Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15% of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18c and 18d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.

Characterization of mRNA therapeutics.

Therapeutic messenger RNAs (mRNAs) have emerged as powerful tools in the treatment of complex diseases, especially for conditions that lack efficacious treatment. The successful application of this modality can be attributed to its ability to encode entire proteins. While the large nature of these molecules has supported their success as therapeutics, its extended size creates several analytical challenges. To further support therapeutic mRNA development and its deployment in clinical trials, appropriate methods to support their characterization must be developed. In this review, we describe current analytical methods that have been used in the characterization of RNA quality, identity, and integrity. Advantages and limitations from several analytical techniques ranging from gel electrophoresis to liquid chromatography-mass spectrometry and from shotgun sequencing to intact mass measurements are discussed. We comprehensively describe the application of analytical methods in the measurements of capping efficiency, poly A tail analysis, as well as their applicability in stability studies.

Detailed characterization of iron-rich tailings after the Fundão dam failure, Brazil, with inclusion of proximal sensors data, as a secure basis for environmental and agricultural restoration.

Following the Fundão dam failure in Brazil, 60 million m3 of iron-rich tailings were released impacting an extensive area. After this catastrophe, a detailed characterization and monitoring of iron-rich tailings is required for agronomic and environmental purposes. This can be facilitated by using proximal sensors which have been an efficient, fast, and cost-effective tool for eco-friendly analysis of soils and sediments. This work hypothesized that portable X-ray fluorescence (pXRF) spectrometry combined with a pocket-sized (Nix™ Pro) color sensor and benchtop magnetic susceptibilimeter can produce substantial data for fast and clean characterization of iron-rich tailings. The objectives were to differentiate impacted and non-impacted areas (soils and sediments) based on proximal sensors data, and to predict attributes of agronomic and environmental importance. A total of 148 composite samples were collected on totally impacted, partially impacted, and non-impacted areas (natural soils). The samples were analyzed via pXRF to obtain the total elemental composition; via Nix™ Pro color sensor to obtain the red (R), green (G), and blue (B) parameters; and assessed for magnetic susceptibility (MS). The same samples used for analyses via the aforementioned sensors were wet-digested (USEPA 3051a method) followed by ICP-OES quantification of potentially toxic elements. Principal component analysis was performed to differentiate impacted and non-impacted areas. The pXRF data alone or combined with other sensors were used to predict soil agronomic properties and semi-total concentration of potentially toxic elements via random forest regression. For that, samples were randomly separated into modeling (70%) and validation (30%) datasets. The pXRF proved to be an efficient method for rapid and eco-friendly characterization of iron-rich tailings, allowing a clear differentiation of impacted and non-impacted areas. Also, important soil agronomic properties (clay, cation exchange capacity, soil organic carbon, pH and macronutrients availability) and semi-total concentrations of Ba, Pb, Cr, V, Cu, Co, Ni, Mn, Ti, and Li were accurately predicted (based upon the lowest RMSE and highest R2 and RPD values). Sensor data fusion (pXRF + Nix Pro + MS) slightly improved the accuracy of predictions. This work highlights iron-rich tailings from the Fundão dam failure can be in detail characterized via pXRF ex situ, providing a secure basis for complementary studies in situ aiming at identify contaminated hot spots, digital mapping of soil and properties variability, and embasing pedological, agricultural and environmental purposes.

Antisense Oligonucleotide In Vitro Protein Binding Determination in Plasma, Brain, and Cerebral Spinal Fluid Using Hybridization LC-MS/MS.

The development of quantitative models for prediction of drug pharmacokinetics based on in vitro data has transformed early drug discovery. Drug unbound fraction (ƒu) characterization is a key consideration in pharmacokinetic and pharmacodynamic (PK/PD) modeling, assuming only unbound drug can interact with the target, and therefore has direct implications in the efficacy and potential toxicity of the drug. The current study describes the implementation of a hybridization liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform for the direct quantitation of antisense oligonucleotide (ASO) ƒu The method provides substantial improvements, including minimal matrix effects and high specificity when compared with previously used oligonucleotide ƒu detection methods such as ligand binding assays or liquid scintillation. The hybridization LC-MS/MS platform was integrated with ultracentrifugation, ultrafiltration, and equilibrium dialysis, and method performance for each technique was evaluated. Although ASO protein binding has been previously characterized in plasma, there were no studies that quantitated ASO ƒu in brain or cerebral spinal fluid (CSF). As ASOs continue to undergo clinical trials for neurologic and neuromuscular indications, ƒu characterization in brain and CSF can provide invaluable information about ASO distribution and target engagement in the central nervous system, therefore providing support for in vivo PK/PD data characterization. SIGNIFICANCE STATEMENT: A novel hybridization LC-MS/MS-based approach was successfully developed for the determination of ASO in vitro protein binding in plasma, and for the first time brain and CSF. Ultrafiltration, equilibrium dialysis, and ultracentrifugation were assessed for the separation of unbound ASO from biological matrices. The hybridization LC-MS/MS platform provided unique advantages, including minimal matrix effects and high specificity, compared with traditional ligand binding assays or liquid scintillation approaches, which enabled efficient and reliable in vitro protein binding assay.

Analysis of Cardiovascular Hemodynamic and Autonomic Variables in Individuals with Systemic Arterial Hypertension, Type 2 Diabetes Mellitus, and Parkinson's Disease: A Comparative Study.

BACKGROUND: Systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2DM), and Parkinson's disease (PD) are highly prevalent chronic diseases that can significantly impact the cardiovascular system. AIM: The aim of this study was to compare hemodynamic and autonomic variables at rest in individuals with SAH, T2DM, or PD. METHODS: Fifty sedentary or insufficiently active individuals (22 men) with SAH (age = 66 ± 5.0 yr), T2DM (age = 52 ± 10 yr) or PD (age = 68 ± 8.0 yr) had their resting blood pressure (BP), arterial stiffness, endothelial function, and heart rate variability (HRV) assessed and compared. RESULTS: Systolic and diastolic BP were higher in SAH (130 ± 10 / 80 ± 10 mmHg) than T2DM (110 ± 14 / 75 ± 11 mmHg) and PD, and (123 ± 20 / 70 ± 11 mmHg) respectively. T2DM individuals showed lower arterial stiffness (8.4 ± 1.1 m/s), when compared to SAH (10.3 ± 2.3 m/s) and PD (10.6 ± 3.0 m/s). T2DM had greater resting tachycardia showed by the mean RR (759 ± 79 ms), than SAH (962 ± 169 ms) and PD (976 ± 134 ms), which was accompanied by higher sympathetic modulation (low frequency [LF]: 62 ± 19 nu) and lower parasympathetic modulation (high frequency [HF]: 32 ± 16 nu) when compared to SAH (LF: 40 ± 16 nu; HF: 61 ± 33 nu). No differences among groups were found on non-linear HRV markers and endothelial reactivity indexes. CONCLUSIONS: Individuals with T2DM showed impaired levels of cardiac autonomic markers when compared to individuals with SAH and PD, despite of having lower levels of BP and arterial stiffness.

Acute high-intensity interval exercise versus moderate-intensity continuous exercise in heated water-based on hemodynamic, cardiac autonomic, and vascular responses in older individuals with hypertension.

OBJECTIVES: This crossover study design aimed to assess hemodynamic, cardiac autonomic, and vascular responses to high-intensity interval (HIIE) vs moderate-intensity continuous exercise (MICE) in older individuals with hypertension. METHODS: Twenty (67 ± 7 y) older individuals with hypertension were randomly assigned to perform HIIE, MICE, or control (CON) sessions in the heated swimming pool (30-32°C). Blood pressure (BP), arterial stiffness, endothelial reactivity, and heart rate variability (HRV) were measured pre, post, and 45 min (recovery) after each intervention followed by 24-h ambulatory BP and HRV. RESULTS: One single aerobic exercise session was not effective to provoke post-exercise hypotension and vascular improvements. HIIE was superior to MICE and CON to increasing parasympathetic modulation at post and recovery. Exercise sessions showed to disturb the autonomic system at nighttime compared to CON. CONCLUSIONS: These results may have important implications in water-based therapy and the elderly with hypertension.

Physical Activity is Associated With Lower Arterial Stiffness in Patients With Resistant Hypertension.

BACKGROUND: Physical activity is associated with reduced arterial stiffness, although such a relationship has not been reported in those with resistant hypertension. Therefore, this study aimed to determine the association between daily physical activity and arterial stiffness in patients with resistant hypertension. METHODS: Fifty-seven (57) patients with resistant hypertension (50.9% men), aged 58.8±9.4 years, were consecutively recruited. Arterial stiffness was evaluated using carotid-femoral pulse wave velocity (cf-PWV). Daily physical activity was objectively assessed with accelerometers during 7 consecutive days. RESULTS: Patients had a body mass index of 29.0±4.0 kg/m2 (84.3% overweight/obese) and were taking an average 4.5 antihypertensive medications. Overall, the cf-PWV was 9.2±2.4 m/s and the majority of participants (n=41, 71.9%) presented a cf-PWV <10 m/s. The cf-PWV showed an inverse correlation with light-intensity physical activity (r = -0.290, p=0.029) and total daily physical activity (r = -0.287, p=0.030). The correlation between light physical activity and cf-PWV remained significant after adjustment for systolic and diastolic blood pressure, but lost significance when further adjusted for age. CONCLUSIONS: Higher daily levels of light-intensity and total physical activity were associated with lower arterial stiffness. Nonetheless, this association is weak and attenuated or abolished when adjusted for blood pressure and age. These results suggest that physical activity may play an important role as a lifestyle intervention for patients with resistant hypertension. Future studies with larger samples sizes are necessary to confirm this preliminary data.

Hypotensive Effect of Heated Water-based Exercise in Older Individuals with Hypertension.

Blood pressure (BP) and hemodynamic response to heated water-based (HEx) vs. land-based exercise (LEx) were assessed in 15 (6 men) older hypertensives (age 66.4±4.9 yr) under pharmacological treatment. Participants were randomly assigned to perform 30 min of moderate-intensity HEx (walking inside the pool), LEx (walking on a treadmill) and non-exercise control (CON) intervention. Resting BP, arterial stiffness, endothelial reactivity and heart rate variability (HRV) were measured before, immediately after, and 45 min after interventions. 24-h ambulatory BP monitoring was performed after interventions. Resting systolic (but not diastolic) BP reduced 9.9±3.1 mmHg (P<0.01) 45 min after HEx only. 24-h systolic and diastolic, daytime diastolic and nightime systolic BP were lower (P<0.05) after HEx than both LEx and CON. Daytime systolic BP was also lower (P<0.05) after HEx than CON. Nighttime diastolic was not different between interventions. HEx-induced ambulatory BP reduction ranged 4.5±1.3 mmHg (24-h diastolic BP) to 9.5±3.0 mmHg (nighttime systolic BP), and persisted for 18/11 h in systolic/diastolic BP, when compared with CON. No significant changes in arterial stiffness, endothelial reactivity and HRV were found during any intervention. These results suggest that HEx may have important implications for managing BP in older hypertensive under pharmacological treatment.

Neurohumoral and Endothelial Responses to Heated Water-Based Exercise in Resistant Hypertensive Patients.

BACKGROUND: The neurohumoral and endothelial responses to the blood pressure (BP) lowering effects of heated water-based exercise (HEx) in resistant hypertension (HT) patients remain undefined.Methods and Results:We investigated these in 44 true resistant HT patients (age 53.3±0.9 years, mean±SEM). They were randomized and allocated to 2 groups, 28 to a HEx training protocol, which consisted of callisthenic exercises and walking in a heated pool for 1 h, three times weekly for 12 weeks and 16 patients to a control group maintaining their habitual activities. Measurements made before and after 12 weeks of HEx included clinic and 24-h BP, plasma levels of nitric oxide, endothelin-1, aldosterone, renin, norepinephrine and epinephrine, as well as peak V̇O2, and endothelial function (reactive hyperemia). After 12 weeks of HEx patients showed a significant decrease in clinic and 24-h systolic and diastolic BPs. Concomitantly, nitric oxide increased significantly (from 25±8 to 75±24 µmol/L, P<0.01), while endothelin-1 (from 41±5 to 26±3 pg/mL), renin (from 35±4 to 3.4±1 ng/mL/h), and norepinephrine (from 720±54 to 306±35 pg/mL) decreased significantly (P<0.01). Plasma aldosterone also tended to decrease, although not significantly (from 101±9 to 76±4 pg/mL, P=NS). Peak V̇O2increased significantly after HEx (P<0.01), while endothelial function was unchanged. No significant change was detected in the control group. CONCLUSIONS: The BP-lowering effects of HEx in resistant HT patients were accompanied by a significant reduction in the marked neurohumoral activation characterizing this clinical condition.

Diagnosis in Bytes: Comparing the Diagnostic Accuracy of Google and ChatGPT 3.5 as an Educational Support Tool.

BACKGROUND: Adopting advanced digital technologies as diagnostic support tools in healthcare is an unquestionable trend accelerated by the COVID-19 pandemic. However, their accuracy in suggesting diagnoses remains controversial and needs to be explored. We aimed to evaluate and compare the diagnostic accuracy of two free accessible internet search tools: Google and ChatGPT 3.5. METHODS: To assess the effectiveness of both medical platforms, we conducted evaluations using a sample of 60 clinical cases related to urological pathologies. We organized the urological cases into two distinct categories for our analysis: (i) prevalent conditions, which were compiled using the most common symptoms, as outlined by EAU and UpToDate guidelines, and (ii) unusual disorders, identified through case reports published in the 'Urology Case Reports' journal from 2022 to 2023. The outcomes were meticulously classified into three categories to determine the accuracy of each platform: "correct diagnosis", "likely differential diagnosis", and "incorrect diagnosis". A group of experts evaluated the responses blindly and randomly. RESULTS: For commonly encountered urological conditions, Google's accuracy was 53.3%, with an additional 23.3% of its results falling within a plausible range of differential diagnoses, and the remaining outcomes were incorrect. ChatGPT 3.5 outperformed Google with an accuracy of 86.6%, provided a likely differential diagnosis in 13.3% of cases, and made no unsuitable diagnosis. In evaluating unusual disorders, Google failed to deliver any correct diagnoses but proposed a likely differential diagnosis in 20% of cases. ChatGPT 3.5 identified the proper diagnosis in 16.6% of rare cases and offered a reasonable differential diagnosis in half of the cases. CONCLUSION: ChatGPT 3.5 demonstrated higher diagnostic accuracy than Google in both contexts. The platform showed satisfactory accuracy when diagnosing common cases, yet its performance in identifying rare conditions remains limited.

Task force of the Brazilian Society of Otology - evaluation and management of peripheral facial palsy.

OBJECTIVE: To review key evidence-based recommendations for the diagnosis and treatment of peripheral facial palsy in children and adults. METHODS: Task force members were educated on knowledge synthesis methods, including electronic database search, review and selection of relevant citations, and critical appraisal of selected studies. Articles written in English or Portuguese on peripheral facial palsy were eligible for inclusion. The American College of Physicians' guideline grading system and the American Thyroid Association's guideline criteria were used for critical appraisal of evidence and recommendations for therapeutic interventions. RESULTS: The topics were divided into 2 main parts: (1) Evaluation and diagnosis of facial palsy: electrophysiologic tests, idiopathic facial palsy, Ramsay Hunt syndrome, traumatic peripheral facial palsy, recurrent peripheral facial palsy, facial nerve tumors, and peripheral facial palsy in children; and (2) Rehabilitation procedures: surgical decompression of the facial nerve, facial nerve grafting, surgical treatment of long-term peripheral facial palsy, and non-surgical rehabilitation of the facial nerve. CONCLUSIONS: Peripheral facial palsy is a condition of diverse etiology. Treatment should be individualized according to the cause of facial nerve dysfunction, but the literature presents better evidence-based recommendations for systemic corticosteroid therapy.

MicroRNAs: new players in heart failure.

MicroRNAs (miRNAs) are a class of non-coding small RNAs representing one of the most exciting areas of modern medical science. miRNAs modulate a large and complex regulatory network of gene expression of the majority of the protein-coding genes. Currently, evidences suggest that miRNAs play a crucial role in the pathogenesis of heart failure. Some miRNAs as miR-1, miR-133 and miR-208a are highly expressed in the heart and strongly associated with the development of cardiac hypertrophy. Recent data indicate that these miRNAs as well as miR-206 change their expression quickly in response to physical activity. The differential regulation of miRNAs in response to exercise suggests a potential value of circulating miRNAs (c-miRNAs) as biomarkers of physiological mediators of the cardiovascular adaptation induced by exercise. Likewise, serum levels of c-miRNAs such as miR-423-5p have been evaluated as potential biomarkers in the diagnosis and prognosis of heart failure. On the other hand, the manipulation of miRNAs levels using techniques such as 'miR mimics' and 'antagomiRs' is becoming evident the enormous potential of miRNAs as promising therapeutic strategies in heart failure.

Leguminous plants nodulated by selected strains of Cupriavidus necator grow in heavy metal contaminated soils amended with calcium silicate.

Increasing concern regarding mining area environmental contamination with heavy metals has resulted in an emphasis of current research on phytoremediation. The aim of the present study was to assess the efficiency of symbiotic Cupriavidus necator strains on different leguminous plants in soil contaminated with heavy metals following the application of inorganic materials. The application of limestone and calcium silicate induced a significant increase in soil pH, with reductions in zinc and cadmium availability of 99 and 94 %, respectively. In addition, improved nodulation of Mimosa caesalpiniaefolia, Leucaena leucocephala and Mimosa pudica in soil with different levels of contamination was observed. Significant increases in the nitrogen content of the aerial parts of the plant were observed upon nodulation of the root system of Leucaena leucocephala and Mimosa pudica by strain UFLA01-659 (36 and 40 g kg(-1)) and by strain UFLA02-71 in Mimosa caesalpiniaefolia (39 g kg(-1)). The alleviating effect of calcium silicate resulted in higher production of dry matter from the aerial part of the plant, an increase in nodule number and an increase in the nitrogen fixation rate. The results of the present study demonstrate that the combination of rhizobia, leguminous plants and calcium silicate may represent a key factor in the remediation of areas contaminated by heavy metals.

Managing nonspecific adsorption to liquid chromatography hardware: A review.

The choice of alternative materials over stainless steel hardware in the construction of liquid chromatography systems has unveiled the degree to which nonspecific adsorption impacts the reproducibility of LC methods. Some of the major contributors to nonspecific adsorption losses are charged metallic surfaces and leached metallic impurities, that may interact with the analyte and result in analyte loss and overall poor chromatographic performance. In this review, we describe several mitigation strategies available to chromatographers to minimize nonspecific adsorption to chromatographic systems. Alternative surfaces to stainless steel such as titanium, PEEK, and hybrid surface technologies are discussed. Furthermore, mobile phase additives used to prevent metal ion-analyte interactions are reviewed. Nonspecific adsorption of analytes is not reserved to metallic surfaces, as analytes may adsorb to the surfaces of filters, tubes, and pipette tips during sample preparation. Identifying the source of nonspecific interactions is paramount, as mitigation strategies may differ depending on what stage nonspecific losses are taking place. With this in mind, we discuss diagnostic methods that may help the chromatographer to differentiate losses resulting from sample preparation, and losses during LC runs.

Microflow liquid chromatography - multi-emitter nanoelectrospray mass spectrometry of oligonucleotides.

While the most sensitive LC-MS methods for oligonucleotide analysis contain ion-pairs in the mobile phase, these modifiers have been associated with instrument contamination and ion suppression. Typically, entire LC-MS systems are reserved for oligonucleotide LC-MS when using ion-pairing buffers. To overcome these limitations, numerous HILIC methods, liberated from ion-pairs, have been recently developed. Since ion-pairs play a role in analyte desorption from ESI droplets, their removal from mobile phases tend to impact method sensitivity. An effective way to recover MS sensitivity is to reduce the LC flow rate and therefore reduce ESI droplet size. With a focus on MS sensitivity, this study investigates the applicability of a microflow LC- nanoelectrospray MS platform in oligonucleotide ion-pair RP and HILIC LC-MS methods. The platform is effective and substantially increased the MS sensitivity of HILIC methods. Furthermore, LC method development for both types of separations provide insight into microflow chromatography of oligonucleotides, an under investigated chromatographic scale.

Mobile Phase Aging and Its Impact on Electrospray Ionization of Oligonucleotides.

The implementation of fluoroalcohol/alkylamine mobile phase systems in oligonucleotide LC-MS provides a good balance between chromatographic separations and MS sensitivity. Since its introduction, several parameters including mobile phase composition, additive concentration, alkylamine hydrophobicity, and different fluoroalcohols have been carefully evaluated and optimized. While our understanding of this mobile phase system has increased over the years, there are challenges that continue to hinder method performance and remain poorly understood. One of these challenges is the constant loss of MS sensitivity over time, commonly termed mobile phase aging. This study investigates two aging mechanisms associated with loss of MS sensitivity: alkylamine oxidation and aggregate formation. The relationship between pH, organic solvent, oxygen, and mobile phase aging is characterized, and mitigation strategies to extend mobile phase lifetime are discussed.

Aerobic exercise improves central blood pressure and blood pressure variability among patients with resistant hypertension: results of the EnRicH trial.

Central blood pressure (BP) and BP variability are associated with cardiovascular disease risk. However, the influence of exercise on these hemodynamic parameters is unknown among patients with resistant hypertension. The EnRicH (The Exercise Training in the Treatment of Resistant Hypertension) was a prospective, single-blinded randomized clinical trial (NCT03090529). Sixty patients were randomized to a 12-week aerobic exercise program or usual care. The outcome measures include central BP, BP variability, heart rate variability, carotid-femoral pulse wave velocity, and circulating cardiovascular disease risk biomarkers including high-sensitivity C-reactive protein, angiotensin II, superoxide dismutase, interferon gamma, nitric oxide, and endothelial progenitor cells. Central systolic BP decreased by 12.22 mm Hg (95% CI, -1.88 to -22.57, P = 0.022) as did BP variability by 2.85 mm Hg (95% CI, -4.91 to -0.78, P = 0.008), in the exercise (n = 26) compared to the control group (n = 27). Interferon gamma -4.3 pg/mL (95%CI, -7.1 to -1.5, P = 0.003), angiotensin II -157.0 pg/mL (95%CI, -288.1 to -25.9, P = 0.020), and superoxide dismutase 0.4 pg/mL (95%CI, 0.1-0.6, P = 0.009) improved in the exercise compared to the control group. Carotid-femoral pulse wave velocity, heart rate variability, high-sensitivity C-reactive protein, nitric oxide, and endothelial progenitor cells were not different between groups (P > 0.05). In conclusion, a 12-week exercise training program improved central BP and BP variability, and cardiovascular disease risk biomarkers in patients with resistant hypertension. These markers are clinically relevant as they are associated with target organ damage and increased cardiovascular disease risk and mortality.

Assessment of biomarkers and clinical parameters as predictors of survival in patients with chagasic heart failure.

BACKGROUND: Chagas disease, endemic in Latin America and spreading globally due to emigration, has a significant health burden, particularly in relation to chagasic heart failure (HF). Chagasic cardiomyopathy (CCM) is characterized by chronic inflammatory myocardial disease. This study aimed to identify inflammatory parameters and biomarkers that could aid in the management of patients with chagasic HF. METHODS AND FINDINGS: A cohort study was conducted at a tertiary cardiology single-center over a mean follow-up period of 2.4 years. The study included patients with HF secondary to CCM enrolled between October 2013 and July 2017. Various clinical parameters, echocardiography findings, parasitemia status, brain natriuretic peptide (BNP) and troponin T (TnT) levels, and inflammatory biomarkers (IL-6, IL-10, IL-12p70, IL-17A, adiponectin, and IFN-γ) were assessed. The study encompassed a cohort of 103 patients, with a median age of 53 years and 70% being male. The left ventricular ejection fraction (LVEF) was 28%, with 40% of patients classified as NYHA II functional class. The median BNP level was 291 pg/ml. The observed mortality rate during the study period was 38.8%. Predictors of lower survival were identified as elevated levels of BNP, TnT, reduced LVEF, and increased adiponectin (thresholds: BNP > 309 pg/ml, TnT > 27.5 ng/ml, LVEF < 25.5%, adiponectin > 38 µg/mL). Notably, there was no evidence indicating a relationship between parasitemia and the inflammatory parameters with lower survival in these patients, including INF-γ, IL-6, IL-10, IL12-(p70), and IL17a. CONCLUSION: Despite the presence of a chronic inflammatory process, the evaluated inflammatory biomarkers in this cohort were not predictive of survival in patients with chagasic HF with reduced ejection fraction (HFrEF). However, reduced LVEF, elevated BNP, adiponectin levels, and troponin T were identified as predictors of lower survival in these patients.

Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment.

OBJECTIVES: To review and provide evidence-based recommendations for the diagnosis and treatment of otosclerosis. METHODS: Task force members were educated on knowledge synthesis methods, including electronic database search, review and selection of relevant citations, and critical appraisal of selected studies. Articles written in English or Portuguese on otosclerosis were eligible for inclusion. The American College of Physicians' guideline grading system and the American Thyroid Association's guideline criteria were used for critical appraisal of evidence and recommendations for therapeutic interventions. RESULTS: The topics were divided into 2 parts: 1) Diagnosis - audiologic and radiologic; 2) Treatment - hearing AIDS, pharmacological therapy, stapes surgery, and implantable devices - bone-anchored devices, active middle ear implants, and Cochlear Implants (CI). CONCLUSIONS: The pathophysiology of otosclerosis has not yet been fully elucidated, but environmental factors and unidentified genes are likely to play a significant role in it. Women with otosclerosis are not at increased risk of worsening clinical condition due to the use of contraceptives or during pregnancy. Drug treatment has shown little benefit. If the patient does not want to undergo stapedotomy, the use of hearing aids is well indicated. Implantable systems should be indicated only in rare cases, and the CI should be indicated in cases of profound deafness.

Antitumor effect of selenium-rich Brazil nuts and selenomethionine dietary supplementation on pre-existing 4T1 mammary tumor growth in mice.

Selenium (Se) is an essential micronutrient known to play an important role in the antioxidant system that can potentially influence tumor growth. We aimed to investigate the effects of dietary Se supplementation after detection of 4T1 mammary tumor growth in BALB/c mice. Thirty female mice received subcutaneous inoculation of 4T1 cells. After five days, all animals presenting palpable tumors were randomly assigned to three groups: a control group (Se-control) receiving a diet with adequate Se (0.15 mg/kg) and two other groups that received Se-supplemented diets (1.4 mg/kg of total Se) with either Brazilian nuts (Se-Nuts) or selenomethionine (SeMet). Data were assessed by either One or Two-way ANOVA followed by Tukey's HSD or Bonferroni's post hoc tests, respectively. Both Se-supplemented diets reduced tumor volume from the thirteenth day of feeding compared with the Se-adequate (control) diet (p < 0.05). The SeMet group presented a higher Se blood concentration (p < 0.05) than the Se-control group, with the Se-Nuts group presenting intermediate values. Selenoprotein P gene expression in the liver was higher in the Se-Nuts group than in the Se-control group (p < 0.05), while the SeMet group presented intermediate expression. Dietary Se supplementation, starting after detection of 4T1 palpable lesions, reduced tumor volume in mice.