RESUMEN
BACKGROUND: Perihematomal edema (PHE) after post-intracerebral hemorrhage (ICH) has complex pathophysiological mechanisms that are poorly understood. The complicated immune response in the post-ICH brain constitutes a crucial component of PHE pathophysiology. In this study, we aimed to characterize the transcriptional profiles of immune cell populations in human PHE tissue and explore the microscopic differences between different types of immune cells. METHODS: 9 patients with basal ganglia intracerebral hemorrhage (hematoma volume 50-100 ml) were enrolled in this study. A multi-stage profile was developed, comprising Group1 (n = 3, 0-6 h post-ICH, G1), Group2 (n = 3, 6-24 h post-ICH, G2), and Group3 (n = 3, 24-48 h post-ICH, G3). A minimal quantity of edematous tissue surrounding the hematoma was preserved during hematoma evacuation. Single cell RNA sequencing (scRNA-seq) was used to map immune cell populations within comprehensively resected PHE samples collected from patients at different stages after ICH. RESULTS: We established, for the first time, a comprehensive landscape of diverse immune cell populations in human PHE tissue at a single-cell level. Our study identified 12 microglia subsets and 5 neutrophil subsets in human PHE tissue. What's more, we discovered that the secreted phosphoprotein-1 (SPP1) pathway served as the basis for self-communication between microglia subclusters during the progression of PHE. Additionally, we traced the trajectory branches of different neutrophil subtypes. Finally, we also demonstrated that microglia-produced osteopontin (OPN) could regulate the immune environment in PHE tissue by interacting with CD44-positive cells. CONCLUSIONS: As a result of our research, we have gained valuable insight into the immune-microenvironment within PHE tissue, which could potentially be used to develop novel treatment modalities for ICH.
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Edema Encefálico , Hemorragia Cerebral , Progresión de la Enfermedad , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Humanos , Edema Encefálico/inmunología , Edema Encefálico/patología , Edema Encefálico/genética , Edema Encefálico/metabolismo , Edema Encefálico/etiología , Hemorragia Cerebral/inmunología , Hemorragia Cerebral/patología , Hemorragia Cerebral/genética , Masculino , Femenino , Persona de Mediana Edad , Análisis de Secuencia de ARN/métodos , Anciano , Hematoma/patología , Hematoma/inmunología , Hematoma/genéticaRESUMEN
The hematoma that forms between broken fragments of bone serves as a natural fibrin scaffold, and its removal from the defect site delays bone healing. The hypothesis of this study is that the microarchitectural and mechanical properties of the initially formed hematoma has a significant effect on the regulation of the biological process, which ultimately determines the outcome of bone healing. To mimic three healing conditions in the rat femur (normal, delayed, and non-healing bone defects), three different defect sizes of 0.5, 1.5, and 5.0 mm, are respectively used. The analysis of 3-day-old hematomas demonstrates clear differences in fibrin clot micro-architecture in terms of fiber diameter, fiber density, and porosity of the formed fibrin network, which result in different mechanical properties (stiffness) of the hematoma in each model. Those differences directly affect the biological processes involved. Specifically, RNA-sequencing reveals almost 700 differentially expressed genes between normally healing and non-healing defects, including significantly up-regulated essential osteogenic genes in normally healing defects, also differences in immune cell populations, activated osteogenic transcriptional regulators as well as potential novel marker genes. Most importantly, this study demonstrates that the healing outcome has already been determined during the hematoma phase of bone healing, three days post-surgery.
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Curación de Fractura , Fracturas Óseas , Animales , Fibrina , Curación de Fractura/genética , Hematoma/genética , Osteogénesis/genética , RatasRESUMEN
Achenbach's syndrome describes the sudden occurrence of bruising, pain and swelling of one or more digits of the hand involving the volar aspect of the proximal and middle phalanges. Also known as the paroxysmal finger hematoma, it presents in dramatic fashion, sometimes with a prodrome of tingling, itching or numbness but despite its dramatic presentation, all investigations are normal. Routine blood investigations, as well as coagulation and thrombophilia screens are all negative as are vascular imaging and echocardiography. The diagnosis is solely clinical. Due to the nature of its presentation, almost all patients are referred for an urgent vascular consultation but the condition resolves spontaneously usually within 2-3 days, although the discoloration may persist for longer. Its appearance usually leads clinicians to start anticoagulation in the belief that it may progress but, in fact, it settles as quickly as it appears. Though there are episodic cases which recur years later, it is generally self-resolving with no complications nor residual morbidity. Although the etiology was previously unknown, there is now a recognized genetic link. Genes related to the acute phase reactive proteins and the coagulation and complement cascades appear to be linked to Achenbach's syndrome. This evidence may explain why only certain individuals seem prone to this acutely painful, bruising disorder. We review this interesting disorder and compare patients from the tropical Caribbean region with similar cases from the temperate United Kingdom and discuss whether there are climatic variations in presentations.
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Dedos/irrigación sanguínea , Hematoma/etiología , Diagnóstico Diferencial , Traumatismos de los Dedos/complicaciones , Hematoma/diagnóstico por imagen , Hematoma/genética , Hematoma/patología , Humanos , Dolor , Recurrencia , SíndromeRESUMEN
Intracerebral hemorrhage (ICH) refers to hemorrhage caused by spontaneous rupture of blood vessels in the brain. Brain injury due to ICH leads to catastrophic effects resulting from the formation of hematoma and oxidative stress caused by components of lysed erythrocytes. However, not all neurons in the area surrounding the hematoma die immediately: A number of neurons remain in a critical, but reversible, state; however, the genes involved in this critical state remain poorly understood. Gene chip technology was used identify changes in the area surrounding the hematoma associated with the upregulation of 210 and downregulation of 173 genes. Gene Ontology functional annotation revealed changes in the gene expression profile in the peripheral region of hematoma following ICH, which were primarily associated with the external stimulation received by the organism, the transmission of harmful information to the cell through the transport of cell membrane proteins, and the regulation of a series of biological processes. Protein interaction network analysis revealed that 11 up[secreted phosphoprotein 1, dual specificity phosphatase 9, catecholOmethyltransferase, BAR/IMD domaincontaining adaptor protein 2like 1, plakophilin 2, homer scaffold protein 3, ret protooncogene (RET), KIT protooncogene, receptor tyrosine kinase, hepsin, connector enhancer of kinase suppressor of Ras 2 and kalirin RhoGEF kinase] and four downregulated genes (transcription factor AP2ß, peptidylprolyl isomerase A, SHOC2 leucine rich repeat scaffold protein and synuclein α) may serve a significant role in the area around hematoma following ICH. Reverse transcriptionquantitative PCR was used to verify that these genes were differentially expressed in the ICH compared with the control group. Causal network analysis suggested that the Achaetescute homolog 1RET signaling axis served a key role in the repair of nerve injury in the peripheral region of hematoma following ICH. Additionally, in vivo experiments revealed that RET expression was upregulated and colocalized with neurons. Taken together, these results suggested that the changes in the gene expression profile in the area around hematoma following ICH were primarily associated with the repair of damage caused to the nervous system.
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Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Hematoma/metabolismo , Hematoma/patología , Animales , Fenómenos Biológicos , Encéfalo/metabolismo , Lesiones Encefálicas/patología , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Hemorragia Cerebral/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hematoma/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Transcriptoma , Regulación hacia ArribaRESUMEN
Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction; however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH.
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Barrera Hematoencefálica/metabolismo , Hemorragia Cerebral/sangre , Claudina-5/genética , Cuerpo Estriado/metabolismo , Hematoma/sangre , Ocludina/genética , Uniones Estrechas/metabolismo , Animales , Animales Recién Nacidos , Transporte Biológico , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Barrera Hematoencefálica/ultraestructura , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/genética , Hemorragia Cerebral/patología , Claudina-5/sangre , Claudina-5/líquido cefalorraquídeo , Colagenasas/administración & dosificación , Cuerpo Estriado/irrigación sanguínea , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Expresión Génica , Hematoma/inducido químicamente , Hematoma/genética , Hematoma/patología , Humanos , Recién Nacido , Recien Nacido Prematuro , Inyecciones Intraventriculares , Ocludina/sangre , Ocludina/líquido cefalorraquídeo , Ratas , Ratas Wistar , Sacarosa/metabolismo , Uniones Estrechas/ultraestructuraRESUMEN
MiR-367 was reported to regulate inflammatory response of microglia. CCAAT/enhancer-binding protein α (C/EBPA) could mediate microglia polarization. In this study, we explored the possible roles of miR-367 and CEBPA in intracerebral hemorrhage (ICH). ICH and normal specimens were obtained from the tissue adjacent to and distant from hematoma of ICH patients, respectively. Microglia were isolated and identified by immunofluorescence. The isolated microglia were treated with erythrocyte lysate and randomly divided into 8 groups using different transfection reagents. The transfection efficiency of miR-367 was determined by qRT-PCR. The expressions of M1 and M2 microglia markers were detected by Western blotting. The relationship between CEBPA and miR-367 was confirmed by dual luciferase reporter system. Flow cytometry was performed to determine the level of apoptosis in the cells transfected with miR-367 and CEBPA in erythrocyte lysate-treated microglia. We found that miR-367 expression level was downregulated in ICH specimens. Erythrocyte lysate-treated microglia was successfully established using erythrocyte lysate, as decreased miR-367 expression was observed. Overexpression of miR-367 could significantly decrease the expressions of MHC-ÐÐ, IL-1ß, and Bax, reduced apoptosis rate, and increased the expressions of CD206, Bal-2, and Arg-1 in erythrocyte lysate-treated microglia. CEBPA was proved to be a direct target for miR-367, which could inhibit microglia M2 polarization and increase apoptosis rate. However, in the presence of both CEBPA and miR-367 mimic, the protein and mRNA expressions of CEBPA were decreased, leading to promoted microglia M2 polarization and a decreased apoptosis rate. MiR-367 regulates microglia polarization by targeting CEBPA and is expected to alleviate ICH-induced inflammatory injury.
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Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Polaridad Celular , Inflamación/genética , MicroARNs/metabolismo , Microglía/patología , Adulto , Apoptosis , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/genética , Regulación hacia Abajo/genética , Eritrocitos/metabolismo , Femenino , Hematoma/complicaciones , Hematoma/genética , Humanos , Masculino , MicroARNs/genética , Microglía/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and soft tissue vulnerable to blunt injury. Early recognition and diagnosis are crucial to patients to provide appropriate treatment, as well as to screen for life-threatening conditions such as aortic dissection and hollow organ perforation. The diagnosis of EDS is made based on clinical presentations, skin biopsy, and electron microscopy findings. To date, mutations in at least 20 genes have been found to cause the Ehlers-Danlos syndromes. However, EDS is still underestimated due to lack of awareness of its variable clinical presentations. Here we reported an EDS case with atypical initial presentation and a novel genetic mutation. CASE PRESENTATION: This 4-year-old Taiwanese male patient presented with easy bruising, multiple ecchymoses, joint hypermobility, hyperextensible skin, and prolonged pretibial haematoma. He was initially suspected of a bleeding tendency due to coagulation disorders. The coagulation test results were normal. DNA sequencing was performed for molecular diagnosis. Subsequently, the diagnosis of classical EDS was made by identifying a novel frameshift mutation in COL5A1 [NM_000093.4:c.4211_4212delAG, p.Gln1404Arg]. This mutation in the type V collagen gene COL5A1 contributes to the phenotype of classical EDS. This novel frameshift mutation may disturb the structural stability of collagen V and interfere with its heparin binding capacity, explaining the chronic haematoma. CONCLUSION: The reported case showed the unusual features of chronic haematoma. This novel frameshift mutation and its phenotype correlation can provide useful information for practitioners about early recognition in Ehlers-Danlos syndrome.
Asunto(s)
Síndrome de Ehlers-Danlos , Mutación del Sistema de Lectura , Preescolar , Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Hematoma/etiología , Hematoma/genética , Humanos , Masculino , Mutación , SíndromeRESUMEN
RATIONALE: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an AMPK (AMP-activated protein kinase)/ATF1 (activating transcription factor-1) pathway that directs Mhem macrophages through coregulation of HO-1 (heme oxygenase-1; HMOX1) and lipid homeostasis genes. OBJECTIVE: We asked whether this pathway had an in vivo role in mice. METHODS AND RESULTS: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow-derived macrophages, heme induced HO-1, lipid regulatory genes including LXR (lipid X receptor), the growth factor IGF1 (insulin-like growth factor-1), and the splenic red pulp macrophage gene Spic. This response was lost in bone marrow-derived macrophages from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between days 8 and 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-; n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent. CONCLUSIONS: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution. Graphic Abstract: An online graphic abstract is available for this article.
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Proteínas Quinasas Activadas por AMP/metabolismo , Factor de Transcripción Activador 1/metabolismo , Hematoma/metabolismo , Macrófagos/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Factor de Transcripción Activador 1/genética , Animales , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Eritrocitos/metabolismo , Femenino , Hematoma/genética , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hierro/metabolismo , Metabolismo de los Lípidos , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Factores de TiempoRESUMEN
Acute aortic syndrome is a group of interlinked conditions with common presenting symptoms, including aortic dissection, penetrating atherosclerotic ulcer, and intramural hematoma. Pharmacological management of acute aortic syndrome is a growing area, with key themes to address the underlying inflammatory pathways believed to be the cause. Research into interleukins, matrix metalloproteinases, and granulocyte macrophage colony-stimulating factor are just some of the many immunological properties being investigated and translated into medical therapies. Stem cell experiments may indicate further advances in the pathologies of acute aortic syndrome. The study of pharmacogenomics to improve treatment across different genomes is also a novel area outlined in this paper.
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Aneurisma de la Aorta/terapia , Disección Aórtica/terapia , Hematoma/terapia , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Trasplante de Células Madre , Úlcera/terapia , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/genética , Disección Aórtica/inmunología , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/inmunología , Hematoma/diagnóstico por imagen , Hematoma/genética , Hematoma/inmunología , Humanos , Factores Inmunológicos/efectos adversos , Trasplante de Células Madre/efectos adversos , Síndrome , Úlcera/diagnóstico por imagen , Úlcera/genética , Úlcera/inmunologíaRESUMEN
BACKGROUND/AIM: Chronic expanding hematoma is defined as a hematoma that gradually expands over 1 month or longer, is without neoplastic features on histological sections, and does not occur in the setting of coagulopathy. The pathogenetic mechanism behind its development is unknown, nor is anything known about its genetic features. CASE REPORT: A 49-year-old man noted a tender lump close to the right femoral trochanter. Examination of a core needle biopsy showed a fibrous capsule with fibrinoid material on one side. The patient underwent surgery with removal of a cystic, encapsulated structure with central bleeding and proliferating vessels in the fibrous capsule. The reactive fibroblasts were without any sign of atypia. Genetic analyses were performed on this chronic expanding hematoma. RESULTS: G-Banding analysis of short-term cultured cells from the chronic expanding hematoma yielded a karyotype with a single clonal chromosome abnormality: 46,XY,t(11;19)(q13;q13)[8]/46,XY[10]. RNA sequencing and examination of the sequencing data using five different programs did not identify fusion genes related to the translocation. CONCLUSION: The acquired translocation t(11;19)(q13;q13) suggested that chronic expanding hematoma is a neoplastic lesion. Since the translocation did not lead to any fusion genes, one can speculate that it causes deregulation of gene expression.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 19 , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hematoma/diagnóstico , Hematoma/genética , Translocación Genética , Biopsia , Bandeo Cromosómico , Enfermedad Crónica , Progresión de la Enfermedad , Humanos , Cariotipificación , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIM: The outcome of patients with advanced hepatocellular carcinoma (HCC) remains poor and therapeutic options, including sorafenib, the first anti-cancer drug proved to prolong survival in patients with advanced HCC, are limited. However, no clinically useful predictive biomarker for sorafenib has been reported. MATERIALS AND METHODS: We exploited two-dimensional gel electrophoresis coupled with mass spectrometry to find de-regulated proteins by using conditioning of a sorafenib-resistant HCC cell line, Huh7. Tumor samples from 60 patients with HCC treated with sorafenib were analyzed and correlated with survival outcome. RESULTS: Comparative proteomics indicated three proteins including, 78 kDa glucose related protein (GRP78), 14-3-3ε, and heat shock protein 90ß (HSP90ß). The three proteins were over-expressed in sorafenib-resistant Huh7 cells. In HCC tumor samples from patients treated with sorafenib, 73% of tumor samples had a high expression of GRP78, 18% had high 14-3-3ε expression and 85% had high HSP90ß expression. Among these, GRP78 was associated with the shortest progression-free survival of HCC patients treated with sorafenib. CONCLUSION: GRP78 can be a predictive biomarker in HCC patients treated with sorafenib. Strategies designed to inhibit the GRP78-related pathway may overcome sorafenib resistance.
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Resistencia a Antineoplásicos/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico/biosíntesis , Hematoma/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteómica , Sorafenib/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/genética , Hematoma/tratamiento farmacológico , Hematoma/genética , Hematoma/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas de Neoplasias/genéticaRESUMEN
This case report describes the first 10-year follow-up report worldwide of a patient with the genetic variation alpha-1-antitrypsin-Pittsburgh mutation (α1-AT-P). The mutation was confirmed in a 16 year-old Chinese girl after she presented with repeated hematomas, and the mutation with bleeding tendency was also verified in her father. α1-AT-P is a spontaneously occurring autosomal dominant point mutation of α1-antitrypsin, in which methionine-358 is substituted by an arginine derivative. α1-AT-P cases are extremely rare, with only eight reported worldwide. Consequently, there is insufficient experience in the diagnosis and treatment of α1-AT-P. We followed up and reviewed the last 10 years of treatment of a young patient who suffered from repeated life-threatening hematomas, underwent emergency surgery five times, and had her ovaries removed in her twenties to avoid ovulation hemorrhage. The purpose of this article is to raise the awareness of α1-AT-P mutation and to improve its prognosis, especially in female patients.
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Hematoma/diagnóstico , Enfermedades del Ovario/diagnóstico , alfa 1-Antitripsina/genética , Adolescente , Adulto , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Hematoma/genética , Hematoma/cirugía , Humanos , Enfermedades del Ovario/genética , Enfermedades del Ovario/cirugía , LinajeRESUMEN
OBJECTIVE: To explore the roles of interleukin-10 (IL-10), proNGF and p75NTR in apoptosis of brain tissues induced by intracerebral hemorrhage (ICH). PATIENTS AND METHODS: According to the time of sample collection after ICH, brain tissue samples were divided into < 6 h group, 6-24 h group (including 24 h), 24-72 h group (including 72 h) and > 72 h group. Meanwhile, 10 tissues that dropped from the beginning at the cortical stoma (distal part of the hematoma) were harvested as controls. AI in brain tissues around the hematoma after ICH was calculated based on TUNEL staining. Expression levels of IL-10, proNGF and p75NTR in brain tissues were determined by quantitative Real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. Protein expressions of Bcl-2 and Bax were detected by Western blot. Rat cortical astrocytes were harvested and cultured in vitro. After transfection of IL-10 overexpression plasmid, expression levels of IL-10, proNGF and p75NTR were detected by Western blot. RESULTS: AI increased in 6-24 h group, 24-72 h group and > 72 h group compared with < 6 h group and control group, which achieved the peak at 24-72 h. However, no significant difference in AI was observed between < 6 h group and control group. With the prolongation of ICH, IL-10 level gradually decreased and achieved the lowest level at 24-72 h. After 72 h, IL-10 level began to increase. Additionally, mRNA and protein levels of proNGF and p75NTR started to upregulate within 6 h of ICH, achieveing the peak at 24-72 h. Bcl-2 level gradually decreased after 6 h of ICH, while Bax level increased. We did not found significant difference in mRNA and protein levels of IL-10 in brain tissues around hematoma between < 6 h group and control group. With the prolongation of ICH, IL-10 level gradually decreased and achieved the lowest level at 24-72 h. After 72 h, IL-10 level began to increase. Transfection with IL-10 overexpression plasmid in rat astrocytes markedly downregulated protein levels of proNGF and p75NTR compared with those of controls. CONCLUSIONS: IL-10 expression is downregulated in brain tissues around the hematoma after ICH. IL-10 alleviates inflammation and apoptosis by inhibiting levels of proNGF, p75NTR and Bax/Bcl-2, thus protecting brain tissue after ICH.
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Apoptosis/fisiología , Encéfalo/metabolismo , Hemorragia Cerebral/metabolismo , Hematoma/metabolismo , Interleucina-10/biosíntesis , Factor de Crecimiento Nervioso/biosíntesis , Precursores de Proteínas/biosíntesis , Anciano , Anciano de 80 o más Años , Animales , Animales Recién Nacidos , Encéfalo/patología , Células Cultivadas , Hemorragia Cerebral/genética , Hemorragia Cerebral/patología , Femenino , Hematoma/genética , Hematoma/patología , Humanos , Interleucina-10/genética , Masculino , Persona de Mediana Edad , Factor de Crecimiento Nervioso/antagonistas & inhibidores , Factor de Crecimiento Nervioso/genética , Precursores de Proteínas/antagonistas & inhibidores , Precursores de Proteínas/genética , Ratas , Ratas WistarAsunto(s)
Contusiones/genética , Predisposición Genética a la Enfermedad , Hemofilia B/genética , Hexaclorociclohexano , Síndrome de Turner/genética , Preescolar , Contusiones/diagnóstico , Diagnóstico Diferencial , Femenino , Frente , Hematoma/diagnóstico , Hematoma/genética , Hemofilia B/diagnóstico , Humanos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Síndrome de Turner/diagnósticoRESUMEN
Aortic intramural hematoma (IMH) can evolve toward reabsorption, dissection or aneurysm. Hypertension is the most common predisposing factor in IMH and aneurysm patients, and the hypertensive mediator angiotensin-II induces both in mice. We have previously shown that constitutive deletion of Rcan1 isoforms prevents Angiotensin II-induced aneurysm in mice. Here we generate mice conditionally lacking each isoform or all isoforms in vascular smooth muscle cells, endothelial cells, or ubiquitously, to determine the contribution to aneurysm development of Rcan1 isoforms in vascular cells. Surprisingly, conditional Rcan1 deletion in either vascular cell-type induces a hypercontractile phenotype and aortic medial layer disorganization, predisposing to hypertension-mediated aortic rupture, IMH, and aneurysm. These processes are blocked by ROCK inhibition. We find that Rcan1 associates with GSK-3ß, whose inhibition decreases myosin activation. Our results identify potential therapeutic targets for intervention in IMH and aneurysm and call for caution when interpreting phenotypes of constitutively and inducibly deficient mice.
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Disección Aórtica/genética , Rotura de la Aorta/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Hematoma/genética , Hipertensión/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Musculares/genética , Quinasas Asociadas a rho/genética , Disección Aórtica/metabolismo , Disección Aórtica/patología , Disección Aórtica/prevención & control , Animales , Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Rotura de la Aorta/metabolismo , Rotura de la Aorta/patología , Rotura de la Aorta/prevención & control , Proteínas de Unión al Calcio , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Eliminación de Gen , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hematoma/metabolismo , Hematoma/patología , Hematoma/prevención & control , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/patología , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Masculino , Ratones , Ratones Noqueados , Proteínas Musculares/deficiencia , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Cultivo Primario de Células , Isoformas de Proteínas/deficiencia , Isoformas de Proteínas/genética , Inhibidores de Proteínas Quinasas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismoRESUMEN
INTRODUCTION: Renal hematomas (RH) are a rare complication of retrograde endoscopic lithotripsy (REL). This study aimed to investigate the incidence and causes of RH after REL in patients with ureteral stones of different locations. MATERIALS AND METHODS: From 2001 to 2016, 1214 REL were performed at the Urology Clinic of the Mechnikov NWSMU. The analyzes of patients who had RH after REL included the following parameters: age, gender, history of upper urinary tract (UUT) surgery and concomitant diseases (diabetes mellitus, hypertension), the baseline kidney function, the stone characteristics and the degree of hydronephrosis observed in the postoperative period, results of laboratory tests, ultrasound and spiral computed tomography (SCT) of the kidneys. RESULTS: Renal hematomas were diagnosed in 4 (0.3%) of 1214 patients aged 36 to 50 years who had obstructive upper ureteral stones measuring from 0.8 to 1.2 cm in diameter. Three of them previously had UUT surgery: two had REL, and one female patient with a solitary left kidney twice underwent percutaneous nephro- and ureterolithotripsy. All four patients had a triad of symptoms: side flank pain, fever, and anemia. In three patients hematomas were diagnosed on day 2-3 and in one it was found two weeks after the surgery. Two of them were managed with conservative therapy, including bed rest and antibiotics. One patient underwent an ultrasound guided puncture and drainage of the hematoma. In the patient with a solitary kidney, laparoscopic drainage of RH was performed due to growing hematoma and aggravating renal insufficiency. Two patients received blood transfusions. Follow-up kidney SCT showed complete resolution of hematomas in all patients. CONCLUSION: Renal hematomas are a rare but serious complication of REL. The presence of side flank pain, fever and anemia may be indicative of REL and requires a kidney ultrasound. Management of RH should be patient specific, depending on the severity of the patients condition.
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Hematoma , Histeroscopía/efectos adversos , Riñón , Litotricia/efectos adversos , Tomografía Computarizada Espiral , Cálculos Ureterales , Adulto , Anciano , Femenino , Hematoma/diagnóstico por imagen , Hematoma/genética , Hematoma/fisiopatología , Hematoma/terapia , Humanos , Histeroscopía/métodos , Riñón/diagnóstico por imagen , Riñón/fisiopatología , Pruebas de Función Renal , Litotricia/métodos , Masculino , Persona de Mediana Edad , Ultrasonografía , Cálculos Ureterales/diagnóstico por imagen , Cálculos Ureterales/fisiopatología , Cálculos Ureterales/terapiaRESUMEN
BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: ß, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: ß, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.
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Hemorragia Cerebral/genética , Cromosomas Humanos Par 17 , Hematoma/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Hemoglobin (Hb) toxicity precipitates secondary brain damage following intracerebral hemorrhage (ICH). CD163 is an anti-inflammatory Hb scavenger receptor and CD163-positive macrophages/microglia locally accumulate post-bleed, yet no studies have investigated the role of CD163 after ICH. ICH was induced in wildtype and CD163-/- mice and various anatomical and functional outcomes were assessed. At 3 d, CD163-/- mice have 43.4 ± 5.0% (p = 0.0002) and 34.8 ± 3.4% (p = 0.0003) less hematoma volume and tissue injury, respectively. Whereas, at 10 d, CD163-/- mice have 49.2 ± 15.0% larger lesions (p = 0.0385). An inflection point was identified, where CD163-/- mice perform better on neurobehavioral testing and have less mortality before 4 d, but increased mortality and worse function after 4 d (p = 0.0389). At 3 d, CD163-/- mice have less Hb, iron, and blood-brain barrier dysfunction, increased astrogliosis and neovascularization, and no change in heme oxygenase 1 (HO1) expression. At 10 d, CD163-/- mice have increased iron and VEGF immunoreactivity, but no significant change in HO1 or astrogliosis. These novel findings reveal that CD163 deficiency has distinct temporal influences following ICH, with early beneficial properties but delayed injurious effects. While it is unclear why CD163 deficiency is initially beneficial, the late injurious effects are consistent with the key anti-inflammatory role of CD163 in the recovery phase of tissue damage.
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Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Hemorragia Cerebral/genética , Receptores de Superficie Celular/genética , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Barrera Hematoencefálica , Encéfalo/patología , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/psicología , Gliosis/etiología , Gliosis/genética , Hematoma/genética , Hematoma/patología , Hemoglobinas/metabolismo , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/genética , Desempeño Psicomotor , Receptores de Superficie Celular/metabolismo , Recuperación de la FunciónRESUMEN
AIM: to identify mutations and hemostatic gene polymorphisms typical for retrochorial hematoma (RCH) and to study its pathogenesis in missed abortion. SUBJECTS AND METHODS: A PCR assay was used to detect the genetic forms of thrombophilia in 270 patients with ultrasonographically verified RCH. Logistic regression analysis revealed that with the F7 (proconvertin, coagulation factor (CF) VII G10976A polymorphism or with the F13 (fibrinase, CF XIII) G>T, or FGB (fibrinogen ß-chain) G455A polymorphism, the risk of RCH was 2.72, 2.16, and 1.92 times higher, respectively. First trimester missed abortion was found in 42 (15.5%) cases; among them there were 24 (8.8%) women with different polymorphism combinations: F7 (G10976A), F13 (fibrinase, G>T), FGB (G455A). A total of 18 cases of missed abortion due to morphologically verified endometritis, endocrinopathies, and antiphospholipid syndrome were excluded from the sample. RESULTS: Compared to the morphology of medical abortions of the same period (16 women), patients with polymorphic genes of hemostasis were found to have statistically significant incomplete endometrial decidualization, thinning or absence of a Rohr's fibrinoid layer, a smaller number and shortening of syncytiotrophoblast microvilli, and the maximum amount of dissecting hemorrhage and RCH in the utero-chorionic region. The stages of RCH pathogenesis were determined; these included penetration of maternal erythrocytes deep into the decidua ~ dissociation of a layer of decidual cells with impairment of a «hemostatic envelope¼ ~ formation of RCH with a dense network of fibrin threads ~ final necrosis of surrounding cells and tissues. CONCLUSION: The investigators identified for the first time the typical combinations of polymorphic genes of predisposition to a high risk for RCH; its complete formation requires additional changes in maternal and placental components that provide local hemostasis.
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Aborto Retenido/genética , Factores de Coagulación Sanguínea/genética , Hematoma/patología , Polimorfismo de Nucleótido Simple , Aborto Retenido/patología , Adulto , Estudios de Casos y Controles , Endometrio/irrigación sanguínea , Endometrio/patología , Femenino , Hematoma/genética , Hemostasis , Humanos , EmbarazoRESUMEN
OBJECTIVE: To measure the differential expression of microRNAs (miRNAs) in peripheral blood samples from patients with intracerebral haemorrhage (ICH) and to measure the levels of hsa-miR-21-5p in peripheral blood and haematoma samples from patients with ICH. METHODS: This case-control study enrolled individuals with ICH in the putamen treated by craniotomy and age- and sex-matched healthy control subjects. Serum miRNA expression profiles were determined in the patient and control groups using miRNA polymerase chain reaction (PCR) arrays. The ICH-related miRNA hsa-miR-21-5p was selected and its differential expression was assessed in peripheral blood and haematoma specimens from patients with ICH compared with peripheral blood samples controls using real-time PCR. RESULTS: Seven patients and five control subjects were included in the miRNA expression profile analysis; and 31 patients and 22 control subjects provided samples for the real-time PCR of hsa-miR-21-5p expression. A total of 59 miRNAs were significantly downregulated in patients with ICH. Relative hsa-miR-21-5p levels of 0.43 and 0.31 for peripheral blood and haematoma samples, respectively, were obtained in the patient group compared with the control subjects. CONCLUSION: Hsa-miR-21-5p levels were significantly reduced in both peripheral blood and haematoma samples in patients with ICH.