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Neonatal and infant aortic thrombosis is a rare albeit life-threatening thrombotic event, particularly seen in premature infants with an arterial catheter in place. We describe our institutional experience and approach to the management of 11 infants with occlusive or nearly occlusive aortic thrombosis. We observed at least partial thrombus resolution in all patients. Complications related to our management included minor bleeding in two children receiving thrombolytic therapy, and two major bleeding events in children receiving anticoagulation alone. Our experience adds to the growing body of evidence that thrombolysis and thrombectomy should be considered in managing neonatal/infant aortic thrombosis.
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Plasticizers are necessary for the usability of various products, including food contact materials. Exposure to plasticizers is most commonly made through the oral route. Several plasticizers have been reported to have adverse effects on humans and the environment. Thus, the present study aimed to determine the long-term toxicity and carcinogenicity of a novel plasticizer called bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), which is an ecofriendly and biologically less harmful replacer. Groups of 50 male and 50 female Han Wistar rats were fed Eco-DEHCH at daily doses of 1,600, 5,000, or 16,000 ppm in their diet for at least 104 weeks. The rats were regularly monitored for mortality, clinical signs, body weight, food consumption, food efficiency, and perceivable mass. All animals were subjected to complete necropsy and histopathological examination. The results indicate that the rats well tolerated chronic exposure to Eco-DEHCH at highest daily doses of 16,000 ppm, with was equivalent to 805.1 mg/kg/day in males and 1060.6 mg/kg/day in females and did not show signs of toxicity or carcinogenicity. In conclusion, Eco-DEHCH could be a safe and promising alternative plasticizer.
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Testes de Carcinogenicidade , Plastificantes , Ratos Wistar , Animais , Plastificantes/toxicidade , Masculino , Feminino , Ratos , Administração Oral , Ácidos Dicarboxílicos/toxicidade , Ácidos Dicarboxílicos/administração & dosagem , Relação Dose-Resposta a Droga , Cicloexanos/toxicidade , Cicloexanos/administração & dosagem , DietaRESUMO
We present a case of a child with congenital thrombotic thrombocytopenic purpura found to have a compound heterozygous variant in the ADAMTS13 gene with a novel variant resulting in a large duplication of exons 9-11 of ADAMTS13 This variant was identified through additional molecular testing via a chromosomal microarray analysis. To our knowledge, this assay had not previously been utilised to identify an ADAMTS13 variant and the additional testing was possible through the involvement of a genetic counsellor.
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Proteína ADAMTS13 , Púrpura Trombocitopênica Trombótica , Humanos , Proteína ADAMTS13/genética , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/diagnóstico , Análise em Microsséries/métodos , Duplicação Gênica , Masculino , Feminino , Éxons/genética , Proteínas ADAM/genéticaRESUMO
Sickle cell disease (SCD) is well recognized as a hypercoagulablestate, however, it remains unclear whether a subgroup of children with SCD at higher risk of venous thromboembolic event (VTE) during hospitalization may benefit from thromboprophylaxis. Our objectives were to describe the clinical characteristics, outcomes and recurrence of hospital acquired VTE in patients with SCD younger than 21 years. This was a single center retrospective study. Data regarding demographics, reason for admission, location of VTE, risk factors like central venous catheter (CVC), intensive care unit (ICU) admission among others were extracted from electronic medical records over a 10-year study period (2011-2021). Recurrence of VTE at 1 and 5 years was assessed. Descriptive statistics were used as indicated. We identified a total of 20 VTE events over the 10-year study period. Six of these events occurred in those younger than 12 years of age. Fourteen (70%) VTE events occurred in the HbSS or HbSßThal0 genotypes compared to 6 (30%) in HbSC. Most common VTE was isolated pulmonary embolism (PE) (n = 10, 50%). VTE were most often associated with acute chest syndrome (ACS) (n = 14, 70%), ICU admissions (n = 10, 50%) and CVC (n = 5/9, 55%). One patient died from the VTE event. One patient with additional underlying risk factors had a recurrent VTE at 13 months. Our study suggests that ICU admission, ACS and presence of CVC increases the risk of VTE in children and young adults with SCD, but larger studies are indicated to validate our findings.
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L-tryptophan, an essential amino acid for physiological processes, metabolism, development, and growth of organisms, is widely utilized in animal nutrition and human health as a feed additive and nutritional supplement, respectively. Despite its known benefits, safety concerns have arisen due to an eosinophilia-myalgia syndrome (EMS) outbreak linked to L-tryptophan consumed by humans. Extensive research has established that the EMS outbreak was caused by an L-tryptophan product that contained certain impurities. Therefore, safety validations are imperative to endorse the use of L-tryptophan as a supplement or a feed additive. This study was conducted in tertiary hybrid [(Landrace × Yorkshire) × Duroc] pigs to assess general toxicity and potential risks for EMS-related symptoms associated with L-tryptophan used as a feed additive. Our investigation elucidated the relationship between L-tryptophan and EMS in swine. No mortalities or clinical signs were observed in any animals during the administration period, and the test substance did not induce toxic effects. Hematological analysis and histopathological examination revealed no changes in EMS-related parameters, such as eosinophil counts, lung lesions, skin lesions, or muscle atrophy. Furthermore, no test substance-related changes occurred in other general toxicological parameters. Through analyzing the tissues and organs of swine, most of the L-tryptophan impurities that may cause EMS were not retained. Based on these findings, we concluded that incorporating L-tryptophan and its impurities into the diet does not induce EMS in swine. Consequently, L-tryptophan may be used as a feed additive throughout all growth stages of swine without safety concerns.
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Ração Animal , Suplementos Nutricionais , Triptofano , Animais , Triptofano/toxicidade , Triptofano/análise , Suínos , Ração Animal/análise , Ração Animal/toxicidade , Suplementos Nutricionais/toxicidade , Masculino , Feminino , Contaminação de MedicamentosRESUMO
Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called "trained immunity." However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to Mycobacterium avium infection. scRNA-seq analysis revealed that HSPCs activate interferon gamma-response genes heterogeneously upon primary challenge, while rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was sufficient to induce similar training. Mice transplanted with influenza-trained HSPCs displayed enhanced immunity against M. avium challenge and vice versa, demonstrating cross protection against antigenically distinct pathogens. Together, these results indicate that heterogeneous responses to infection by HSPCs can lead to long-term production of bone marrow derived macrophages with enhanced function and confer cross-protection against alternative pathogens.
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Phthalate esters (PEs) are the most widely used class of plasticizers. Several PEs, however, were found to have adverse effects on the health of animals. A new phthalate-free plasticizer, Eco-DEHCH (bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate), was recently developed as an ecofriendly replacement for phthalate plasticizers and to be less harmful to organisms. The present study evaluated the long-term toxicity of Eco-DEHCH in Wistar Han rats to explore adverse effects and predict hazardous potential to humans. Forty male and forty female Wistar Han rats were exposed to Eco-DEHCH in dietary feed for 52 weeks, and their hematologic, coagulation, and serum biochemical parameters were monitored. The rats were subjected to close clinical, ophthalmic, and histopathologic examinations and urinalysis throughout the consumption of Eco-DEHCH. The effects of this plasticizer on food consumption and organ weight were also determined. Chronic exposure to Eco-DEHCH was generally safe, although it also resulted in α2u-globulin accumulation, a parameter with no human relevance. In conclusion, Eco-DEHCH can serve as a safe and promising alternative plasticizer.
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Dietilexilftalato , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ácidos Ftálicos , Humanos , Masculino , Ratos , Feminino , Animais , Plastificantes/toxicidade , Ratos Wistar , Ácidos Ftálicos/toxicidade , Ácidos Carboxílicos , Cicloexanos , Ésteres/química , Dietilexilftalato/toxicidadeRESUMO
Marmosets are becoming more utilized in biomedical research due to multiple advantages including (1) a nonhuman primate of a smaller size with less cost for housing, (2) physiologic similarities to humans, (3) translatable hepatic metabolism, (4) higher numbers of litters per year, (5) genome is sequenced, molecular reagents are available, (6) immunologically similar to humans, (7) transgenic marmosets with germline transmission have been produced, and (8) are naturally occurring hematopoietic chimeras. With more use of marmosets, disease surveillance over a wide range of ages of marmosets has been performed. This has led to a better understanding of the disease management of spontaneous diseases that can occur in colonies. Knowledge of clinical signs and histologic lesions can assist in maximizing the colony's health, allowing for improved outcomes in translational studies within biomedical research. Here, we describe some basic husbandry, biology, common spontaneous diseases, and animal model applications for the common marmoset in biomedical research.
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Pesquisa Biomédica , Callithrix , Animais , Callithrix/fisiologia , Modelos Animais de Doenças , HumanosRESUMO
Antibiotic therapy, especially when administered long term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota. We reported previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined. We sought to identify the cell type(s) through which STAT1 promotes microbiota-mediated hematopoiesis and to elucidate which upstream signaling pathways trigger STAT1 signaling. Using conditional knockout and chimeric mice, we found that the microbiota induced STAT1 signaling in non-myeloid hematopoietic cells to support hematopoiesis and that STAT1 signaling was specifically dependent on type I interferons (IFNs). Indeed, basal type I IFN signaling was reduced in hematopoietic progenitor cells with antibiotic treatment. In addition, we discovered that oral administration of a commensal-derived product, NOD1 ligand, rescues the hematopoietic defects induced by antibiotics in mice. Using metabolomics, we identified additional microbially produced candidates that can stimulate type I IFN signaling to potentially rescue the hematopoietic defects induced by antibiotics, including phosphatidylcholine and γ-glutamylalanine. Overall, our studies define a signaling pathway through which microbiota promotes normal hematopoiesis and identify microbial metabolites that may serve as therapeutic agents to ameliorate antibiotic-induced bone marrow suppression and cytopenia.
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Interferon Tipo I , Microbiota , Animais , Hematopoese , Células-Tronco Hematopoéticas , Interferon Tipo I/farmacologia , Camundongos , Transdução de SinaisRESUMO
The transfusion of red blood cells (RBCs) is a crucial treatment for sickle cell disease (SCD). While often beneficial, the frequent use of transfusions is associated with numerous complications. Transfusions should be offered with specific guidelines in mind. Here we present updates to the indications for transfusion of RBCs in SCD. We review recent publications and include expert perspectives from hematology and transfusion medicine. For some clinical indications, such as ischemic stroke, the role of transfusion has been well studied and can be applied almost universally. For many other clinical scenarios, the use of transfusion therapy has less conclusive data and therefore must be tailored to individual needs. We highlight the roles of RBC transfusions in preventing or mitigating neurological disease, in reducing perioperative complications, in managing acute chest syndrome, and in optimizing pregnancy outcomes in SCD. We further highlight various transfusion techniques and when each might be considered. Potential complications of transfusion are also briefly discussed.
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Anemia Falciforme/terapia , Transfusão de Eritrócitos/métodos , Síndrome Torácica Aguda/etiologia , Síndrome Torácica Aguda/prevenção & controle , Anemia Falciforme/complicações , Pré-Escolar , Transfusão de Eritrócitos/efeitos adversos , Feminino , Humanos , Gravidez , Complicações Hematológicas na Gravidez/terapia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controleRESUMO
Despite several improvements in the drug development pipeline over the past decade, drug failures due to unexpected adverse effects have rapidly increased at all stages of clinical trials. To improve the success rate of clinical trials, it is necessary to identify potential loser drug candidates that may fail at clinical trials. Therefore, we need to develop reliable models for predicting the outcomes of clinical trials of drug candidates, which have the potential to guide the drug discovery process. In this study, we propose an outer product-based convolutional neural network (OPCNN) model which integrates effectively chemical features of drugs and target-based features. The validation results via 10-fold cross-validations on the dataset used for a data-driven approach PrOCTOR proved that our OPCNN model performs quite well in terms of accuracy, F1-score, Matthews correlation coefficient (MCC), precision, recall, area under the curve (AUC) of the receiver operating characteristic, and area under the precision-recall curve (AUPRC). In particular, the proposed OPCNN model showed the best performance in terms of MCC, which is widely used in biomedicine as a performance metric and is a more reliable statistical measure. Through 10-fold cross-validation experiments, the accuracy of the OPCNN model is as high as 0.9758, F1 score is as high as 0.9868, the MCC reaches 0.8451, the precision is as high as 0.9889, the recall is as high as 0.9893, the AUC is as high as 0.9824, and the AUPRC is as high as 0.9979. The results proved that our OPCNN model shows significantly good prediction performance on outcomes of clinical trials and it can be quite helpful in early drug discovery.
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Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of the intestinal microbiota is an important factor. Based on our earlier studies of blood and bone marrow changes in a mouse model of prolonged antibiotic administration, we studied whether changes in megakaryocytes or regulatory T cells (Tregs), two cell types that are critical in the maintenance of hematopoietic stem cells, contribute to antibiotic-mediated bone marrow suppression. Despite increased platelet numbers, megakaryocytes were unchanged in the bone marrow of antibiotic-treated mice; however, Tregs were found to be significantly depleted. Exogenous addition of Tregs was insufficient to rescue the function of bone marrow from antibiotic-treated mice in both colony formation and transplantation assays. These findings indicate that the intestinal microbiota support normal Treg development to protect healthy hematopoiesis, but that the restoration of Tregs alone is insufficient to restore normal bone marrow function.
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Células da Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Antibacterianos , Feminino , Humanos , Masculino , CamundongosRESUMO
The diagnosis of coagulopathy or thrombophilia in pediatric patients can be challenging. Congenital coagulopathies often present in the pediatric period and require appropriate work-up for diagnosis and ongoing management. Acquired coagulopathies of childhood are frequently encountered in hospitalized children and warrant appropriate coagulation testing for goal-directed therapy. The incidence of thrombosis is increasing in pediatric patients. After identifying the presence of thrombus, acute management includes initiating therapeutic anticoagulation. Choice of anticoagulant depends on patient's clinical status, along with availability of the anticoagulant. Thrombophilia evaluation is performed when children present with spontaneous thrombosis. Thrombophilia tests are inaccurate during acute illness.
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Trombofilia , Anticoagulantes/uso terapêutico , Criança , Humanos , Trombofilia/complicações , Trombofilia/diagnóstico , Trombofilia/terapiaRESUMO
Comet assay is a widely used method, especially in the field of genotoxicity, to quantify and measure DNA damage visually at the level of individual cells with high sensitivity and efficiency. Generally, computer programs are used to analyze comet assay output images following two main steps. First, each comet region must be located and segmented, and next, it is scored using common metrics (e.g., tail length and tail moment). Currently, most studies on comet assay image analysis have adopted hand-crafted features rather than the recent and effective deep learning (DL) methods. In this paper, however, we propose a DL-based baseline method, called DeepComet, for comet segmentation. Furthermore, we created a trainable and testable comet assay image dataset that contains 1037 comet assay images with 8271 manually annotated comet objects. From the comet segmentation test results with the proposed dataset, the DeepComet achieves high average precision (AP), which is an essential metric in image segmentation and detection tasks. A comparative analysis was performed between the DeepComet and the state-of-the-arts automatic comet segmentation programs on the dataset. Besides, we found that the DeepComet records high correlations with a commercial comet analysis tool, which suggests that the DeepComet is suitable for practical application.
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PKM2 is a pyruvate kinase isoform that is the final and rate-limiting step in aerobic glycolysis in tumor cells. Increased expression of PKM2 has been detected in human cancers. The present study examined the expression of PKM2 in canine mammary tumors and assessed its prognostic significance. Paraffin sections of 5 adenomas, 67 carcinomas, and 5 samples of nonneoplastic hyperplasia from 77 dogs, aged 8 to 18 y, were evaluated. Significantly higher levels of PKM2 were detected among the carcinomas compared with all other tissues examined. The level of PKM2 expression in carcinoma tissue correlated positively with the tumor grade. These findings suggest that PKM2 may have a similar role in canine mammary tumors to its role in human breast cancer. As such, canine mammary tumors may be useful models for studies focused on the progression of human neoplastic disease.
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Adenoma/genética , Adenoma/veterinária , Doenças do Cão/genética , Neoplasias Mamárias Animais/genética , Piruvato Quinase/metabolismo , Adenoma/metabolismo , Adenoma/patologia , Animais , Neoplasias da Mama/genética , Modelos Animais de Doenças , Doenças do Cão/metabolismo , Doenças do Cão/patologia , Cães , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Piruvato Quinase/genéticaRESUMO
Transient abnormal myelopoiesis (TAM) is a common and potentially fatal neonatal complication of newborn babies with Down syndrome (DS). Children born with mosaic DS are also at risk of developing TAM. However, due to their variable phenotypes, early identification of patients with mosaic DS may be difficult; thus, early diagnosis of TAM is just as challenging. In this report, we describe a case of a phenotypically normal newborn who presented with concerns for neonatal leukemia. The diagnosis of mosaic DS and TAM was confirmed with abnormal GATA1 mutation testing, highlighting the importance of early GATA1 mutation testing in newborn leukemia with high suspicion for TAM.
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Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. We established three-dimensional (3D) human liver organoids as described previously and investigated their liver characteristics through multiple analyses. Drug-induced PL was initiated in these organoids and in monolayer HepG2 cultures, and cellular changes were systemically examined. Organoids that underwent differentiation showed characteristics of hepatocytes rather than HepG2 cells. The organoids also survived under PL-inducing drug conditions for 48 h and maintained a more stable albumin secretion level than the HepG2 cells. More cytoplasmic vacuoles were observed in organoids and HepG2 cells treated with more potent PL-induced drugs, but to a greater extent in organoids than in HepG2 cells. Lysosome-associated membrane protein 2, a marker of lysosome membranes, showed a stronger immunohistochemical signal in the organoids. PL-distinctive lamellar bodies were observed only in amiodarone-treated organoids by transmission electron microscopy. Human liver organoids are thus more sensitive to drug-induced PL and less affected by cytotoxicity than HepG2 cells. Since PL is a chronic condition, these results indicate that organoids better reflect metabolite-mediated hepatotoxicity in vivo and could be a valuable system for evaluating the phospholipidogenic effects of different compounds during drug development.