High expression of PD-L1 on conventional dendritic cells in tumour-draining lymph nodes is associated with poor prognosis in oral cancer.

INTRODUCTION: Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph nodes. Early detection of lymph node metastasis via biomarkers could enhance the therapeutic strategy for OSCC. Here, we explored dendritic cells (DCs) and cytotoxic T-cells in tumour-draining lymph nodes (TDLNs) as potential biomarkers. METHOD: Dendritic cells and cytotoxic T-cells in 33 lymph nodes were analyzed with multi-parameter flow cytometry in TDLNs, regional non-TDLNs surgically excised from 12 OSCC patients, and compared to 9 lymph nodes from patients with benign conditions. RESULTS: Our results displayed a higher proportion of conventional cDC1s with immunosuppressive features in TDLN. Further, high PD-L1 expression on cDC1 in TDLNs was associated with metastasis and/or recurrent disease risk. Also, elevated levels of memory CD8+ T-cells and terminally exhausted PD-1+TCF-1-CD8+ T-cells were observed in TDLNs and non-TDLNs compared to healthy lymph nodes. CONCLUSIONS: We conclude that TDLNs contain cells that could trigger an anti-tumor adaptive response, as evidenced by activated cDC1s and progenitor-like TCF-1+ T-cells. The detection of high PDL1 expression on cDC1s was indicative of TDLN metastasis and an adverse prognosis, proposing that PD-L1 on dendritic cells in TDLN could serve as a predictive biomarker of OSCC patients with a worse prognosis.

Safety and Biodistribution of an Autologous Bone Marrow-Derived Mononuclear Cell Infusion into Renal Arteries in Patients with Focal Segmental Glomerulosclerosis: A Phase 1 Study.

Patients with focal segmental glomerulosclerosis (FSGS) who are refractory to drug treatment may present progressive loss of kidney function, leading to chronic kidney disease stage 5 under dialysis treatment. The safety of systemic administration of bone marrow-derived mononuclear cells (BMDMCs) has been shown in different preclinical models of kidney diseases. However, to date, no study has evaluated the safety and biodistribution of BMDMCs after infusion in renal arteries in patients with FSGS. We used a prospective, non-randomized, single-center longitudinal design to investigate this approach. Five patients with refractory FSGS and an estimated glomerular filtration rate (eGFR) between 20 and 40 ml/min/1.73 m2 underwent bone marrow aspiration and received an arterial infusion of autologous BMDMCs (5 × 107) for each kidney. In addition, BMDMCs labeled with technetium-99m (99mTc-BMDMCs) were used to assess the biodistribution by scintigraphy. All patients completed the 270-day follow-up protocol with no serious adverse events. A transient increase in creatinine was observed after the cell therapy, with improvement on day 30. 99mTc-BMDMCs were detected in both kidneys and counts were higher after 2 hr compared with 24 hr. The arterial infusion of BMDMCs in both kidneys of patients with FSGS was considered safe with stable eGFR at the end of follow-up. This trial is registered with NCT02693366.

Age, Renal Failure and Transfusion are Risk Predictors of Prolonged Hospital Stay after Coronary Artery Bypass Grafting Surgery. / Idade, Insuficiência Renal e Transfusão são Preditores de Risco de Longa Permanência Hospitalar após Cirurgia de Revascularização do Miocárdio.

BACKGROUND: Identifying risk factors in cardiovascular surgery assists in predictability, resulting in optimization of outcomes and cost reduction. OBJECTIVE: This study aimed to identify preoperative and intraoperative risk predictors for prolonged hospitalization after coronary artery bypass grafting (CABG) surgery in the state of São Paulo, Brazil. METHODS: A cross-sectional analysis using data from the REPLICCAR II database, a prospective, consecutive, multicenter registry that included CABG surgeries performed between August 2017 and July 2019. The primary outcome was a prolonged hospital stay (PHS), defined as a postoperative period exceeding 14 days. Univariate and multivariate logistic regression analyses were performed to identify the predictors with significance set at p <0.05. RESULTS: The median age was 63 (57-70) years and 26.55% of patients were female. Among the 3703 patients analyzed, 228 (6.16%) had a PHS after CABG, with a median hospital stay of 17 (16-20) days. Predictors of PHS after CABG included age >60 years (OR 2.05; 95% CI 1.43-2.87; p<0.001); renal failure (OR 1.73; 95% CI 1.29-2.32; p <0.001) and intraoperative red blood cell transfusion (OR 1.32; 95% CI 1.07-2.06; p=0.01). CONCLUSION: Age >60 years, renal failure, and intraoperative red blood cell transfusion were independent predictors of PHS after CABG. The identification of these variables can help in multiprofessional strategic planning aimed to enhance results and resource utilization in the state of São Paulo.

FUNDAMENTO: A identificação de fatores de riscos na cirurgia cardiovascular auxilia na previsibilidade resultando na otimização de desfechos e redução de custos. OBJETIVO: Identificação dos preditores de risco pré e intraoperatórios para internação prolongada após cirurgia de revascularização do miocárdio (CRM) no Estado de São Paulo. MÉTODOS: Análise transversal no banco de dados REPLICCAR II, registro prospectivo, consecutivo, multicêntrico que incluiu cirurgias de revascularização miocárdica realizadas entre agosto de 2017 e julho de 2019. O desfecho principal foi o tempo de internação prolongado, definida como período de pós-operatório superior a 14 (quatorze) dias. Para a identificação dos preditores foram realizadas análises de regressão logística uni- e multivariada. Os valores de p menores de 0,05 foram considerados significativos. RESULTADOS: A mediana de idade foi de 63 (57-70) anos e 26,55% eram do sexo feminino. Dos 3703 pacientes analisados, 228 (6,16%) apresentaram longa permanência hospitalar (LPH) após a CRM e a mediana da internação foi de 17 (16-20) dias. Foram preditores da LPH após a CRM: idade >60 anos (OR 2,05; IC95% 1,43 - 2,87; p<0,001); insuficiência renal (OR 1,73; IC95% 1,29 - 2,32; p<0,001) e transfusão de hemácias no intraoperatório (OR 1,32; IC 1,07 - 2,06; p=0,01). CONCLUSÃO: Nesta análise, a idade > 60 anos, insuficiência renal e a transfusão de hemácias no intraoperatório foram preditores independentes de LPH após a CRM. A identificação destas variáveis pode ajudar no planejamento estratégico multiprofissional visando melhoria de resultados e otimização de recursos no estado de São Paulo.

Lippia alba essential oil: A powerful and valuable antinociceptive and anti-inflammatory medicinal plant from Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. AIM OF THE STUDY: to evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. MATERIAL AND METHODS: Lippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. RESULTS: The constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). CONCLUSION: Lippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Analysis of Genes Involved in Oxidative Stress and Iron Metabolism in Heart Failure: A Step Forward in Risk Stratification.

INTRODUCTION: Heart failure (HF) is a clinical syndrome characterized by cardinal symptoms that may be accompanied by signs. It results from structural and/or functional abnormalities of the heart leading to elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. The prevalence of iron deficiency and anemia justifies the current guidelines recommendation of screening. Genes HP, ACE, MTHFR, HFE, and CYBA are involved in oxidative mechanisms, iron metabolism, and hematologic homeostasis. This study investigates the contribution of variants Hp1/2 (HP), I/D (ACE), C677T (MTHFR), C282Y and H63D (HFE), and C242T (CYBA) to the development of HF, either independently or in epistasis. METHODS: We used a database of 389 individuals, 143 HF patients, and 246 healthy controls. Genotypes were characterized through PAGE electrophoresis, PCR, PCR-RFLP, and multiplex-ARMS. Data analysis was performed with the SPSS® 26.0 software (IBM Corp., Armonk, NY). RESULTS: We observed a significant association between the MTHFR gene and HF predisposition. The presence of allele T and genotype CT constituted risk, while genotype CC granted protection. Epistatic interactions revealed risk between genotype II of the ACE gene and genotypes CC (C282Y) or HH (H63D) of the HFE gene. Risk was also observed for interactions between genotype CC (CYBA)and genotypes 2-2 (HP), CT (MTHFR), or HH (HFE-H63D). CONCLUSION: We concluded that genes HP, ACE, MTHFR, HFE, and CYBA contribute to the susceptibility for HF, individually or in epistasis. This study contributes to the clarification of the role that genes involved in oxidative mechanisms and iron metabolism play in the physiopathology of HF. It is, therefore, a step forward in risk stratification and personalized medicine.

Dual excitation spectral autofluorescence lifetime and reflectance imaging for fast macroscopic characterization of tissues.

Advancements in optical imaging techniques have revolutionized the field of biomedical research, allowing for the comprehensive characterization of tissues and their underlying biological processes. Yet, there is still a lack of tools to provide quantitative and objective characterization of tissues that can aid clinical assessment in vivo to enhance diagnostic and therapeutic interventions. Here, we present a clinically viable fiber-based imaging system combining time-resolved spectrofluorimetry and reflectance spectroscopy to achieve fast multiparametric macroscopic characterization of tissues. An essential feature of the setup is its ability to perform dual wavelength excitation in combination with recording time-resolved fluorescence data in several spectral intervals. Initial validation of this bimodal system was carried out in freshly resected human colorectal cancer specimens, where we demonstrated the ability of the system to differentiate normal from malignant tissues based on their autofluorescence and reflectance properties. To further highlight the complementarity of autofluorescence and reflectance measurements and demonstrate viability in a clinically relevant scenario, we also collected in vivo data from the skin of a volunteer. Altogether, integration of these modalities in a single platform can offer multidimensional characterization of tissues, thus facilitating a deeper understanding of biological processes and potentially advancing diagnostic and therapeutic approaches in various medical applications.

Scissor-assisted vs. conventional endoscopic submucosal dissection for colorectal lesions: Systematic review and meta-analysis.

OBJECTIVES: Colorectal endoscopic submucosal dissection (ESD) is a technically complex procedure. The scissor knife mechanism may potentially provide easier and safer colorectal ESD. The aim of this meta-analysis is to evaluate the efficacy and safety of scissor-assisted vs. conventional ESD for colorectal lesions. METHODS: A search strategy was conducted in MEDLINE, Embase, and Lilacs databases from January 1990 to November 2023 according to PRISMA guidelines. Fixed and random-effects models were used for statistical analysis. Heterogeneity was assessed using I2 test. Risk of bias was assessed using the ROBINS-I and RoB-2 tools. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. RESULTS: A total of five studies (three retrospective and two randomized controlled trials, including a total of 1575 colorectal ESD) were selected. The intraoperative perforation rate was statistically lower (risk difference [RD] -0.02; 95% confidence interval [CI] -0.04 to -0.01; P = 0.001; I2 = 0%) and the self-completion rate was statistically higher (RD 0.14; 95% CI 0.06, 0.23; P = 0.0006; I2 = 0%) in the scissor-assisted group compared with the conventional ESD group. There was no statistical difference in R0 resection rate, en bloc resection rate, mean procedure time, or delayed bleeding rate between the groups. CONCLUSION: Scissor knife-assisted ESD is as effective as conventional knife-assisted ESD for colorectal lesions with lower intraoperative perforation rate and a higher self-completion rate.

Lipectomia e lipoaspiração seriadas para manejo de síndrome de Madelung: A respeito de um caso / Serial lipectomy and liposuction for management of Madelung syndrome: About a case

A doença de Madelung é caracterizada pelo acúmulo simétrico e difuso de tecido adiposo com crescimento tumoral lento e progressivo. Neste relato de caso, um paciente portador dessa síndrome foi atendido no Hospital das Clínicas, em Recife, PE, com o objetivo de realizar uma redução do conteúdo lipomatoso através de lipectomia. O paciente apresentava volumosas massas de tecido adiposo elástico ao redor do pescoço e região supraclavicular e a proposta terapêutica consistiu em uma cirurgia em dois tempos, com lipoaspiração e lipectomia cervical anterior, seguida de lipoaspiração e lipectomia cervical posterior. Antes da cirurgia, foi solicitado um parecer cardiológico, que indicou um risco intermediário, mas não contraindicou o procedimento. Após 4 dias da cirurgia, o paciente apresentou equimoses e edema periférico na ferida operatória cervical, porém estava assintomático. As técnicas de lipectomia e lipoaspiração são consideradas os métodos de tratamento mais eficazes para a doença de Madelung. No entanto, a escolha da cirurgia deve ser baseada em uma avaliação abrangente da gravidade da doença, localização da massa e expectativas do paciente, uma vez que ambas as técnicas possuem vantagens e desvantagens.

Madelung's disease is characterized by the symmetric and diffuse accumulation of adipose tissue with slow and progressive tumor growth. In this case report, a patient with this syndrome was treated at Hospital das Clínicas, in Recife, PE, to reduce the lipomatous content through a lipectomy. The patient presented large masses of elastic adipose tissue around the neck and supraclavicular region and the therapeutic proposal consisted of a two-stage surgery, with liposuction and anterior cervical lipectomy, followed by liposuction and posterior cervical lipectomy. Before surgery, a cardiological opinion was requested, which indicated an intermediate risk but did not contraindicate the procedure. Four days after surgery, the patient presented bruises and peripheral edema in the cervical surgical wound but was asymptomatic. Lipectomy and liposuction techniques are considered the most effective treatment methods for Madelung disease. However, the choice of surgery should be based on a comprehensive assessment of the severity of the disease, location of the mass, and patient expectations, as both techniques have advantages and disadvantages.

Minimally Invasive Treatment for Lumbar Disc Herniation: A Matched Comparison Between Tubular Microdiscectomy and Percutaneous Endoscopic Lumbar Discectomy.

Background and objectives Discectomy for lumbar disc herniation is the most common spinal surgical procedure. Technological advances have led to the emergence of minimally invasive surgical approaches such as tubular microdiscectomy (TMD) and percutaneous endoscopic lumbar discectomy (PELD). The purpose of this study was to compare the clinical outcomes of PELD to those of TMD at one-year follow-up. Materials and methods This observational registry-based (Spine Tango) cohort study included patients with symptomatic lumbar disc herniation submitted to PELD or TMD. The inclusion criteria were patients who underwent minimally invasive lumbar discectomy (PELD or TMD), patients who attended a follow-up after a minimum of 12 months post surgery, and valid pre- and postoperative questionaries. The primary endpoint was defined as the difference between pre- and postoperative Core Outcome Measures Index (COMI) for the back. The matching was based on a 1:1 nearest neighbor matching without replacement. Results A total of 109 patients were included in this study. Propensity score matching (PSM) was performed achieving 86 patients in the matched sample. Regarding COMI improvement, we found no significant difference between the PELD and TMD groups (paired t-test: estimate, -0.23; standard error, 0.6; p=0.7), and we also did not find any significant difference between groups concerning Oswestry Disability Index (ODI) and EuroQol 5 Dimension (EQ-5D). Medication usage and return to work were similar among the matched groups. Conclusions PELD is a technique that minimizes tissue damage achieving good clinical outcomes similar to TMD. This was observed one year after surgery from patient-reported outcome measures (PROMs) that measured pain improvement, disability, and quality of life.

Individualized positive end-expiratory pressure reduces driving pressure in obese patients during laparoscopic surgery under pneumoperitoneum: a randomized clinical trial.

Introduction: During pneumoperitoneum (PNP), airway driving pressure (ΔPRS) increases due to the stiffness of the chest wall and cephalic shift of the diaphragm, which favors atelectasis. In addition, depending on the mechanical power (MP) formulas, they may lead to different interpretations. Methods: Patients >18 years of age with body mass index >35 kg/m2 were included in a single-center randomized controlled trial during their admission for bariatric surgery by abdominal laparoscopy. Intra-abdominal pressure was set at 15 mmHg at the pneumoperitoneum time point (PNP). After the recruitment maneuver, the lowest respiratory system elastance (ERS) was detected during the positive end-expiratory pressure (PEEP) step-wise decrement. Patients were randomized to the 1) CTRL group: ventilated with PEEP of 5 cmH2O and 2) PEEPIND group: ventilated with PEEP value associated with ERS that is 5% higher than its lowest level. Respiratory system mechanics and mean arterial pressure (MAP) were assessed at the PNP, 5 min after randomization (T1), and at the end of the ventilation protocol (T2); arterial blood gas was assessed at PNP and T2. ΔPRS was the primary outcome. Three MP formulas were used: MPA, which computes static PEEP × volume, elastic, and resistive components; MPB, which computes only the elastic component; and MPC, which computes static PEEP × volume, elastic, and resistive components without inspiratory holds. Results: Twenty-eight patients were assessed for eligibility: eight were not included and 20 patients were randomized and allocated to CTRL and PEEPIND groups (n = 10/group). The PEEPIND ventilator strategy reduced ΔPRS when compared with the CTRL group (PEEPIND, 13 ± 2 cmH2O; CTRL, 22 ± 4 cmH2O; p < 0.001). Oxygenation improved in the PEEPIND group when compared with the CTRL group (p = 0.029), whereas MAP was comparable between the PEEPIND and CTRL groups. At the end of surgery, MPA and MPB were correlated in both the CTRL (rho = 0.71, p = 0.019) and PEEPIND (rho = 0.84, p = 0.020) groups but showed different bias (CTRL, -1.9 J/min; PEEPIND, +10.0 J/min). At the end of the surgery, MPA and MPC were correlated in both the CTRL (rho = 0.71, p = 0.019) and PEEPIND (rho = 0.84, p = 0.020) groups but showed different bias (CTRL, -1.9 J/min; PEEPIND, +10.0 J/min). Conclusion: Individualized PEEP was associated with a reduction in ΔPRS and an improvement in oxygenation with comparable MAP. The MP, which solely computes the elastic component, better reflected the improvement in ΔPRS observed in the individualized PEEP group. Clinical Trial Registration: The protocol was registered at the Brazilian Registry of Clinical Trials (U1111-1220-7296).

Toll like receptor 4 mediates the inhibitory effect of SARS-CoV-2 spike protein on proximal tubule albumin endocytosis.

Tubular proteinuria is a common feature in COVID-19 patients, even in the absence of established acute kidney injury. SARS-CoV-2 spike protein (S protein) was shown to inhibit megalin-mediated albumin endocytosis in proximal tubule epithelial cells (PTECs). Angiotensin-converting enzyme type 2 (ACE2) was not directly involved. Since Toll-like receptor 4 (TLR4) mediates S protein effects in various cell types, we hypothesized that TLR4 could be participating in the inhibition of PTECs albumin endocytosis elicited by S protein. Two different models of PTECs were used: porcine proximal tubule cells (LLC-PK1) and human embryonic kidney cells (HEK-293). S protein reduced Akt activity by specifically inhibiting of threonine 308 (Thr308) phosphorylation, a process mediated by phosphoinositide-dependent kinase 1 (PDK1). GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect. S protein did not change total TLR4 expression but decreased its surface expression. LPS-RS, a TLR4 antagonist, also counteracted the effects of the S protein on Akt phosphorylation at Thr308, albumin endocytosis, and megalin expression. Conversely, these effects of the S protein were replicated by LPS, an agonist of TLR4. Incubation of PTECs with a pseudovirus containing S protein inhibited albumin endocytosis. Null or VSV-G pseudovirus, used as control, had no effect. LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression.

Binding Evolution of the Dengue Virus Envelope Against DC-SIGN: A Combined Approach of Phylogenetics and Molecular Dynamics Analyses Over 30 Years of Dengue Virus in Brazil.

The Red Queen Hypothesis (RQH), derived from Lewis Carroll's "Through the Looking-Glass", postulates that organisms must continually adapt in response to each other to maintain relative fitness. Within the context of host-pathogen interactions, the RQH implies an evolutionary arms race, wherein viruses evolve to exploit hosts and hosts evolve to resist viral invasion. This study delves into the dynamics of the RQH in the context of virus-cell interactions, specifically focusing on virus receptors and cell receptors. We observed multiple virus-host systems and noted patterns of co-evolution. As viruses evolved receptor-binding proteins to effectively engage with cell receptors, cells countered by altering their receptor genes. This ongoing mutual adaptation cycle has influenced the molecular intricacies of receptor-ligand interactions. Our data supports the RQH as a driving force behind the diversification and specialization of both viral and host cell receptors. Understanding this co-evolutionary dance offers insights into the unpredictability of emerging viral diseases and potential therapeutic interventions. Future research is crucial to dissect the nuanced molecular changes and the broader ecological consequences of this ever-evolving battle. Here, we combine phylogenetic inferences, structural modeling, and molecular dynamics analyses to describe the epidemiological characteristics of major Brazilian DENV strains that circulated from 1990 to 2022 from a combined perspective, thus providing us with a more detailed picture on the dynamics of such interactions over time.

Ruptured Intracranial Aneurysm in a 60-Day-Old Infant: An Extreme Case.

The prevalence of aneurysms in children is low when compared to adults, being even rarer in the first year of life. They can be secondary to infections, traumatic brain injury, autoimmune diseases, or connective tissue diseases. Dissecting etiology is rare. A 60-day-old female infant, previously healthy, presented to the emergency department (ED) with irritability and loss of appetite since the preceding day, a fever of one-hour duration, and vomiting. Laboratory analysis revealed a hemoglobin level of 6.5 g/dL, without elevation of inflammatory markers. In the ED, she experienced two episodes, with a one-hour interval, of clonic movements of the upper eyelid and right upper limb, along with conjugate gaze deviation to the same side, which resolved after intravenous diazepam. Levetiracetam was initiated after the second episode. The anterior fontanelle became progressively tense. Brain computed tomography (CT) showed a voluminous intraparenchymal and subarachnoid hemorrhage with an aneurysm at the bifurcation of the left middle cerebral artery (MCA). Initially, an endovascular approach was tried but was not successful due to technical problems. Consequently, a Vaso-CT scan was performed that confirmed a dissecting aneurysm/pseudoaneurysm (8 mm × 10 mm × 10 mm) of the left MCA, originating from the upper wall of the M1 segment. Next, she underwent microsurgical exclusion of the aneurysm using microclips. Post-surgery brain CT showed acute ischemia in the entire MCA region. Follow-up angiography showed complete exclusion of the aneurysm. She evolved to grade 3 monoparesis of the upper limb at the six-month interval follow-up, which has been gradually improving with physical rehabilitation. The next-generation sequencing (NGS) panel for aneurysms and arterial dissections did not detect any pathogenic variants. Clinical presentation of cerebral aneurysms in infants can be subtle, and a high index of suspicion is required in cases of irritability, altered consciousness, seizures, bulging fontanelle, and motor deficits. Early detection is of utmost importance as it is associated with moderate mortality. Surgical treatment with the use of clips proved to be effective in this case.

Structural Characterization and Rat Aortic Vascular Reactivity of Bradykinin-Potentiating Peptides (BPPs) from the Snake Venom of Bothrops moojeni from Delta do Parnaíba Region, Brazil.

Snake venoms contain various bradykinin-potentiating peptides (BPPs). First studied for their vasorelaxant properties due to angiotensin converting enzyme (ACE) inhibition, these molecules present a range of binding partners, among them the argininosuccinate synthase (AsS) enzyme. This has renewed interest in their characterization from biological sources and the evaluation of their pharmacological activities. In the present work, the low molecular weight fraction of Bothrops moojeni venom was obtained and BPPs were characterized by mass spectrometry. Eleven BPPs or related peptides were sequenced, and one of them, BPP-Bm01, was new. Interestingly, some oxidized BPPs were detected. The three most abundant peptides were BPP-Bm01, BPP-Bax12, and BPP-13a, and their putative interactions with the AsS enzyme were investigated in silico. A binding cavity for these molecules was predicted, and docking studies allowed their ranking. Three peptides were synthesized and submitted to vasorelaxation assays using rat aortic rings. While all BPPs were active, BPP-Bm01 showed the highest potency in this assay. This work adds further diversity to BPPs from snake venoms and suggests, for the first time, a putative binding pocket for these molecules in the AsS enzyme. This can guide the design of new and more potent AsS activators.

Cellular energy regulates mRNA degradation in a codon-specific manner.

Codon optimality is a major determinant of mRNA translation and degradation rates. However, whether and through which mechanisms its effects are regulated remains poorly understood. Here we show that codon optimality associates with up to 2-fold change in mRNA stability variations between human tissues, and that its effect is attenuated in tissues with high energy metabolism and amplifies with age. Mathematical modeling and perturbation data through oxygen deprivation and ATP synthesis inhibition reveal that cellular energy variations non-uniformly alter the effect of codon usage. This new mode of codon effect regulation, independent of tRNA regulation, provides a fundamental mechanistic link between cellular energy metabolism and eukaryotic gene expression.

Identification of Peptides in Spider Venom Using Mass Spectrometry.

Spider venoms are composed of hundreds of proteins and peptides. Several of these venom toxins are cysteine-rich peptides in the mass range of 3-9 kDa. Small peptides (<3 kDa) can be fully characterized by mass spectrometry analysis, while proteins are generally identified by the bottom-up approach in which proteins are first digested with trypsin to generate shorter peptides for MS/MS characterization. In general, it is sufficient for protein identification to sequence two or more peptides, but for venom peptidomics it is desirable to completely elucidate peptide sequences and the number of disulfide bonds in the molecules. In this chapter, we describe a methodology to completely sequence and determine the number of disulfide bonds of spider venom peptides in the mass range of 3-9 kDa by multiple enzyme digestion, mass spectrometry of native and digested peptides, de novo analysis, and sequence overlap alignment.

Data-driven coaching to improve statewide outcomes in CABG: before and after interventional study.

BACKGROUND: The impact of quality improvement initiatives program (QIP) on coronary artery bypass grafting surgery (CABG) remains scarce, despite improved outcomes in other surgical areas. This study aims to evaluate the impact of a package of QIP on mortality rates among patients undergoing CABG. MATERIALS AND METHODS: This prospective cohort study utilized data from the multicenter database Registro Paulista de Cirurgia Cardiovascular II (REPLICCAR II), spanning from July 2017 to June 2019. Data from 4018 isolated CABG adult patients were collected and analyzed in three phases: before-implementation, implementation, and after-implementation of the intervention (which comprised QIP training for the hospital team). Propensity Score Matching was used to balance the groups of 2170 patients each for a comparative analysis of the following outcomes: reoperation, deep sternal wound infection/mediastinitis ≤30 days, cerebrovascular accident, acute kidney injury, ventilation time >24 h, length of stay <6 days, length of stay >14 days, morbidity and mortality, and operative mortality. A multiple regression model was constructed to predict mortality outcomes. RESULTS: Following implementation, there was a significant reduction of operative mortality (61.7%, P =0.046), as well as deep sternal wound infection/mediastinitis ( P <0.001), sepsis ( P =0.002), ventilation time in hours ( P <0.001), prolonged ventilation time ( P =0.009), postoperative peak blood glucose ( P <0.001), total length of hospital stay ( P <0.001). Additionally, there was a greater use of arterial grafts, including internal thoracic ( P <0.001) and radial ( P =0.038), along with a higher rate of skeletonized dissection of the internal thoracic artery. CONCLUSIONS: QIP was associated with a 61.7% reduction in operative mortality following CABG. Although not all complications exhibited a decline, the reduction in mortality suggests a possible decrease in failure to rescue during the after-implementation period.

Exploring the impact of seasonal variations on the chemical composition, antinociceptive, and anti-inflammatory properties of Pogostemon heyneanus Benth. essential oil.

Background: Pogostemon heyneanus leaves infusions are relevant in ethnopharmacology for treating colds, coughs, headaches, and asthma. Purpose: The essential oil chemical composition of a Pogostemon heyneanus specimen was monthly monitored from October 2021 to July 2022 to evaluate the climatic influences on its yield and chemical composition and antinociceptive, andanti-inflammatory properties. Methods: The leaves, collected monthly over a 10-month period, were submitted to hydrodistillation. The oils obtained were analyzed by gas chromatography coupled to a mass spectrometer and gas chromatography coupled to flame ionization detector. The P. heyneanus essential oil (PhEO) was tested in vivo to evaluate its peripheral analgesic actions through the abdominal writhing test induced by acetic acid, and peripheral analgesia by tail immersion. Neurogenic and inflammatory pain were evaluated by formalin test, and acute oral toxicity of the oil was also verified. Results: PhEO presented 27 chemical constituents with the highest predominance of patchoulol (43.6%-76.9%), α-bulnesene (0.2%-12.7%), α-guaiene (0.4%-8.9%), seychellene (3.8%-5.1%) and pogostol (0.0%-8.2%). The climatic parameters insolation, humidity, rainfall, and temperature did not influence the essential oil yield or the main chemical constituents, except for pogostol, which presented a strong (r = 0.73) and statistically significant (p < 0.05) correlation with temperature. PhEO did not display toxicity at the maximum 300 mg/kg dosage. The oil showed low peripheral and central analgesic action at 100 mg/kg, while in the neurogenic and inflammatory pain inhibition tests, no actions related to PhEO were observed. In the carrageenan-induced peritonitis test, PhEO did not reduce the migration of leukocytes to the peritoneal cavity compared to the control group. Conclusion: Pogostemon heyneanus is a resistant plant to seasonal influences and a source of patchoulol. Despite ethnopharmacological indications, no in-vivo biological activities such as neurogenic or inflammatory pain were identified in the present work. So, the low influence of the climatic parameters on chemical composition can infer that the low pharmacological activity is also not subject to climatic variations, that is, it does not change due to the climate.