and higher IL-10 levels compared to the Control group., Conclusion: Early administration of MB in combination with standard treatment for septic shock might be reduce vasopressors dose. Continuous infusion of MB for 48 h was considered safe and there was no adverse events. These results highlight the potential of MB as a safe adjuvant therapeutic option in the treatment of septic shock., Clinical Trial Registration: https://clinicaltrials.gov/, identifier RBR-96584w4., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Luis-Silva, Menegueti, Peres, Sepeda, Jordani, Mestriner, Petroski-Moraes, Brito-de-Sousa, Costa-Rocha, Cruz, Donadel, de Souza, Reis, Bellissimo-Rodrigues, Basile-Filho, Becari, Evora, Martins-Filho and Auxiliadora-Martins.)

Overweight and obesity are closely linked to gut dysbiosis/dysmetabolism and disrupted De-Ritis ratio [aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio], which may contribute to chronic noncommunicable diseases onset. Concurrently, extensive research explores nutraceuticals, and health-enhancing supplements, for disease prevention or treatment. Thus, sedentary overweight volunteers were double-blind randomized into two groups: Novel Nutraceutical_(S) (without silymarin) and Novel Nutraceutical (with silymarin). Experimental formulations were orally administered twice daily over 180 consecutive days. We evaluated fecal gut microbiota, based on partial 16S rRNA sequences, biochemistry and endocrine markers, steatosis biomarker (AST/ALT ratio), and anthropometric parameters. Post-supplementation, only the Novel Nutraceutical group reduced Clostridium clostridioforme (Firmicutes), Firmicutes/Bacteroidetes ratio (F/B ratio), and De-Ritis ratio, while elevating Bacteroides caccae and Bacteroides uniformis (Bacteroidetes) in Brazilian sedentary overweight volunteers after 180 days. In summary, the results presented here allow us to suggest the gut microbiota as the action mechanism of the Novel Nutraceutical promoting metabolic hepatic recovery in obesity/overweight non-drug interventions., Competing Interests: The authors Nehmi‐Filho, V., and Otoch, J.P making part of Efeom Nutrition S.A that may in any way gain or lose financially from the publication of the manuscript, either now or in the future. The authors Freitas, J.A and Pessoa, A.F.M. received a salary from Efeom Nutrition S.A. The authors Nehmi‐Filho, V., Otoch, J.P, and Pessoa, A.F.M hold patents relating to the content of the manuscript. The authors Franco, L.A.M, Fonseca, J.V.S; Martins, R.C.R; M. Murata, M.G; Costa, S.F, Sabino, E.C; Souza, E; Santamarina, A.B, Alcântara, P.M.D, Turri, J.A.O and Costa, S.F have no competing interests., (© 2024 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Critical patients have conditions that may favor the occurrence of hospital-acquired pressure injury (HAPI). The objective of this study was to identify the incidence and factors associated with the occurrence of HAPI in patients with coronavirus disease 2019 admitted to the intensive care unit (ICU) who used the prone position. Retrospective cohort study carried out in an ICU of a tertiary university hospital. Two hundred four patients with positive real-time polymerase chain reactions were evaluated, of which 84 were placed in the prone position. All patients were sedated and submitted to invasive mechanical ventilation. Of the prone patients, 52 (62%) developed some type of HAPI during hospitalization. The main place of occurrence of HAPI was the sacral region, followed by the gluteus and thorax. Of the patients who developed HAPI, 26 (50%) had this event in places possibly associated with the prone position. The factors associated with the occurrence of HAPI in patients prone to coronavirus disease 2019 were the Braden Scale and the length of stay in the ICU. The incidence of HAPI in prone patients was extremely high (62%), which denotes the need to implement protocols in order to prevent the occurrence of these events., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Protein kinase M zeta, PKMζ, is a brain enriched kinase with a well characterized role in Long-Term Potentiation (LTP), the activity-dependent strengthening of synapses involved in long-term memory formation. However, little is known about the molecular mechanisms that maintain the tissue specificity of this kinase. Here, we characterized the epigenetic factors, mainly DNA methylation, regulating PKMζ expression in the human brain. The PRKCZ gene has an upstream promoter regulating Protein kinase C ζ (PKCζ), and an internal promoter driving PKMζ expression. A demethylated region, including a canonical CREB binding site, situated at the internal promoter was only observed in human CNS tissues. The induction of site-specific hypermethylation of this region resulted in decreased CREB1 binding and downregulation of PKMζ expression. Noteworthy, CREB binding sites were absent in the upstream promoter of PRKCZ locus, suggesting a specific mechanism for regulating PKMζ expression. These observations were validated using a system of human neuronal differentiation from induced pluripotent stem cells (iPSCs). CREB1 binding at the internal promoter was detected only in differentiated neurons, where PKMζ is expressed. The same epigenetic mechanism in the context of CREB binding site was identified in other genes involved in neuronal differentiation and LTP. Additionally, aberrant DNA hypermethylation at the internal promoter was observed in cases of Alzheimer's disease, correlating with decreased expression of PKMζ in patient brains. Altogether, we present a conserved epigenetic mechanism regulating PKMζ expression and other genes enhanced in the CNS with possible implications in neuronal differentiation and Alzheimer's disease., Competing Interests: Declaration of competing interest The authors no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rationale: Methylene blue (MB) has been used to increase blood pressure in septic shock, acting on the activity of guanylate cyclase and nitric oxide synthase., Patience Concerns: The aim of this study is to demonstrate the benefit of MB in early phase of septic shock.Diagnoses: We report 6 cases of patients with septic shock with up to 72 hours of evolution., Interventions: We used MB after fluid replacement, use of norepinephrine and vasopressin. Patients received a loading dose of MB and maintenance for 48 hours., Outcomes: All patients presented a reduction in the dose of vasopressors and lactate levels soon after the administration of the loading dose of MB, an effect that was maintained with the maintenance dose for 48 hours. Interleukin 6 and interleukin 8 were elevated at the beginning of the septic condition, with a progressive and marked reduction after the beginning of MB infusion, demonstrating a role of MB in reducing the inflammatory activity., Lessons: This case series suggests that MB used early in the treatment of septic shock may be useful in reducing vasopressor dose and lactate levels. Further studies are still required to further validate these findings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.

Introduction: Septic shock is a lethal disease responsible for a large proportion of deaths in the Intensive Care Unit (ICU), even with therapy centered on fluid resuscitation, use of vasopressors and empirical antibiotic therapy applied within the first hour of diagnosis. Considering the multifactorial pathophysiology of septic shock and the mechanism of action of vasopressors, some patients may not respond adequately, which can lead to the maintenance of vasodilatation, hypotension and increased morbidity, and mortality. This protocol aims to verify whether the use of methylene blue in septic patients with an early diagnosis can contribute to an earlier resolution of a shock compared to standard treatment., Methods and Analysis: This is a study protocol for a single-center randomized clinical trial design in an ICU of a tertiary university hospital. In this study, we intend to include 64 patients aged between 18 and 80 years with a diagnosis of septic shock, of any etiology, with up to 72 hours of evolution after volume restoration, using norepinephrine at a dose ≥0.2 μg/kg/min and vasopressin at a dose of 0.04 IU/min. After the initial approach, we will randomize patients into two groups, standard care, and standard care plus methylene blue. The sample size was calculated in order to show 30% differences in septic shock resolution between groups. The Research Ethics Committee approved the study, and all patients included will sign an informed consent form (Clinical registration: RBR-96584w4)., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Respiratory symptoms are one of COVID-19 manifestations, and the metalloproteinases (MMPs) have essential roles in the lung physiology. We sought to characterize the plasmatic levels of matrix metalloproteinase-2 and 9 (MMP-2 and MMP-9) in patients with severe COVID-19 and to investigate an association between plasma MMP-2 and MMP-9 levels and clinical outcomes and mortality. MMP-2 and MMP-9 levels in plasma from patients with COVID-19 treated in the ICU (COVID-19 group) and Control patients were measured with the zymography. The study groups were matched for age, sex, hypertension, diabetes, BMI, and obesity profile. MMP-2 levels were lower and MMP-9 levels were higher in a COVID-19 group (p < 0.0001) compared to Controls. MMP-9 levels in COVID-19 patients were not affected by comorbidity such as hypertension or obesity. MMP-2 levels were affected by hypertension (p < 0.05), but unaffected by obesity status. Notably, hypertensive COVID-19 patients had higher MMP-2 levels compared to the non-hypertensive COVID-19 group, albeit still lower than Controls (p < 0.05). No association between MMP-2 and MMP-9 plasmatic levels and corticosteroid treatment or acute kidney injury was found in COVID-19 patients. The survival analysis showed that COVID-19 mortality was associated with increased MMP-2 and MMP-9 levels. Age, hypertension, BMI, and MMP-2 and MMP-9 were better predictors of mortality during hospitalization than SAPS3 and SOFA scores at hospital admission. In conclusion, a significant association between MMP-2 and MMP-9 levels and COVID-19 was found. Notably, MMP-2 and MMP-9 levels predicted the risk of in-hospital death suggesting possible pathophysiologic and prognostic roles., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The dynamics of dengue transmission are multifactorial and involve socioeconomic, ecological, and environmental aspects, the latter being closely related to local climatic conditions that affect the vector's reproductive cycle. Climate depends in turn on tropical oceanic mechanisms such as phases of El Niño/La Niña over the Pacific. The study contributes to this discussion and reports on the correlations between the Multivariate ENSO Index (MEI) in the Pacific and the number of reported dengue cases in seven state capitals in the Brazilian Amazon from 2001 to 2012. The study also analyzes the seasonality pattern (quarterly mean values) in dengue cases throughout the region. Evidence that El Niño/La Niña causes a decrease versus increase in the local rainfall pattern is consistent with the lower versus higher number of reported dengue cases in most of the state capitals in the Amazon, a result proven by the statistically significant negative correlations seen in Manaus (Amazonas), São Luís (Maranhão), Belém (Pará) and Palmas (Tocantins). The 12-years means (2001-2012) revealed the presence of pronounced seasonality in dengue incidence in the majority of the state capitals, with sharp peaks from January to March [Rio Branco (Acre), Manaus, Belém and Palmas] and from April to June (São Luís), corresponding to 50-70% of the annual total. State capitals farther north [Boa Vista (Roraima) and Macapá (Amapá)] showed dengue reporting in all quarters of the year, with no pronounced seasonality.

Limnological characteristics of the Violão and Amendoim lakes, in the Serra dos Carajás, Amazon, were studied interannually (2013-2014). Climate data indicate anomalous conditions during the 2013 rainy period with higher rainfall and lower temperature in the beginning (November). Lake levels were influenced after the first and second hour of each rainfall, which showed a strong synchronization between seasonal fluctuation of lake levels and local weather patterns. Based on the water quality, both lakes are classified as classes "1" and "2" in the CONAMA (Conselho Nacional do Meio Ambiente) scheme and as "excellent" to "good" in the WQI (Water Quality Index) categories. However, the limnology is distinctly different between the lakes and seasons. Higher trophic state and phytoplankton productivity were observed mainly during the rainy period in Violão Lake compared to Amendoim Lake. This may be due to deposition of leached nutrients in the former, mainly total phosphorus (TP), which was probably derived from mafic soils and guano. This is consistent with the significant positive correlation between Chlorophyll-a and TP at the end of the rainy period (March-April), whereas this was not observed in the beginning (November). This could possibly be a consequence of the more intense cloud cover, and unusual high rainfall that limits nutrient availability.

Empirical orthogonal functions (EOF) and composites analysis were employed on pentad data in order to investigate the tropical atmospheric-ocean patterns over the Atlantic Ocean and the spatial-temporal characteristics of the rainfall in eastern Amazon during the peak of the rainy season (February to April). The EOF results evidenced that the Intertropical Convergence Zone (ITCZ) is the main rainfall-producing system in eastern Amazon during the rainy season. Conditions associated with the southward SST gradient in the intertropical Atlantic formed the dynamic patterns that favored the position of the ITCZ to south of the equator, thus explaining the predominance of positive precipitation anomalies in eastern Amazon, especially in the state of Maranhão and northeastern Pará during the February and April months.