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OBJECTIVE: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG. METHODS: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG. RESULTS: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m2. Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m2 (35.3%) versus the BAWL group, who lost 8.8 kg/m2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities. CONCLUSIONS: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG.
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Índice de Massa Corporal , Gastrectomia , Redução de Peso , Humanos , Feminino , Masculino , Adolescente , Gastrectomia/métodos , Gastrectomia/efeitos adversos , Resultado do Tratamento , Obesidade Mórbida/cirurgia , Obesidade Infantil/cirurgia , Dislipidemias/epidemiologia , Cirurgia Bariátrica/métodos , Período Pré-OperatórioRESUMO
Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of NF1 and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment.
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Citofagocitose , Neurofibroma Plexiforme , Humanos , Macrófagos/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Neurofibroma Plexiforme/patologia , Transdução de Sinais , Microambiente TumoralRESUMO
Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30 °C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity.
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Influenza Humana , Doenças Metabólicas , Obesidade Mórbida , Infecções por Orthomyxoviridae , Orthomyxoviridae , Masculino , Feminino , Animais , Camundongos , Humanos , Obesidade Mórbida/complicações , Camundongos Endogâmicos C57BL , Obesidade , Gravidade do PacienteRESUMO
The dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy.
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Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.
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Melanoma , Neoplasias Uveais , Neoplasias Vasculares , Animais , Camundongos , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Células Endoteliais/metabolismo , Apoptose , Melanoma/genética , Neoplasias Uveais/genética , Mutação , Modelos Animais de Doenças , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Linhagem Celular TumoralRESUMO
Introduction: Inflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied. Methods: Here, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice. Results: We show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score. Discussion: Collectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression.
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Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Camundongos Endogâmicos C57BL , Tetracloreto de Carbono , Habitação , Cirrose Hepática , Metionina , Alanina Transaminase , Colina , Modelos Animais de Doenças , InflamaçãoRESUMO
Clinically significant endemic mycoses (fungal infections) in the United States (U.S.) include Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis/posadasii. While the majority of infections go clinically unnoticed, symptomatic disease can occur in immunocompromised or hospitalized patients, and occasionally in immune-competent individuals. Clinical manifestations vary widely and their diagnosis may require fungal culture, making the rapid diagnosis a challenge. Imaging can be helpful in making a clinical diagnosis prior to laboratory confirmation, as well as assist in characterizing disease extent and severity. In this review, we discuss the three major endemic fungal infections that occur in the U.S., including mycology, epidemiology, clinical presentations, and typical imaging features with an emphasis on the pediatric population.
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Blastomicose , Coccidioidomicose , Histoplasmose , Micoses , Criança , Humanos , Blastomicose/diagnóstico por imagem , Blastomicose/epidemiologia , Histoplasmose/diagnóstico por imagem , Histoplasmose/epidemiologia , Coccidioidomicose/diagnóstico por imagem , Coccidioidomicose/epidemiologia , Micoses/diagnóstico por imagem , América do Norte/epidemiologiaRESUMO
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
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Neurofibroma Plexiforme , Neurofibroma , Neurofibromatose 1 , Animais , Humanos , Camundongos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo , Estresse do Retículo Endoplasmático/genética , Resposta a Proteínas não Dobradas/genéticaRESUMO
BACKGROUND: There are no consensus guidelines regarding the use of percutaneous needle biopsy for the diagnosis of soft tissue and bone tumors. The aim of this study was to understand the efficacy of image-guided percutaneous biopsy for pediatric patients with soft tissue and bony masses, the role of intraoperative image guidance, and diagnostic accuracy. PATIENTS AND METHODS: A retrospective institutional chart review was performed on patients who underwent percutaneous biopsy of soft tissue or bone tumors between 2007 and 2017. Data collected included preoperative imaging, type of biopsy, demographics, insurance status, number of samples taken, and pathologic results. RESULTS: One hundred forty-one children and young adults underwent 169 biopsies. Female patients received 48.2% of biopsies. The mean age was 14.3 ± 7.0 years. Core needle biopsies made up 89.4% of procedures, while 10.6% were fine needle aspirate. The mean number of samples per patient was 3.6 ± 2.5. All patients had imaging guidance, with computed tomography used in 44.7% of patients, 9.9% using fluoroscopy, 7.1% using ultrasound for guidance, and 53 (37.6%) patients had more than one modality. Diagnostic specimens were obtained in 97.9% of biopsies. The most common overall pathology was osteoid osteoma. The most common malignant tumors were osteosarcoma and Ewing's sarcoma. CONCLUSION: Image-guided percutaneous biopsy is a safe and effective method of obtaining accurate tissue samples in children and young adults with soft tissue or bone masses. LEVEL OF EVIDENCE: Level 4-Study of diagnostic test.
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Neoplasias Ósseas , Padrão de Cuidado , Humanos , Criança , Feminino , Adulto Jovem , Adolescente , Adulto , Estudos Retrospectivos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/cirurgia , Neoplasias Ósseas/patologia , Biópsia com Agulha de Grande Calibre , Biópsia Guiada por Imagem/métodosRESUMO
BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.
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Sarcoma , Neoplasias de Tecidos Moles , Lactente , Humanos , Ifosfamida , Etoposídeo , Carboplatina , Estudos Retrospectivos , Vincristina , Proteínas Repressoras/genética , Proteínas Proto-Oncogênicas , Recidiva Local de Neoplasia , Sarcoma/terapia , Sarcoma/patologia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Doxorrubicina , Ciclofosfamida , Biomarcadores TumoraisRESUMO
BACKGROUND: Radioiodine therapy for Graves disease can be achieved with dosing based on estimated thyroid gland mass. Thyroid mass can be estimated using linear ultrasound measurements, and conversion factors for volume and density. The choice of conversion factors could impact estimated thyroid mass and thus administered radioiodine dose. OBJECTIVE: The objective of this study was to define the relationship between thyroid mass estimated by ultrasound and measured thyroid mass following thyroidectomy. MATERIALS AND METHODS: This was a retrospective, exempt study that included patients < 18 years of age with < 6 months between thyroid ultrasound and thyroidectomy January 2010-June 2020. Thyroid dimensions by ultrasound, thyroid mass at thyroidectomy and histopathological diagnosis were collected. Published conversion factors were used to estimate thyroid volume with conversion to mass using a density of 1.05 g/cm3. Pearson correlations and Bland-Altman difference analyses were used to define the relationship between estimated mass and specimen weight. Linear regression was used to calculate an optimal conversion factor for estimating thyroid mass. RESULTS: We included 86 patients, 67 female (78%), with a mean age of 14.5 ± 3.15 years. Mass estimated using all tested conversion factors had similar strong, positive correlation with specimen weight (r = 0.95). The mean difference between thyroid mass estimated by ultrasound and measured mass ranged from - 0.34 g (conversion factor = 0.523) to 1.69 g (conversion factor = 0.554). The optimal simplified factor for estimation of thyroid mass for the study sample was 0.537. CONCLUSION: All published conversion factors for estimating thyroid mass based on linear ultrasound measurements produce good estimates of thyroid mass. Errors in estimated mass are less than 2 g on average.
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Doença de Graves , Radioisótopos do Iodo , Glândula Tireoide , Adolescente , Criança , Feminino , Humanos , Lactente , Doença de Graves/tratamento farmacológico , Doença de Graves/patologia , Doença de Graves/cirurgia , Radioisótopos do Iodo/uso terapêutico , Estudos Retrospectivos , Tireoidectomia/métodosRESUMO
Introduction: 177Lu-DOTATATE, a radionuclide therapy that binds somatostatin type-2A receptors (SST2A), has demonstrated efficacy in neuroendocrine tumors and evidence of central nervous system (CNS) penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. Methods: SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by an experienced pathologist (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (<10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (Range: 0-12). Results: A total of 120 tumor samples from 114 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean ± SD: 7.5 ± 3.6 [n=38]) and meningioma (5.7 ± 3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3 ± 0.6 [n=3]), ETMR (1.0 ± 0 [n=3]), ependymoma (grades I-III; 0.2 ± 0.7 [n=27]), and high-grade glioma (grades III-IV; 0.4 ± 0.7 [n=23]). Pineoblastoma (3.8 ± 1.5 [n=4]) and other embryonal tumors (2.0 ± 4.0 [n=7]) exhibited intermediate, variable expression. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.5 ± 3.1) than SHH (5.0 ± 3.3) molecular subgroups (p=0.033). In a subset of paired primary and recurrent specimens from four patients, SST2A IHC scores remained largely unchanged. Discussion: High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.
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Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin+ cells have been implicated as tumor stem cells in MPNST; unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.
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Neoplasias de Bainha Neural , Neurofibroma , Neurofibrossarcoma , Humanos , Animais , Camundongos , Neoplasias de Bainha Neural/patologia , Nestina , Transformação Celular Neoplásica/genéticaRESUMO
Transplant-associated thrombotic microangiopathy (TA-TMA) and atypical hemolytic uremic syndrome (aHUS) are complement-mediated TMAs. The central nervous system (CNS) is the most common extrarenal organ affected by aHUS, and, despite mechanistic overlap between aHUS and TA-TMA, CNS involvement is rarely reported in TA-TMA, suggesting that CNS involvement in TA-TMA may be underdiagnosed and that these patients may benefit from complement blockers. In addition, there are no widely used histologic or radiologic criteria for the diagnosis of TMA in the brain. Thirteen recipients of pediatric hematopoietic cell transplants (HCTs) who had TA-TMA and who underwent autopsy were studied. Seven of 13 brains had vascular injury, and 2 had severe vascular injury. Neurologic symptoms correlated with severe vascular injury. Classic TMA histology was present and most often observed in the cerebellum, brainstem, and cerebral white matter. Abnormalities in similar anatomic regions were seen on imaging. Brain imaging findings related to TMA included hemorrhages, siderosis, and posterior reversible encephalopathy syndrome. We then studied 100 consecutive HCT recipients to identify differences in neurologic complications between patients with and those without TA-TMA. Patients with TA-TMA were significantly more likely to have a clinical concern for seizure, have an electroencephalogram performed, and develop altered mental status. In summary, our study confirms that TA-TMA involves the brains of recipients of HCT and is associated with an increased incidence of neurologic symptoms. Based on these findings, we propose that patients with low- or moderate-risk TA-TMA who develop neurologic complications should be considered for TA-TMA-directed therapy.
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Síndrome Hemolítico-Urêmica Atípica , Transplante de Células-Tronco Hematopoéticas , Síndrome da Leucoencefalopatia Posterior , Microangiopatias Trombóticas , Lesões do Sistema Vascular , Criança , Proteínas do Sistema Complemento , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Síndrome da Leucoencefalopatia Posterior/complicações , Microangiopatias Trombóticas/diagnóstico , Lesões do Sistema Vascular/complicaçõesRESUMO
Although elevated liver enzymes are common in hospitalized children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pediatric acute liver failure is an uncommon manifestation of COVID-19 disease. We describe the case of a 3-year-old previously healthy female who developed acute liver failure secondary to type 2 autoimmune hepatitis preceded by mild infection with SARS-CoV-2. Testing for viral hepatitis was negative, and the patient did not meet diagnostic criteria for multisystem inflammatory disease in children (MIS-C). A liver biopsy showed acute submassive hepatocyte necrosis with brisk CD3+ T lymphocyte infiltration and no evidence of fibrosis or chronic liver disease. Treatment with high-dose methylprednisolone resulted in rapid normalization of alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), and ammonia levels, and liver transplantation was avoided. This case highlights a possible association between SARS-CoV-2 infection and subsequent development of autoimmune liver disease presenting with acute liver failure.
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Masses and masslike lesions of the pancreas are uncommon in the pediatric population. However, owing to overlapping clinical and imaging features, it can be challenging to differentiate the various causes of pediatric pancreatic masses at initial patient presentation. Clinical data such as patient age, signs and symptoms at presentation, laboratory test results, and potential underlying cancer predisposition syndrome can be helpful when formulating a differential diagnosis. US may be the first imaging study to depict a pancreatic mass in a child, as this examination is frequently performed in children with nonspecific abdominal signs and symptoms because of its wide availability and relatively low cost and the lack of a need for sedation or anesthesia. CT or MRI is typically required for more thorough characterization of the mass and surgical planning. Complete characterization of pancreatic masses includes assessment of vascular involvement, local invasion, and extrapancreatic spread of tumor. The authors provide an up-to-date comprehensive review of the clinical manifestations, histopathologic features, and imaging findings of primary and secondary tumors of the pancreas in children and young adults. Advances in imaging, current prognostic information, and treatment paradigms also are highlighted. Finally, nontumorous masslike lesions of the pediatric pancreas, including vascular malformations, cystic disorders (eg, von Hippel-Lindau syndrome, cystic fibrosis), intrapancreatic accessory spleen, and autoimmune pancreatitis, are discussed. Online supplemental material is available for this article. ©RSNA, 2021.
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Neoplasias Pancreáticas , Doença de von Hippel-Lindau , Criança , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Imagem Multimodal , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Adulto JovemRESUMO
OBJECTIVE: The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown. METHODS: WT, IL-4Rα-deficient (IL-4Rα-/-) and STAT6-deficient mice (STAT6-/-) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting. RESULTS: We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways. CONCLUSION: Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.