RESUMO
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical molecule in Toll-like receptor/interleukin-1 receptor signaling and an attractive therapeutic target for a wide range of inflammatory and autoimmune diseases as well as cancers. In our search for novel IRAK4 inhibitors, we conducted structural modification of a thiazolecarboxamide derivative 1, a lead compound derived from high-throughput screening hits, to elucidate structure-activity relationship and improve drug metabolism and pharmacokinetic (DMPK) properties. First, conversion of the thiazole ring of 1 to an oxazole ring along with introduction of a methyl group at the 2-position of the pyridine ring aimed at reducing cytochrome P450 (CYP) inhibition were conducted to afford 16. Next, modification of the alkyl substituent at the 1-position of the pyrazole ring of 16 aimed at improving CYP1A2 induction properties revealed that branched alkyl and analogous substituents such as isobutyl (18) and (oxolan-3-yl)methyl (21), as well as six-membered saturated heterocyclic groups such as oxan-4-yl (2), piperidin-4-yl (24, 25), and dioxothian-4-y (26), are effective for reducing induction potential. Representative compound AS2444697 (2) exhibited potent IRAK4 inhibitory activity with an IC50 value of 20 nM and favorable DMPK properties such as low risk of drug-drug interactions mediated by CYPs as well as excellent metabolic stability and oral bioavailability.
Assuntos
Citocromo P-450 CYP1A2 , Quinases Associadas a Receptores de Interleucina-1 , Anticonvulsivantes/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Oxazóis , Pirazóis/farmacologia , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Fresh peripheral blood (PB) samples from 432 outpatients with stable chronic obstructive pulmonary disease (COPD) were examined. Patients were classified into Group A (large SRA+ cells were undetected) and Group B (large SRA+ cells were detected) and followed-up for 1 year. Patients were further subdivided according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Cox proportional hazard model had shown that Gold, Group, home oxygen therapy (HOT), and treatment were significant predictors of severe exacerbation. Six of 353 patients in Group A and 29 of 79 in Group B developed severe exacerbation. The rates of severe exacerbation were significantly higher in Group B patients, GOLD stage 2 than Group A, GOLD stage 2; in Group B, GOLD stage 3 than Group A, GOLD stage 3; and in all of Group B compared with in all of Group A. The Kaplan-Meier curves of Group B, GOLD stages 1-4, and of all of Group B showed significantly worse rates of severe exacerbation than those of Group A, Gold 1-4, and all of Group A, respectively. The appearance of large SRA+ cells in the PB of patients with stable COPD may represent a useful biomarker for severe COPD exacerbation.
Assuntos
Doença Pulmonar Obstrutiva Crônica/patologia , Receptores Depuradores Classe A/sangue , Idoso , Biomarcadores/sangue , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/mortalidade , Fatores de RiscoRESUMO
BACKGROUND: Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren's syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. CASE PRESENTATION: A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. CONCLUSION: Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.
Assuntos
Imunoglobulina A/sangue , Linfócitos/metabolismo , Nefrite Intersticial/sangue , Paraproteinemias/sangue , Plasmócitos/metabolismo , Síndrome de Sjogren/sangue , Idoso , Feminino , Humanos , Nefrite Intersticial/complicações , Nefrite Intersticial/diagnóstico por imagem , Paraproteinemias/complicações , Paraproteinemias/diagnóstico por imagem , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico por imagemRESUMO
Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.
Assuntos
Adjuvantes Imunológicos/farmacologia , Descoberta de Drogas , Janus Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Administração Oral , Animais , Disponibilidade Biológica , Permeabilidade da Membrana Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração , Humanos , Janus Quinases/metabolismo , Masculino , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Piridinas/administração & dosagem , Piridinas/química , Pirróis/administração & dosagem , Pirróis/química , Ratos , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The pathophysiologic mechanisms underlying acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not fully understood. Few studies have examined autopsy findings in patients who have died from an acute exacerbation of IPF. The pathologic findings in systemic organs have not been described. METHODS: We retrospectively reviewed the autopsy findings in 12 patients who had died from an acute exacerbation of IPF and two of connective tissue disease- associated interstitial lung disease between 2005 and 2015. We recorded demographic and clinical characteristics, autopsy findings and cytologic findings in peripheral blood. RESULTS: The median age at autopsy was 68 years (range 45-87 years); 11 subjects (78.5 %) were men. High-dose corticosteroid, cyclophosphamide and oxygen therapy had been administered to all patients. Underlying lesions had the usual interstitial pneumonia pattern; diffuse alveolar damage and contraction band necrosis were observed in all cases. Large cells expressing scavenger receptor A (SRA+) had been observed in the systemic circulation of 11 of the 14 cases (78.6 %) before acute exacerbation, and cells expressing tumor necrosis factor-α (TNF-α+) were detected after its diagnosis in nine (64.3 %). Both were detected in all cases at autopsy. There was neutrophil and platelet accumulation predominantly in capillaries, and extensive capillary endothelial cells injury. CONCLUSIONS: Our findings suggest that acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury.
Assuntos
Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Insuficiência de Múltiplos Órgãos/patologia , Receptores Depuradores Classe A/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Idoso , Idoso de 80 Anos ou mais , Autopsia , Progressão da Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Receptores Depuradores Classe A/análise , Fator de Necrose Tumoral alfa/análiseRESUMO
AIMS: To investigate the mechanisms underlying the acute exacerbation of idiopathic pulmonary fibrosis, and in particular the role of minute lesions of alveolar damage. METHODS AND RESULTS: We examined surgical lung biopsy samples from 38 patients with stable idiopathic pulmonary fibrosis, and evaluated the association between the foci and development of acute exacerbation. Mild extravasation, probably resulting from lung injury and intra-alveolar oedema fluid, were observed in narrow areas of architecturally intact lung tissue. Minute lesions of alveolar damage were detected in these areas. Alveolar epithelial cells in these lesions were injured. Hypoxia-inducible factor-2α-positive macrophages, tumour necrosis factor-α-positive macrophages and neutrophils had accumulated in alveolar spaces in and around these lesions. Cases were classified into patients without (17) and with (21) minute lesions of alveolar damage. Development to acute exacerbation (five cases) occurred only in patients with minute lesions of alveolar damage (P = 0.03). CONCLUSIONS: The formation of minute lesions of alveolar damage may be initiated by hypoxia, and such lesions play important roles in the development of acute exacerbation.
Assuntos
Fibrose Pulmonar Idiopática/patologia , Alvéolos Pulmonares/lesões , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biópsia , Feminino , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Assuntos
Amidas/química , Fatores Imunológicos/síntese química , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Cães , Rejeição de Enxerto/prevenção & controle , Meia-Vida , Haplorrinos , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interleucina-2/metabolismo , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Piridinas/química , Ratos , Ratos Endogâmicos Lew , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Transplante HeterotópicoRESUMO
A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.
Assuntos
Doença de Alexander , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/genética , Códon/genética , Proteína Glial Fibrilar Ácida/genética , Imageamento por Ressonância Magnética/métodos , Bulbo/diagnóstico por imagem , Bulbo/patologia , MutaçãoRESUMO
UNLABELLED: There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti-mitochondrial antibodies, there is no correlation of anti-mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft-versus-host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls; the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti-mitochondrial antibodies. CONCLUSION: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity.
Assuntos
Colangite/patologia , Colangite/fisiopatologia , Cirrose Hepática Biliar/patologia , Cirrose Hepática Biliar/fisiopatologia , Plasmócitos/patologia , Plasmócitos/fisiologia , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Anticorpos Anti-Idiotípicos/metabolismo , Biópsia , Estudos de Casos e Controles , Colangite/metabolismo , Colangite Esclerosante/metabolismo , Colangite Esclerosante/patologia , Colangite Esclerosante/fisiopatologia , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Hepatite C Crônica/metabolismo , Hepatite C Crônica/patologia , Hepatite C Crônica/fisiopatologia , Hepatite Autoimune/metabolismo , Hepatite Autoimune/patologia , Hepatite Autoimune/fisiopatologia , Humanos , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Plasmócitos/metabolismoRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) arising from cranial nerves are rare and usually affect adults. Here we report the clinicopathologic features of a young adult patient with a trigeminal nerve MPNST, in whom another tumor involving the oculomotor nerve on the contralateral side was evident. The patient, an 18-year-old woman, had suffered recurrent paroxysmal sharp stabbing pain over her cheek and forehead on the right side for 1 month. A brain MRI study disclosed a mass, 35 mm in diameter, in the right Meckel's cave, and another mass, 10 mm in diameter, involving the intracranial portion of the left oculomotor nerve. Following gadolinium administration, the former and latter tumors exhibited strong and weak enhancement, respectively. The patient had no clinical stigmata characteristic of neurofibromatosis type 1. Following a tentative diagnosis of schwannoma, total resection of the trigeminal nerve tumor was performed. Histologically, the tumor consisted of highly cellular, spindle-shaped cells arranged in a fascicular pattern, with occasional mitotic figures, nuclear pleomorphism and necrosis. Immunohistochemically, the tumor cells showed variable intensities and frequencies of reactivity for S-100 protein, myelin basic protein, CD34, podoplanin and p53, but no reactivity for Smarcb1. Thus, the tumor exhibited features of MPNST. This case appears to provide information that is useful for accurate diagnosis and surgical planning in patients with bilateral or multiple cranial nerve tumors.
Assuntos
Neoplasias dos Nervos Cranianos/patologia , Neurilemoma/patologia , Doenças do Nervo Trigêmeo/patologia , Adolescente , Feminino , HumanosRESUMO
Autoimmune polyendocrine (or polyglandular) syndrome (APS) is a relatively rare clinical condition characterized by functional impairment of multiple endocrine glands due to loss of immune tolerance. APS is broadly categorized as rare monogenic forms, such as autoimmune polyendocrine syndrome type 1 (APS-1), and a more common polygenic variety, autoimmune polyendocrine syndrome type 2 (APS-2). Although many autoimmune conditions including autoimmune rheumatic diseases can develop in APS-2, systemic sclerosis or myositis as a complication is quite rare and no treatment strategy has yet been established. A 25-year-old man who had been diagnosed as having type 1 diabetes developed finger stiffness. Although the subjective symptoms were relatively mild, extensive examinations including various autoantibodies, hormones and biopsy of the skin and minor salivary glands revealed that he had APS-2 (type 1 diabetes and autoimmune thyroid disease) accompanied by systemic sclerosis, myositis and Sjögren's syndrome. Rituximab therapy was initiated for the progressive skin sclerosis, and this resulted in significant alleviation of both the sclerosis and the myositis. In APS, early diagnosis and immunomodulatory therapy may arrest the autoimmune process before irreversible organ damage has occurred. This case report suggests that rituximab may be a promising therapy for autoimmune rheumatic diseases associated with APS-2.
RESUMO
To evaluate the roles of apoptotic cells in peripheral blood (PB) on multiple organ injury, five patients with hematopoietic stem cell transplantation (HSCT) and one with refractory anemia were examined. The following findings were confirmed. 1) High-dose alkylating agents were administrated as conditioning regimens to all HSCT patients. 2) Many organs were injured in all cases. 3) Neutrophils accumulated in the capillaries of injured organs, and endothelial cells were extensively injured. 4) Large numbers of apoptotic cells and γH2AX(+) cells were observed in the foci of large cells with hyperchromatic nuclei. 5) Increased numbers of apoptotic cells (6/6), γH2AX(+) cells (6/6), scavenger receptor A positive (SRA(+) ) cells (6/6), and tumor necrosis factor (TNF)-α(+) cells (5/6) were observed in PB smear preparations. 6) Cytokines exceeded the normal levels in most patients. From these findings, apoptotic cells were considered to be produced by the administration of high-dose alkylating agents in HSCT patients, and apoptotic cells and SRA(+) cells in PB were thought to play important roles in the development of multiple organ injury in HSCT and MDS patients.
Assuntos
Anemia Refratária/sangue , Apoptose/fisiologia , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/patologia , Adulto , Idoso de 80 Anos ou mais , Alquilantes/farmacologia , Anemia Refratária/patologia , Anemia Refratária/cirurgia , Apoptose/efeitos dos fármacos , Citocinas/sangue , Relação Dose-Resposta a Droga , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/cirurgia , Neutrófilos/metabolismo , Neutrófilos/patologia , Receptores Depuradores Classe A/metabolismo , Condicionamento Pré-Transplante/métodosRESUMO
Lymphoplasmacyte-rich meningioma (LPM) is a rare, benign variant of meningioma, characterized by massive inflammatory cell infiltration and a variable proportion of meningothelial tumorous elements. Here we report the clinicopathological features of an LPM located at the right frontal convexity in a 37-year-old woman. The patient had suffered an initial generalized tonic-clonic seizure when she was 32 weeks pregnant. The lesion exhibited low intensity on T1-weighted MRI and high intensity on T2-weighted images, with surrounding parenchymal edema. The mass exhibited gadolinium enhancement with dural tail signs. Moreover, multiple foci of linear enhancement spreading through the sulci and into the nearby brain parenchyma were evident. At 1 month after parturition, en bloc removal of the mass, the attached dura mater and adjacent brain tissue was performed. Histologically, the mass located in the subdural space was composed of a mixture of B- and T-lymphocytes and plasma cells. Within the mass, multiple small lobules of meningothelial cells showing immunoreactivity for epithelial membrane antigen and vimentin were observed. The inflammatory cells had also infiltrated the subarachnoid and Virchow-Robin spaces, and the dura mater. The cerebral cortex showed ischemic changes, but no tumor cell invasion. On the basis of these histological features, the lesion appeared to be LPM with an inconspicuous meningothelial component and extensive inflammatory infiltration. This case appears to provide useful information on the pathogenesis of this variant.
Assuntos
Linfócitos/patologia , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Plasmócitos/patologia , Complicações Neoplásicas na Gravidez/diagnóstico , Adulto , Feminino , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Gravidez , Complicações Neoplásicas na Gravidez/patologiaRESUMO
Von Hippel-Lindau disease (VHL) is frequently associated with pancreatic neuroendocrine tumors (PNETs). Here, we report a case of tumor-to-tumor metastasis in a VHL patient in whom colon cancer metastasized to the interior of a PNET. A 65-year-old man had undergone bilateral adrenalectomy for pheochromocytomas in both adrenal glands in his 50 s. Genetic screening was performed considering his family history of pheochromocytoma, and he was diagnosed with VHL. PNET was detected, for which the patient was regularly monitored by follow-up imaging. One year ago, the patient underwent right hemicolectomy to remove a tumor in the ascending colon (pT3N0M0, pStage IIA). He was admitted to our department for detailed examination because the pancreatic tumor had grown, and thus, pancreaticoduodenectomy was performed. Diagnostic imaging and histological findings indicated tumor-to-tumor metastasis, in which the patient's previous colon cancer had metastasized to and proliferated within the PNET. Colon cancer metastasizing to a PNET is extraordinarily rare and has never been reported in the literature. Thus, practitioners should be vigilant for tumor-to-tumor metastasis when performing imaging surveillance of PNETs.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasias do Colo , Segunda Neoplasia Primária , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Feocromocitoma , Doença de von Hippel-Lindau , Masculino , Humanos , Idoso , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genética , Tumores Neuroendócrinos/cirurgia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias do Colo/cirurgia , Neoplasias do Colo/complicações , Tumores Neuroectodérmicos Primitivos/complicaçõesRESUMO
We investigated the association of scavenger receptor A-positive (SRA(+) ) cells in peripheral blood (PB) with mortality in subjects with systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). A total of 467 subjects with SIRS (62 of 467 satisfied the diagnostic criteria of MODS) were prospectively examined. The subjects were classified into three groups according to the SRA index (number of small SRA(+) cells in 10 high power field, normal upper limit < 30) and the appearance of large SRA(+) cells as follows: group A, large SRA(+) cells were not detected; group B, large SRA(+) cells were detected but SRA index did not exceed 30; group C, the two factors (appearance of large SRA(+) cells and SRA index > 30) coincided. The duration from the diagnosis of SIRS to death in groups A and B was significantly shorter than in group C. The mortality rate in group C was significantly higher than in groups A and B. Kaplan-Meier curves of group C showed significantly worse survival than groups A and B. These results indicate that the coincidence of two factors (appearance of large SRA(+) cells and SRA index > 30) may be useful to predict the outcome in patients with SIRS or MODS.
Assuntos
Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/mortalidade , Receptores Depuradores Classe A/sangue , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
To evaluate the pathophysiological mechanisms underlying sudden infant death syndrome (SIDS), four sudden unexpected death in infancy (SUDI) and four sudden deaths in children over 1 year of age were examined. In the SUDI cases, increased numbers of scavenger receptor A positive (SRA(+) ) cells (4/4), numerous platelet aggregates (3/4), and tumor necrosis factor (TNF)-α(+) cells (4/4) were observed in the peripheral blood (PB) smear preparations. Macrophage colony stimulating factor, interleukin (IL)-6, IL-8, TNF-α and IL-1ß all exceeded the normal levels. Minute foci of inflammatory lung injury (4/4), numerous platelet emboli in lungs and among cardiac myocytes (3/4) and appreciable contraction band necrosis (1/4) were observed. And neutrophils accumulated in the capillaries of injured organs and endothelial cells were extensively injured. From these findings, cytokine abnormality induced by SRA(+) cells in PB was considered to play an important role in the development of tissue injury, and platelet emboli or contraction band necrosis might have been the leading cause of death in our SUDI cases. Patients with characteristics thought to be similar to our SUDI cases were included in the SIDS group; cytokine abnormality was considered to be one of the underlying mechanisms in SIDS.
Assuntos
Morte Súbita do Lactente/patologia , Biomarcadores/metabolismo , Pré-Escolar , Citocinas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Agregação Plaquetária , Receptores Depuradores Classe A/metabolismo , Morte Súbita do Lactente/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
To examine the relationship between the scavenger receptor A (SRA) index (the number of SRA+ cells observed in 10 high power fields of peripheral blood (PB) smear samples; normal upper limit <30) and coronary thrombus, 389 thrombi obtained from 393 patients with acute ST elevation myocardial infarction were examined. Thrombi were classified into platelets (PT), mixed (MT), fibrin-rich (FT) and organizing thrombi (OT); 387, 269, 57 and 29 cases were detected, respectively. Patients were divided into group A (PT only, 89 cases), B (containing MT and PT but not FT, 243 cases), and C (containing FT, 57 cases). SRA+ cells had infiltrated into all FT cases and 147 of the 269 MT, but no PT. At hospitalization, the SRA index exceeded 30 in 276 patients. PT was observed in 274 cases, and MT and FT (residual mural thrombus; RMT) observed in 230. Infarct-related coronary artery was thought to be totally and rapidly occluded by PT that had formed as a result of severe stenosis due to extrusion of plaque content or growth of RMT. An abnormal increase of SRA+ cells is considered to be a useful finding to detecting the presence of PT and, probably, RMT.
Assuntos
Plaquetas/metabolismo , Trombose Coronária/complicações , Infarto do Miocárdio/complicações , Receptores Depuradores Classe A/metabolismo , Idoso , Biomarcadores/sangue , Trombose Coronária/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Receptores Depuradores Classe A/sangue , TrombectomiaRESUMO
To evaluate the role of small scavenger receptor A (SRA)-positive (SRA(+)) cells and large SRA(+) cells in the peripheral blood (PB) in the pathophysiological mechanisms underlying multiple organ dysfunction syndromes (MODS), 24 autopsy cases with MODS were examined. In addition to histopathological and immunohistochemical examination, cytokine levels of cardiac blood, the SRA index (number of small SRA(+) cells in 10 high power fields, upper limit <30), and appearance of large SRA(+) cells in PB were examined. The SRA index exceeded 30 in all cases. Large SRA(+) cells and tumor necrosis factor (TNF)-alpha(+) cells were detected in PB in all cases. Macrophage colony stimulating factor (M-CSF), interleukin (IL)-6 and IL-8 levels exceeded the normal level in all cases, and 18 and 15 cases had TNF-alpha and IL-1beta levels above the normal threshold, respectively. Lung injury and necrosis of cardiac myocyte were observed in all cases. Neutrophils and platelets accumulated in the capillaries of injured organs and endothelial cells were extensively injured. From these results, large SRA(+) cells differentiated from monocytes in PB were considered to play an important role in the development of MODS, and necrosis of cardiac myocytes together with lung injury might be the leading cause of death in MODS patients.