The development or persistence of pulmonary arterial hypertension (PAH) after atrial septal defect (ASD) closure at adult age is associated with a poor prognosis. The objective of this review was to ...investigate the prevalence of PAH before and after ASD closure and to identify factors that are associated with PAH.
EMBASE and MEDLINE databases were searched for publications until March 2017. All studies reporting the prevalence of PAH or data on pulmonary artery pressures both before and after surgical or percutaneous ASD closure in an adult population (≥16 years of age) were included. Papers were methodologically checked and data was visualized in tables, bar charts and plots.
A total of 30 papers were included. The prevalence of PAH ranged from 29% to 73% before ASD closure and from 5% to 50% after closure; being highest in older studies, small study cohorts, and studies with high rates of loss to follow-up. The pooled systolic pulmonary artery pressure (PAP) was 43±13 before ASD closure and 32±10 after closure. The overall mean PAP was 34±10 before closure and 28±8 after closure. Studies with a higher mean PAP before closure and a higher mean age of the study cohort reported greater PAP reductions.
The prevalence of PAH and mean pulmonary pressures decreased in all studies, regardless of the mean age or pulmonary pressures of the cohort. The reported prevalence of PAH after ASD closure is substantial, although widely varying (5%-50%), which is likely affected by selection of the study cohort.
We sought to develop and test a clinically feasible 1-point Dixon, three-dimensional (3D) radial acquisition strategy to create isotropic 3D MR images of (129)Xe in the airspaces, barrier, and red ...blood cells (RBCs) in a single breath. The approach was evaluated in healthy volunteers and subjects with idiopathic pulmonary fibrosis (IPF).
A calibration scan determined the echo time at which (129)Xe in RBCs and barrier were 90° out of phase. At this TE, interleaved dissolved and gas-phase images were acquired using a 3D radial acquisition and were reconstructed separately using the NUFFT algorithm. The dissolved-phase image was phase-shifted to cast RBC and barrier signal into the real and imaginary channels such that the image-derived RBC:barrier ratio matched that from spectroscopy. The RBC and barrier images were further corrected for regional field inhomogeneity using a phase map created from the gas-phase (129)Xe image.
Healthy volunteers exhibited largely uniform (129)Xe-barrier and (129)Xe-RBC images. By contrast, (129)Xe-RBC images in IPF subjects exhibited significant signal voids. These voids correlated qualitatively with regions of fibrosis visible on CT.
This study illustrates the feasibility of acquiring single-breath, 3D isotropic images of (129)Xe in the airspaces, barrier, and RBCs using a 1-point Dixon 3D radial acquisition.
•VectorBase (VB) integrates diverse data for invertebrates related to human health.•VB provides tools to mine ‘omics and population data.•Develop new hypothesis by mining data using VB’s Search ...Strategy system.•Visualize data across VB with custom graphics, for example, JBrowse and MapVEu.•Analyze and integrate your own data using Galaxy workflows and VB integration.
VectorBase (VectorBase.org) is part of the VEuPathDB Bioinformatics Resource Center, providing free online access to multi-omics and population biology data, focusing on arthropod vectors and invertebrates of importance to human health. VectorBase includes genomics and functional genomics data from bed bugs, biting midges, body lice, kissing bugs, mites, mosquitoes, sand flies, ticks, tsetse flies, stable flies, house flies, fruit flies, and a snail intermediate host. Tools include the Search Strategy system and MapVEu, enabling users to interrogate and visualize diverse ‘omics and population-level data using a graphical interface (no programming experience required). Users can also analyze their own private data, such as transcriptomic sequences, exploring their results in the context of other publicly-available information in the database. Help Desk: help@vectorbase.org.
Mitosis induces cellular rearrangements like spindle formation, Golgi fragmentation, and nuclear envelope breakdown. Similar to certain retroviruses, nuclear delivery during entry of human ...papillomavirus (HPV) genomes is facilitated by mitosis, during which minor capsid protein L2 tethers viral DNA to mitotic chromosomes. However, the mechanism of viral genome delivery and tethering to condensed chromosomes is barely understood. It is unclear, which cellular proteins facilitate this process or how this process is regulated. This work identifies crucial phosphorylations on HPV minor capsid protein L2 occurring at mitosis onset. L2's chromosome binding region (CBR) is sequentially phosphorylated by the master mitotic kinases CDK1 and PLK1. L2 phosphorylation, thus, regulates timely delivery of HPV vDNA to mitotic chromatin during mitosis. In summary, our work demonstrates a crucial role of mitotic kinases for nuclear delivery of viral DNA and provides important insights into the molecular mechanism of pathogen import into the nucleus during mitosis.
Abstract
Background
Since the onset of the COVID-19 pandemic, the worldwide prevalence of maternal depression has risen sharply; it is now estimated that one quarter of mothers experience clinically ...significant depression symptoms. Exposure to maternal depression during early childhood increases the risk for the development of childhood mental illness (MI) in offspring, with altered parenting practices mediating the association between maternal depression and child outcomes. Dual-generation interventions, which aim to simultaneously treat parent and child mental health, show promise for improving outcomes for mothers with depression and their young children. The Building Regulation in Dual Generations (BRIDGE) program combines Dialectical Behavior Therapy (DBT) and parenting skills training to concurrently treat maternal depression and improve parenting practices. In pilot within-group studies, BRIDGE has led to large reductions in maternal depression and child MI symptoms. The aim of the current study is to evaluate the efficacy of BRIDGE in reducing maternal depression and child MI symptoms (primary outcomes) as well as parenting stress and harsh parenting (secondary outcomes).
Methods
A three-armed randomized control trial with equal group sizes will be conducted to compare the efficacy of (1) BRIDGE (DBT + parenting skills), (2) DBT skills training, and (3) services-as-usual. Participants (
n
= 180) will be mothers of 3- to 5-year-old children who report elevated depression symptoms. Those randomized to BRIDGE or DBT skills training will complete a 16-week group therapy intervention. Assessments will be administered at pre-intervention(T1) post-intervention (T2), and 6-month follow-up (T3).
Discussion
Dual-generation programs offer an innovative approach to prevent the intergenerational transmission of mental illness. The current study will add to the evidence base for BRIDGE by comparing it to a stand-alone mental health intervention and a services-as-usual group. These comparisons will provide valuable information on the relative efficacy of including parenting support in a mental health intervention for parents. The results will contribute to our understanding of how maternal depression affects children’s development and how intervening at both a mental health and parenting level may affect child and family outcomes.
Trial registration
Name of registry: Clinical Trials Protocol Registration and Results System; trial registration number: NCT05959538; date of registry: July 24, 2023; available:
https://classic.clinicaltrials.gov/ct2/show/NCT05959538
•Intestinal and biliary epithelia were cultured from cystic fibrosis organoids.•Elexacaftor/ivacaftor/tezacaftor rescued chloride transport in both epithelia.•CFTR modulators enhanced bicarbonate ...transport only in intestinal cells.•Biliary cells secrete bicarbonate and chloride via anoctamin-1, independent of CFTR.
In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport.
Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls. Transcriptome sequencing was performed, and bicarbonate and chloride transport were assessed in the presence or absence of ELX/IVA/TEZ, using the intestinal current measurement technique.
ELX/IVA/TEZ markedly enhanced bicarbonate and chloride transport across intestinal epithelium. In biliary epithelium, it failed to enhance CFTR-mediated bicarbonate transport but effectively rescued CFTR-mediated chloride transport, known to be requisite for bicarbonate secretion through the chloride-bicarbonate exchanger AE2 (SLC4A2), which was highly expressed by cholangiocytes. Biliary but not intestinal epithelial cells expressed an alternative anion channel, anoctamin-1/TMEM16A (ANO1), and secreted bicarbonate and chloride upon purinergic receptor stimulation.
ELX/IVA/TEZ has the potential to restore both chloride and bicarbonate secretion across CF intestinal and biliary epithelia and may counter luminal hyper-acidification in these tissues.
Graphical abstract
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Prenatal opioid exposure is a major health concern in the United States, with the incidence of neonatal opioid withdrawal syndrome (NOWS) escalating in recent years. NOWS occurs upon cessation of in ...utero opioid exposure and is characterized by increased irritability, disrupted sleep patterns, high-pitched crying, and dysregulated feeding. The main pharmacological strategy for alleviating symptoms is treatment with replacement opioids. The neural mechanisms mediating NOWS and the long-term neurobehavioral effects are poorly understood. We used a third trimester-approximate model in which neonatal outbred pups (Carworth Farms White; CFW) were administered once-daily morphine (15 mg/kg, s.c.) from postnatal day (P) day 1 through P14 and were then assessed for behavioral and transcriptomic adaptations within the nucleus accumbens (NAc) on P15. We also investigated the long-term effects of perinatal morphine exposure on adult learning and reward sensitivity. We observed significant weight deficits, spontaneous thermal hyperalgesia, and altered ultrasonic vocalization (USV) profiles following repeated morphine and during spontaneous withdrawal. Transcriptome analysis of NAc from opioid-withdrawn P15 neonates via bulk mRNA sequencing identified an enrichment profile consistent with downregulation of myelin-associated transcripts. Despite the neonatal behavioral and molecular effects, there were no significant long-term effects of perinatal morphine exposure on adult spatial memory function in the Barnes Maze, emotional learning in fear conditioning, or in baseline or methamphetamine-potentiated reward sensitivity as measured via intracranial self-stimulation. Thus, the once daily third trimester-approximate exposure regimen, while inducing NOWS model traits and significant transcriptomic effects in neonates, had no significant long-term effects on adult behaviors.
•We replicated some NOWS model traits via 1x-daily morphine (P1-P14).•We found a downregulation of myelination genes in nucleus accumbens on P15.•There were no effects on learning/memory or reward sensitivity in adults.
Reasons for the highly variable and often poor protection conferred by the Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine are multifaceted and poorly understood.
We aimed to determine ...whether early-life exposure to PCBs (polychlorinated biphenyls) and DDE 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene reduces 6-month infant BCG vaccine response.
Data came from families participating in a prospective birth cohort in eastern Slovakia. At birth, maternal and cord blood were collected for chemical analyses, and infants were immunized with BCG. Blood was collected from infants for chemical analyses and to determine 6-month BCG-specific immunoglobulin (Ig) G and IgA levels. Multivariable linear regression models were fit to examine chemical-BCG associations among approximately 500 mother-infant pairs, with adjustment for confounders.
The median 6-month infant concentration of the prevalent congener PCB-153 was 113 ng/g lipid interquartile range (IQR): 37-248, and 388 ng/g lipid (IQR: 115-847) for DDE. Higher 6-month infant concentrations of PCB-153 and DDE were strongly associated with lower 6-month BCG-specific antibody levels. For instance, BCG-specific IgG levels were 37% lower for infants with PCB-153 concentrations at the 75th percentile compared to the 25th percentile (95% CI: -42, -32; p < 0.001). Results were similar in magnitude and precision for DDE. There was also evidence of PCB-DDE additivity, where exposure to both compounds reduced anti-BCG levels more than exposure to either compound alone.
The associations observed in this study indicate that environmental exposures may be overlooked contributors to poorer responses to BCG vaccine. The overall association between these exposures and tuberculosis incidence is unknown.
Jusko TA, De Roos AJ, Lee SY, Thevenet-Morrison K, Schwartz SM, Verner MA, Palkovicova Murinova L, Drobná B, Kočan A, Fabišiková A, Čonka K, Trnovec T, Hertz-Picciotto I, Lawrence BP. 2016. A birth cohort study of maternal and infant serum PCB-153 and DDE concentrations and responses to infant tuberculosis vaccination. Environ Health Perspect 124:813-821; http://dx.doi.org/10.1289/ehp.1510101.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Aims
Theory‐driven, exploratory study to: (i) identify a reward drinking phenotype in young adults; (ii) evaluate this phenotype as a predictor of naltrexone response; and (iii) examine mechanisms of ...naltrexone in reward drinkers.
Design
Secondary analysis of a randomized controlled trial.
Setting
USA.
Participants
A total of 128 young adult (ages 18–25) heavy drinkers.
Interventions
Naltrexone versus placebo.
Measurements
Daily surveys assessed affect, urge, drinking, and context. The Drinking Motives Questionnaire was used to identify phenotypes based on reward (enhancement motives) and relief (coping motives) drinking.
Findings
We identified three profiles: “Low reward/Low relief” (14.1%; low enhancement/low coping motives); “Reward drinkers” (62.2%; high enhancement/low coping motives); and “High reward/High relief” (22.7%; high enhancement/high coping motives). Among reward drinkers (versus low profile), naltrexone significantly reduced percent days drinking to intoxication (blood alcohol concentration BAC ≥0.08) (PDI) (d = 0.56; 95% CI 0.17, 0.96) and percent high intensity drinking days (PHID) (8/10 drinks for women/men) (d = 0.32; 95% CI 0.01, 0.68). Among the high reward/high relief profile drinkers (versus low profile), naltrexone reduced PHID (d = 0.69; 95% CI 0.02, 1.50). Using profile‐informed cutoffs and observed scores (for clinical applicability): (i) among cutoff‐derived reward drinkers, we found a medium‐to‐large (d = 0.66; 95% CI 0.24, 1.16) and small effect (d = 0.28; 95% CI 0.04, 0.72) of naltrexone in reducing PDI and PHID, respectively; and (ii) among the cutoff‐derived high reward/high relief subgroup, we found a medium‐to‐large effect (d = 0.63; 95% CI 0.05, 1.1) of naltrexone in reducing PHID. Among reward drinkers (not other profiles), naltrexone reduced drinking on days a drinking event occurred by weakening the within‐day association between positive affect and urges (P < 0.05).
Conclusions
Naltrexone has pronounced effects in reducing risky drinking among young adult reward drinkers (high reward/low relief) by reducing urges on days when individuals have higher positive affect and are exposed to a drinking event. Naltrexone also appears to reduce risky drinking among young adult high reward/high relief drinkers, but not via the same mechanism.
The aim of this review was to assess the association of ACTN3 R577X and ACE I/D polymorphisms with athlete status in football and determine which allele and/or genotypes are most likely to influence ...this phenotype via a meta-analysis. A comprehensive search identified 17 ACTN3 and 19 ACE studies. Significant associations were shown between the presence of the ACTN3 R allele and professional footballer status (OR = 1.35, 95% CI: 1.18-1.53) and the ACE D allele and youth footballers (OR = 1.18, 95% CI: 1.01-1.38). More specifically, the ACTN3 RR genotype (OR = 1.48, 95% CI: 1.23-1.77) and ACE DD genotype (OR = 1.29, 95% CI: 1.02-1.63) exhibited the strongest associations, respectively. These findings may be explained by the association of the ACTN3 RR genotype and ACE DD genotype with power-orientated phenotypes and the relative contribution of power-orientated phenotypes to success in football. As such, the results of this review provide further evidence that individual genetic variation may contribute towards athlete status and can differentiate athletes of different competitive playing statuses in a homogenous team-sport cohort. Moreover, the ACTN3 R577X and ACE I/D polymorphisms are likely (albeit relatively minor) contributing factors that influence athlete status in football.
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