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Respiratory Research Oct 2023Microbiome dysbiosis can have long-lasting effects on our health and induce the development of various diseases. Bronchopulmonary dysplasia (BPD) is a multifactorial... (Observational Study)
Observational Study
BACKGROUND
Microbiome dysbiosis can have long-lasting effects on our health and induce the development of various diseases. Bronchopulmonary dysplasia (BPD) is a multifactorial disease with pre- and postnatal origins including intra-amniotic infection as main risk factor. Recently, postnatal pathologic lung microbiota colonization was associated with BPD. The objectives of this prospective observational cohort study were to describe differences in bacterial signatures in the amniotic fluid (AF) of intact pregnancies without clinical signs or risk of preterm delivery and AF samples obtained during preterm deliveries and their variations between different BPD disease severity stages.
METHODS
AF samples were collected under sterile conditions during fetal intervention from intact pregnancies (n = 17) or immediately before preterm delivery < 32 weeks (n = 126). Metabarcoding based approaches were used for the molecular assessment of bacterial 16S rRNA genes to describe bacterial community structure.
RESULTS
The absolute amount of 16S rRNA genes was significantly increased in AF of preterm deliveries and detailed profiling revealed a reduced alpha diversity and a significant change in beta diversity with a reduced relative abundance of 16S rRNA genes indicative for Lactobacillus and Acetobacter while Fusobacterium, Pseudomonas, Ureaplasma and Staphylococcus 16S rRNA gene prevailed. Although classification of BPD by disease severity revealed equivalent absolute 16S rRNA gene abundance and alpha and beta diversity in no, mild and moderate/severe BPD groups, for some 16S rRNA genes differences were observed in AF samples. Bacterial signatures of infants with moderate/severe BPD showed predominance of 16S rRNA genes belonging to the Escherichia-Shigella cluster while Ureaplasma and Enterococcus species were enriched in AF samples of infants with mild BPD.
CONCLUSIONS
Our study identified distinct and diverse intrauterine 16S rRNA gene patterns in preterm infants immediately before birth, differing from the 16S rRNA gene signature of intact pregnancies. The distinct 16S rRNA gene signatures at birth derive from bacteria with varying pathogenicity to the immature lung and are suited to identify preterm infants at risk. Our results emphasize the prenatal impact to the origins of BPD.
Topics: Infant; Pregnancy; Female; Infant, Newborn; Humans; Premature Birth; Infant, Premature; Bronchopulmonary Dysplasia; Amniotic Fluid; RNA, Ribosomal, 16S; Prospective Studies; Bacteria
PubMed: 37845700
DOI: 10.1186/s12931-023-02560-w -
Journal of Personalized Medicine Aug 2023We aimed to assess the feasibility of using confocal laser scanning microscopy (CLSM) for the real-time ex vivo examination of histological samples of laryngeal lesions...
We aimed to assess the feasibility of using confocal laser scanning microscopy (CLSM) for the real-time ex vivo examination of histological samples of laryngeal lesions and to evaluate the correlation between CLSM and definitive histological results. This preliminary study included eight consecutive patients with "suspected" laryngeal lesions who were candidates for endoscopic laryngeal surgery. The obtained samples were evaluated using CLSM and classified as "inadequate" or "adequate" (high- and low-grade dysplasia, in situ and invasive carcinoma, positive surgical margin, and inflammatory outbreaks). CLSM showed the macro image in all cases and generated a digital version. All the samples were defined as adequate during CLSM and confirmed at histopathology: low-grade dysplasia ( = 5), low- and high-grade dysplasia ( = 2), and high-grade dysplasia ( = 1). Four samples had an involved resection margin, and three samples revealed the presence of inflammatory outbreaks. CLSM can be applied to larynx pathology with excellent agreement with final histological results.
PubMed: 37623502
DOI: 10.3390/jpm13081252 -
JBMR Plus Dec 2023The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is...
The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold ( < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower ( < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
PubMed: 38130766
DOI: 10.1002/jbm4.10816 -
BMC Medical Genomics Dec 2023Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal...
BACKGROUND
Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.
METHODS
Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.
RESULTS
The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.
CONCLUSION
Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.
Topics: Pregnancy; Female; Humans; DNA Copy Number Variations; Ellis-Van Creveld Syndrome; Prenatal Diagnosis; Osteochondrodysplasias; Polydactyly; Ciliopathies; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 38062428
DOI: 10.1186/s12920-023-01753-y -
Aging and Disease Feb 2024Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms...
Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms underlying this disease remain elusive. We established a conditional knockout system by crossing Prx1cre and Osxcre with Ror2 mice. and conducted histological and immunofluorescence analyses to investigate the phenotypes during skeletal development. In the Prx1cre line, we observed RS-like skeletal abnormities, including short stature and an arched skull. Additionally, we found inhibition of chondrocyte differentiation and proliferation. In the Osxcre line, loss of ROR2 in osteoblast lineage cells led to reduced osteoblast differentiation during both embryonic and postnatal stages. Furthermore, ROR2 mutant mice exhibited increased adipogenesis in the bone marrow compared to their littermate controls. To further explore the underlying mechanisms, bulk RNA-seq analysis of Prx1cre; Ror2 embryos was performed, results revealed decreased BMP/TGF-β signaling. Immunofluorescence analysis further confirmed the decreased expression of p-smad1/5/8, accompanied by disrupted cell polarity in the developing growth plate. Pharmacological treatment using FK506 partially rescued the skeletal dysplasia and resulted in increased mineralization and osteoblast differentiation. By modeling the phenotype of RS in mice, our findings provide evidence for the involvement of mesenchymal progenitors as the cell origin and highlight the molecular mechanism of BMP/TGF-β signaling in skeletal dysplasia.
Topics: Mice; Animals; Chondrocytes; Cell Differentiation; Osteogenesis; Osteoblasts; Transforming Growth Factor beta; Dwarfism; Urogenital Abnormalities; Limb Deformities, Congenital; Craniofacial Abnormalities
PubMed: 37307827
DOI: 10.14336/AD.2023.0531 -
Diagnostics (Basel, Switzerland) Jul 2023Paxillin is a cytoskeletal protein involved in the pathogenesis of several types of cancers. However, the roles of paxillin in epithelial dysplasia (ED), oral squamous...
Evaluation of Paxillin Expression in Epithelial Dysplasia, Oral Squamous Cell Carcinoma, Lichen Planus with and without Dysplasia, and Hyperkeratosis: A Retrospective Cross-Sectional Study.
BACKGROUND
Paxillin is a cytoskeletal protein involved in the pathogenesis of several types of cancers. However, the roles of paxillin in epithelial dysplasia (ED), oral squamous cell carcinoma (OSCC), oral lichen planus with dysplasia (OLPD), hyperkeratosis (HK), and oral lichen planus (OLP) have remained unnoticed in the literature. This study aimed to evaluate its attainable functions in the pathogenesis and malignant transformation of potentially malignant oral epithelium and benign lesions.
METHODS
In this retrospective cross-sectional study, paxillin expression was investigated in 99 tissue samples, including 18 cases of OSCC, 21 ED, 23 OLP, 21 OLPD, and 16 cases of HK. The tissue sections also underwent immunohistochemical paxillin staining using 3,3-diaminobenzidine (DAB) chromogen. The intensity, location, and percentage of staining were examined across all groups. Data were analyzed using the Shapiro-Wilk test, ANOVA, Pearson chi-square, Kruskal-Wallis, and Dunn's post hoc test.
RESULTS
The cytoplasmic percentage and intensity staining of Paxillin expression were evident in the central/suprabasal and basal/peripheral layers of all the obtained samples. The final staining score was significantly higher in OSCC and dysplasia compared to HK and OLP ( = 0.004). It was found that paxillin expression is associated with the grade of dysplastic samples ( < 0.001).
CONCLUSION
The present study provides evidence that paxillin may be involved in the pathogenesis of OSCC and the development and progression of dysplastic tissue, since the paxillin expression was higher than that of HK and OLP.
PubMed: 37568839
DOI: 10.3390/diagnostics13152476 -
BMJ Paediatrics Open Dec 2023Dexamethasone is widely used as a systemic corticosteroid to treat and prevent bronchopulmonary dysplasia (BPD) in preterm infants. We evaluated the current epidemiology...
BACKGROUND
Dexamethasone is widely used as a systemic corticosteroid to treat and prevent bronchopulmonary dysplasia (BPD) in preterm infants. We evaluated the current epidemiology of dexamethasone use to prevent BPD and analyse the factors associated with the response to dexamethasone in very low birthweight infants using a nationwide database.
METHODS
We included very low birthweight infants born between January 2013 and December 2020 with a gestational age of 23-31 weeks using data from the Korean Neonatal Network registry. Patients were grouped based on their dexamethasone use into 'Dex' or 'No Dex' groups. Clinical variables and data were collected, and the annual trends of dexamethasone use and the proportion of patients who received dexamethasone according to gestational age were analysed. Respiratory outcomes were compared between the groups. Univariate and multivariate analyses were performed to analyse factors associated with the response to dexamethasone in BPD.
RESULTS
Of 11 261 eligible infants, 2313 (20.5%) received dexamethasone, and 1714 (74.1%) of them were diagnosed with moderate-to-severe BPD. The 8-year annual prevalence of dexamethasone use was 17.7-22.3%. The 'Dex' group had more moderate-to-severe BPD, more frequent invasive ventilation use at a postmenstrual age of 36 weeks and longer ventilator duration. Birth weight, 5-minute APGAR score, pulmonary hypertension within the first 28 days, surgical treatment of patent ductus arteriosus, medical treatment of patent ductus arteriosus, pathological chorioamnionitis, hydrocortisone or budesonide use, surgical management of necrotising enterocolitis and fungal sepsis were associated with BPD after dexamethasone use.
CONCLUSIONS
Approximately 20.5% of preterm infants received dexamethasone, and the frequency increased as gestational age decreased. Poor response to dexamethasone was associated with antenatal and postnatal inflammation, low birth weight and early pulmonary hypertension.
Topics: Infant; Infant, Newborn; Humans; Female; Pregnancy; Infant, Premature; Dexamethasone; Hypertension, Pulmonary; Cohort Studies; Ductus Arteriosus, Patent; Infant, Very Low Birth Weight; Bronchopulmonary Dysplasia
PubMed: 38114242
DOI: 10.1136/bmjpo-2023-002302 -
Frontiers in Cell and Developmental... 2023Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene...
Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established. In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity. Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.
PubMed: 38078000
DOI: 10.3389/fcell.2023.1294748 -
Medicine Jul 2023Ferroptosis is a recently identified form of cell death that is distinct from the conventional modes such as necrosis, apoptosis, and autophagy. Its role in...
Ferroptosis is a recently identified form of cell death that is distinct from the conventional modes such as necrosis, apoptosis, and autophagy. Its role in bronchopulmonary dysplasia (BPD) remains inadequately understood. To address this gap, we obtained BPD-related RNA-seq data and ferroptosis-related genes (FRGs) from the GEO database and FerrDb, respectively. A total of 171 BPD-related differentially expressed ferroptosis-related genes (DE-FRGs) linked to the regulation of autophagy and immune response were identified. Least absolute shrinkage and selection operator and SVM-RFE algorithms identified 23 and 14 genes, respectively, as marker genes. The intersection of these 2 sets yielded 9 genes (ALOX12B, NR1D1, LGMN, IFNA21, MEG3, AKR1C1, CA9, ABCC5, and GALNT14) with acceptable diagnostic capacity. The results of the functional enrichment analysis indicated that these identified marker genes may be involved in the pathogenesis of BPD through the regulation of immune response, cell cycle, and BPD-related pathways. Additionally, we identified 29 drugs that target 5 of the marker genes, which could have potential therapeutic implications. The ceRNA network we constructed revealed a complex regulatory network based on the marker genes, further highlighting their potential roles in BPD. Our findings offer diagnostic potential and insight into the mechanism underlying BPD. Further research is needed to assess its clinical utility.
Topics: Infant, Newborn; Humans; Ferroptosis; Bronchopulmonary Dysplasia; Apoptosis; Algorithms; Biomarkers
PubMed: 37478211
DOI: 10.1097/MD.0000000000034371 -
World Journal of Orthopedics Nov 2023Spondyloepiphyseal dysplasia congenita (SEDC) is a rare autosomal dominant hereditary disease caused by COL2A1 mutations. SEDC primarily involves the skeletal system,...
BACKGROUND
Spondyloepiphyseal dysplasia congenita (SEDC) is a rare autosomal dominant hereditary disease caused by COL2A1 mutations. SEDC primarily involves the skeletal system, with typical clinical manifestations, including short stature, hip dysplasia, and spinal deformity. Due to the low incidence of SEDC, there are only a few case reports regarding the surgical treatment of SEDC complicated with spinal deformities.
CASE SUMMARY
We report a case of a 16-year-old male patient with SEDC. He presented with typical short stature, atlantoaxial dysplasia, scoliosis, and hip dysplasia. Cervical magnetic resonance imaging showed spinal canal stenosis at the atlas level and cervical spinal cord compression with myelopathy. The scoliosis was a right thoracic curve with a Cobb angle of 65°. He underwent atlantoaxial reduction, decompression, and internal fixation from C1-C2 to relieve cervical myelopathy. Three months after cervical surgery, posterior correction surgery for scoliosis was performed from T3 to L4. Scoliosis was corrected from 66° to 8° and remained stable at 2-year follow-up.
CONCLUSION
This is the first case report of a patient with SEDC who successfully underwent surgery for atlantoaxial dysplasia and scoliosis. The study provides an important reference for the surgical treatment of SEDC complicated with spinal deformities.
PubMed: 38075470
DOI: 10.5312/wjo.v14.i11.827