Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). ...This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine TTSTAND velocity, week 24 least squares mean LSM SE 0.052 0.0130 rises/s vs week 48 LSM SE 0.0446 0.0138). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM SE 0.49 1.14; 95% CI -1.80 to 2.78,
= 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
ClinicalTrials.gov Identifier: NCT03439670.
This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
Lipids are a class of molecules that play an important role in cellular structure and metabolism in all cell types. In the last few decades, it has been reported that long-chain fatty acids (FAs) are ...involved in several biological functions from transcriptional regulation to physiological processes. Several fatty acids have been both positively and negatively implicated in different biological processes in skeletal muscle and other tissues. To gain insight into biological processes associated with fatty acid content in skeletal muscle, the aim of the present study was to identify differentially expressed genes (DEGs) and functional pathways related to gene expression regulation associated with FA content in cattle.
Skeletal muscle transcriptome analysis of 164 Nellore steers revealed no differentially expressed genes (DEGs, FDR 10%) for samples with extreme values for linoleic acid (LA) or stearic acid (SA), and only a few DEGs for eicosapentaenoic acid (EPA, 5 DEGs), docosahexaenoic acid (DHA, 4 DEGs) and palmitic acid (PA, 123 DEGs), while large numbers of DEGs were associated with oleic acid (OA, 1134 DEGs) and conjugated linoleic acid cis9 trans11 (CLA-c9t11, 872 DEGs). Functional annotation and functional enrichment from OA DEGs identified important genes, canonical pathways and upstream regulators such as SCD, PLIN5, UCP3, CPT1, CPT1B, oxidative phosphorylation mitochondrial dysfunction, PPARGC1A, and FOXO1. Two important genes associated with lipid metabolism, gene expression and cancer were identified as DEGs between animals with high and low CLA-c9t11, specifically, epidermal growth factor receptor (EGFR) and RNPS.
Only two out of seven classes of molecules of FA studied were associated with large changes in the expression profile of skeletal muscle. OA and CLA-c9t11 content had significant effects on the expression level of genes related to important biological processes associated with oxidative phosphorylation, and cell growth, survival, and migration. These results contribute to our understanding of how some FAs modulate metabolism and may have protective health function.
To assess the associations between TSH and free thyroxine (FT4) levels and decline in functional status in euthyroid older patients at risk of frailty.
Longitudinal prospective study.
Participants ...from the geriatric outpatient clinic of a university hospital, who fulfilled the criteria for frailty or were at risk of frailty, were recruited. Only those euthyroid, defined by age-specific reference range of TSH, were included. Serum was collected during enrollment and at the third and sixth years of follow-up to assess the mean value of all follow-up levels of serum TSH and FT4. Functional status assessing activities of daily living (ADL) and instrumental ADL were evaluated using the Katz Index and the Health Assessment Questionnaire, respectively. Functional decline was defined by a positive variation in any of the applied scales in the absence of disagreement between the scales or if the patient was institutionalized.
Of the 273 participants (72.5% females) enrolled (mean age 80 years old), 48 died and 102 presented functional decline at the end of follow-up (mean 3.6 ± 1.7 years). Each 0.1 ng/dL increase in baseline and mean follow-up serum FT4 levels increased the risk of functional decline by 14.1% and 7.7%, respectively. The risk of functional decline was 9 times greater with baseline FT4 levels in the fourth and fifth quintiles (p = 0.049) and 50% lower with baseline FT4 levels in the first quintile (p = 0.046). No association between TSH and the outcome was found.
Higher and lower FT4 levels were, respectively, a risk and a protective factor for the decline in functional status in a cohort of euthyroid older adults at risk of frailty.
Meat from Bos taurus and Bos indicus breeds are an important source of nutrients for humans and intramuscular fat (IMF) influences its flavor, nutritional value and impacts human health. Human ...consumption of fat that contains high levels of monounsaturated fatty acids (MUFA) can reduce the concentration of undesirable cholesterol (LDL) in circulating blood. Different feeding practices and genetic variation within and between breeds influences the amount of IMF and fatty acid (FA) composition in meat. However, it is difficult and costly to determine fatty acid composition, which has precluded beef cattle breeding programs from selecting for a healthier fatty acid profile. In this study, we employed a high-density single nucleotide polymorphism (SNP) chip to genotype 386 Nellore steers, a Bos indicus breed and, a Bayesian approach to identify genomic regions and putative candidate genes that could be involved with deposition and composition of IMF.
Twenty-three genomic regions (1-Mb SNP windows) associated with IMF deposition and FA composition that each explain ≥1% of the genetic variance were identified on chromosomes 2, 3, 6, 7, 8, 9, 10, 11, 12, 17, 26 and 27. Many of these regions were not previously detected in other breeds. The genes present in these regions were identified and some can help explain the genetic basis of deposition and composition of fat in cattle.
The genomic regions and genes identified contribute to a better understanding of the genetic control of fatty acid deposition and can lead to DNA-based selection strategies to improve meat quality for human consumption.
Feed efficiency is jointly determined by productivity and feed requirements, both of which are economically relevant traits in beef cattle production systems. The objective of this study was to ...identify genes/QTLs associated with components of feed efficiency in Nelore cattle using Illumina BovineHD BeadChip (770 k SNP) genotypes from 593 Nelore steers. The traits analyzed included: average daily gain (ADG), dry matter intake (DMI), feed-conversion ratio (FCR), feed efficiency (FE), residual feed intake (RFI), maintenance efficiency (ME), efficiency of gain (EG), partial efficiency of growth (PEG) and relative growth rate (RGR). The Bayes B analysis was completed with Gensel software parameterized to fit fewer markers than animals. Genomic windows containing all the SNP loci in each 1 Mb that accounted for more than 1.0% of genetic variance were considered as QTL region. Candidate genes within windows that explained more than 1% of genetic variance were selected by putative function based on DAVID and Gene Ontology.
Thirty-six QTL (1-Mb SNP window) were identified on chromosomes 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 19, 20, 21, 22, 24, 25 and 26 (UMD 3.1). The amount of genetic variance explained by individual QTL windows for feed efficiency traits ranged from 0.5% to 9.07%. Some of these QTL minimally overlapped with previously reported feed efficiency QTL for Bos taurus. The QTL regions described in this study harbor genes with biological functions related to metabolic processes, lipid and protein metabolism, generation of energy and growth. Among the positional candidate genes selected for feed efficiency are: HRH4, ALDH7A1, APOA2, LIN7C, CXADR, ADAM12 and MAP7.
Some genomic regions and some positional candidate genes reported in this study have not been previously reported for feed efficiency traits in Bos indicus. Comparison with published results indicates that different QTLs and genes may be involved in the control of feed efficiency traits in this Nelore cattle population, as compared to Bos taurus cattle.
The aim of the present work was to evaluate the impact of xerostomia on the quality of life of patients who underwent radiotherapy in the head and neck region.
This was a cross-sectional, ...quantitative study. The sample comprised 40 patients whose xerostomia was classified through the xerostomia inventory and the quality of life evaluated through the oral health impact profile questionnaire (OHIP).
The majority of participants were male (75%), mean age 58.7 years. According to the degree of severity of the xerostomia, the average score among the participants was 36 points, this being considered moderate xerostomia. A significant impact was observed, with the median score 11 points, with the highest scores in the domains related to functional limitation, physical pain and physical disability. The majority of the participants (97.5%) had reduced salivary flow after the end of radiotherapy. There was a significant positive correlation between the degree of xerostomia and reduced quality of life, Pearson correlation 0.5421, (p<0.05).
Based upon the results it is concluded that xerostomia has a negative impact on the quality of life of patients who undergo radiotherapy in the head and neck region.
This study aimed to determine the agreement between fat-free mass (FFM) estimates from bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA) and their use in estimating ...resting metabolic rate (RMR) in men undergoing resistance training.BACKGROUNDThis study aimed to determine the agreement between fat-free mass (FFM) estimates from bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA) and their use in estimating resting metabolic rate (RMR) in men undergoing resistance training.Thirty healthy resistance-trained men (22.7 ± 4.4 years, 70.0 ± 8.7 kg, 174.6 ± 6.7 cm, and 22.9 ± 2.3 kg/m2) were evaluated. The equation developed by Tinsley et al. (RMR = 25.9 × fat-free mass FFM + 284) was adopted to calculate the RMR. DXA was used as the reference method for FFM.METHODSThirty healthy resistance-trained men (22.7 ± 4.4 years, 70.0 ± 8.7 kg, 174.6 ± 6.7 cm, and 22.9 ± 2.3 kg/m2) were evaluated. The equation developed by Tinsley et al. (RMR = 25.9 × fat-free mass FFM + 284) was adopted to calculate the RMR. DXA was used as the reference method for FFM.Furthermore, FFM was also estimated by BIA using a spectral device. No significant difference (p > 0.05) was observed between DXA (1884.2 ± 145.5 kcal) and BIA (1849.4 ± 167.7 kcal) to estimate RMR. A positive and significant correlation (r = 0.89, p < 0.05) was observed between DXA and BIA estimates of RMR. The mean difference between methods indicated that BIA presented a bias of -34.8 kcal.RESULTSFurthermore, FFM was also estimated by BIA using a spectral device. No significant difference (p > 0.05) was observed between DXA (1884.2 ± 145.5 kcal) and BIA (1849.4 ± 167.7 kcal) to estimate RMR. A positive and significant correlation (r = 0.89, p < 0.05) was observed between DXA and BIA estimates of RMR. The mean difference between methods indicated that BIA presented a bias of -34.8 kcal.These findings suggest that using FFM derived from DXA or BIA results in similar RMR estimates in resistance-trained men.CONCLUSIONThese findings suggest that using FFM derived from DXA or BIA results in similar RMR estimates in resistance-trained men.
•Both rehydrated corn grain silage and high-moisture corn were well conserved.•Inoculation with L. buchneri increased the aerobic stability of both grain silages.•Ruminal degradability increased with ...storage length due to decreased prolamin.•Main changes in the silages occurred during the first two months of storage.
The objective of this study was to compare the conservation of rehydrated corn grain silage (RCGS) and high-moisture corn (HMC), treated or not with Lactobacillus buchneri, and to determine the minimum storage length necessary to improve ruminal in situ dry matter (DM) degradability. The treatments consisted of two grain sources, HMC and RCGS (rehydrated to 350 g/kg of moisture), inoculated with L. buchneri NCIMB 40788 at 1 × 105 cfu/g (LB) or chlorine free water (Control), and stored for 15, 30, 60, 90, 120, 180, 240, and 300 days. The concentrations of lactic, acetic, and propionic acids, and 1,2-propanediol were higher (P < 0.044), whereas butyric acid was lower (P < 0.001) in RCGS compared with HMC. Inoculation with LB reduced (P < 0.001) the concentration of lactic acid and increased (P < 0.001) the pH, acetic acid, and lactic acid bacteria counts. Therefore, silages inoculated with LB had prolonged aerobic stability. Silages inoculated with LB had more (P < 0.001) ammonia and less (P < 0.001) prolamin than that in Control silage, although ruminal in situ DM degradability was not affected by inoculation (P > 0.588). The content of ammonia and ruminal in situ DM degradability increased (P < 0.001) with the storage length, which coincided with a gradual decrease (P < 0.001) in prolamin concentration. According to a broken-line regression, higher gains in ruminal in situ DM degradability occurred up to 71 and 52 days of storage for HMC and RCGS, respectively. In summary, RCGS is an alternative to HMC, and L. buchneri improved the aerobic stability of RCGS and HMC. Based on the ruminal in situ DM degradability, it is recommended storing corn grain silages for at least two months before feeding.
Axon guidance is required for the establishment of brain circuits. Whether much of the molecular basis of axon guidance is known from animal models, the molecular machinery coordinating axon growth ...and pathfinding in humans remains to be elucidated. The use of induced pluripotent stem cells (iPSC) from human donors has revolutionized in vitro studies of the human brain. iPSC can be differentiated into neuronal stem cells which can be used to generate neural tissue-like cultures, known as neurospheres, that reproduce, in many aspects, the cell types and molecules present in the brain. Here, we analyzed quantitative changes in the proteome of neurospheres during differentiation. Relative quantification was performed at early time points during differentiation using iTRAQ-based labeling and LC-MS/MS analysis. We identified 6438 proteins, from which 433 were downregulated and 479 were upregulated during differentiation. We show that human neurospheres have a molecular profile that correlates to the fetal brain. During differentiation, upregulated pathways are related to neuronal development and differentiation, cell adhesion, and axonal guidance whereas cell proliferation pathways were downregulated. We developed a functional assay to check for neurite outgrowth in neurospheres and confirmed that neurite outgrowth potential is increased after 10 days of differentiation and is enhanced by increasing cyclic AMP levels. The proteins identified here represent a resource to monitor neurosphere differentiation and coupled to the neurite outgrowth assay can be used to functionally explore neurological disorders using human neurospheres as a model.
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•Quantitative proteomic analysis of human neurospheres during differentiation using isobaric labeling (iTRAQ).•Axon guidance proteins are increased during differentiation.•Increased neurite outgrowth during differentiation is shown in a neuron outgrowth assay.•Neuron outgrowth in neurospheres is regulated by PKA and cAMP.•Axon guidance proteins related to neurological disorders are highlighted.
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