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Rafael dos Reis Vieira Olher,1,2,* Danilo Sales Bocalini,3,* Reury Frank Bacurau,4 Daniel Rodriguez,5 Aylton Figueira Jr,5 Francisco Luciano Pontes Jr,4 Francisco Navarro,6 Herbert Gustavo Simões,1 Ronaldo Carvalho Araujo,7 Milton Rocha Moraes8 1Universidade Católica de Brasília, Distrito Federal, 2Universidade Gama Filho, Rio de Janeiro, 3Universidade Nove de Julho (UNINOVE), São Paulo, 4Universidade de São Paulo – Escola de Artes, Ciências e Humanidades, São Paulo, 5Universidade São Judas Tadeu (USJT), São Paulo, Brazil, 6Universidade Federal do Maranhão, Maranhão, 7Universidade de São Paulo, Instituto de Ciências Biomédicas, São Paulo, 8Universidade Federal de São Paulo – Escola Paulista de Medicina, São Paulo, Brazil *These authors contributed equally to this work Background: Arterial hypertension is a serious health problem affecting mainly the elderly population. Recent studies have considered both aerobic and resistance exercises as a non-pharmacological aid for arterial hypertension treatment. However, the cardiovascular responses of the elderly to isometric resistance exercise (eg, isometric handgrip [IHG]) have not yet been documented. Objective: The purpose of this study was to investigate cardiovascular responses to different intensities of isometric exercise, as well as the occurrence of post-isometric exercise hypotension in hypertensive elderly people under antihypertensive medication treatment. Patients and methods: Twelve women volunteered to participate in the study after a maximal voluntary contraction test (MVC) and standardization of the intervention workload consisting of two sessions of IHG exercise performed in four sets of five contractions of a 10-second duration. Sessions were performed both at 30% of the MVC and 50% of the MVC, using a unilateral IHG protocol. Both intensities were compared with a control session without exercise. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at rest (R), during peak exercise (PE), and after 5, 10, 15, 30, 45, and 60 minutes of post-exercise recovery were evaluated. Results: No significant changes were observed after isometric exercise corresponding to 30% MVC for either SBP (R: 121 ± 10; PE: 127 ± 14; 5 min: 125 ± 13; 10 min: 123 ± 12; 15 min: 122 ± 11; 30 min: 124 ± 11; 45 min: 124 ± 10; 60 min: 121 ± 10 mmHg) or DBP (R: 74 ± 9; PE: 76 ± 6; 5 min: 74 ± 5; 10 min: 72 ± 8; 15 min: 72 ± 5; 30 min: 72 ± 8; 45 min: 73 ± 6; 60 min: 75 ± 7 mmHg). Similarly, the 50% MVC did not promote post-isometric exercise hypotension for either SBP (R: 120 ± 7; PE: 125 ± 11; 5 min: 120 ± 9; 10 min: 122 ± 9; 15 min: 121 ± 11; 30 min: 121 ± 9; 45 min: 121 ± 9; 60 min: 120 ± 7 mmHg) or DBP (R: 72 ± 8; PE: 78 ± 7; 5 min: 72 ± 7; 10 min: 72 ± 8; 15 min: 71 ± 7; 30 min: 72 ± 8; 45 min: 75 ± 10; 60 min: 75 ± 7 mmHg). Conclusion: Our data reveal that cardiovascular overload or post-exercise hypotension did not occur in elderly women with controlled hypertension when they undertook an IHG session. Thus this type of resistance exercise, with mild to moderate intensity, with short time of contraction appears to be safe for this population. Keywords: hypertension, resistance exercise, elderly, cardiovascular response, antihypertensive medication, isometric exercise

Imbalance and weakness of the serratus anterior and upper trapezius force couple have been described in patients with shoulder dysfunction. There is interest in identifying exercises that selectively activate these muscles and including it in rehabilitation protocols. This study aims to verify the UT/SA electromyographic (EMG) amplitude ratio, performed in different upper limb exercises and on two bases of support. Twelve healthy men were tested (average age = 22.8 +/- 3.1 years), and surface EMG was recorded from the upper trapezius and serratus anterior using single differential surface electrodes. Volunteers performed isometric contractions over a stable base of support and on a Swiss ball during the wall push-up (WP), bench press (BP), and push-up (PU) exercises. All SEMG data are reported as a percentage of root mean square or integral of linear envelope from the maximal value obtained in one of three maximal voluntary contractions for each muscle studied. A linear mixed-effect model was performed to compare UT/SA ratio values. The WP, BP, and PU exercises showed UT/SA ratio mean +/- SD values of 0.69 +/- 0.72, 0.14 +/- 0.12, and 0.39 +/- 0.37 for stable surfaces, respectively, whereas for unstable surfaces, the values were 0.73 +/- 0.67, 0.43 +/- 0.39, and 0.32 +/- 0.30. The results demonstrate that UT/SA ratio was influenced by the exercises and by the upper limb base of support. The practical application is to show that BP on a stable surface is the exercise preferred over WP and PU on either surfaces for serratus anterior muscle training in patients with imbalance between the UT/SA force couple or serratus anterior weakness. [ABSTRACT FROM AUTHOR]

The objective of this work was to determine whether the addition of phytogenic compounds based on essential oils (carvacrol, eugenol, cinnamaldehyde) and resinous pepper oil (capsaicin) to the diet of Jersey cows at the beginning of lactation affects anti-inflammatory, antioxidant and immunomodulatory responses, as well as whether there are effects of EO on blood metabolites, ruminal fermentation, digestibility and milk production and composition. Six primiparous cows (370.00 ± 17 kg body weight (BW); 13.02 kg dry matter intake (DMI); 21 days of lactation and average milk production of 20 ± 2 L per day) were allocated to crossed experimental design (2 × 2) with two experimental periods of 28 days and two treatments. Blood, milk and rumen fluid were collected and, at the end of each period, feed and feces samples were collected to evaluate the apparent digestibility of nutrients. The groups were control (CLT) without supplementation and treated (BEO) with the addition of 150 mg/kg of dry matter of the phytogenic to the concentrated portion of the diet. Cows in the BEO group had lower numbers of leukocytes (P ≤ 0.05) and lymphocytes (P ≤ 0.02), but total protein and globulin levels were higher on days 21 and 28 (P ≤ 0.01). In the BEO group, the levels of immunoglobulin A, immunoglobulin heavy chain and transferrin were higher (P ≤ 0.05). The levels of ceruloplasmin, haptoglobin and C-reactive protein were lower in the BEO group (P ≤ 0.05). Lipid peroxidation levels and protein carbonyl content were lower in the BEO group. The total antioxidant capacity (P ≤ 0.09) and the activity of glutathione S-transferase (P ≤ 0.03) and glutathione peroxidase (P ≤ 0.05) were higher in the BEO group. Cows in the BEO group had lower pH (P ≤ 0.05), acetic acid concentrations (P ≤ 0.01) and higher protozoa counts (P ≤ 0.01). Our results suggest that phytogenic supplementation has positive effects on the health of Jersey cows in early lactation, characterized by immunostimulant, antioxidant and anti-inflammatory effects., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: An active search for tuberculosis cases through mass screening is widely described as a tool to improve case detection in hyperendemic settings. However, its effectiveness in high-risk populations, such as incarcerated people, is debated., Methods: Between 2017 and 2021, 3 rounds of mass screening were carried out in 3 Brazilian prisons. Social and health questionnaires, chest X-rays, and Xpert MTB/RIF were performed., Results: More than 80% of the prison population was screened. Overall, 684 cases of pulmonary tuberculosis were diagnosed. Prevalence across screening rounds was not statistically different. Among incarcerated persons with symptoms, the overall prevalence of tuberculosis per 100 000 persons was 8497 (95% confidence interval [CI], 7346-9811), 11 115 (95% CI, 9471-13 082), and 7957 (95% CI, 6380-9882) in screening rounds 1, 2, and 3, respectively. Similar to our overall results, there were no statistical differences between screening rounds and within individual prisons. We found no statistical differences in Computer-Aided Detection for TB version 5 scores across screening rounds among people with tuberculosis-the median scores in rounds 1, 2, and 3 were 82 (interquartile range [IQR], 63-97), 77 (IQR, 60-94), and 81 (IQR, 67-92), respectively., Conclusions: In this environment with hyperendemic rates of tuberculosis, 3 rounds of mass screening did not reduce the overall tuberculosis burden. In prisons, where a substantial number of tuberculosis cases is undiagnosed annually, a range of complementary interventions and more frequent tuberculosis cases screening may be required., Competing Interests: Potential conflicts of interest . The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The kallikrein-kinin system is a versatile regulatory network implicated in various biological processes encompassing inflammation, nociception, blood pressure control, and central nervous system functions. Its physiological impact is mediated through G-protein-coupled transmembrane receptors, specifically the B1 and B2 receptors. Dopamine, a key catecholamine neurotransmitter widely distributed in the CNS, plays a crucial role in diverse physiological functions including motricity, reward, anxiety, fear, feeding, sleep, and arousal. Notably, the potential physical interaction between bradykinin and dopaminergic receptors has been previously documented. In this study, we aimed to explore whether B2R modulation in catecholaminergic neurons influences the dopaminergic pathway, impacting behavioral, metabolic, and motor aspects in both male and female mice. B2R ablation in tyrosine hydroxylase cells reduced the body weight and lean mass without affecting body adiposity, substrate oxidation, locomotor activity, glucose tolerance, or insulin sensitivity in mice. Moreover, a B2R deficiency in TH cells did not alter anxiety levels, exercise performance, or motor coordination in female and male mice. The concentrations of monoamines and their metabolites in the substantia nigra and cortex region were not affected in knockout mice. In essence, B2R deletion in TH cells selectively influenced the body weight and composition, leaving the behavioral and motor aspects largely unaffected.

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo , consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Post-menopausal women have impaired cardiorespiratory responses to exercise compared to young women. Exercise training may counterbalance impairments, but the time-dependent effects of exercise training remain unclear. The current study aims to investigate the effects of rowing training on maximal aerobic capacity and time-course cardiorespiratory adaptations in older women., Methods: Female participants ( n = 23) were randomly allocated to the experimental group (EXP; n = 23; 66 ± 5 years old) enrolled in rowing exercise training and control group (CON; n = 10; 64 ± 4 years old). The cardiopulmonary exercise test (CET) was performed in a cycle ergometer pre- and post-interventions. Oxygen uptake (VO 2 ), stroke volume (SV), cardiac output (CO), and HR were recorded during CET and analyzed at the peak of the exercise. HR was monitored during exercise recovery, and the index of HRR was calculated by ΔHRR (HR peak -HR one-minute recovery). Every two weeks, Rowing Stepwise Exercise (RSE) in a rowing machine was performed to track specific adaptations to the exercise modality. HR was continuously recorded during RSE and corrected for the average power of each step (HR/watts). The rowing training protocol consisted of three weekly sessions of 30 min at an intensity corresponding to 60-80% of peak HR for ten weeks., Results: Rowing exercise training increased VO 2 , SV, and CO at the peak of the CET, and ΔHRR. Increased workload (W) and reduced HR response to a greater achieved workload (HR/W) during RSE were observed after six weeks of training., Conclusions: Rowing exercise training is a feasible method to improve cardiorespiratory performance, vagal reactivation and heart rate adjustments to exercise in older women.

The Kallikrein-Kinin System (KKS) plays an important role in energy metabolism. We have previously described the importance of the kinin B1 receptor (B1R) in metabolism regulation. Considering that the liver manages the different energy demands of different body tissues, we combined two stressful conditions - fasting and voluntary exercise - to address how B1R may affect liver metabolism, focusing on mitochondrial function., Aims: To investigate how the kinin B1 receptor (B1R) modulates mitochondrial activity under stress conditions, focusing on the rate of energy expenditure and shift in metabolism., Main Methods: Wild-type and B1R-knockout (B1KO) male mice remained in a calorimetric cage with a wheel for 7 days; 48 h before euthanasia, half of the animals from both groups were submitted to fasting conditions. Mitochondrial activity, ketone bodies, and gene expression involving mitochondrial activity were evaluated., Key Findings: B1R modulates the mitochondrial activity under fasting and voluntary exercise, reducing the VO 2 expenditure and HEAT. B1KO animals who exercised and underwent fasting did not have increased glucose levels, suggesting a preference for lipids as an energy source. Moreover, these animals displayed RER around 0.8, which indicates a β-oxidation increment. Interestingly, the lack of B1R did not induce mitochondrial activity and biogenesis, suggesting interference in metabolism responsivity, a condition modulated by sirtuins under PGC-1α control., Significance: B1R modulates mitochondrial respiratory control ratios, which suggests metabolic suppression, influencing hepatic metabolism and, consequently, energy homeostasis., (Copyright © 2022. Published by Elsevier Inc.)

This study assessed the association between encapsulated nitrate product (ENP) and monensin (MON) to mitigate enteric methane (CH4) in vitro and possible effects on ruminal degradability, enteric fermentation characteristics, and microbial populations. Six treatments were used in randomized complete design in a 2×3 factorial arrangement with two levels of MON (0 and 2.08 mg/mL of buffered rumen fluid) and three levels of ENP (0, 1.5 and 3.0%). The substrate consisted of 50% Tifton-85 hay and 50% concentrate mixture (ground corn and soybean meal). ENP replaced soybean meal to achieve isonitrogenous diets (15% CP). No ENP×MON interaction was observed for any measured variable (P > 0.05) except for the relative abundance of F. succinogenes (P = 0.02) that linearly increased in diets with MON when ENP was added. The ENP addition decreased CH4 production (P < 0.01) without affecting (P > 0.05) truly degraded organic matter nor the relative abundance of methanogens. Hydrogen production was reduced with MON (P = 0.04) and linearly decreased with ENP inclusion (P = 0.02). We concluded that use of nitrate is a viable strategy for CH4 reduction, however, no additive effect of ENP and MON was observed for mitigating CH4 production.

We aimed to investigate the effects of calcium-ammonium nitrate (CAN) fed to lactating dairy goats on dry matter (DM) intake, digestibility of nutrients, milk properties (composition, antioxidant capacity, fatty acid profile, and nitrate residues), and ruminal fermentation parameters. Twelve lactating Saanen goats averaging 98.5 ± 13.1 days in milk, 53.5 ± 3.3 kg of body weight, and 2.53 ± 0.34 kg of milk/day were randomly assigned in four 3 × 3 Latin squares to receive the following diets: a control group (without CAN) with 7.3 g/kg DM of urea (URE), 10 g/kg DM of CAN (CAN10), and 20 g/kg DM of CAN (CAN20). Each period lasted 21 days, with 14 days for diet adaptation and seven days for data and sample collection. The DM intake, digestibility of nutrients, yields of milk, 3.5% fat-corrected milk, and energy-corrected milk were not affected by treatments. Similarly, there were no treatment effects on the yields and concentrations of milk fat, true protein, and lactose, along with minor effects on milk fatty acid profile. Total antioxidant capacity in milk was unaffected by treatments; however, concentration of conjugated dienes increased, while thiobarbituric acid reactive substances in milk decreased linearly. Nitrate and nitrite residues in milk were elevated by treatments, while the total of volatile fatty acids and ammonia-N concentration in the rumen were unaffected. Collectively, feeding CAN (up to 20 g/kg of DM) to lactating dairy goats did not affect feed intake, nutrient digestibility, and milk composition; however, it may increase milk lipid oxidation, as evidenced by increased conjugated diene concentration.

We evaluated the effects of supplemental calcium ammonium nitrate (CAN) fed to dairy cows on dry matter (DM) intake, nutrient digestibility, milk quality, microbial protein synthesis, and ruminal fermentation. Six multiparous Holstein cows at 106 ± 14.8 d in milk, with 551 ± 21.8 kg of body weight were used in a replicated 3 × 3 Latin square design. Experimental period lasted 21 d, with 14 d for an adaptation phase and 7 d for sampling and data collection. Cows were randomly assigned to receive the following treatments: URE, 12 g of urea/kg of DM as a control group; CAN15, 15 g of CAN/kg of DM; and CAN30, 30 g of CAN/kg of DM. Supplemental CAN reduced DM intake (URE 19.0 vs. CAN15 18.9 vs. CAN30 16.5 kg/d). No treatment effects were observed for apparent digestibility of DM, organic matter, crude protein, ether extract, and neutral detergent fiber; however, CAN supplementation linearly increased nonfiber carbohydrate digestibility. Milk yield was not affected by treatments (average = 23.1 kg/d), whereas energy-corrected milk (ECM) and 3.5% fat-corrected milk (FCM) decreased as the levels of CAN increased. Nitrate residue in milk increased linearly (URE 0.30 vs. CAN15 0.33 vs. CAN30 0.38 mg/L); however, treatments did not affect nitrite concentration (average: 0.042 mg/L). Milk fat concentration was decreased (URE 3.39 vs. CAN15 3.35 vs. CAN30 2.94%), and the proportion of saturated fatty acids was suppressed by CAN supplementation. No treatment effects were observed on the reducing power and thiobarbituric acid reactive substances of milk, whereas conjugated dienes increased linearly (URE 47.6 vs. CAN15 52.7 vs. CAN30 63.4 mmol/g of fat) with CAN supplementation. Treatments had no effect on microbial protein synthesis; however, molar proportion of ruminal acetate and acetate-to-propionate ratio increased with CAN supplementation. Based on the results observed, supplementing CAN at 30 g/kg of DM should not be recommended as an optimal dose because it lowered DM intake along with ECM and 3.5% FCM, although no major changes were observed on milk quality and ruminal fermentation., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background and Aims: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality in Latin America, yet the impact of public health policies (PHP) on liver disease is unknown. We aimed to assess the association between alcohol PHP and deaths due to ALD in Latin American countries., Approach and Results: We performed an ecological multinational study including 20 countries in Latin America (628,466,088 inhabitants). We obtained country-level sociodemographic information from the World Bank Open Data source. Alcohol-related PHP data for countries were obtained from the World Health Organization Global Information System of Alcohol and Health. We constructed generalized linear models to assess the association between the number of PHP (in 2010) and health outcomes (in 2016). In Latin America, the prevalence of obesity was 27% and 26.1% among male and female populations, respectively. The estimated alcohol per capita consumption among the population at 15 years old or older was 6.8 L of pure alcohol (5.6 recorded and 1.2 unrecorded). The overall prevalence of alcohol use disorders (AUD) was 4.9%. ALD was the main cause of cirrhosis in 64.7% of male and 40.0% of female populations. A total of 19 (95%) countries have at least one alcohol-related PHP on alcohol. The most frequent PHP were limiting drinking age (95%), tax regulations (90%), drunk-driving policies and countermeasures (90%), and government monitoring systems and community support (90%). A higher number of PHP was associated with a lower ALD mortality (PR, 0.76; 95% CI, 0.61-0.93; P = 0.009), lower AUD prevalence (PR, 0.80; 95% CI, 0.65-0.99; P = 0.045), and lower alcohol-attributable road traffic deaths (PR, 0.81; 95% CI, 0.65-1.00; P = 0.051)., Conclusions: Our study indicates that in Latin America, countries with higher number of PHP have lower mortality due to ALD, lower prevalence of AUD, and lower alcohol-attributable road traffic mortality., (© 2021 by the American Association for the Study of Liver Diseases.)

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH., Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method., Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247)., Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39., Lay Summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51)., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Two experiments were performed to evaluate the effects of bismuth subsalicylate (BSS) and calcium-ammonium nitrate (CAN) on in vitro ruminal fermentation, growth, apparent total tract digestibility of nutrients, liver mineral concentration, and carcass quality of beef cattle. In Exp. 1, four ruminally cannulated steers (520 ± 30 kg body weight [BW]) were used as donors to perform a batch culture and an in vitro organic matter digestibility (IVOMD) procedure. Treatments were arranged in a 2 × 2 factorial with factors being BSS (0 or 0.33% of substrate dry matter [DM]) and CAN (0 or 2.22% of substrate DM). In Exp. 2, 200 Angus-crossbred steers (385 ± 27 kg BW) were blocked by BW and allocated to 50 pens (4 steers/pen) in a randomized complete block design with a 2 × 2 + 1 factorial arrangement of treatments. Factors included BSS (0 or 0.33% of the diet DM) and nonprotein nitrogen (NPN) source (urea or encapsulated CAN [eCAN] included at 0.68% or 2.0% of the diet, respectively) with 0.28% ruminally available S (RAS). A low S diet was included as a positive control containing urea (0.68% of DM) and 0.14% RAS. For Exp. 1, data were analyzed using the MIXED procedure of SAS with the fixed effects of BSS, CAN, BSS × CAN, and the random effect of donor. For Exp. 2, the MIXED procedure of SAS was used for continuous variables and the GLIMMIX procedure for categorical data. For Exp. 1, no differences (P > 0.230) were observed for IVOMD. There was a tendency (P = 0.055) for an interaction regarding H2S production. Acetate:propionate increased (P = 0.003) with the addition of CAN. In Exp. 2, there was a NPN source effect (P = 0.032) where steers consuming urea had greater carcass-adjusted final shrunk BW than those consuming eCAN. Intake of DM (P < 0.001) and carcass-adjusted average daily gain (P = 0.024) were reduced by eCAN; however, it did not affect (P = 0.650) carcass-adjusted feed efficiency. Steers consuming urea had greater (P = 0.032) hot carcass weight, and a BSS × NPN interaction (P = 0.019) was observed on calculated yield grade. Apparent absorption of S decreased (P < 0.001) with the addition of BSS. Final liver Cu concentration was reduced (P = 0.042) by 58% in cattle fed BSS, indicating that BSS may decrease Cu absorption and storage in the liver. The results observed in this experiment indicate that BSS does not have negative effects on feedlot steer performance, whereas CAN may hinder performance of steers fed finishing diets., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In addition to its health benefits, exercise training has been noted as a modulator of the gut microbiota. However, the effects of resistance training (RT) on gut microbiota composition remain unknown. Wistar rats underwent 12 weeks of RT. Body mass, glucose tolerance, visceral body fat, triglyceride concentration and food consumption were evaluated. The gut microbiota was analyzed by 16S rRNA gene sequencing. Rats that underwent RT showed lower body mass (P=0.0005), lower fat content (P=0.02) and better glucose kinetics (P=0.047) when compared with the control. Improvements in the diversity and composition of the gut microbiota were identified in the RT group. The relative abundance of Pseudomonas, Serratia and Comamonas decreased significantly after 12 weeks of RT (P<0.001). These results suggest that RT has the potential to enhance the diversity of the gut microbiota and improve its biological functions., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

High-protein diets (HPDs) are widely accepted as a way to stimulate muscle protein synthesis when combined with resistance training (RT). However, the effects of HPDs on adipose tissue plasticity and local inflammation are yet to be determined. This study investigated the impact of HPDs on glucose control, adipocyte size, and epididymal adipose inflammatory biomarkers in resistance-trained rats. Eighteen Wistar rats were randomly assigned to four groups: normal-protein (NPD; 17% protein total dietary intake) and HPD (26.1% protein) without RT and NPD and HPD with RT. Trained groups received RT for 12 weeks with weights secured to their tails. Glucose and insulin tolerance tests, adipocyte size, and an array of cytokines were determined. While HPD without RT induced glucose intolerance, enlarged adipocytes, and increased TNF-α, MCP-1, and IL1-β levels in epididymal adipose tissue ( p < 0.05), RT diminished these deleterious effects, with the HPD + RT group displaying improved blood glucose control without inflammatory cytokine increases in epididymal adipose tissue ( p < 0.05). Furthermore, RT increased glutathione expression independent of diet ( p < 0.05). RT may offer protection against adipocyte hypertrophy, pro-inflammatory states, and glucose intolerance during HPDs. The results highlight the potential protective effects of RT to mitigate the maladaptive effects of HPDs.

Several cytokines have been reported to participate in spermatogenesis, including interleukin-6 (IL6). However, not many studies have been conducted on the loss of Il6 on the male reproductive tract. Nonetheless, there is considerable knowledge regarding the pathological and physiological role of IL6 on spermatogenesis. In this way, this study evaluated the impact of Il6 deficiency on mice testicles in the absence of infection or inflammation. We showed that Il6 deficiency increases daily sperm production, the number of spermatids, and the testicular testosterone and dihydrotestosterone levels. Besides that, mice with a deleted Il6 (IL6KO) showed increased testicular SOCS3 levels, with no changes in pJAK/JAK and pSTAT3/STAT3 ratios. It is worth noting that the aforementioned pathway is not the only pathway to up-regulate SOCS3, nor is it the only SOCS3 target, thus proposing that the increase of SOCS3 in the testis occurs independently of the JAK-STAT signaling in IL6KO mice. Therefore, we suggest that the lack of Il6 drives androgenic production by increasing SOCS3 in the testis, thus leading to an increase in spermatogenesis.

There is a need to increase efficiency of beef production. Decreasing losses of CH 4 and improving byproduct utilization are popular strategies. Two feed additives were tested to find potential solutions. Three randomized complete block design experiments were performed using batch culture systems to evaluate the effects of bismuth subsalicylate (BSS) and calcium-ammonium nitrate (CAN) on in vitro ruminal fermentation of bahiagrass hay and supplemental molasses. The first experiment contained four treatments: (1) basal substrate; (2) basal substrate with 0.75% urea (DM basis); (3) basal substrate with 1.2% CAN and 0.38% urea (DM basis); and (4) basal substrate with 2.4% CAN (DM basis). Treatments 2, 3, and 4 were isonitrogenous. The second experiment had a 4 × 3 factorial arrangement of treatments with 4 concentrations of BSS (0.00, 0.33, 0.66, and 1.00%; DM basis) and 3 concentrations of CAN (0.0, 1.2, and 2.4%; DM basis). The third experiment had the following treatments: (1) basal substrate; (2) basal substrate with 0.05% BSS (DM basis); (3) basal substrate with 0.10% BSS (DM basis); and (4) basal substrate with 0.33% BSS (DM basis). For all experiments, basal substrate consisted of Pensacola bahiagrass hay (Paspalum notatum Flüggé; 80% substrate DM) and molasses (20% substrate DM). All data were analyzed using the MIXED procedure of SAS. In Exp. 1, in vitro organic matter (OM) digestibility (IVOMD) was linearly reduced (P < 0.001) with the inclusion of CAN, and CH 4 , in mmol/g OM fermented, was decreased linearly (P < 0.001). The volatile fatty acid (VFA) profile was not impacted by the inclusion of nonprotein nitrogen (NPN) or CAN (P > 0.05). In Exp. 2, except for CH 4 production (P < 0.05), there were no BSS × CAN interactions. Linear reductions in total gas production (P < 0.001), IVOMD (P < 0.001), and total concentration of VFA (P = 0.007) were observed with the inclusion of BSS up to 1%. The inclusion of BSS decreased H 2 S production in a quadratic manner (P = 0.024). In Exp. 3, IVOMD was not impacted by the inclusion of BSS (P > 0.05); however, production of H 2 S was linearly decreased (P = 0.004) with the inclusion of BSS up to 0.33%. In conclusion, in vitro fermentation was negatively impacted by the inclusions of BSS, up to 1%, and CAN, up to 2.4%; however, BSS decreased production of H 2 S when included up to 0.33% without impeding fermentation, while CAN decreased CH 4 production., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Previous reports reveal that +9/-9 polymorphism of the bradykinin B2 receptor (BDKRB2) is suggestive of cardiometabolic diseases. The aim of this study was to examine the impact of BDKRB2 + 9/-9 polymorphism genotypes on the blood pressure parameters and microvascular function in prepubescent children. We screened for BDKRB2 + 9/-9 polymorphism in the DNA of 145 children (86 boys and 59 girls), and its association with body composition, blood pressure levels, biochemical parameters, and endothelial function was determined. No significant association of the BDKRB2 genotypes with gender (P=0.377), race (P=0.949) or family history of cardiovascular disease (CVD) (P=0.858) was observed. Moreover, we did not identify any interaction between BDKRB2 genotypes with a phenotype of obesity (P=0.144). Children carrying the +9/+9 genotype exhibited a significant linear trend with higher levels of systolic blood pressure and pulse pressure (P<0.001). Moreover, the presence of +9 allele resulted in a decrease of reactive hyperemia index, showing a decreasing linear trend from -9/-9 to +9/+9, wherein this parameter of endothelial function was the lowest in the +9/+9 children, intermediate in the +9/-9 children, and the highest in the -9/-9 children (P<0.001). There was a significant inverse correlation between reactive hyperemia index and systolic blood pressure (r= - 0.348, P< 0.001) and pulse pressure (r= - 0.399, P< 0.001). Our findings indicate that the +9/+9 BDKRB2 genotype was associated with high blood pressure and microvascular dysfunction in prepubescent Brazilian children., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The genetic influence in obesity prevalence is well described, but the role of genetic markers related to athletic strength/ endurance performance remains controversial. We investigated associations between obesity and the genetic polymorphisms alpha-actinin-3 (ACTN3) R577X and angiotensin-converting enzyme (ACE) I/D in schoolchildren aged 4-13 years from Southern Brazil. We collected sociodemographic data from parents through a questionnaire and conducted an anthropometric assessment. DNA was extracted from buccal cells and genotyping was performed by PCR. We found that 1.9% of the individuals were classified as low weight-for-age, 57.6% as normal weight and 40.5% as overweight/ obesity. Regarding allelic distribution, we found that 52.5% of individuals were DD, 30.8% ID, and 16.7% II for ACE; and 38.8% of individuals were RR, 40.2% RX and 21.0% XX for ACTN3. When both polymorphisms were combined, we observed a clear association between the composed genetic profile of these alleles and severe obesity in schoolchildren. Our data suggest that the combined analysis of ACTN3 R577X and ACE I/D polymorphisms may serve as a predictor for the risk of severe obesity in children. These data can contribute to a better understanding of the relationship between these polymorphisms and the body weight development of school-age children.

There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob ) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.

Cytomegalovirus (CMV) reactivation remains one of the main infectious complications following hematopoietic stem cell transplantation (HSCT). In this study, we explored the role of anti-CMV antibody titers in HSCT from alternative donors and to compare the risk of CMV reactivation between posttransplant cyclophosphamide-based haploidentical HSCT and antithymocyte globulin-based unrelated donor (URD) HSCT. We included 98 CMV-positive patients, 30 undergoing haploidentical HSCT and 68 undergoing URD HSCT. The majority of patients had a malignant disease (84%), received a myeloablative conditioning regimen (78%), and received a bone marrow graft (90%). The median pretransplantation anti-CMV IgG level was 109 U/mL. With median follow-up of 2.2 years, a total of 72 CMV reactivations occurred in 50 patients. There was no difference in CMV reactivation pattern between haploidentical HSCT recipients and URD HSCT recipients. In multivariable analysis until the first event, the incidence of CMV reactivation was higher in patients with anti-CMV IgG levels >100 U/mL (hazard ratio [HR], 2.38; P = .005) and in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) (HR, 10.8; P = .003) after day +50 and lower in patients who received higher doses of CD34 cells (HR, .44; P = .006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning (HR, 1.69: P = .04) and in patients with acute GVHD (HR, 1.88; P = .02), and lower in those who received higher doses of CD34 cells (HR, .55; P = .01). In summary, we have shown that pretransplantation anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in HSCT. The use of high-dose cellular grafts, a modifiable risk factor, also protects against CMV reactivation., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.

Patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy have a dismal prognosis. Hematopoietic stem cell transplantation (HSCT) from an unrelated donor (URD) is one of the most effective treatment options. Two institutions have independently adopted a post-transplantation cyclophosphamide (PTCy) approach for patients with SAA undergoing HSCT from a URD. Thirteen patients were included, 11 of whom had been treated with immunosuppressive therapy. Eight patients had a mismatched URD. All patients were conditioned with fludarabine, cyclophosphamide, and total body irradiation, in various dosage combinations. PTCy was given at a dose of 100 mg/kg. Two patients died, and overall survival was 85% at 2 years. All patients engrafted, but 1 patient developed secondary graft failure. Of the 11 patients alive after 2 years, 9 had complete donor chimerism. All surviving patients were transfusion-independent. Ten patients (77%) had cytomegalovirus reactivation, and 2 patients had more than 1 reactivation. No Epstein-Barr virus reactivation or post-transplantation lymphoproliferative disease was observed. Four patients had mild hemorrhagic cystitis. In summary, our findings show that PTCy is a promising treatment for patients with SAA undergoing URD HSCT., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

A replicated 5 × 5 Latin square design with a 2 × 2 + 1 factorial arrangement of treatments was used to determine the effects of bismuth subsalicylate (BSS) and encapsulated calcium ammonium nitrate (eCAN) on ruminal fermentation of beef cattle consuming bahiagrass hay (Paspalum notatum) and sugarcane molasses. Ten ruminally cannulated steers (n = 8; 461 ± 148 kg of body weight [BW]; average BW ± SD) and heifers (n = 2; 337 ± 74 kg of BW) were randomly assigned to one of five treatments as follows: 1) 2.7 g/kg of BW of molasses (NCTRL), 2) NCTRL + 182 mg/kg of BW of urea (U), 3) U + 58.4 mg/kg of BW of BSS (UB), 4) NCTRL + 538 mg/kg of BW of eCAN (NIT), and 5) NIT + 58.4 mg/kg of BW of BSS (NITB). With the exception of NCTRL, all treatments were isonitrogenous. Beginning on day 14 of each period, ruminal fluid was collected and rectal temperature was recorded 4× per day for 3 d to determine ruminal changes every 2 h from 0 to 22 h post-feeding. Ruminal gas cap samples were collected at 0, 3, 6, 9, and 12 h on day 0 of each period followed by 0 h on days 1, 2, 3, and 14. Microbial N flow was determined using Cr-Ethylenediaminetetraacetic acid, YbCl3, and indigestible neutral detergent fiber for liquid, small particle, and large particle phases, respectively. Data were analyzed using the MIXED procedure of SAS. Orthogonal contrasts were used to evaluate the effects of nonprotein nitrogen (NPN) inclusion, NPN source, BSS, and NPN source × BSS. There was no treatment effect (P > 0.05) on concentrations of H2S on day 0, 1, 2, or 14; however, on day 3, concentrations of H2S were reduced (P = 0.018) when NPN was provided. No effect of treatment (P = 0.864) occurred for ruminal pH. There was an effect of NPN source on total concentrations of VFA (P = 0.011), where a 6% reduction occurred when eCAN was provided. There were effects of NPN (P = 0.001) and NPN source (P = 0.009) on the concentration of NH3-N, where cattle consuming NPN had a greater concentration than those not consuming NPN, and eCAN reduced the concentration compared with urea. Total concentrations of VFA and NH3-N were not affected (P > 0.05) by BSS. There was an effect of BSS (P = 0.009) on rectal temperature, where cattle not consuming BSS had greater temperatures than those receiving BSS. No differences for NPN, NPN source, nor BSS (P > 0.05) were observed for microbial N flow. In conclusion, eCAN does not appear to deliver equivalent ruminal fermentation parameters compared with urea, and BSS has limited effects on fermentation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Two randomized block designs were performed to evaluate the effects of bismuth subsalicylate (BSS) and encapsulated calcium-ammonium nitrate (eCAN) on enteric methane production, nutrient digestibility, liver mineral concentration, and performance of beef cattle consuming bahiagrass hay (Paspalum notatum; ad libitum) and sugar cane molasses [1.07 kg/d; dry matter basis]. Experiment 1, used 25 crossbred steers [335 ± 46 kg of initial body weight (BW)] with a 2 × 2 + 1 factorial arrangement of treatments for two 20 d periods. Factors were nonprotein nitrogen (NPN) source (350 mg/kg BW of nitrate or 182 mg/kg BW of urea), BSS (0 or 58.4 mg/kg BW), and a negative control (NCTRL; bahiagrass hay and molasses only). Steers were re-randomized for a second period (n = 10/treatment total). Intake, apparent total tract digestibility and enteric methane were evaluated. Experiment 2 used 75 crossbred heifers in 25 pens (3 heifers/pen; 279 ± 57 kg of initial BW), consuming the same diet and treatments as experiment 1, to determine liver mineral concentration and growth performance over 56 d. Orthogonal contrasts were used to evaluate the effects of NPN (NCTRL vs. others), source of NPN (NS; urea vs. eCAN), BSS, and NS × BSS. For experiment 1, no interactions were observed for any variables, nor were there any effects of NPN on total tract digestibility of nutrients, except for crude protein. Digestibility of all nutrients was reduced (P ≤ 0.021) for steers consuming eCAN compared with urea. There was no effect (P > 0.155) of BSS on digestibility of nutrients; however, BSS reduced (P = 0.003) apparent S retention. Enteric CH4 emission (g/kg BW0.75) was decreased (P = 0.051) by 11% with the addition of eCAN compared with urea. For experiment 2, no NS × BSS interactions (P ≥ 0.251) were observed to affect liver mineral concentration; however, the addition of BSS decreased liver concentration of Cu (P = 0.002) while increasing Fe concentration (P = 0.016). There was an NS × BSS interaction (P = 0.048) where heifers consuming eCAN and BSS had lesser final BW compared with heifers consuming urea and BSS. While eCAN may be a viable resource for mitigating enteric CH4 production of forage-fed cattle, the negative effects on digestibility should be considered. Furthermore, BSS, at the amount provided, appears to have no negative effects on digestibility of nutrients in forage-fed cattle; however, there may be deleterious impacts on performance depending upon what nitrogen source is supplied., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha ( HIF-2α ) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice.

Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.

β-hydroxy-β-methyl butyrate (HMB) is a bioactive metabolite derived from the amino acid leucine, usually applied for muscle mass increase during physical training, as well as for muscle mass maintenance in debilitating chronic diseases. The hypothesis of the present study is that HMB is a safe supplement for muscle mass gain by strength training. Based on this, the objective was to measure changes in body composition, glucose homeostasis and hepatic metabolism of HMB supplemented mice during strength training. Two of four groups of male mice (n = 6/group) underwent an 8-week training period session (climbing stairs) with or without HMB supplementation (190 mg/kgBW per day). We observed lower body mass gain (4.9 ± 0.43% versus 1.2 ± 0.43, p < 0.001) and increased liver mass (40.9 ± 0.9 mg/gBW versus 44.8 ± 1.3, p < 0.001) in the supplemented trained group compared with the non-supplemented groups. The supplemented trained group had an increase in relative adipose tissue mass (12.4 ± 0.63 mg/gBW versus 16.1 ± 0.88, P < 0.01) compared to the non-supplemented untrained group, and an increase in fasting blood glucose (111 ± 4.58 mg/dL versus 122 ± 3.70, P < 0.05) and insulin resistance (3.79 ± 0.19 % glucose decay/min versus 2.45 ± 0.28, P < 0.05) comparing with non-supplemented trained group. Adaptive heart hypertrophy was observed only in the non-supplemented trained group (4.82 ± 0.05 mg/gBW versus 5.12 ± 0.13, P < 0.05). There was a higher hepatic insulin-like growth factor-1 expression (P = 0.002) in supplemented untrained comparing with non-supplemented untrained group. Gene expression of gluconeogenesis regulatory factors was increased by training and reduced by HMB supplementation. These results confirm that HMB supplementation associated with intensive training protocol drives changes in glucose homeostasis and liver metabolism in mice.

This experiment evaluated the effect of a blend of essential oils ( BEO ) on intake, lactation performance, diet digestibility, ruminal fermentation profile, eating behavior, body thermoregulation, blood acid-base balance, and milk fatty acid profile of lactating cows. Twenty-eight Holstein cows were individually fed a standard diet for 14 d and treatments control or BEO (a microencapsulated blend of pepper extract containing capsaicin and pure forms of carvacrol, cinnamaldehyde, and eugenol; 150 mg/kg of diet dry matter) for 56 d. Significance was declared at P ≤ 0.05 and trends at 0.05 < P ≤ 0.10. Dry matter intake ( DMI ) was reduced (19.5 vs. 20.1 kg/d) and milk yield was increased (30.1 vs. 30.8 kg/d) by BEO, inducing improved milk to DMI ratio (1.53 vs. 1.62). Milk fat concentration tended to be increased by BEO, but total solids yield did not differ. There was a trend for increased total tract non-neutral detergent fiber organic matter digestibility with BEO. The molar proportion of acetate in ruminal fluid was reduced (51.4 vs. 57.8%) and that of propionate was increased (26.1 vs. 31.3%) by BEO. Ruminal microbial yield and total protozoa count in ruminal fluid did not differ. Cows fed BEO ingested a greater proportion of the daily intake in the morning (30.6 vs. 36.6%) and tended to ingest a lower proportion at night, tended to have longer meals, and had fewer meals per day (11.9 vs. 13.7) and larger meal size (1.5 vs. 1.7 kg of dry matter per meal). Blood urea-N and glucose concentrations did not differ. The BEO increased jugular blood oxygenation. The sweating rate on a hot and dry day was increased (160 vs. 221 g/m 2 /h) by BEO. The mean rectal and skin temperatures and respiration rate did not differ, but the proportion of rectal temperature measurements ≥39.2 °C was reduced by BEO at 1400 h (17.8 vs. 28.5%) and 2000 h (23.2 vs. 34.8%). The BEO increased the secretion (g/d) of 18:2 trans -10, cis -12 and the concentration of 18:0 iso fatty acids in milk fat. When one sample of milk from BEO cows was offered with two samples of milk from control, 59% of regular consumers of milk ( n = 63) identified the odd sample correctly. The gain in feed efficiency induced by BEO was associated with reduced acetate-to-propionate ratio in ruminal fluid, altered eating behavior, lower frequency of high rectal temperature, and increased blood oxygenation. Essential oils had positive effects on ruminal fermentation and systemic variables of dairy cows., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science.)

The objective of this study was to evaluate the effects of using encapsulated nitrate product (ENP) replacing soybean meal in diets differing in concentrate to forage ratio on ruminal fermentation and methane production in vitro using a semi-automatic gas production technique. Eight treatments were used in a randomized complete design with a 2 × 4 factorial arrangement: two diet (20C:80F and 80C:20F concentrate to forage ratio) and four levels of ENP addition (0%, 1.5%, 3.0%, and 4.5% of DM) replacing soybean meal. There was a diet × ENP interaction (p = 0.02) for methane production. According to ENP addition, diets with 80C:20F showed more intense reduction on methane production that 20C:80F. A negative linear effect was observed for propionate production with ENP addition in diet with 80C:20F and to the relative abundance of methanogens Archaea, in both diet. The replacement of soybean meal by ENP in levels up to 3% of DM inhibited methane production due to a reduction in the methanogens community without affecting the organic matter degradability. However, ENP at 4.5% of DM level affected fiber degradability, abundance of cellulolytic bacteria, and propionic acid production, indicating that this level of inclusion is not recommended for ruminant production., (© 2019 Japanese Society of Animal Science.)

This study investigated the long-term effects (13 months) of encapsulated nitrate supplementation (ENS) on enteric methane emissions, rumen fermentation parameters, ruminal bacteria, and diversity of archaea in grazing beef cattle. We used a total of thirty-two Nellore steers (initial BW of 197 ± 15.3 kg), 12 of which were fitted with rumen cannulas. For 13 months, the animals were maintained in 12 paddocks and fed a concentrate of ground corn, soybean meals, mineral supplements, and urea (URS) or encapsulated nitrate (EN) containing 70 g of EN/100 kg of BW (corresponding to 47 g NO 3 - /100 kg BW). Encapsulated nitrate supplementation resulted in similar forage, supplement and total DMI values as URS ( P > 0.05), but ENS tended to increase (+48 g/d; P = 0.055) average daily weight gain. Daily reductions in methane emissions (-9.54 g or 18.5%) were observed with ENS when expressed as g of CH 4 /kg of forage dry matter intake (fDMI) ( P = 0.037). Lower concentrations of NH 3 -N and a higher ruminal pH were observed in ENS groups 6 h after supplementation ( P < 0.05). Total VFA rumen concentration 6 h ( P = 0.009) and 12 h after supplementation with EN resulted in lower acetate concentrations in the rumen ( P = 0.041). Steers supplemented with EN had a greater ruminal abundance of Bacteroides, Barnesiella, Lactobacillus , Selenomonas, Veillonella, Succinimonas, Succinivibrio , and Duganella sp. ( P < 0.05), but a lower abundance of Methanobrevibacter sp. ( P = 0.007). Strong negative correlations were found between daily methane emissions and Proteobacteria, Erysipelotrichaceae, Prevotellaceae, and Roseburia , Kandleria , Selenomonas , Veillonella , and Succinivibrio sp. ( P < 0.05) in the rumen of ENS steers. Encapsulated nitrate is a feed additive that persistently affects enteric methane emission in grazing steers, thereby decreasing Methanobrevibacter abundance in the rumen. In addition, ENS can promote fumarate-reducer and lactate-producer bacteria, thereby reducing acetate production during rumen fermentation.

Molecules from natural sources, such as essential oils, have shown activity against parasites in vitro, but have not yet been explored extensively in vivo. Anethole and carvone (10% each), encapsulated with 80% of a solid matrix, referred to as EO (encapsulated oils), were tested in vivo in 2 experiments. In Experiment 1: Lambs were artificially infected with multidrug resistant Haemonchus contortus, or left uninfected, and treated (or not) with 50 mg/kg bw (body weight) of EO in a controlled environment. Thirty-two male lambs were kept in individual cages for a period of 45 days, after which animals were evaluated for parasitological, hematological, toxicological, and nutritional parameters. After 45 days of treatment, EO at 50 mg/kg bw provided a significant (P ≤ 0.05) reduction in fecal egg count (FEC). Although FEC was reduced, animals from both treatments had similar counts of total adult worms. The low FEC was caused probably by a significant reduction (P ≤ 0.05) in both male worm size and female fecundity. Dry matter intake of uninfected controls was significantly (P ≤ 0.05) reduced, although no toxicity was observed in treated animals. Thus, in Experiment 2, conducted for five months we used an EO dose of 20 mg/kg bw. Thirty-four weaned lambs, free of parasites, were divided in two groups and kept in collective pens. One group received EO at 20 mg/kg bw mixed with concentrate for 5 months and the other was kept as a control group (CTL). Parasitological and hematological parameters as well as body weight were evaluated. In the first 2.5 months, CTL and EO groups were confined, and both presented similar clinical parameters. Then, animals were allotted to graze on contaminated pastures to acquire natural infection for the next 2.5 months. The infection was patent after 25 days and both groups had similar decreases in weight gain, increases in FEC, and decreases in blood parameters. Coprocultures from CTL and EO groups established that parasite population was 90% Haemonchus sp. We concluded that the technology of encapsulation is safe and practical to deliver to lambs at the farm level and anethole and carvone at 50 mg/kg bw caused a significant decrease in FEC and, consequently, in pasture contamination by free living stages of H. contortus. However, EO at 20 mg/kg bw was not effective to prevent or treat sheep naturally-infected with gastrointestinal nematodes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A long-term study (112 days) was conducted to examine the effect of feeding encapsulated nitrate (NO₃ - ), microencapsulated blend of essential oils (EO), and their combination on growth performance, feeding behavior, and enteric methane (CH₄) emissions of beef cattle. A total of 88 crossbred steers were purchased and assigned to one of four treatments: (i) control, backgrounding high-forage diet supplemented with urea (1.17% in dietary DM); (ii) encapsulated NO₃ - (EN), control diet supplemented with 2.5% encapsulated NO₃ - as a replacement for urea (1.785% NO₃ - in the dietary DM); (iii) microencapsulated blend of EO (MBEO), control diet supplemented with 150 mg/kg DM of microencapsulated blend of EO and pepper extract; and (iv) EN + MBEO, control diet supplemented with EN and MBEO. There was no interaction ( p ≥ 0.080) between EN and MBEO on average dry matter intake (DMI), average daily gain (ADG), gain to feed ratio (G:F), feeding behavior, and CH₄ emission (using GreenFeed system), implying independent effects of feeding EN and MBEO. Feeding MBEO increased CH₄ production (165.0 versus 183.2 g/day; p = 0.005) and yield (18.9 versus 21.4 g/kg DMI; p = 0.0002) but had no effect ( p ≥ 0.479) on average DMI, ADG, G:F, and feeding behavior. However, feeding EN had no effect on ADG and G:F ( p ≥ 0.119) but reduced DMI (8.9 versus 8.4 kg/day; p = 0.003) and CH₄ yield (21.5 versus 18.7 g/kg DMI; p < 0.001). Feeding EN slowed ( p = 0.001) the feeding rate (g of DM/min) and increased ( p = 0.002) meal frequency (events/day). Our results demonstrate that supplementing diets with a blend of EO did not lower CH₄ emissions and there were no advantages of feeding MBEO with EN. Inclusion of EN as a replacement for urea reduced CH₄ emissions but had no positive impact on animal performance.

Acute intra-renal infusion of bradykinin increases diuresis and natriuresis via inhibition of vasopressin activity. However, the consequences of chronically increased bradykinin in the kidneys have not yet been studied. A new transgenic animal model producing an excess of bradykinin by proximal tubular cells (KapBK rats) was generated and submitted to different salt containing diets to analyze changes in blood pressure and other cardiovascular parameters, urine excretion, and composition, as well as levels and expression of renin-angiotensin system components. Despite that KapBK rats excrete more urine and sodium, they have similar blood pressure as controls with the exception of a small increase in systolic blood pressure (SBP). However, they present decreased renal artery blood flow, increased intrarenal expression of angiotensinogen, and decreased mRNA expression of vasopressin V1A receptor (AVPR1A), suggesting a mechanism for the previously described reduction of renal vasopressin sensitivity by bradykinin. Additionally, reduced heart rate variability (HRV), increased cardiac output and frequency, and the development of cardiac hypertrophy are the main chronic effects observed in the cardiovascular system. In conclusion: (1) the transgenic KapBK rat is a useful model for studying chronic effects of bradykinin in kidney; (2) increased renal bradykinin causes changes in renin angiotensin system regulation; (3) decreased renal vasopressin sensitivity in KapBK rats is related to decreased V1A receptor expression; (4) although increased renal levels of bradykinin causes no changes in mean arterial pressure (MAP), it causes reduction in HRV, augmentation in cardiac frequency and output and consequently cardiac hypertrophy in rats after 6 months of age.

Physical exercise is a strong external effector that induces precursor cell proliferation in the adult mouse hippocampus. Research into mechanisms has focused on central changes within the hippocampus and we have established that serotonin is the signaling factor that transduces physical activity into adult neurogenesis. Less focus has been given on potential peripheral signals that may cause pro-mitotic running effects. Vasoactive kinin peptides are important for blood pressure regulation and inflammatory processes to maintain cardiovascular homeostasis. Acting via the two receptors termed B1 (B1R) and B2R, the peptides also function in the brain. In particular, studies attribute B2R a role in cell proliferation and differentiation into neurons in vitro. Here, we determined B1R and B2R mRNA expression levels in the adult mouse hippocampus and prefrontal cortex in vivo, and in response to running exercise. Using mice depleted in either or both receptors, B1-knockout (KO), B2KO and B1/2KO we observed changes in running performance overnight and in running distances. However, voluntary exercise led to the known pro-mitotic effect in the dentate gyrus of B1KO mice while it was attenuated in B2KO accompanied by an increase in microglia cells. Our data identify B2R as an important factor in running-induced precursor cell proliferation.

Angiotensin-I-converting enzyme (ACE) is involved in the synthesis and degradation of important bioactive peptides. The ACE gene has a 287-bp insertion/deletion polymorphism that controls ACE expression through a mechanism that remains elusive. In this study, we found that the 287-bp polymorphic element of the ACE gene, a member of the AluYa5 sub-family of Alu elements, codes for an RNA molecule that controls the levels of ACE mRNA. Transient transfection of a plasmid containing a CMV promoter upstream of the ACE polymorphic element resulted in significant expression of an AluYa5 RNA and reduced ACE mRNA expression as well as ACE enzymatic activity in AD 293 cells. The AluYa5 element also independently reduced the expression of other genes, regardless of whether these genes harbored Alu elements within their genomic context. Interestingly, the CMV promoter was not required for the expression of the AluYa5 element in AD 293 cells. The 287-bp sequence was sufficient to produce AluYa5 RNA and led to a significant reduction in ACE gene expression. Moreover, the removal of an 11-bp fragment of the 3' end of the ACE polymorphic sequence, which is specific to this particular AluYa5 element, did not prevent this element from being expressed but did affect its ability to target ACE expression. Thus, the expression of the AluYa5 polymorphic element within the ACE gene could explain why patients carrying the ACE insertion polymorphism have reduced risk of developing several chronic diseases.

The supplementation of dairy cows with yeast culture may increase diet digestibility, plasma niacin concentration, heat dissipation, and lactation performance. Our objective was to evaluate the response of Holstein cows in late lactation (234 ± 131 d in milk) to dead yeast culture (YC, 15 g/d, Factor SC, GRASP, Saccharomyces cerevisiae) during Brazilian summer (temperature-humidity index >68 for 92.2% of the time). Thirty-two cows were individually fed a standard total mixed ration for 14 d and control (CTL) or YC treatments for 35 d, in a covariate adjusted complete randomized block design. Response was evaluated in wk 5 or as repeated measures over time. Cows were milked 3 times per day and treatments (YC or placebo) were orally dosed to each cow before each milking. Plasma niacin was 1.50 for CTL and 1.66 µg/mL for YC. The YC reduced rectal temperature, respiration rate, and skin temperature, whereas it tended to increase sweating rate. The proportion of cows with rectal temperature ≥39.2°C on CTL and YC was, respectively, 8 and 0% at 0730 h, 52 and 25% at 1500 h, and 35 and 26% at 2200 h. Plasma glucose was increased by YC. The total-tract apparent digestibility of nutrients, plasma urea N concentration, molar proportion of ruminal VFA, and urinary allantoin excretion were not affected by YC. Cows fed YC were less selective against feed particles >19 mm in the morning, in the afternoon were more selective against long feed particles and in favor of particles <8 mm, and refused short particles at night. Milk yield was not different (30.5 kg/d for CTL and 30.2 kg/d for YC). Feeding YC reduced dry matter intake (20.3 vs. 19.4 kg/d) and the digestible organic matter intake (15.6 vs. 13.9 kg/d). The inclusion of YC increased the ratios of milk to dry matter intake (1.50 vs. 1.64) and energy-corrected milk to dry matter intake (1.81 vs. 1.98). The covariate adjusted body weight (648 kg) and body condition score (3.0) did not differ. Milk solids yields and concentrations, linear somatic cell count, and milk urea N were also similar. The supplementation of YC increased plasma niacin concentration, body heat loss, and feed efficiency of late lactation dairy cows by reducing intake at similar milk yield., (Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Anthelmintic resistance in sheep gastrointestinal nematodes is a worldwide problem. Multi-drug resistant haemonchosis is the most serious impediment for small ruminant systems, and there are no new drug candidates currently under development. Molecules from natural sources have demonstrated anthelmintic activity against parasites. In this work, the monoterpenoids carvacrol, carvone, cineole, linalool, limonene, and thymol and the phenylpropanoids cinnamaldehyde, anethole, vanillin, and eugenol were assessed individually or in mixtures of ten binary, three ternary, and three quaternary combinations using the in vitro egg hatch assay with eggs of a multi-drug resistant strain of Haemonchus contortus. The main objective of this study was to identify the most effective interaction among essential oils with the greatest individual anthelmintic efficacy and to determine the most powerful combinations. The essential oils were ranked by their 50% lethal concentration (LC 50 ) as follows (mg/mL): cinamaldehyde (0.018), anethole (0.070), carvone (0.085), carvacrol (0.11), thymol (0.13), linalool (0.29), vanillin (0.57), eugenol (0.57), cineole (4.74), and limonene (207.5). Quantification of synergism, additive effect, and antagonism were calculated for binary, ternary, and quaternary combinations. The best anthelmintic effect resulting from synergistic activity among 16 different combinations was for cinnamaldehyde:carvacrol (CL 50 0.012mg/mL) and anethole:carvone (CL 50 0.013mg/mL). These results indicate that these binary combinations would be promising to be tested in sheep infected with H. contortus., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A finishing feedlot study was conducted with beef steers to determine effects of encapsulated nitrate (EN) on growth performance, carcass characteristics, methane production, and nitrate (NO) residues in tissues. The 132 crossbred steers were backgrounded in a feedlot for 91 d and transitioned for 28 days to the high-concentrate diets evaluated in the present study, maintaining the treatment and pen assignments designated at the start of the backgrounding period. The steers were initially assigned to 22 pens (6 animals per pen) in a randomized complete block design with BW (18 pens) and animals designated for methane measurement (4 pens) as blocking factors. Five animals in each pen designated for methane measurement (total of 20 animals) were monitored for methane emissions in respiratory chambers twice during the experiment. Pens received 3 dietary treatments (7 pens each): Control, a finishing diet supplemented with urea; 1.25% EN, control diet supplemented with 1.25% encapsulated NO in dietary DM that partially replaced urea; and 2.5% EN, control diet supplemented with 2.5% EN (DM basis) fully replacing urea. The final pen designated only for methane measurement received a fourth dietary treatment, 2.3% UEN, the control diet supplemented with unencapsulated NO (UEN) fully replacing urea. The cattle weighed 449 ± SD 32 kg at the start of the 150-d finishing period. The 2.5% EN diet decreased ( < 0.01) DMI compared with Control and 1.25% EN diets. Feeding EN tended to increase ( = 0.092) ADG compared with Control, and G:F was improved ( < 0.01) for EN compared with Control. No differences in methane production (g/d) and yield (g/kg DMI) were observed among treatments. Inclusion of EN in the diets increased ( ≤ 0.03) sorting in favor of large and medium particles and against small and fine particles. Plasma NO and NO concentrations were elevated ( < 0.01) with EN in a dose-response manner, but total blood methemoglobin levels for all treatments were low, below the detection limit. Feeding EN increased ( < 0.01) NO concentrations of samples from muscle, fat, liver, and kidney; NO concentrations of these tissues were similar between 1.25% EN and 2.3% UEN. In conclusion, inclusion of 2.5% EN in a finishing diet (DM basis; about 2% NO) did not cause NO toxicity or any health problems in the long term. In comparison with supplemental urea, feeding EN improved feed efficiency despite increases in sorting against dietary EN.

A long-term experiment was conducted to examine the effects of feeding encapsulated nitrate (EN) on growth, enteric methane production, and nitrate (NO) toxicity in beef cattle fed a backgrounding diet. A total of 108 crossbred steers (292 ± 18 kg) were blocked by BW and randomly assigned to 18 pens. The pens (experimental unit; 6 animals per pen) received 3 dietary treatments: Control, a backgrounding diet supplemented with urea; 1.25% EN, control diet supplemented with 1.25% encapsulated calcium ammonium NO (i.e., EN) in dietary DM, which partially replaced urea; or 2.5% EN, control diet supplemented with 2.5% EN (DM basis) fully replacing urea. Additionally, 24 steers were located in 4 pens and randomly assigned to 1 of the above 3 dietary treatments plus a fourth treatment: 2.3% UEN, control diet supplemented with 2.3% unencapsulated calcium ammonium NO (UEN) fully replacing urea. Animals in the additional 4 pens were used for methane measurement in respiratory chambers, and the pens (except UEN) were also part of the performance study (i.e., = 7 pens/treatment). The experiment was conducted for 91 d in a randomized complete block design. During the experiment, DMI was not affected by inclusion of EN in the diet. Feeding EN had no effect on BW, ADG, and G:F ( ≥ 0.57). Methane production (g/d) tended to decrease ( = 0.099) with EN and UEN, but yield (g/kg DMI) did not differ ( = 0.56) among treatments. Inclusion of EN in the diet increased ( ≤ 0.02) sorting of the diets in favor of large and medium particles and against small and fine particles, resulting in considerable increases in NO concentrations of orts without affecting DMI. Plasma NO-N and NO-N concentrations increased ( ≤ 0.05) for EN compared with Control in a dose response manner, but blood methemoglobin levels were below the detection limit. Nitrate concentration in fecal samples slightly increased (from 0.01% to 0.14% DM; < 0.01) with increasing levels of EN in the diet. In conclusion, EN can be used as a feed additive replacing urea in beef cattle during a backgrounding phase in the long term without NO intoxication or any negative effects on growth performance. In addition, the study confirmed that feeding EN tended to decrease enteric methane production in the long term.

Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.