Search Results (165)

Fetal growth restriction (FGR), a condition in which the fetus fails to achieve its growth and developmental potential, affects 5% to 10% of pregnancies and is associated with high rates of perinatal morbidity and mortality. There is currently insufficient high-quality evidence to define the optimal approach for diagnosing fetal growth restriction. In 2016, with the aim of standardizing clinical practice and enabling comparability across scientific studies, an expert opinion-based consensus was published. This document proposed unified terminology and clear diagnostic criteria for early- and late-onset fetal growth restriction (FGR). Because no effective treatment is available, careful assessment of fetal well-being and appropriate timing of delivery are the main tools for managing these fetuses. This decision should be based on gestational age and the severity of abnormalities identified on fetal surveillance tests, balancing the risks of prematurity against the risks of severe permanent sequelae or fetal death. The objective of this update is to analyze the most recent evidence on when and how to deliver pregnancies complicated by fetal growth restriction, emphasizing that specific abnormalities on fetal surveillance examinations warrant delivery at different gestational ages. To this end, a literature search of the PubMed/Medline and Latin America and the Caribbean Literature on Health Sciences (LILACS) databases was conducted using the terms fetal growth restriction, management, and delivery over the past ten years. Results were grouped into gestational age at delivery, mode of delivery, and methods of labor induction. The main fetal surveillance abnormalities prompting delivery in each gestational-age range were discussed, leading to the development of management flowcharts. Despite the lack of consensus in the literature and the limited number of randomized clinical trials guiding clinical decisions in FGR, the available evidence was summarized to assist clinicians in managing pregnancies complicated by FGR. It should be emphasized that there are few randomized clinical trials to guide management decisions in FGR. Full article

Sphingolipids (SL) are essential structural and bioactive components of cell membranes, remarkably involved in inflammatory signaling and membrane dynamics. Dysregulation of SL metabolism contributes to pathological inflammation and cellular stress. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (FXT), are known inhibitors of acid sphingomyelinase (aSMase), although their impact on macrophage SL remodeling and inflammatory responses remains unclear. Here, we investigated the modulation of FXT on SL species composition and inflammatory activation in THP-1-derived macrophages stimulated with inactivated SARS-CoV-2 particles, which is a model of viral-induced inflammation. Sphingolipidomic profiling revealed that FXT pre-treatment markedly reduced ceramide (Cer) species while increasing sphingomyelin (SM) and sphingosine-1-phosphate (S1P) levels, consistent with inhibition of the aSMase-Cer axis. These changes were accompanied by attenuation of proinflammatory components, including interleucin (IL)-6, IL-1β, and matrix metalloproteinase (MMP)-9, indicating that SL remodeling correlates with reduced macrophage activation. Despite pronounced alterations in membrane lipid composition, the quantification of extracellular vesicles (EVs) released by FXT-treated macrophages remained unchanged, however the EVs size distribution was smaller compared to non-treated cells. Altogether, our findings demonstrate that FXT reshapes SL metabolism and lipid membrane composition, thereby diminishing macrophage activation without affecting EVs biogenesis. This study emphasizes the immunometabolic role of SL on membrane reprogramming as a mechanism by which pharmacological aSMase inhibition modulates viral inflammation responses. Full article

Background: Fragile X Syndrome (FXS) is an X-linked neurodevelopmental disorder characterised by intellectual disability, developmental delays, anxiety, and social and behavioural challenges. Currently, no effective treatments exist to address the root cause of FXS. Mouse models are the most widely used for studying molecular pathogenesis and conducting preclinical treatment testing. However, therapeutic interventions that show promise in rodent models have yet to succeed in clinical trials. After evaluating the current models, we have developed an ovine model to address this clinical translation gap. We expect this model to more accurately reflect the human condition in brain size, structure, and neurodevelopmental trajectory. We aim to establish this model as a valuable preclinical platform for testing therapies for FXS. Methods: To generate the sheep model, we used CRISPR-Cas9 dual-guide editing to knock out the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene in ovine embryos. Results: Two founder animals were created, one ram (male) and one ewe (female), both of which carried FMR1 gene knockouts. The ewe carries inactivating mutations on both alleles, with the edits in both animals resulting in no detectable Fragile X Messenger Ribonucleoprotein (FMRP) as expected. Both founders have undergone molecular characterisation and basic health checks, with the female founder showing increased joint flexibility, a characteristic of FXS. The ram has been used for breeding, with the successful transmission of the edited allele to his offspring. Importantly, specific lamb cohorts for postnatal treatment testing can be produced efficiently utilising accelerated breeding methods and preimplantation selection. Full article

Background/Objectives: Dietary inorganic nitrate (NO₃⁻), primarily sourced from vegetables such as beetroot, has been shown to enhance nitric oxide (NO) bioavailability, with emerging evidence suggesting its potential to modulate autonomic function. However, the effects of NO₃⁻ supplementation on cardiac autonomic recovery post-exercise in hypertensive postmenopausal women remain poorly understood. Using data from a previously conducted randomised controlled trial, this study investigated the effects of acute (800 mg) and seven-day (400 mg/day) beetroot juice NO₃⁻ supplementation on ultra-short-term post-exercise cardiac parasympathetic recovery in hypertensive older women. Methods: In a triple-blind, placebo-controlled crossover design, fourteen postmenopausal women (59 ± 4 y) with hypertension completed two intervention arms (NO₃⁻ and placebo). Ultra-short-term heart rate variability (HRV) indices (SDNN, RMSSD, HF) were assessed across 5 min post-exercise recovery using 60 s windows. Plasma NO₂⁻ and NO₃⁻ concentrations were measured via chemiluminescence. Results: Both acute and seven-day NO₃⁻ supplementation significantly increased plasma NO₂⁻ and NO₃⁻ concentrations compared to placebo (p < 0.001). Cardiac vagal recovery, assessed via SDNN and RMSSD, was significantly enhanced in both conditions, with greater and more sustained improvements observed after the seven-day protocol. HF power was significantly higher, but only after seven-day supplementation (p = 0.009). Conclusions: Inorganic NO₃⁻ supplementation enhances post-exercise cardiac parasympathetic reactivation in hypertensive postmenopausal women. Notably, the seven-day intake (400 mg/day) protocol elicited superior autonomic benefits compared to an acute high dose. These findings highlight the potential of NO₃⁻ as a non-pharmacological strategy for improving cardiovascular autonomic recovery in high-risk populations. Full article

Chikungunya virus (CHIKV) infection during pregnancy represents an increasing public health concern, especially in endemic and epidemic regions. The main concern is vertical transmission, particularly during the peripartum period, which can lead to severe neonatal outcomes such as encephalopathy, hematologic abnormalities, and long-term neurodevelopmental impairment. This review synthesizes current knowledge on pathophysiology, clinical manifestations, diagnosis, maternal and neonatal outcomes, and management of CHIKV infection in pregnancy. Diagnosis relies on clinical evaluation supported by laboratory confirmation, RT-PCR in the acute phase and IgM serology thereafter. Treatment is supportive, using acetaminophen as first-line therapy and corticosteroids for selected refractory cases. No antivirals or vaccines are approved for use in pregnancy as of 2025. Prevention is centered on vector control, personal protection, and epidemiological surveillance. Delivery planning and neonatal monitoring are essential when infection occurs close to term due to the high risk of peripartum transmission. Despite growing recognition of CHIKV’s maternal–fetal impact, significant gaps remain regarding long-term outcomes and optimal management strategies. Strengthening prenatal care, neonatal preparedness, and surveillance systems is crucial to mitigate adverse outcomes and inform future clinical and public health policies. Full article

Fragile X syndrome (FXS, OMIM#300624) is the most common inherited cause of X-linked intellectual disability and behavior difficulties. In 99% of cases, it is caused by the pathological expansion (>200 repeats, full mutation -FM) of the CGG trinucleotide located at the 5′ UTR of the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene, leading to the lack of production of the FMRP. Clinical manifestations are well known in boys but are sometimes overlooked in girls, who may remain underdiagnosed. Premutation (PM) populations (55–200 repeats) may present other medical issues, such as FXPOI or FXTAS. Mosaic conditions, such as a combination of PM and FM lines in the same patient, may lead to milder phenotypes. With the improvement of genetic testing, information regarding the exact number of CGG triplet repeats and methylation status could help explain milder phenotypes in patients who may produce some FMRP. Chromosome X preferential inactivation (XCI) in FXS women can also play a role in clinical severity. We present four non-related families who were followed up in our FXS clinic. Some of their members showed FM on Southern blot, but had milder symptoms than expected. To rule out size mosaicism, a RT-PCR was performed, giving a different and more consistent molecular diagnosis. When mosaicism was not present, methylation status was performed, excluding full methylation. For females, XCI showed preferential inactivation in one case. Revisiting old molecular diagnoses should be considered in clinical practice, especially for patients with a milder phenotype than expected from their molecular reports. This personalized follow up may change their former diagnosis, prognosis, and expectations. Full article

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article

Background/Objectives: Iodine is an important nutrient for the human body, used in the production of thyroid hormones. During pregnancy, a deficiency can cause miscarriage and hypothyroidism, while an excess can cause thyroid dysfunction. Therefore, the objective of this study was to evaluate the factors associated with the iodine nutritional status of pregnant Brazilian women. Methods: This was a cross-sectional, multicenter study conducted with pregnant women over 18 years of age, users of the Unified Health System (SUS). A semi-structured questionnaire was used to obtain sociodemographic information. Iodine status was assessed by urinary iodine concentration (UIC). The iodine content of salt and homemade and industrial seasonings was determined by the titrimetric method. Dietary intake was estimated through a 24-hour dietary recall. The chi-square test and hierarchical multinomial logistic regression were used for statistical analysis. The significance level was set at p ≤ 0.05. Results: Among Brazilian pregnant women, the median UIC was 186.7 µg/L (P25: 118.05 µg/L-P75: 280.93 µg/L). Regarding iodine nutritional status, the prevalence of deficiency was 36.7% (n = 694), above the requirement was 28.7% (n = 543), and excess iodine intake was 3.6% (n = 68). We observed that non-white pregnant women were more likely (OR = 1.83; 95% CI: 1.27–2.64) to have iodine deficiency, and those who did not work were less likely (OR = 0.71; 95% CI: 0.52–0.98). Pregnant women in the last trimester of pregnancy were less likely to have iodine intake above the requirements (OR = 0.52; 95% CI: 0.31–0.88). Conclusions: A substantial proportion of pregnant women had iodine deficiency or intake above the required level. Iodine deficiency is more chance among non-white pregnant women and less chance among those not employed during pregnancy. On the other hand, pregnant women who were in their third trimester of pregnancy were less likely to have iodine intake above the required level. Full article

Background/Objectives: Global warming and rising CO₂ concentrations pose significant challenges to plant systems. Amid these pressures, this study contributes to understanding how tropical species respond by simultaneously evaluating reproductive and genetic traits. It specifically investigates the effects of maternal exposure to warming and elevated CO₂ on progeny physiology, genetic diversity, and population structure in Stylosanthes capitata, a resilient forage legume native to Brazil. Methods: Maternal plants were cultivated under controlled treatments, including ambient conditions (control), elevated CO₂ at 600 ppm (eCO₂), elevated temperature at +2 °C (eTE), and their combined exposure (eTEeCO₂), within a Trop-T-FACE field facility (Temperature Free-Air Controlled Enhancement and Free-Air Carbon Dioxide Enrichment). Seed traits (seeds per inflorescence, hundred-seed mass, abortion, non-viable seeds, coat color, germination at 32, 40, 71 weeks) and abnormal seedling rates were quantified. Genetic diversity metrics included the average (A) and effective (Ae) number of alleles, observed (Ho) and expected (He) heterozygosity, and inbreeding coefficient (Fis). Population structure was assessed using Principal Coordinates Analysis (PCoA), Analysis of Molecular Variance (AMOVA), number of migrants per generation (Nm), and genetic differentiation index (Fst). Two- and three-way Analysis of Variance (ANOVA) were used to evaluate factor effects. Results: Compared to control conditions, warming increased seeds per inflorescence (+46%), reduced abortion (−42.9%), non-viable seeds (−57%), and altered coat color. The germination speed index (GSI +23.5%) and germination rate (Gr +11%) improved with warming; combined treatments decreased germination time (GT −9.6%). Storage preserved germination traits, with warming enhancing performance over time and reducing abnormal seedlings (−54.5%). Conversely, elevated CO₂ shortened GSI in late stages, impairing germination efficiency. Warming reduced Ae (−35%), He (−20%), and raised Fis (maternal 0.50, progeny 0.58), consistent with the species’ mixed mating system; A and Ho were unaffected. Allele frequency shifts suggested selective pressure under eTE. Warming induced slight structure in PCoA, and AMOVA detected 1% (maternal) and 9% (progeny) variation. Fst = 0.06 and Nm = 3.8 imply environmental influence without isolation. Conclusions: Warming significantly shapes seed quality, reproductive success, and genetic diversity in S. capitata. Improved reproduction and germination suggest adaptive advantages, but higher inbreeding and reduced diversity may constrain long-term resilience. The findings underscore the need for genetic monitoring and broader genetic bases in cultivars confronting environmental stressors. Full article

The study’s aim was to evaluate electroretinographic (ERG) alterations in Fragile X syndrome (FXS), FMR1 premutation carriers, and controls, and to explore correlations with peripheral blood FMRP expression levels and behavioral outcomes. ERG recordings were obtained using a handheld device across three stimulus protocols in 43 premutation carriers, 39 individuals with FXS, and 23 controls. Peripheral blood FMRP expression levels were quantified using TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer). Correlations were assessed with cognitive and behavioral measures including IQ (Intelligence Quotient), ABC_FX (Aberrant Behavior Checklist for Fragile X Syndrome), SNAP-IV (Swanson, Nolan, and Pelham Teacher and Parent Rating Scale), SEQ (Sensory Experiences Questionnaire), ADAMS (Anxiety, Depression, and Mood Scale), and the Vineland III Adaptive Behavior Scale standard score. Significant group differences were observed in multiple ERG parameters, particularly in 2 Hz b-wave amplitude (p = 0.0081), 2 Hz b-wave time to peak (p = 0.0164), 28.3 Hz flash combined amplitude (p = 0.0139), 3.4 Hz red/blue flash b-wave amplitude (p = 0.0026), and PhNR amplitude (p = 0.0026), indicating both outer and inner retinal dysfunction in FXS and premutation groups. Despite high test–retest reliability for ERG (ICC range = 0.71–0.92) and FMRP (ICC = 0.70), no correlation was found between ERG metrics and FMRP or behavioral measures. However, FMRP levels strongly correlated with IQ (ρ = 0.69, p < 0.0001) and inversely with behavioral impairment [ABC_FX (ρ = −0.47, p = 0.0041), SNAP-IV (ρ = −0.48, p = 0.0039), SEQ (ρ = −0.43, p = 0.0146), and the Vineland III standard score (ρ = 0.56, p = 0.0019)]. ERG reveals distinct retinal functional abnormalities in FMR1-related conditions but does not correlate with peripheral FMRP expression levels, highlighting the need for multimodal biomarkers integrating radiological, physiological, behavioral, and molecular measures. Full article

Background/Objective: Pulmonary fungal infections are a significant diagnostic challenge, primarily affecting immunocompromised individuals, such as those with HIV, cancer, or organ transplants, and they often lead to substantial morbidity and mortality if untreated. These infections trigger acute inflammatory and immune responses, which may progress to chronic inflammation. This process involves myofibroblast recruitment, the deposition of extracellular matrix, and vascular remodeling, ultimately contributing to pulmonary hypertension. Despite its clinical relevance, pulmonary hypertension secondary to fungal infections remains under-recognized in practice and poorly studied in research. Results/Conclusion: This narrative mini-review explores three key mechanisms underlying vascular remodeling in this context: (1) endothelial injury caused by fungal emboli or autoimmune reactions, (2) direct vascular remodeling during chronic infection driven by inflammation and fibrosis, and (3) distant vascular remodeling post-infection, as seen in granulomatous diseases like paracoccidioidomycosis. Further research and clinical screening for pulmonary hypertension in fungal infections are crucial to improving patient outcomes. Full article

Accessible tools for post-stroke motor rehabilitation are critically needed to promote recovery beyond clinical settings. This pilot study evaluated the impact of a posture correction intervention using the Postural SmartVest, a wearable device that delivers multisensory feedback via a smartphone app. Forty individuals with post-stroke hemiparesis participated in a single supervised session, during which each patient completed the same four-phase functional protocol: multidirectional walking, free walking toward a refrigerator, an upper-limb reaching and object-handling task, and walking back to the starting point. Under the supervision of their therapists, each patient performed the full protocol twice—first without feedback and then with feedback—which allowed within-subject comparisons across multiple metrics, including upright posture duration, number and frequency of posture-related events, and temporal distribution. Additional analyses explored associations with demographic and clinical variables and identified predictors through regression models. Wilcoxon signed-rank and Mann–Whitney U tests showed significant improvements with feedback, including an increase in upright posture time ($p<0.001$), an increase in the frequency of upright posture events ($p<0.001$), and a decrease in the total task time ($p=0.038$). No significant subgroup differences were found for age, sex, lateralization, or stroke chronicity. Regression models did not identify significant predictors of improvement. Full article

Fragile X syndrome is characterized by the diminished expression of the fragile X messenger ribonucleoprotein (FMRP), a ubiquitously expressed RNA binding protein with numerous functions in cells. Our prior work found significant differences in physiological and behavioral outcomes as a function of FMRP levels and in response to diet in mice. Here, we assess protein biomarker levels as a function of FMRP levels, sex and matched casein and soy protein isolate-based purified ingredient diets in Fmr1^KO and littermate mice. Brain regions (cortex, hippocampus, and hypothalamus) and blood plasma were analyzed by RayBiotech’s Quantibody^® Mouse Cytokine Antibody Array 640 to quantitate the expression of 640 proteins. The main findings were the identification of numerous proteins that were differentially expressed in response to diet, sex and/or genotype. Of note, prolactin (PRL) levels in blood plasma were significantly elevated in Fmr1^KO female mice as a function of genotype and sex selectively with the AIN-93G/casein diet. Also, using a moderately stringent significance cutoff, growth differentiation factor 9 (GDF-9) in plasma from mice fed AIN-93G/soy was the only protein studied by Quantibody arrays that was differentially expressed between WT and Fmr1^KO male mice. When comparing the results from a pelleted infant formula study with AIN-93G-based diets, insulin-like growth factor binding protein 5 (IGFBP5) in plasma was the only protein differentially expressed as a function of soy in the diet. There was no overlap in statistically significant results when comparing tissue analyzed by mass spectrometry versus Quantibody arrays from mice maintained on AIN-93G-based diets. In conclusion, gene–diet interactions affect protein expression in Fmr1^KO and littermate mice and need to be considered in study design. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized advanced melanoma treatment, yet many patients fail to achieve sustained clinical benefit. Several biomarkers, including tumor microenvironment (TME) signature, PD-1/PD-L1 expression, and IFN-γ signaling, have been proposed. However, robust predictive markers remain elusive. This study aimed to identify molecular markers of response by analyzing tumor and peripheral immune signatures. Methods: This study analyzed 21 advanced melanoma patients treated with ICIs. Formalin-fixed, paraffin-embedded tumors underwent RNA-sequencing targeting 1392 immuno-oncology probes. Genes significantly associated with progression-free survival (PFS) by log-rank test underwent hierarchical clustering analysis (HCA). Differential expression and xCell analyses were then performed on the resulting clusters. Cox multivariate analysis was applied to identify independent PFS predictors. Pre-treatment peripheral blood mononuclear cells were analyzed by mass cytometry, followed by FlowSOM and UMAP clustering. Results: Fifty-five genes significantly associated with PFS identified two molecular clusters via HCA. Cluster A demonstrated prolonged PFS (59.4 vs. 2.4 months, p = 0.0004), while Cluster B was characterized by downregulated IFN-γ signaling, antigen presentation pathways, and reduced immune score. Multivariate Cox analysis confirmed molecular cluster as an independent PFS predictor (p < 0.001). Mass cytometry revealed higher frequencies of circulating PD-1+ CD4+ effector memory (EM) T subpopulations among responders. Conclusions: This study highlights the potential role of molecular and immune profiling in predicting ICI response in advanced melanoma. The identification of distinct molecular clusters underscores significant TME heterogeneity, with immune-cold tumor clusters associated with poorer outcomes. Furthermore, circulating PD-1+ T subpopulations emerged as potential markers of ICI response, suggesting their value in improving patient stratification. Full article

The Fragile X Mental Retardation 1 (FMR1) gene is well-known for its role in Fragile X syndrome, a neurodevelopmental disorder, but emerging evidence suggests its involvement in regulating cellular metabolism, with implications for cancer biology. FMR1 encodes the Fragile X mental retardation protein (FMRP), an RNA-binding protein that controls various cellular processes, including translation, synaptic plasticity, and RNA metabolism. Recent studies have uncovered novel links between FMR1, metabolic regulation, and tumorigenesis. This review discusses the role of FMR1 in cellular metabolism and its potential involvement in cancer, focusing on glycolysis, mitochondrial metabolism, lipid metabolism, immune cell metabolism, and tumor immune evasion, and as a potential target to enhance immunotherapy, and highlights future research directions to elucidate its mechanistic roles in cancer. Full article