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How the central innate immune protein, STING, is activated by its ligands remains unknown. Here, using structural biology and biochemistry, we report that the metazoan second messenger 2'3'-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2'3'-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a therapeutic hypothesis for autoimmune syndrome treatment.
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Proteínas de la Membrana/metabolismo , Sitios de Unión , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , Dimerización , Retículo Endoplásmico/metabolismo , Células HEK293 , Humanos , Ligandos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Nucleótidos Cíclicos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Transducción de SeñalRESUMEN
It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin's role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients.
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COVID-19 , SARS-CoV-2 , Humanos , Animales , Ratones , Células Endoteliales , Proteoma , PéptidosRESUMEN
Worldwide, over 150 million adolescent and adult women use oral contraceptives (OC). An association between OC-use and the emergence of symptoms of mental disorders has been suggested. This systematic review and meta-analysis provide an overview of published research regarding symptoms of mental disorders in association with OC-use, factoring the influence of OC types, age of first-use, duration of OC-intake, and previous diagnoses of mental disorders. A systematic literature search was conducted between June-July 2022. 22 studies were included. While most found no significant OC-use effects on mental symptoms, some hinted at OCs as a potential risk. The existing evidence regarding the potential link between progestin-only OC-use and an elevated risk of mental symptoms in comparison to combined OC-use remains inconclusive. However, due to emerging indications suggesting that the formulation of OC might play a role in mental health outcomes, this topic warrants further investigation. Moreover, indications of an increased risk for depressive symptoms in adolescent OC-users should be noted. Hence, while general population effects seem unlikely, they cannot be completely disregarded. The decision on OC-use should depend on the patient's medical history and should be re-evaluated regularly.
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Anticonceptivos Orales , Trastornos Mentales , Adulto , Adolescente , Humanos , Femenino , Anticonceptivos Orales/efectos adversos , AnticoncepciónRESUMEN
INTRODUCTION: Understanding the pneumococcal serotypes causing community-acquired pneumonia (CAP) is essential for evaluating the impact of pneumococcal vaccines. METHODS: We conducted a prospective surveillance study of adults aged ≥18 years hospitalized with CAP at 3 hospitals in Tennessee and Georgia between 1 September 2018 and 31 October 2022. We assessed for pneumococcal etiology with cultures, the BinaxNOW urinary antigen detection test, and serotype-specific urinary antigen detection assays that detect 30 pneumococcal serotypes contained in the investigational pneumococcal conjugate vaccine V116, as well as licensed vaccines PCV15 and PCV20 (except serotype 15B). The distribution of pneumococcal serotypes was calculated based on serotype-specific urinary antigen detection results. RESULTS: Among 2917 hospitalized adults enrolled with CAP, 352 (12.1%) patients had Streptococcus pneumoniae detected, including 51 (1.7%) patients with invasive pneumococcal pneumonia. The 8 most commonly detected serotypes were: 3, 22F, 19A, 35B, 9N, 19F, 23A, and 11A. Among 2917 adults with CAP, 272 (9.3%) had a serotype detected that is contained in V116, compared to 196 (6.7%) patients with a serotype contained in PCV20 (P < .001), and 168 (5.8%) patients with a serotype contained in PCV15 (P < .001). A serotype contained in V116 but not PCV15 or PCV20 was detected in 120 (4.1%) patients, representing 38.0% of serotype detections. CONCLUSIONS: Approximately 12% of adults hospitalized with CAP had S. pneumoniae detected, and approximately one-third of the detected pneumococcal serotypes were not contained in PCV15 or PCV20. Development of new pneumococcal vaccines with expanded serotype coverage has the potential to prevent a substantial burden of disease.
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Normothermic machine perfusion (NMP) is increasingly considered for pretransplant kidney quality assessment. However, fundamental questions about differences between in vivo and ex vivo renal function, as well as the impact of ischemic injury on ex vivo physiology, remain unanswered. This study utilized magnetic resonance imaging (MRI), alongside conventional parameters to explore differences between in vivo and ex vivo renal function and the impact of warm ischemia on a kidney's behavior ex vivo. Renal MRI scans and samples were obtained from living pigs (n = 30) in vivo. Next, kidney pairs were procured and exposed to minimal, or 75 minutes of warm ischemia, followed by 6 hours of hypothermic machine perfusion. Both kidneys simultaneously underwent 6-hour ex vivo perfusion in MRI-compatible NMP circuits to obtain multiparametric MRI data. Ischemically injured ex vivo kidneys showed a significantly altered regional blood flow distribution compared to in vivo and minimally damaged organs. Both ex vivo groups showed diffusion restriction relative to in vivo. Our findings underscore the differences between in vivo and ex vivo MRI-based renal characteristics. Therefore, when assessing organ viability during NMP, it should be considered to incorporate parameters beyond the conventional functional markers that are common in vivo.
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INTRODUCTION: WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the progression of chronic liver diseases (CLD) was investigated. METHODS: WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. RESULTS: In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-ß1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. CONCLUSIONS: WISP1 expression is induced by TGF-ß1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.
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Regular participation in sports results in a series of physiological adaptations. However, little is known about the brain adaptations to physical activity. Here we aimed to investigate whether young endurance athletes and non-athletes differ in the gray and white matter of the brain and whether cardiorespiratory fitness (CRF) is associated with these differences. We assessed the CRF, volumes of the gray and white matter of the brain using structural magnetic resonance imaging (sMRI), and brain white matter connections using diffusion magnetic resonance imaging (dMRI) in 20 young male endurance athletes and 21 healthy non-athletes. While total brain volume was similar in both groups, the white matter volume was larger and the gray matter volume was smaller in the athletes compared to non-athletes. The reduction of gray matter was located in the association areas of the brain that are specialized in processing of sensory stimuli. In the microstructure analysis, significant group differences were found only in the association tracts, for example, the inferior occipito-frontal fascicle (IOFF) showing higher fractional anisotropy and lower radial diffusivity, indicating stronger myelination in this tract. Additionally, gray and white matter brain volumes, as well as association tracts correlated with CRF. No changes were observed in other brain areas or tracts. In summary, the brain signature of the endurance athlete is characterized by changes in the integration of sensory and motor information in the association areas.
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Imagen de Difusión Tensora , Sustancia Blanca , Masculino , Humanos , Imagen de Difusión Tensora/métodos , Encéfalo/fisiología , Sustancia Blanca/patología , Sustancia Gris , AtletasRESUMEN
BACKGROUND: Paediatric thoracolumbar spine injuries are rare, and meaningful epidemiological data are lacking. OBJECTIVES: The aim of this study was to provide epidemiological data for paediatric patients with thoracolumbar spinal trauma in Germany with a view to enhancing future decision-making in relation to the diagnostics and treatment of these patients. MATERIALS AND METHODS: A retrospective multicentre study includes patients up to 16 years of age who were suffering from thoracolumbar spine injuries who had been treated in six German spine centres between 01/2010 and 12/2016. The clinical database was analysed for patient-specific data, trauma mechanisms, level of injury, and any accompanying injuries. Diagnostic imaging and subsequent treatment were investigated. Patients were divided into three age groups for further evaluation: age group I (0-6 years), age group II (7-9 years) and age group III (10-16 years). RESULTS: A total of 153 children with 345 thoracolumbar spine injuries met the inclusion criteria. The mean age at the time of hospitalization due to the injury was 12.9 (± 3.1) years. Boys were likelier to be affected (1:1.3). In all age groups, falls and traffic accidents were the most common causes of thoracolumbar spine injuries. A total of 95 patients (62.1%) were treated conservatively, while 58 (37.9%) of the children underwent surgical treatment. Minimally invasive procedures were the most chosen procedures. Older children and adolescents were likelier to suffer from higher-grade injuries according to the AOSpine classification. The thoracolumbar junction (T11 to L2) was the most affected level along the thoracolumbar spine (n = 90). Neurological deficits were rarely seen in all age groups. Besides extremity injuries (n = 52, 30.2%), head injuries represented the most common accompanying injuries (n = 53, 30.8%). Regarding spinal injuries, most of the patients showed no evidence of complications during their hospital stay (96.7%). CONCLUSIONS: The thoracolumbar junction was more frequently affected in older children and adolescents. The majority of thoracolumbar spinal column injuries were treated conservatively. Nevertheless, 37.9% of hospitalized children had to be treated surgically, and there was an acceptable complication rate for the surgeries that were performed.
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Fracturas de la Columna Vertebral , Traumatismos Vertebrales , Masculino , Adolescente , Humanos , Niño , Recién Nacido , Lactante , Preescolar , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/cirugía , Vértebras Torácicas/lesiones , Traumatismos Vertebrales/diagnóstico por imagen , Traumatismos Vertebrales/epidemiología , Traumatismos Vertebrales/terapia , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Vértebras Lumbares/lesiones , Alemania/epidemiología , Estudios Retrospectivos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/terapiaRESUMEN
Amyloid beta (Aß) plays a major role in the pathogenesis of Alzheimer's disease and, more recently, has been shown to protect against liver fibrosis. Therefore, we studied Aß-42 levels and the expression of genes involved in the generation, degradation, and transport of Aß proteins in liver samples from patients at different stages of metabolic dysfunction-associated liver disease (MASLD) and under steatotic conditions in vitro/in vivo. Amyloid precursor protein (APP), key Aß-metabolizing proteins, and Aß-42 were analyzed using RT-PCR, Western blotting, Luminex analysis in steatotic in vitro and fatty liver mouse models, and TaqMan qRT-PCR analysis in hepatic samples from patients with MASLD. Hepatocytes loaded with palmitic acid induced APP, presenilin, and neprilysin (NEP) expression, which was reversed by oleic acid. Increased APP and NEP, decreased BACE1, and unchanged Aß-42 protein levels were found in the steatotic mouse liver compared to the normal liver. Aß-42 concentrations were low in MASLD samples of patients with moderate to severe fibrosis compared to the livers of patients with mild or no MASLD. Consistent with the reduced Aß-42 levels, the mRNA expression of proteins involved in APP degradation (ADAM9/10/17, BACE2) and Aß-42 cleavage (MMP2/7/9, ACE) was increased. In the steatotic liver, the expression of APP- and Aß-metabolizing proteins is increased, most likely related to oxidative stress, but does not affect hepatic Aß-42 levels. Consistent with our previous findings, low Aß-42 levels in patients with liver fibrosis appear to be caused by the reduced production and enhanced non-amyloidogenic processing of APP.
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Péptidos beta-Amiloides , Hígado Graso , Hígado , Animales , Humanos , Péptidos beta-Amiloides/metabolismo , Ratones , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado/metabolismo , Hígado/patología , Masculino , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Fragmentos de Péptidos/metabolismo , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/patología , Femenino , Modelos Animales de Enfermedad , Neprilisina/metabolismo , Neprilisina/genéticaRESUMEN
BACKGROUND: Gluten composition is an important quality parameter of wheat flour. Reversed-phase high-performance liquid chromatography (RP-HPLC) is a state-of-the-art method for its analysis. As this is a very labour-intensive and time-consuming procedure, alternative faster methods are desirable. Enzyme-linked immunosorbent assay (ELISA) is a high-throughput method often used for the analysis of gluten traces in gluten-free products. In this proof-of-principle study, we introduce an experimental triple ELISA for the relative quantitation of gliadins, high-molecular-weight glutenin subunits (HMW-GS) and low-molecular-weight glutenin subunits (LMW-GS) of one wheat flour extract. RESULTS: The results of 80 common wheat flour samples obtained from the triple ELISA and RP-HPLC were correlated. The results for gliadins (r = 0.69) and HMW-GS (r = 0.81) showed a medium and high correlation, respectively. Only a very weak correlation of ELISA and RP-HPLC results was observed for LMW-GS (r = 0.49). Results for glutenins (r = 0.69) and gluten (r = 0.72) had a medium correlation. The gliadin/glutenin ratio (r = 0.47) and LMW-GS/HMW-GS ratio (r = 0.40) showed a weak or no correlation. The gliadin, LMW-GS and gluten contents were lower and the HMW-GS content was higher in the ELISA measurement compared to RP-HPLC. CONCLUSION: The quantitation of gliadins and HMW-GS by the experimental triple ELISA showed comparable results to RP-HPLC, whereas no strong correlation between the results from the two methods was found for LMW-GS. Overall, the experimental triple ELISA is suitable for relative gluten quantitation, especially for the analysis of large sample sets. Further work will focus on improving the experimental procedure of the ELISA. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
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Ensayo de Inmunoadsorción Enzimática , Harina , Gliadina , Glútenes , Triticum , Glútenes/análisis , Triticum/química , Ensayo de Inmunoadsorción Enzimática/métodos , Harina/análisis , Gliadina/análisis , Gliadina/química , Cromatografía Líquida de Alta Presión/métodos , Peso MolecularRESUMEN
Brachial plexus blocks at the interscalene level are frequently chosen by physicians and recommended by textbooks for providing regional anesthesia and analgesia to patients scheduled for shoulder surgery. Published data concerning interscalene single-injection or continuous brachial plexus blocks report good analgesic effects. The principle of interscalene catheters is to extend analgesia beyond the duration of the local anesthetic's effect through continuous infusion, as opposed to a single injection. However, in addition to the recognized beneficial effects of interscalene blocks, whether administered as a single injection or through a catheter, there have been reports of consequences ranging from minor side effects to severe, life-threatening complications. Both can be simply explained by direct mispuncture, as well as undesired local anesthetic spread or misplaced catheters. In particular, catheters pose a high risk when advanced or placed uncontrollably, a fact confirmed by reports of fatal outcomes. Secondary catheter dislocations explain side effects or loss of effectiveness that may occur hours or days after the initial correct function has been observed. From an anatomical and physiological perspective, this appears logical: the catheter tip must be placed near the plexus in an anatomically tight and confined space. Thus, the catheter's position may be altered with the movement of the neck or shoulder, e.g., during physiotherapy. The safe use of interscalene catheters is therefore a balance between high analgesia quality and the control of side effects and complications, much like the passage between Scylla and Charybdis. We are convinced that the anatomical basis crucial for the brachial plexus block procedure at the interscalene level is not sufficiently depicted in the common regional anesthesia literature or textbooks. We would like to provide a comprehensive anatomical survey of the lateral neck, with special attention paid to the safe placement of interscalene catheters.
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Bloqueo del Plexo Braquial , Humanos , Bloqueo del Plexo Braquial/métodos , Anestésicos Locales/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Hombro/cirugía , CatéteresRESUMEN
The cell-cell adhesion cadherin-catenin complexes recruit vinculin to the adherens junction (AJ) to modulate the mechanical couplings between neighboring cells. However, it is unclear how vinculin influences the AJ structure and function. Here, we identified two patches of salt bridges that lock vinculin in the head-tail autoinhibited conformation and reconstituted the full-length vinculin activation mimetics bound to the cadherin-catenin complex. The cadherin-catenin-vinculin complex contains multiple disordered linkers and is highly dynamic, which poses a challenge for structural studies. We determined the ensemble conformation of this complex using small-angle x-ray and selective deuteration/contrast variation small-angle neutron scattering. In the complex, both α-catenin and vinculin adopt an ensemble of flexible conformations, but vinculin has fully open conformations with the vinculin head and actin-binding tail domains well separated from each other. F-actin binding experiments show that the cadherin-catenin-vinculin complex binds and bundles F-actin. However, when the vinculin actin-binding domain is removed from the complex, only a minor fraction of the complex binds to F-actin. The results show that the dynamic cadherin-catenin-vinculin complex employs vinculin as the primary F-actin binding mode to strengthen AJ-cytoskeleton interactions.
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Actinas , Cadherinas , Cadherinas/metabolismo , Actinas/metabolismo , Vinculina/metabolismo , alfa Catenina/química , Unión Proteica , Citoesqueleto de Actina/metabolismo , Adhesión CelularRESUMEN
Coronary artery disease (CAD) is frequently encountered in patients evaluated for transcatheter aortic valve replacement (TAVR) due to severe aortic stenosis. The prognostic relevance of chronic total occlusions (CTOs) in this setting is poorly understood. We conducted a search of MEDLINE and EMBASE to identify studies evaluating patients who underwent TAVR and evaluated outcomes depending on the presence of coronary CTOs. Pooled analysis was performed to estimate the rate and risk ratio for mortality. Four studies involving 25,432 patients fulfilled the inclusion criteria. The follow up ranged from in-hospital outcomes to 8-years follow-up. Coronary artery disease was present in 67.8% to 75.5% of patients in 3 studies which reported this variable. The prevalence of CTOs varied between 2% and 12.6% in this cohort. The presence of CTOs was associated with increase in length of stay (8.1 ± 8.2 vs. 5.9 ± 6.5, p < 0.01), cardiogenic shock (5.1% vs. 1.7%, p < 0.01), acute myocardial infarction (5.8% vs. 2.8%, p = 0.02) and acute kidney injury (18.6% vs. 13.9%, p = 0.048). The pooled 1-year death rate revealed 41 deaths in 165 patients in the CTO group and 396 deaths in 1663 patients with no CTO ((24.8%) vs. (23.8%)). The meta-analysis of death with CTO versus no CTO showed a nonsignificant trend toward increased mortality with CTOs (risk ratio 1.11 95% CI 0.90-1.40, I2 = 0%). Our analysis suggests that concomitant CTO lesions in patients undergoing TAVR are common, and its presence was associated with increased in-hospital complications. However, CTO presence by itself was not associated with increased long-term mortality, only a nonsignificant trend toward an increased risk of death in patients with CTO was found. Further studies are warranted to assess the prognostic relevance of CTO lesion in TAVR patients.
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Estenosis de la Válvula Aórtica , Enfermedad de la Arteria Coronaria , Oclusión Coronaria , Infarto del Miocardio , Intervención Coronaria Percutánea , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Resultado del Tratamiento , Factores de Riesgo , Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugíaRESUMEN
BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2006 and the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010 in the UK. PCVs are active immunization for the prevention of invasive disease, pneumonia and acute otitis media (AOM) caused by Streptococcus pneumoniae in children. The aim of this observational study was to estimate incidence rates (IRs) of AOM in children ≤17 years from 2003 to 2019 in England, before and after the introduction of pneumococcal conjugate vaccines (PCVs). METHODS: AOM episodes were identified using Read diagnosis codes in children aged ≤17 years in the Clinical Practice Research Datalink (CPRD) Gold database from 2003 to 2019. Annual IRs with 95% confidence intervals (CI) by age group were calculated as the number of episodes/person-years (PY) at risk. Interrupted time series analyses were conducted to estimate incidence rate ratios (IRR) across post-PCV7 (2007-2009), early post-PCV13 (2011-2014) and late post-PCV13 (2015-2019) periods compared to the pre-PCV7 period (2003-2005) using generalized linear models. RESULTS: From 2003 to 2019, 274,008 all-cause AOM episodes were identified in 1,500,686 children. The overall AOM IR was 3690.9 (95% CI 3677.1-3704.8) per 100,000 PY. AOM IRs were highest in children aged < 5 years and decreased by age; < 2 years: 8286.7 (95% CI 8216.8-8357.1); 2-4 years: 7951.8 (95% CI 7902.5-8001.4); 5-17 years: 2184.4 (95% CI 2172.1-2196.8) (per 100,000 PY). Overall AOM IRs declined by 40.3% between the pre-PCV7 period and the late-PCV13 period from 4451.9 (95% CI 4418.1-4485.9) to 2658.5 (95% CI 2628.6-2688.7) per 100,000 PY, and across all age groups. IRRs indicated a significant decrease in AOM IRs in all the post-vaccination periods, compared to the pre-PCV7 period: post-PCV7 0.87 (95% CI 0.85-0.89), early post-PCV13 0.88 (95% CI 0.86-0.91), and late post-PCV13 0.75 (95% CI 0.73-0.78). CONCLUSIONS: The AOM IRs declined during the 2003-2019 period; however, the clinical burden of AOM remains substantial among children ≤17 years in England.
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Otitis Media , Infecciones Neumocócicas , Niño , Humanos , Lactante , Incidencia , Vacunas Conjugadas , Otitis Media/epidemiología , Otitis Media/prevención & control , Vacunas Neumococicas , Streptococcus pneumoniae , Inglaterra/epidemiología , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & controlRESUMEN
OBJECTIVES: The aim of this study was to provide epidemiological data of pediatric patients suffering from cervical spinal trauma in Germany, in order to integrate these data in future decision-making processes concerning diagnosis and therapy. MATERIALS AND METHODS: Retrospective multicenter study includes all patients up to 16 years suffering from cervical spine injuries who were treated in six German spine centers between 01/2010 and 12/2016. The clinical databases were screened for specific trauma mechanism, level of injury as well as accompanying injuries. Diagnostic imaging and the chosen therapy were analyzed. Patients were divided into three age groups for further evaluation: age group I (0-6 years), age group II (7-9 years), age group III (10-16 years). RESULTS: A total of 214 children with 265 cervical spine injuries were included during the mentioned period. The mean age at the time of injury was 11.9 (± 3.9) years. In age group I, 24 (11.2%) patients were included, age group II consisted of 22 patients (10.3%), and 168 patients belonged to age group III (78.5%). Girls and boys were equally affected. In all age groups, falls and traffic accidents were the most common causes of cervical spine injuries. A total of 180 patients (84.1%) were treated conservatively, while 34 (15.9%) children underwent surgery. Distorsion/whiplash injury was the most common entity (n = 165; 68.2%). Children aged 0-9 years had significantly (p < 0.001) more frequent injuries of the upper cervical spine (C0-C2) compared to older age groups. Patients of age group III were more likely to suffer from injuries in subaxial localizations. Neurological deficits were rarely seen in all age groups. Head injuries did represent the most common accompanying injuries (39.8%, n = 92). CONCLUSIONS: The upper cervical spine was more frequently affected in young children. Older children more often suffered from subaxial pathologies. The majority of cervical spinal column injuries were treated conservatively. Nevertheless, 15% of the hospitalized children had to be treated surgically.
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Traumatismos del Cuello , Traumatismos Vertebrales , Masculino , Femenino , Niño , Humanos , Anciano , Adolescente , Preescolar , Traumatismos Vertebrales/epidemiología , Traumatismos Vertebrales/terapia , Traumatismos Vertebrales/diagnóstico , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Vértebras Cervicales/lesiones , Estudios Retrospectivos , Accidentes de TránsitoRESUMEN
BACKGROUND: Streptococcus pneumoniae remains a leading cause of morbidity, mortality, and healthcare resource utilization (HRU) among children. This study quantified HRU and cost of acute otitis media (AOM), pneumonia, and invasive pneumococcal disease (IPD). METHODS: The IBM MarketScan® Commercial Claims and Encounters and Multi-State Medicaid databases from 2014 to 2018 were analyzed. Children with AOM, all-cause pneumonia, or IPD episodes were identified using diagnosis codes in inpatient and outpatient claims. HRU and costs were described for each condition in the commercial and Medicaid-insured populations. National estimates of the number of episodes and total cost ($US 2019 for each condition were extrapolated using data from the US Census Bureau. RESULTS: Approximately 6.2 and 5.6 million AOM episodes were identified in commercial and Medicaid-insured children, respectively, during the study period. Mean cost per AOM episode was $329 (SD $1505) for commercial and $184 (SD $1524) for Medicaid-insured children. A total of 619,876 and 531,095 all-cause pneumonia cases were identified among commercial and Medicaid-insured children, respectively. Mean cost per all-cause pneumonia episode was $2304 (SD $32,309) in the commercial and $1682 (SD $19,282) in the Medicaid-insured population. A total of 858 and 1130 IPD episodes were identified among commercial and Medicaid-insured children, respectively. Mean cost per IPD episode was $53,213 (SD $159,904) for commercial and $23,482 (SD $86,209) for the Medicaid-insured population. Nationally, there were over 15.8 million cases of AOM annually, with total estimated cost of $4.3 billion, over 1.5 million cases of pneumonia annually, with total cost of $3.6 billion, and about 2200 IPD episodes annually, for a cost of $98 million. CONCLUSIONS: The economic burden of AOM, pneumonia, and IPD among US children remains substantial. IPD and its manifestations were associated with higher HRU and costs per episode, compared to AOM and all-cause pneumonia. However, owing to their higher frequencies, AOM and all-cause pneumonia were the main contributors to the economic burden of pneumococcal disease nationally. Additional interventions, such as the development of pneumococcal conjugate vaccinees with sustained protection of existing vaccine type serotypes as well as broader inclusion of additional serotypes, are necessary to further reduce the burden of disease caused by these manifestations.
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Otitis Media , Infecciones Neumocócicas , Neumonía , Niño , Humanos , Estados Unidos/epidemiología , Lactante , Vacunas Conjugadas/uso terapéutico , Estrés Financiero , Incidencia , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/uso terapéutico , Otitis Media/epidemiología , Otitis Media/prevención & control , Neumonía/epidemiología , Neumonía/prevención & controlRESUMEN
Surface layers (S-layers) are crystalline protein coats surrounding microbial cells. S-layer proteins (SLPs) regulate their extracellular self-assembly by crystallizing when exposed to an environmental trigger. However, molecular mechanisms governing rapid protein crystallization in vivo or in vitro are largely unknown. Here, we demonstrate that the Caulobacter crescentus SLP readily crystallizes into sheets in vitro via a calcium-triggered multistep assembly pathway. This pathway involves 2 domains serving distinct functions in assembly. The C-terminal crystallization domain forms the physiological 2-dimensional (2D) crystal lattice, but full-length protein crystallizes multiple orders of magnitude faster due to the N-terminal nucleation domain. Observing crystallization using a time course of electron cryo-microscopy (Cryo-EM) imaging reveals a crystalline intermediate wherein N-terminal nucleation domains exhibit motional dynamics with respect to rigid lattice-forming crystallization domains. Dynamic flexibility between the 2 domains rationalizes efficient S-layer crystal nucleation on the curved cellular surface. Rate enhancement of protein crystallization by a discrete nucleation domain may enable engineering of kinetically controllable self-assembling 2D macromolecular nanomaterials.
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Proteínas Bacterianas/metabolismo , Caulobacter crescentus/metabolismo , Membrana Celular/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/ultraestructura , Calcio/metabolismo , Caulobacter crescentus/genética , Caulobacter crescentus/ultraestructura , Membrana Celular/química , Membrana Celular/ultraestructura , Microscopía por Crioelectrón , Cristalización , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/ultraestructura , MutagénesisRESUMEN
Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.
Asunto(s)
Colestasis , Enfermedad del Hígado Graso no Alcohólico , Humanos , Colestasis/metabolismo , Citocinas/metabolismo , Interleucinas/metabolismo , Hígado/metabolismo , Regeneración Hepática , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases, ranging from liver steatosis to metabolic dysfunction-associated steatohepatitis (MASH), increasing the risk of developing cirrhosis and hepatocellular carcinoma (HCC). Fibrosis within MASLD is critical for disease development; therefore, the identification of fibrosis-driving factors is indispensable. We analyzed the expression of interleukin 32 (IL-32) and chemokine CC ligand 20 (CCL20), which are known to be linked with inflammation and fibrosis, and for their expression in MASLD and hepatoma cells. RT-PCR, ELISA and Western blotting analyses were performed in both human liver samples and an in vitro steatosis model. IL-32 and CCL20 mRNA expression was increased in tissues of patients with NASH compared to normal liver tissue. Stratification for patatin-like phospholipase domain-containing protein 3 (PNPLA3) status revealed significance for IL-32 only in patients with I148M (rs738409, CG/GG) carrier status. Furthermore, a positive correlation was observed between IL-32 expression and steatosis grade, and between IL-32 as well as CCL20 expression and fibrosis grade. Treatment with the saturated fatty acid palmitic acid (PA) induced mRNA and protein expression of IL-32 and CCL20 in hepatoma cells. This induction was mitigated by the substitution of PA with monounsaturated oleic acid (OA), suggesting the involvement of oxidative stress. Consequently, analysis of stress-induced signaling pathways showed the activation of Erk1/2 and p38 MAPK, which led to an enhanced expression of IL-32 and CCL20. In conclusion, cellular stress in liver epithelial cells induced by PA enhances the expression of IL-32 and CCL20, both known to trigger inflammation and fibrosis.
Asunto(s)
Hígado Graso , Hepatocitos , Enfermedades Metabólicas , Humanos , Carcinoma Hepatocelular/genética , Quimiocina CCL20/genética , Quimiocinas , Hepatocitos/metabolismo , Ligandos , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Ácido Palmítico , Regulación hacia Arriba , Grasas Insaturadas/metabolismoRESUMEN
Here, we introduce a quasi-analytic model that allows studying mode formation in low refractive index core waveguides through solely focusing on the cladding properties. The model isolates the reflection properties of the cladding from the modes via correlating the complex amplitude reflection coefficient of the cladding to the complex effective index of the fundamental core mode. The relevance and validity of the model are demonstrated by considering a single-ring anti-resonant fiber, revealing unexpected situations of exceptionally low loss. Our model explains mode formation by light scattering, which conceptually provides deep insights into the relevant physics.