-
FASEB Journal : Official Publication of... Jul 2024Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the...
Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-β1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-β1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-β1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-β1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.
Topics: Asthma; Animals; Sirtuin 2; Glycolysis; Mice; Airway Remodeling; Humans; Forkhead Transcription Factors; Epithelial-Mesenchymal Transition; Mice, Inbred BALB C; Female; Transforming Growth Factor beta1; Lung; Cell Line
PubMed: 38949649
DOI: 10.1096/fj.202302284R -
The Journal of Experimental Medicine Sep 2024Children resist COVID-19, and previous studies reported increased innate immunity in their upper airways. A new paper by Watkins et al....
Children resist COVID-19, and previous studies reported increased innate immunity in their upper airways. A new paper by Watkins et al. (https://doi.org/10.1084/jem.20230911) shows that the nasal mucosa of children is characterized by often asymptomatic viral and/or bacterial infections that dynamically regulate distinct innate immune programs.
Topics: Humans; COVID-19; Child; Immunity, Innate; SARS-CoV-2; Nasal Mucosa
PubMed: 38949639
DOI: 10.1084/jem.20241027 -
The Journal of Experimental Medicine Sep 2024Studies during the COVID-19 pandemic showed that children had heightened nasal innate immune responses compared with adults. To evaluate the role of nasal viruses and...
Studies during the COVID-19 pandemic showed that children had heightened nasal innate immune responses compared with adults. To evaluate the role of nasal viruses and bacteria in driving these responses, we performed cytokine profiling and comprehensive, symptom-agnostic testing for respiratory viruses and bacterial pathobionts in nasopharyngeal samples from children tested for SARS-CoV-2 in 2021-22 (n = 467). Respiratory viruses and/or pathobionts were highly prevalent (82% of symptomatic and 30% asymptomatic children; 90 and 49% for children <5 years). Virus detection and load correlated with the nasal interferon response biomarker CXCL10, and the previously reported discrepancy between SARS-CoV-2 viral load and nasal interferon response was explained by viral coinfections. Bacterial pathobionts correlated with a distinct proinflammatory response with elevated IL-1β and TNF but not CXCL10. Furthermore, paired samples from healthy 1-year-olds collected 1-2 wk apart revealed frequent respiratory virus acquisition or clearance, with mucosal immunophenotype changing in parallel. These findings reveal that frequent, dynamic host-pathogen interactions drive nasal innate immune activation in children.
Topics: Humans; Immunity, Innate; Child, Preschool; Infant; COVID-19; Child; SARS-CoV-2; Female; Male; Nasopharynx; Viral Load; Nasal Mucosa; Cytokines; Host-Pathogen Interactions; Adolescent; Nose; Coinfection
PubMed: 38949638
DOI: 10.1084/jem.20230911 -
Obstetrics and Gynecology Jul 2024To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
OBJECTIVE
To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial.
METHODS
We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding.
RESULTS
Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine.
CONCLUSION
No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT02299414.
Topics: Humans; Pregnancy; Female; Labetalol; Nifedipine; Antihypertensive Agents; Adult; Pregnancy Outcome; Hypertension; Infant, Newborn; Pregnancy Complications, Cardiovascular; Hypertension, Pregnancy-Induced; Administration, Oral; Infant, Small for Gestational Age; Pre-Eclampsia; Chronic Disease
PubMed: 38949541
DOI: 10.1097/AOG.0000000000005613 -
Journal of Visualized Experiments : JoVE Jun 2024Lung transplantation is hampered by the lack of suitable donors. Previously, donors that were thought to be marginal or inadequate were discarded. However, new and...
Lung transplantation is hampered by the lack of suitable donors. Previously, donors that were thought to be marginal or inadequate were discarded. However, new and exciting technology, such as ex vivo lung perfusion (EVLP), offers lung transplant providers extended assessment for marginal donor allografts. This dynamic assessment platform has led to an increase in lung transplantation and has allowed providers to use donors that were previously discarded, thus expanding the donor pool. Current perfusion techniques use cellular or acellular perfusates, and both have distinct advantages and disadvantages. Perfusion composition is critical to maintaining a homeostatic environment, providing adequate metabolic support, decreasing inflammation and cellular death, and ultimately improving organ function. Perfusion solutions must contain sufficient protein concentration to maintain appropriate oncotic pressure. However, current perfusion solutions often lead to fluid extravasation through the pulmonary endothelium, resulting in inadvertent pulmonary edema and damage. Thus, it is necessary to develop novel perfusion solutions that prevent excessive damage while maintaining proper cellular homeostasis. Here, we describe the application of a polymerized human hemoglobin (PolyhHb)-based oxygen carrier as a perfusate and the protocol in which this perfusion solution can be tested in a model of rat EVLP. The goal of this study is to provide the lung transplant community with key information in designing and developing novel perfusion solutions, as well as the proper protocols to test them in clinically relevant translational transplant models.
Topics: Animals; Rats; Lung Transplantation; Hemoglobins; Perfusion; Lung; Humans; Oxygen; Blood Substitutes; Male; Organ Preservation Solutions
PubMed: 38949382
DOI: 10.3791/66702 -
American Journal of Respiratory Cell... Jul 2024
Topics: Humans; Mast Cells; Lung; Thymic Stromal Lymphopoietin; Signal Transduction; Transcriptome; Airway Obstruction; Cytokines; Smokers; Male; Smoking; Female
PubMed: 38949326
DOI: 10.1165/rcmb.2023-0416LE -
Journal of Medical Virology Jul 2024Donor and recipient human cytomegalovirus (HCMV) seropositive (D+R+) lung transplant recipients (LTRs) often harbor multiple strains of HCMV, likely due to transmitted...
Donor and recipient human cytomegalovirus (HCMV) seropositive (D+R+) lung transplant recipients (LTRs) often harbor multiple strains of HCMV, likely due to transmitted donor (D) strains and reactivated recipient (R) strains. To date, the extent and timely occurrence of each likely source in shaping the post-transplantation (post-Tx) strain population is unknown. Here, we deciphered the D and R origin of the post-Tx HCMV strain composition in blood, bronchoalveolar lavage (BAL), and CD45+ BAL cell subsets. We investigated either D and/or R formalin-fixed paraffin-embedded blocks or fresh D lung tissue from four D+R+ LTRs obtained before transplantation. HCMV strains were characterized by short amplicon deep sequencing. In two LTRs, we show that the transplanted lung is reseeded by R strains within the first 6 months after transplantation, likely by infiltrating CD14+ CD163+/- alveolar macrophages. In three LTRs, we demonstrate both rapid D-strain dissemination and persistence in the transplanted lung for >1 year post-Tx. Broad inter-host diversity contrasts with intra-host genotype sequence stability upon transmission, during follow-up and across compartments. In D+R+ LTRs, HCMV strains of both, D and R origin can emerge first and dominate long-term in subsequent episodes of infection, indicating replication of both sources despite pre-existing immunity.
Topics: Humans; Lung Transplantation; Cytomegalovirus; Cytomegalovirus Infections; Transplant Recipients; Male; Middle Aged; Female; Tissue Donors; Adult; Genotype; Lung; Bronchoalveolar Lavage Fluid
PubMed: 38949200
DOI: 10.1002/jmv.29770 -
Journal of Medical Primatology Aug 2024Tuberculosis (TB) kills approximately 1.6 million people yearly despite the fact anti-TB drugs are generally curative. Therefore, TB-case detection and monitoring of...
An exploratory deep learning approach to investigate tuberculosis pathogenesis in nonhuman primate model: Combining automated radiological analysis with clinical and biomarkers data.
BACKGROUND
Tuberculosis (TB) kills approximately 1.6 million people yearly despite the fact anti-TB drugs are generally curative. Therefore, TB-case detection and monitoring of therapy, need a comprehensive approach. Automated radiological analysis, combined with clinical, microbiological, and immunological data, by machine learning (ML), can help achieve it.
METHODS
Six rhesus macaques were experimentally inoculated with pathogenic Mycobacterium tuberculosis in the lung. Data, including Computed Tomography (CT), were collected at 0, 2, 4, 8, 12, 16, and 20 weeks.
RESULTS
Our ML-based CT analysis (TB-Net) efficiently and accurately analyzed disease progression, performing better than standard deep learning model (LLM OpenAI's CLIP Vi4). TB-Net based results were more consistent than, and confirmed independently by, blinded manual disease scoring by two radiologists and exhibited strong correlations with blood biomarkers, TB-lesion volumes, and disease-signs during disease pathogenesis.
CONCLUSION
The proposed approach is valuable in early disease detection, monitoring efficacy of therapy, and clinical decision making.
Topics: Animals; Macaca mulatta; Deep Learning; Biomarkers; Mycobacterium tuberculosis; Tomography, X-Ray Computed; Tuberculosis; Disease Models, Animal; Tuberculosis, Pulmonary; Male; Female; Lung; Monkey Diseases
PubMed: 38949157
DOI: 10.1111/jmp.12722 -
JPMA. the Journal of the Pakistan... Jun 2024Giant cell tumour is a growth predominantly found in long bones of the body. Giant cell tumour has a rare occurrence in the head and neck. A case of a 31 year old male...
Giant cell tumour is a growth predominantly found in long bones of the body. Giant cell tumour has a rare occurrence in the head and neck. A case of a 31 year old male with no known comorbidities at the ENT Department, Shifa International Hospital, Islamabad presented with anterior neck swelling and hoarseness of voice. Patient was diagnosed as having Giant Cell Tumour of Larynx (GTCL) proven on FNA cytology and post-operative biopsy. GCTL is an uncommon entity with only 45 reported cases in the world.
Topics: Humans; Male; Laryngeal Neoplasms; Adult; Giant Cell Tumors; Laryngeal Cartilages; Hoarseness
PubMed: 38948992
DOI: 10.47391/JPMA.10483 -
JPMA. the Journal of the Pakistan... Jun 2024To assess functional and aesthetic outcomes in patients having undergone dorsal nasal augmentation with costochondral graft in a tertiary care setting. (Observational Study)
Observational Study
OBJECTIVE
To assess functional and aesthetic outcomes in patients having undergone dorsal nasal augmentation with costochondral graft in a tertiary care setting.
METHODS
The single-centre, retrospective, observational study was conducted at Shifa International Hospital, Islamabad, Pakistan, and comprised data of patients who underwent dorsal nasal augmentation using costochondral graft between January 1, 2018, and December 31, 2022. Aesthetic outcomes in terms of patient satisfaction were assessed using Facial Appearance, Health-related Quality of Life and Adverse Effects scores. Data was analysed using SPSS 26.
RESULTS
Of the 46 patients, 28(61%) were males and 18(39%) were females. The overall mean age was 28.39±9.13 years. Dorsal nasal deficiency occurred secondary to congenital causes in 12(26.1%) patients, trauma 19(41.3%) and prior surgery 15(32.6%). Postoperative complication rate was 7(15%); 3(6.5%) had recipient site infection and 2(4.3%) had rib graft resorption. Besides, 1(2.2%) patient reported pain 2 months postoperatively and 1(2.2%) had hypertrophic scarring. Patient satisfaction with the outcome was noted in all the 10 parameters analysed. Most commonly reported problem was that the nose was 'looking thick/swollen' by 12(26.1%) patients, but the issue resolved during 1-year follow-up.
CONCLUSION
Costochondral graft was found to be an ideal material for dorsal nasal augmentation, with high patient satisfaction rate.
Topics: Humans; Female; Male; Adult; Rhinoplasty; Retrospective Studies; Patient Satisfaction; Young Adult; Adolescent; Postoperative Complications; Esthetics; Quality of Life; Nose; Treatment Outcome; Costal Cartilage; Cicatrix, Hypertrophic; Pain, Postoperative
PubMed: 38948980
DOI: 10.47391/JPMA.10844