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Kidney International Jun 2024Baseline kidney function following kidney transplantation is often used in research and clinical decision-making yet is not well defined. Here, a method to determine...
Baseline kidney function following kidney transplantation is often used in research and clinical decision-making yet is not well defined. Here, a method to determine baseline function was proposed and validated on three single-center retrospective cohorts consisting of 922 patients from Belgium (main cohort) and two validation cohorts of 987 patients from the Netherlands and 519 patients from Germany. For each transplant, a segmented regression model was fitted on the estimated glomerular filtration rate (eGFR) evolution during the first-year post-transplantation. This yielded estimates for change point timing, rate of eGFR change before and after change point and eGFR value at change point, now considered the "baseline function". Associations of eGFR evolution with recipient/donor characteristics and the graft failure rate were assessed with linear regression and Cox regression respectively. The change point occurred on average at an eGFR value of 43.7±14.6 mL/min/1.73m, at a median time of 6.5 days post-transplantation. Despite significant associations with several baseline donor-recipient characteristics (particularly, donor type; living vs deceased), the predictive value of these characteristics for eGFR value and timing of the change point was limited. This followed from a large heterogeneity within eGFR trajectories, which in turn indicated that favorable levels of kidney function could be reached despite a suboptimal initial evolution. Segmented regression consistently provided a good fit to early eGFR evolution, and its estimate of the change point can be a useful reference value in future analyses. Thus, our study shows that baseline kidney function after transplantation is heterogeneous and partly related to pretransplant donor characteristics.
PubMed: 38945395
DOI: 10.1016/j.kint.2024.05.030 -
Biological Psychiatry Jun 2024Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can...
BACKGROUND
Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Since such qualities were found crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR.
METHODS
ELISA-based binding assay and NMR spectroscopy were accomplished to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to address whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis, and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75KO mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verifying how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male WT mice and rats.
RESULTS
Antidepressants were found binding to p75NTR, FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes.
CONCLUSION
We thus hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain ability for remodeling.
PubMed: 38945387
DOI: 10.1016/j.biopsych.2024.06.021 -
The Journal of Pain Jun 2024The human brain is a dynamic system that shows frequency-specific features. Neuroimaging studies have shown that both healthy individuals and those with chronic pain...
The human brain is a dynamic system that shows frequency-specific features. Neuroimaging studies have shown that both healthy individuals and those with chronic pain disorders experience pain influenced by various processes that fluctuate over time. Primary dysmenorrhea is a chronic visceral pain that disrupts the coordinated activity of brain's functional network. However, it remains unclear whether the dynamic interactions across the whole-brain network over time and their associations with neurobehavioral symptoms are dependent on the frequency bands in patients with primary dysmenorrhea during the pain-free periovulation phase. In this study, we used an energy landscape analysis to examine the interactions over time across the large-scale network in a sample of 59 patients with primary dysmenorrhea and 57 healthy controls at different frequency bands. Compared to healthy controls, patients with primary dysmenorrhea exhibit aberrant brain dynamics, with more significant differences in the slow-4 frequency band. Patients with primary dysmenorrhea show more indirect neural transition times due to an unstable intermediate state, whereas neurotypical brain activity frequently transitions between two major states. This data-driven approach further revealed that the brains of individuals with primary dysmenorrhea have more abnormal brain dynamics than healthy controls. Our results suggested that unstable brain dynamics were associated with the strength of brain functional segregation and the Pain Catastrophizing Scale (PCS) score. Our findings provide preliminary evidence that atypical dynamics in the functional network may serve as a potential key feature and biological marker of patients with PDM during the pain-free phase. PERSPECTIVE: We applied energy landscape analysis on brain-imaging data to identify relatively stable and dominant brain activity patterns for patients with primary dysmenorrhea(PDM). More atypical brain dynamics were found in the slow-4 band and were related to the strength of functional segregation, providing new insights into the dysfunction brain dynamics.
PubMed: 38945381
DOI: 10.1016/j.jpain.2024.104618 -
Pharmacological Research Jun 2024Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer...
Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.
PubMed: 38945380
DOI: 10.1016/j.phrs.2024.107252 -
Pharmacological Research Jun 2024Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has...
Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has been linked to an increased risk of intestinal fibrosis in patients of Crohn's disease (CD). In this study, oral administration of either live F. prausnitzii or its extracellular vesicles (FEVs) can markedly mitigate the severity of fibrosis in mice induced by repetitive administration of DSS. In vitro experiment revealed that FEVs were capable of directing the polarization of peripheral blood mononuclear cells (PBMCs) towards an M2b macrophage phenotype, which has been associated with anti-fibrotic activities. This effect of FEV was found to be stable under various conditions that promote the development of pro-fibrotic M1/M2a/M2c macrophages. Proteomics and RNA sequencing were performed to uncover the molecular modulation of macrophages by FEVs. Notably, we found that FEVs reprogramed every metabolism of macrophages by damaging the mitochondria, and inhibited oxidative phosphorylation and glycolysis. Moreover, FEV-treated macrophages showed a decreased expression of PPARγ and an altered lipid processing phenotype characterized by decreased cholesterol efflux, which may promote energy reprogramming. Taken together, these findings identify FEV as a driver of macrophage reprogramming, suggesting that triggering M2b macrophage polarization by oral admiration of FEV may serve as strategy to alleviate hyperfibrotic intestine conditions in CD.
PubMed: 38945379
DOI: 10.1016/j.phrs.2024.107277 -
Journal of Vascular Surgery. Venous and... Jun 2024We evaluated the impact of completion intraoperative venography on clinical outcomes for axillosubclavian vein (AxSCV) thrombosis due to venous thoracic outlet syndrome...
INTRODUCTION
We evaluated the impact of completion intraoperative venography on clinical outcomes for axillosubclavian vein (AxSCV) thrombosis due to venous thoracic outlet syndrome (vTOS).
METHODS
We performed a retrospective, single-center review of all patients with vTOS treated with First Rib Resection and intraoperative venography from 2011 - 2023. We reviewed intraoperative venographic films to classify findings, collected demographics, clinical and perioperative variables, and clinical outcomes. Primary endpoints were symptomatic relief and primary patency at 3 months and 1 year. Secondary endpoints were time free from symptoms, reintervention rate, perioperative complications, and mortality.
RESULTS
Fifty-one AxSCVs (49 patients, mean age of 31.3 ± 12.6, 52.9% female) were treated for vTOS with first rib resection and external venolysis followed by completion intraoperative venography with a mean follow up of 15.5 ± 13.5 months. Prior to FRR, 32 underwent catheter-directed thrombolysis (62.7%). Completion intraoperative venography identified 16 patients with No Stenosis (Group 1, 31.3%), 17 with No Stenosis after Angioplasty (Group 2, 33.3%), 10 with Residual Stenosis after Angioplasty (Group 3, 19.7%), and 8 with Complete Occlusion (Group 4, 15.7%). The overall symptomatic relief was 44 of 51 (86.3%) and did not differ between venographic classifications (Group 1: 14 of 16, Group 2: 13 of 17, Group 3: 10 of 10, and Group 4: 7 of 8; Log-Rank Test, p = 0.5). The overall 3-month and 1-year primary patency was 42 of 43 (97.7%) and 32 of 33 (97.0%), respectively (Group 1: 16 of 16 and 9 of 9; Group 2: 16 of 17 and 12 of 13; Group 3: 10 of 10, 5 of 5; Group 4: primary patency not obtained). There was one asymptomatic re-thrombosis that resolved with anticoagulation, and three patients underwent reintervention with venous angioplasty for significant symptom recurrence an average 2.89 ± 1.7 months after FRR.
CONCLUSION
Our single-center retrospective study demonstrates that FRR with completion intraoperative venography has excellent symptomatic relief, short- and mid-term patency despite residual venous stenosis and complete occlusion. While completion intraoperative venographic classification did not correlate with adverse outcomes, this protocol yielded excellent results and provides important clinical data for postoperative management. Our results also support a conservative approach to AxSCV occlusion identified after FRR.
PubMed: 38945363
DOI: 10.1016/j.jvsv.2024.101936 -
Journal of Vascular Surgery. Venous and... Jun 2024
Review
PubMed: 38945362
DOI: 10.1016/j.jvsv.2024.101940 -
Journal of Vascular Surgery. Venous and... Jun 2024AND OBJECTIVES: Large vein diameter is associated with higher recanalization rates after endovenous thermal ablation procedures of the great and small saphenous veins....
INTRODUCTION
AND OBJECTIVES: Large vein diameter is associated with higher recanalization rates after endovenous thermal ablation procedures of the great and small saphenous veins. However, relatively few studies have explored the relationship between vein diameter and recanalization rates after mechanochemical ablation (MOCA).
METHODS
We conducted a retrospective review of patients with chronic venous insufficiency who underwent MOCA of the great or small saphenous vein from 2017-2021 at a single hospital. Patients with no follow-up ultrasound were excluded. Patients were classified as having a large (≥ 1 cm) or small (< 1 cm) treated vein. The primary outcomes were 2-year recanalization and reintervention of the treated segment.
RESULTS
A total of 186 MOCA procedures during the study period were analyzed. There was no difference in age, gender, history of venous thromboembolic events, use of anticoagulation, obesity, or length of treated segment between cohorts. Patients with large veins were less likely to have stasis ulcers compared to those with small veins (3.2% vs 21.5%; p<.05 on Fisher exact test). Patients with large veins had a higher incidence of local post-operative local complications (24.2% vs 7.2%, p<.05 on Chi-squared test). A survival analysis with Cox proportional hazards showed no significant difference in recanalization rates with larger vein diameters. However, obesity was found to significantly correlate with recanalization.
CONCLUSIONS
Large vein diameter was not associated with higher recanalization rates following MOCA of the great and small saphenous veins. However, obesity was found to correlate with recanalization rates.
PubMed: 38945360
DOI: 10.1016/j.jvsv.2024.101935 -
Chest Jun 2024Childhood asthma is a prevalent condition with potential impact on adult life.
BACKGROUND
Childhood asthma is a prevalent condition with potential impact on adult life.
RESEARCH QUESTION
In a 60-year follow-up study of adults with a history of severe childhood asthma, what are the potential differences in characteristics between individuals with persistent asthma and asthma remission in adulthood?
STUDY DESIGN AND METHODS
Danish adults with a history of childhood asthma and a 4-month stay in at an asthma care facility in Kongsberg, Norway (1950-1979) in childhood were included. Recruitment was done through social media and personal invitation letters. Participants completed questionnaires and underwent spirometry, bronchial provocation, and bronchodilator reversibility and blood tests. Asthma remission was defined as no use of asthma medication and no asthma symptoms within the past 12 months with the remaining participants being classified as having current asthma.
RESULTS
Among 1394 eligible participants, 232 completed the follow-up. Ninety percent had current asthma, of whom 26% reported exacerbations in the past year. Only 16% of all the participants were managed in secondary care. Common comorbidities were allergic rhinitis (60%), hypertension (21%), eczema (16%), and cataract (8%). Compared to participants in remission, participants with persistent asthma had higher total immunoglobulin E (p=0.03), and both lower FEV%pred (p=0.03), and FEV/FVC ratio (p<0.001), as well as numerically higher fractional exhaled nitric oxide and blood eosinophil count.
INTERPRETATION
Our 60-year follow-up study of adults with a history of severe childhood asthma revealed that nine out of ten still had current asthma. Persistent asthma was associated with lower lung function and higher levels of type 2 inflammatory biomarkers compared to those with asthma remission.
PubMed: 38945358
DOI: 10.1016/j.chest.2024.06.005 -
American Journal of Ophthalmology Jun 2024To investigate the clinical, functional, and imaging characteristics in patients affected by inherited retinal diseases associated with RDH5 and RLBP1 gene variants, and...
PURPOSE
To investigate the clinical, functional, and imaging characteristics in patients affected by inherited retinal diseases associated with RDH5 and RLBP1 gene variants, and to report novel genotype-phenotype correlations.
DESIGN
Retrospective single-center cohort study.
METHODS
Twenty-two patients with molecularly confirmed RLBP1-associated retinopathy and 5 with RDH5-associated retinopathy. Medical records were reviewed to obtain data on family history and ophthalmologic examinations, including retinal imaging and full-field electroretinography (ffERG). Genotype was determined by targeted next-generation sequencing followed by confirmation and familial segregation by Sanger sequencing.
RESULTS
The median (IQR) age at baseline for the RDH5 and RLBP1 cohort was 44.6 (38.2-67.9) years and 36.9 (23.1-45.2) years, respectively. Macular atrophy was found in approximately 80% of eyes from both cohorts. The RLBP1 genotype was associated with a lower macular volume by 0.28 mm (95% CI, -0.46 to -0.11; P = .005) compared to the RDH5 genotype. In both genotypic cohorts, we found a significant annual rate of macular volume loss, estimated at -0.007 mm/y (95% CI, -0.012 to -0.001; P = .02), without any significant difference the two genotypes. Three unrelated patients homozygous for the c.361C>T p.(Arg121Trp) RLBP1 variant showed minimal impairment of both the rod and cone systems function on ffERG and absence of macular atrophy.
CONCLUSIONS
Progressive macular atrophy in addition to congenital night blindness can be identified in adult patients with RDH5-associated retinopathy. Vice versa, hypomorphic RLBP1 variants may cause milder retinal phenotypes rather than the typical severe rod-cone dystrophy with macular atrophy. These findings could prove beneficial to improve the prognostication of patients and help in designing future interventional trials.
PubMed: 38945349
DOI: 10.1016/j.ajo.2024.06.016