Introduction
Heterozygotes (HZs) for 21‐hydroxylase deficiency (21OHD) are highly prevalent, ranging from 1:60 to 1:11 for classic and nonclassic (NC) forms, respectively. Detection of HZ and ...asymptomatic NC by CYP21A2 genotyping is valuable for genetic counselling, but costly, complex and narrowly available. Adrenocorticotropic hormone (ACTH)‐stimulated serum 17‐hydroxyprogesterone (17P) and 21‐deoxycortisol (21DF) discriminate 21OHD phenotypes effectively, notably if measured simultaneously by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS).
Objective
This study was performed to reassess former LC‐MS/MS‐defined post‐ACTH 21DF, 17P and cortisol (F) cutoffs in family members at risk for 21OHD.
Design and Patients
Prospective study in which we screened 58 asymptomatic relatives from families with 21OHD patients and compared post‐ACTH steroid phenotypes with subsequent genotypes.
Results
Post‐ACTH 21DF, 17P, F and (21DF + 17P)/F ratio segregate NC, HZ and wild‐type (WT) phenotypes (subsequently genotyped) with some overlap. New receiver operating characteristic curve‐defined cutoffs for post‐ACTH 21DF, 17P and (21DF + 17P)/F ratio are 60 ng/dl, 310 ng/dl and 12 (unitless). Twenty‐six of 33 HZ and all 6 NC (82.1%) had post‐ACTH 21DF > 60 and 17P > 310 ng/dl, whereas 17/19 WT (89.5%) had values below cutoffs. Post‐ACTH 21DF and 17P had a strong positive correlation (r = .9558; p < .001). A (21DF + 17P)/F ratio > 12 correctly identified 36 of 39 HZ plus NC (92.3% sensitivity) with 84.2% specificity (16 of 19 WT). Given the high frequency of 21OHD HZ, the negative prediction of ratio values below 12 excludes heterozygosity in 99.8% and 99.1% for classic and NC mutations, respectively.
Conclusions
Reassessed ACTH‐stimulated 21DF and 17P cutoffs by LC‐MS/MS (60 and 310 ng/dl, respectively) correctly recognised 82.5% HZ plus NC, but combined precursor‐to‐product ratio (21DF + 17P/F) cutoff of 12 was superior, identifying 92.3% HZ plus NC. Since one WT subject is an outlier (potential HZ), these values would be somewhat better reinforcing their utility for screening asymptomatic relatives at risk for 21OHD.
The Iguaçu National Park (INP) is the largest remnant of Atlantic Forest in southern Brazil, representing an ecological continuum with Argentina. The INP harbours a diverse fauna, with ring‐tailed ...coatis (Nasua nasua Linnaeus, 1976, Carnivora: Procyonidae) in close contact with tourists either begging and/or snatching food from visitors. A potentially novel haemotropic Mycoplasma sp. has been previously detected in the ring‐tailed coatis from central‐western and southern Brazil. Therefore, the aims of this study were to investigate the occurrence of haemotropic Mycoplasma sp. and tick‐borne pathogens in wild ring‐tailed coatis from the INP, Foz do Iguaçu municipality, Paraná State, southern Brazil. Blood samples were collected from 18 wild ring‐tailed coatis and evaluated by conventional PCR (cPCR) assays for haemotropic Mycoplasma spp. (16S and 23S rRNA), Theileria/Babesia spp. (18S rRNA) and Ehrlichia/Anaplasma spp. (16S rRNA, sodB, dsb and groEL). Eight out of 18 (44.44%; 95% CI: 24.56%–66.28%) animals were positive for haemotropic Mycoplasma spp. All ring‐tailed coatis tested negative for Theileria/Babesia spp. and only one out of 18 (5.56%; 95% CI: 0.99%–25.76%) animals tested positive for Ehrlichia/Anaplasma spp. by the 16S rRNA cPCR. Unfortunately, multiple attempts to sequence the 16S rRNA gene of the Ehrlichia/Anaplasma‐positive sample have failed. Phylogenetic and network analysis of the hemoplasma 16S and 23S rRNA gene fragments confirmed that animals were infected by a potentially novel haemotropic Mycoplasma sp. previously reported in ring‐tailed coatis from Brazil. The name ‘Candidatus Mycoplasma haematonasua’ is proposed for this novel organism.
Proposals for innovating language education at school are always affected by cultures of teaching and teacher education. This article takes an inquisitive look at task-based language teaching (TBLT) ...as a learner-centred approach, arguing in favour of a realistic understanding of possibilities for educational change. This entails confronting theoretical discourses with the realities of schooling and teacher education, as well as investigating TBLT in particular contexts. An interpretative study is presented, focusing on the use of TBLT by two student teachers (STs) during their English language teaching (ELT) practicum in an initial teacher education (ITE) programme where autonomy-oriented action research projects are developed. Their portfolios and reports account for the feasibility of a weak approach to TBLT that transcends current practices and whose potential for promoting autonomy derives from a professional development framework where teaching and teacher education are conceived as empowering processes. Constraints and shortcomings relate to dominant cultures of teaching, STs' condition as learners, and the practicum model itself. Understanding how language teaching is shaped by contexts and developing empowering approaches to teacher education will help us enhance educational change as an interspace between reality and ideals, where possibilities for transformation are explored.
The transition to a low‐carbon economy endangered the revenues of many oil‐dependent regions. This is the case in Rio de Janeiro state, Brazil, which has become highly dependent on oil and gas ...royalties since the 1970s. At the same time, the circular blue bioeconomy has emerged as a pathway for environmentally sound socioeconomic development. In such a context, a biological resource in many oil‐dependent regions is fish processing residue, from which high added‐value compounds can be obtained, such as collagen, hydroxyapatite, gelatin, lipids, enzymes, hydrolysates, and bioactive peptides. The present study aims to understand the potential for a future fish waste hydroxyapatite (FHAp) market in the state of Rio de Janeiro (SRJ). The methodological approach integrates technology roadmapping with market and innovation ecosystem assessment. We found that the main techniques for obtaining FHAp were chemical hydrolysis and calcination, and the most innovative and value‐added applications were biomaterial for tissue regeneration (BTR) and physical sunblock (PS). The mapping of SRJ companies showed that the state has qualified players in cosmetic and biomedical industries that could develop innovations in BTR and PS made of FHAp. However, the mapping also showed a gap in the FHAp extraction stage, which is essential for the value chain. To find and encourage players to compound this innovation ecosystem, the public power can therefore act as an articulator, providing financial incentives and creating infrastructural conditions, such as a waste pretreatment plant next to the state fishing pole.
Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The
enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and
choline in ...the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the
neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching
the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh
present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE),
forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity
choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the
nucleus basalis of Meynert, are severely lost in Alzheimer's disease (AD). AD is the most ordinary cause of dementia
affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and
amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive
impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons
contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option
to treat AD patients.
BACKGROUND:Methadone is a potent opioid exerting an analgesic effect through N-methyl-D-aspartate receptor antagonism and the inhibition of serotonin and noradrenaline reuptake. It has also been used ...in several procedures to reduce postoperative pain and opioid use. This meta-analysis aimed to determine whether the intraoperative use of methadone lowers postoperative pain scores and opioid consumption in comparison to other opioids.
METHODS:Double-blinded, controlled trials without language restrictions were included from MEDLINE, Embase, LILACS, The Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL via EBSCOhost. The included studies tracked total opioid consumption, postoperative pain scores, opioid-related side effects, and patient satisfaction until 72 hours postoperatively. Mean difference (MD) was used for effect size.
RESULTS:In total, 476 articles were identified and 13 were considered eligible for inclusion in the meta-analysis. In 486 patients (7 trials), pain at rest (MD, 1.09; 95% confidence interval (CI), 1.47–0.72; P < .00001) and at movement (MD, 2.48; 95% CI, 3.04–1.92; P = .00001) favored methadone 24 hours after surgery. In 374 patients (6 trials), pain at rest (MD, 1.47; 95% CI, 3.04–1.02; P < .00001) and at movement (MD, 2.03; 95% CI, 3.04–1.02; P < .00001) favored methadone 48 hours after surgery. In 320 patients (4 trials), pain at rest (MD, 1.02; 95% CI, 1.65–0.39; P = .001) and at movement (MD, 1.34; 95% CI, 1.82–0.87; P < .00001) favored methadone 72 hours after surgery. A Trial Sequential Analysis was performed and the Z-cumulative curve for methadone crossed the monitoring boundary at all evaluations, additionally crossing Required Information Size at 24 and 48 hours at rest. Methadone group also showed lower postoperative opioid consumption in morphine equivalent dosage (mg) at 24 hours (MD, 8.42; 95% CI, 12.99–3.84 lower; P < .00001), 24–48 hours (MD, 14.33; 95% CI, 26.96–1.91 lower; P < .00001), 48–72 hours (MD, 3.59; 95% CI, 6.18–1.0 lower; P = .007) postoperatively.
CONCLUSIONS:Intraoperative use of methadone reduced postoperative pain scores compared to other opioids, and Trial Sequential Analysis suggested that no more trials are required to confirm pain reduction at rest until 48 hours after surgery. Methadone also reduced postoperative opioid consumption and led to better patient satisfaction scores through 72 hours postoperatively compared to other opioids.
•Esketamine 0.25 mg/kg was noninferior to ketamine 0.5 mg/kg in promoting remission of major depression symptoms 24 h after a single intravenous administration in subjects with treatment-resistant ...depression.•Esketamine and ketamine demonstrated a similar safety pattern and were well tolerated by most participants.•This is the first head-to-head randomized clinical trial comparing racemic ketamine and esketamine in patients with treatment-resistant depression.
Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD).
This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%.
63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects.
Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated.
Registered in Japan Primary Registries Network: UMIN000032355.
•VPA revealed antidepressant-like effect in FS and TS tests in mice.•VPA increased hippocampal phospho-Akt levels in WT, but not in PI3Kγ−/− mice.•The antidepressant-like effect of VPA was not ...observed in PI3Kγ−/− mice.•Rapamycin, a mTOR inhibitor, blocked the VPA antidepressant-like effect in FS test.
Few studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation.
C57Bl/6 (WT) and PI3Kγ−/− mice received VPA injections (30, 100 or 300mg/kg, i.p.) and 30min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5mg/kg, i.p.) 150min before VPA administration. Akt phosphorylation levels were measured by Western blotting.
In WT mice, VPA (30mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ−/− mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ−/− mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30mg/kg) in FS test.
These data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.
Language teacher education programmes can promote autonomy-oriented change when they are based on a transformative rationale regarding learner and teacher development. This involves adopting an ...experience-based approach whereby dominant ideas and practices are problematized and opportunities are provided for teachers to learn about, experience, and inquire into autonomy-oriented language teaching practices. A proposal based on the analysis and construction of cases in post-graduate teacher education is presented, in which teachers analyse and design autonomy-oriented action research experiences and produce narratives of inquiry. Six teacher narratives are analysed, showing that experience-based teacher education may enhance teachers’ agency to challenge mainstream practices and explore learner-centred teaching, thus developing professional autonomy in seeking to promote learner autonomy.
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