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Background: Epigenetic regulation of gene expression and host defense is well established in microbial communities, with dozens of DNA modifications comprising the epigenomes of prokaryotes and bacteriophage. Phosphorothioation (PT) of DNA, in which a chemically-reactive sulfur atom replaces a non-bridging oxygen in the sugar-phosphate backbone, is catalyzed by dnd and ssp gene families widespread in bacteria and archaea. However, little is known about the role of PTs or other microbial epigenetic modifications in the human microbiome. Here we optimized and applied fecal DNA extraction, mass spectrometric, and metagenomics technologies to characterize the landscape and temporal dynamics of gut microbes possessing PT modifications. Results: Exploiting the nuclease-resistance of PTs, mass spectrometric analysis of limit digests of PT-containing DNA reveals PT dinucleotides as part of genomic consensus sequences, with 16 possible dinucleotide combinations. Analysis of mouse fecal DNA revealed a highly uniform spectrum of 11 PT dinucleotides in all littermates, with PTs estimated to occur in 5-10% of gut microbes. Though at similar levels, PT dinucleotides in fecal DNA from 11 healthy humans possessed signature combinations and levels of individual PTs. Comparison with a widely distributed microbial epigenetic mark, m6dA, suggested temporal dynamics consistent with expectations for gut microbial communities based on Taylor's Power Law. Application of PT-seq for site-specific metagenomic analysis of PT-containing bacteria in one fecal donor revealed the larger consensus sequences for the PT dinucleotides in Bacteroidota, Firmicutes, Actinobacteria, and Proteobacteria, which differed from unbiased metagenomics and suggested that the abundance of PT-containing bacteria did not simply mirror the spectrum of gut bacteria. PT-seq further revealed low abundance PT sites not detected as dinucleotides by mass spectrometry, attesting to the complementarity of the technologies. Conclusions: The results of our studies provide a benchmark for understanding the behavior of an abundant and chemically-reactive epigenetic mark in the human gut microbiome, with implications for inflammatory conditions of the gut.
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Titin is the largest protein produced by living cells and its function as a molecular spring in striated muscle is well characterized (1, 2). Here we demonstrate that titin isoforms in the same size range as found in muscle are prominent neuronal proteins in both the central and peripheral nervous systems, including motor neurons in the spinal cord and brain. Within these neurons, titin localizes to the dense fibrillar component of the nucleolus, the site of ribosomal RNA biogenesis and modification, and a critical site of dysfunction in neurodegenerative disease (3-5). Additionally, we show that the levels of both titin mRNA and protein are altered in the spinal cord of SOD1G93A mice, a commonly used model of amyotrophic lateral sclerosis, indicating that titin mediated nucleolar events may in fact contribute to the pathobiology of disease.
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IMPORTANCE: H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.
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Coinfección , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Ratones , Animales , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Modelos Animales de Enfermedad , Biomarcadores de Tumor , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Proteína Forkhead Box M1/genéticaRESUMEN
Recent studies have suggested the presence of moonlight mediated behaviour in avian aerial insectivores, such as swifts. Here, we use the combined analysis of state-of-the-art activity logger data across three swift species, the common, pallid and alpine swifts, to quantify flight height and activity in responses to moonlight-driven crepuscular and nocturnal light conditions. Our results show a significant response in flight heights to moonlight illuminance for common and pallid swifts, i.e. when moon illuminance increased flight height also increased, while a moonlight-driven response is absent in alpine swifts. We show a weak relationship between night-time illuminance-driven responses and twilight ascending behaviour, suggesting a decoupling of both crepuscular and night-time behaviour. We suggest that swifts optimize their flight behaviour to adapt to favourable night-time light conditions, driven by light-responsive and size-dependent vertical insect stratification and weather conditions.
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Aves , Vuelo Animal , Animales , Vuelo Animal/fisiología , Aves/fisiología , InsectosRESUMEN
The brain is traditionally viewed as an immunologically privileged site; however, there are known to be multiple resident immune cells that influence the CNS environment and are reactive to extra-CNS signaling. Microglia are an important component of this system, which influences early neurodevelopment in addition to modulating inflammation and regenerative responses to injury and infection. Microglia are influenced by gut microbiome-derived metabolites, both as part of their normal function and potentially in pathological patterns that may induce neurodevelopmental disabilities or behavioral changes. This review aims to summarize the mounting evidence indicating that, not only is the Gut-Brain axis mediated by metabolites and microglia throughout an organism's lifetime, but it is also influenced prenatally by maternal microbiome and diet, which holds implications for both early neuropathology and neurodevelopment.
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Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, with several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six patients with SCD at pre- and post-GT time points to map the somatic mutation and clonal landscape of gene-modified and unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified among gene-modified or unmodified cells; however, an increased frequency of potential driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) was observed in both genetically modified and unmodified cells, suggesting positive selection of mutant clones during GT. This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms.
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Anemia de Células Falciformes , Neoplasias , Humanos , Hematopoyesis/genética , Filogenia , Mutación/genética , Células Madre Hematopoyéticas/patología , Células Clonales , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/patología , Terapia Genética , Neoplasias/patologíaRESUMEN
Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1ß transgenic mice, expressing human interleukin (IL)-1ß in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett's esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1ß-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive. We report for the first time that in addition to the previously described Barrett's esophagus-like metaplasia, the L2-IL-1ß mice also develop squamous epithelial dysplasia with progression to squamous cell carcinoma (SCC) in the esophagus and the tongue. L2-IL-1ß showed age-dependent progression of squamous dysplasia to SCC with approximately 40% (n = 49) and 23.5% (n = 17) incidence rates for esophageal and tongue invasive SCC respectively, by 12-15 months of age. Interestingly, SCC development and progression in L2-IL-1ß was similar in both Germ Free (GF) and Specific Pathogen Free (SPF) conditions. Immunohistochemistry revealed a T cell predominant inflammatory profile with enhanced expression of Ki67, Sox2 and the DNA double-strand break marker, γ-H2AX, in the dysplastic squamous epithelia of L2-IL-1ß mice. Pro-inflammatory cytokines, immunomodulatory players, chemoattractants for inflammatory cells (T cells, neutrophils, eosinophils, and macrophages) and oxidative damage marker, iNOS, were significantly increased in the esophageal and tongue tissues of L2-IL-1ß mice. Our recent findings have expanded the translational utility of the IL-1ß mouse model to aid in further characterization of the key pathways of inflammation driven BE and EAC as well as ESCC and Oral SCC.
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Adenocarcinoma , Esófago de Barrett , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Preescolar , Humanos , Ratones , Adenocarcinoma/patología , Esófago de Barrett/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/complicaciones , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias de Cabeza y Cuello/complicaciones , Inflamación/genética , Inflamación/complicaciones , Metaplasia , Ratones Transgénicos , Neoplasias de la Boca/genética , Neoplasias de la Boca/complicaciones , Carcinoma de Células Escamosas de Cabeza y Cuello/complicacionesRESUMEN
While sustained-release buprenorphine (BSR) is used as a long-lasting opioid analgesic in common marmosets (Callithrix jacchus), there are no published studies on pharmaceutical-grade extended-release buprenorphine options such as Ethiqa XR (EXR) for this species. However, BSR is a compounded product and has been reported to cause injection site reactions in multiple species, including marmosets. Additionally, now with the availability of EXR, a pharmaceutical-grade veterinary product, the use of BSR in laboratory animals is not compliant with the Guide for the Care and Use of Laboratory Animals (Guide) unless scientifically justified and approved by the IACUC. We compared pharmacokinetic and safety profiles of BSR (0.15 mg/kg) and EXR (0.1-0.2 mg/kg) administered subcutaneously to adult marmosets. Blood was collected by venipuncture of the saphenous vein at multiple time points (0.25-72 h) and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). EXR between 0.1 and 0.2 mg/kg resulted in a dose-dependent increase in Cmax (1.43-2.51 ng/mL) and were not statistically different from BSR (1.82 ng/mL). Tmax, lambdaz, and t1/2 were not statistically different between formulations. Mean plasma buprenorphine concentrations for BSR and EXR exceeded the therapeutic threshold (0.1 ng/mL) within 0.25 h and lasted for > 72 h. Mild sedation, but neither respiratory depression nor ataxia, was observed for both formulations. BSR injection sites had significantly higher histopathological scores compared to EXR. Video recordings for monitoring drug-induced behavioral changes showed increased animal activity levels after BSR and EXR versus saline controls. Norbuprenorphine, a buprenorphine metabolite associated with respiratory depression, was detected in the plasma after BSR and EXR administration as well as by in vitro liver microsome assays. In conclusion, we recommend using EXR over BSR as a long-lasting buprenorphine analgesic in marmosets because EXR is a pharmaceutical-grade formulation that is compliant with FDA guidelines and the Guide as well as exhibits comparable PK and safety profiles as BSR.
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Buprenorfina , Callithrix , Animales , Preparaciones de Acción Retardada , Cromatografía Liquida , Espectrometría de Masas en Tándem , CallitrichinaeRESUMEN
Along with Helicobacter pylori infection, the gastric microbiota is hypothesized to modulate stomach cancer risk in susceptible individuals. Whole metagenomic shotgun sequencing (WMS) is a sequencingâ¯approach to characterize the microbiome with advantages over traditional culture and 16S rRNA sequencing including identification of bacterial and non-bacterial taxa, species/strain resolution, and functional characterization of the microbiota. In this study, we used WMS to survey the microbiome in extracted DNA from antral gastric biopsy samples from Colombian patients residing in the high-risk gastric cancer town Túquerres (n = 10, H. pylori-positive = 7) and low-risk town of Tumaco (n = 10, H. pylori-positive = 6). Kraken2/Bracken was used for taxonomic classification and abundance. Functional gene profiles were inferred by InterProScan and KEGG analysis of assembled contigs and gene annotation. The most abundant taxa represented bacteria, non-human eukaryota, and viral genera found in skin, oral, food, and plant/soil environments including Staphylococus, Streptococcus, Bacillus, Aspergillus, and Siphoviridae. H. pylori was the predominant taxa present in H. pylori-positive samples. Beta diversity was significantly different based on H. pylori-status, risk group, and sex. WMS detected more bacterial taxa than 16S rRNA sequencing and aerobic, anaerobic, and microaerobic culture performed on the same gastric biopsy samples. WMS identified significant differences in functional profiles found between H. pylori-status, but not risk or sex groups. H. pylori-positive samples were significantly enriched for H. pylori-specific genes including virulence factors such as vacA, cagA, and urease, while carbohydrate and amino acid metabolism genes were enriched in H. pylori-negative samples. This study shows WMS has the potential to characterize the taxonomy and function of the gastric microbiome as risk factors for H. pylori-associated gastric disease. Future studies will be needed to compare and validate WMS versus traditional culture and 16S rRNA sequencing approaches for characterization of the gastric microbiome.
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Gastritis , Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Microbiota , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/microbiología , Colombia , ARN Ribosómico 16S/genética , Infecciones por Helicobacter/microbiología , Gastritis/patología , Helicobacter pylori/genética , Biopsia , Factores de Riesgo , América del SurRESUMEN
Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known to participate in immune responses and play significant functions during infections, the role of MKs within the immune system remains largely unexplored. Histological studies of sepsis patients identified increased nucleated CD61+ cells (MKs) in the lungs, and CD61+ staining (likely platelets within microthrombi) in the kidneys, which correlated with the development of organ dysfunction. Detailed imaging cytometry of peripheral blood from patients with sepsis found significantly higher MK counts, which we predict would likely be misclassified by automated hematology analyzers as leukocytes. Utilizing in vitro techniques, we show that both stem cell derived MKs (SC MKs) and cells from the human megakaryoblastic leukemia cell line, Meg-01, undergo chemotaxis, interact with bacteria, and are capable of releasing chromatin webs in response to various pathogenic stimuli. Together, our observations suggest that MK cells display some basic innate immune cell behaviors and may actively respond and play functional roles in the pathophysiology of sepsis.
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Megacariocitos , Sepsis , Humanos , Megacariocitos/metabolismo , Plaquetas/metabolismo , Línea Celular , Inmunidad Innata , Sepsis/metabolismoRESUMEN
The loss of IL-10R function leads to severe early onset colitis and, in murine models, is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed, STAT1-/- mice exhibit defects in colonic macrophage accumulation after Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNγR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both wild-type and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R inhibits the generation of cell extrinsic signals that promote the accumulation of immature macrophages. These results define the essential mechanisms controlling the inflammatory macrophage accumulation in inflammatory bowel diseases.
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Colitis , Ratones , Animales , Colitis/metabolismo , Macrófagos/metabolismo , Receptores de Interleucina-10/genética , Receptores de Interleucina-10/metabolismo , Transducción de Señal , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Patients eligible for lung cancer screening (LCS) are those at high risk of lung cancer due to their smoking histories and age. While screening for LCS is effective in lowering lung cancer mortality, primary care providers are challenged to meet beneficiary eligibility for LCS from the Centers for Medicare & Medicaid Services, including a patient counseling and shared decision-making (SDM) visit with the use of patient decision aid(s) prior to screening. METHODS: We will use an effectiveness-implementation type I hybrid design to: 1) identify effective, scalable smoking cessation counseling and SDM interventions that are consistent with recommendations, can be delivered on the same platform, and are implemented in real-world clinical settings; 2) examine barriers and facilitators of implementing the two approaches to delivering smoking cessation and SDM for LCS; and 3) determine the economic implications of implementation by assessing the healthcare resources required to increase smoking cessation for the two approaches by delivering smoking cessation within the context of LCS. Providers from different healthcare organizations will be randomized to usual care (providers delivering smoking cessation and SDM on site) vs. centralized care (smoking cessation and SDM delivered remotely by trained counselors). The primary trial outcomes will include smoking abstinence at 12-weeks and knowledge about LCS measured at 1-week after baseline. CONCLUSION: This study will provide important new evidence about the effectiveness and feasibility of a novel care delivery model for addressing the leading cause of lung cancer deaths and supporting high-quality decisions about LCS. GOV PROTOCOL REGISTRATION: NCT04200534 TRIAL REGISTRATION: ClinicalTrials.govNCT04200534.
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Neoplasias Pulmonares , Cese del Hábito de Fumar , Anciano , Humanos , Estados Unidos , Cese del Hábito de Fumar/métodos , Neoplasias Pulmonares/diagnóstico , Toma de Decisiones Conjunta , Detección Precoz del Cáncer/métodos , Medicare , Atención a la Salud , Toma de Decisiones , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Helicobacter spp., including the well-known human gastric pathogen H. pylori, can cause gastric diseases in humans and other mammals. They are Gram-negative bacteria that colonize the gastric epithelium and use their multiple flagella to move across the protective gastric mucus layer. The flagella of different Helicobacter spp. vary in their location and number. This review focuses on the swimming characteristics of different species with different flagellar architectures and cell shapes. All Helicobacter spp. use a run-reverse-reorient mechanism to swim in aqueous solutions, as well as in gastric mucin. Comparisons of different strains and mutants of H. pylori varying in cell shape and the number of flagella show that their swimming speed increases with an increasing number of flagella and is somewhat enhanced with a helical cell body shape. The swimming mechanism of H. suis, which has bipolar flagella, is more complex than that of unipolar H. pylori. H. suis exhibits multiple modes of flagellar orientation while swimming. The pH-dependent viscosity and gelation of gastric mucin significantly impact the motility of Helicobacter spp. In the absence of urea, these bacteria do not swim in mucin gel at pH < 4, even though their flagellar bundle rotates.
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DNA-methylating environmental carcinogens such as N-nitrosodimethylamine (NDMA) and certain alkylators used in chemotherapy form O 6-methylguanine (m6G) as a functionally critical intermediate. NDMA is a multi-organ carcinogen found in contaminated water, polluted air, preserved foods, tobacco products, and many pharmaceuticals. Only ten weeks after exposure to NDMA, neonatally-treated mice experienced elevated mutation frequencies in liver, lung and kidney of â¼35-fold, 4-fold and 2-fold, respectively. High-resolution mutational spectra (HRMS) of liver and lung revealed distinctive patterns dominated by GCâAT mutations in 5'-Pu-G-3' contexts, very similar to human COSMIC mutational signature SBS11. Commonly associated with alkylation damage, SBS11 appears in cancers treated with the DNA alkylator temozolomide (TMZ). When cells derived from the mice were treated with TMZ, N-methyl-N-nitrosourea, and streptozotocin (two other therapeutic methylating agents), all displayed NDMA-like HRMS, indicating mechanistically convergent mutational processes. The role of m6G in shaping the mutational spectrum of NDMA was probed by removing MGMT, the main cellular defense against m6G. MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs.
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Local environmental factors influence CD8+ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8+ T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8+/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.
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Neoplasias Pulmonares , Linfocitos T Reguladores , Humanos , Linfocitos T CD8-positivos , Interferón gamma , Linfocitos T CitotóxicosRESUMEN
The purpose of this study was to evaluate the effectiveness of telemedicine appointments in a tertiary orthopedic hip clinic during the COVID-19 pandemic, as a substitute for traditional in-person visits. One hundred sixty-three patients had a telemedicine visit from March to September 2020. Patients were divided into two cohorts. The presurgical group included all patients who had not undergone any prior surgical hip procedures. The pre-surgical group was further subdivided into two groups based on the purpose of the visit: conservative treatment and imaging review. Patients who were indicated for surgical treatment from these two groups were identified to assess their compliance with the surgical indication. The effectiveness was measured by assessing whether patients required an in-person visit before the scheduled follow-up after the telemedicine visit for further medical assessment. Fifty (30.7%) men and 113 (69.3%) women had a telemedicine visit during the 6-month period. The mean age was 43.68 (±16.95) years. There were 92 (56.4%) patients in the presurgical group, of whom 41% followed up after indication for conservative treatment and 59% visited to review imaging. From these groups, 27% were indicated for surgical treatment. The postsurgical group contained 71 (43.6%) patients, divided into three groups based on their surgery date: 0 to 3 months (27%), 4 to 12 months (59%), and more than 12 months (14%). All patients were compliant with the scheduled follow-up after their telemedicine visit. This study showed that telemedicine can be an effective tool for patient-physician communication, obviating the need for subsequent follow-up beyond regularly scheduled visits. [Orthopedics. 2023;46(3):e173-e178.].
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COVID-19 , Médicos , Telemedicina , Masculino , Humanos , Femenino , Adulto , COVID-19/epidemiología , Pandemias , Instituciones de Atención Ambulatoria , ComunicaciónRESUMEN
Previous studies have yielded widely divergent conclusions about the percentage of all mass public shootings globally that take place in the US, ranging from a low of 3% to a high of 36%. Because of documented underreporting of lower-severity attacks involving fewer than 10 victim fatalities in US cases in these studies, it is reasonable to assume that this underreporting issue also applies to their measurement of mass public shootings outside the US. To estimate the total number of mass public shootings worldwide, we use multiple assumptions and modeling approaches, including a hierarchical Bayesian model. Our estimates show the US accounted for anywhere between 16% and 26% of the world's mass public shootings during the 1976 to 2012 period. These estimates suggest the US share of the total is between four and six times higher than its 4% share of the world's population.
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Armas de Fuego , Heridas por Arma de Fuego , Humanos , Estados Unidos/epidemiología , Heridas por Arma de Fuego/epidemiología , Teorema de Bayes , PrevalenciaRESUMEN
Iron deficiency, the most common micronutrient deficiency in humans, is associated with long-term deficits in cognition and memory if left untreated. Infection with the gastric pathogen Helicobacter pylori has been linked to iron deficiency anemia (IDA). The H. pylori virulence factor cytotoxin-associated gene A (cagA) is proposed to be especially pertinent in iron deficiency. Male INS-GAS/FVB mice were infected with the CagA+ strain pre-murine Sydney strain 1 (PMSS1) for 12-13 or 27-29 weeks to investigate the role of chronic H. pylori infection in iron deficiency and neurological sequelae. Mice at both timepoints demonstrated significantly elevated gastric histopathology scores and inflammatory cytokines compared to sham-dosed controls. However, only mice at 27-29 weeks post infection had changes in hematological parameters, with significantly decreased erythrocyte count, hematocrit, serum hemoglobin, and increased serum total iron binding capacity. Gastric transcription of iron-regulatory genes Hamp and Bmp4 were significantly downregulated at both timepoints. In the brain, iron-dependent myelingergic and synaptic markers were significantly downregulated at 27-29 weeks. These results indicated that long-term infection of the CagA + PMSS1 strain of H. pylori in this study caused anemia, altered gastric iron homeostasis, and neurological changes similar to those reported in other rodent H. pylori CagA- strain infection models.
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Anemia Ferropénica , Infecciones por Helicobacter , Helicobacter pylori , Deficiencias de Hierro , Humanos , Masculino , Ratones , Animales , Helicobacter pylori/genética , Hierro/metabolismo , Anemia Ferropénica/complicaciones , Anemia Ferropénica/patología , Encéfalo/patología , Infecciones por Helicobacter/patología , Antígenos Bacterianos/genética , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismoRESUMEN
The field of plastic surgery, formally organized in 1931 with the founding of the American Society of Plastic and Reconstructive Surgery, was shaped in many ways by a small practice of Philadelphia physicians. At the center of the practice was Warren B. Davis, a Philadelphia otolaryngologist and plastics pioneer whose innovations in cleft palate surgery would lead to significant improvements in functional and cosmetic outcomes in his time. In addition to his own innovations, Davis was responsible for the training of John Reese, the inventor of the Reese dermatome that changed the face of burn medicine during World War II. Aside from his contributions to surgery and the founding of the American Society of Plastic and Reconstructive Surgery, Dr. Davis was also the founder and first editor of the Plastic and Reconstructive Surgery journal which to this day is the premiere, authoritative journal of plastic surgery. Lastly, Dr. Davis established a plastic surgical practice, now Jefferson Plastic Surgery. Unique in its longevity, this practice would continue to shape the field of plastic surgery and continues to improve lives today-109 years after its founding in 1913.
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[This corrects the article DOI: 10.3389/fimmu.2022.903796.].