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2.
Periodontol 2000 ; 82(1): 78-92, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31850633

RESUMO

Neutrophils have been historically associated with antimicrobial functions in acute infections but are now appreciated as functionally versatile cells with critical roles in chronic inflammation. Recent advances in neutrophil biology have contributed to a better understanding of periodontal disease pathogenesis and, reciprocally, the study of periodontitis has led to important insights into neutrophil regulation and function. Here, the contributions by our group to this field through interdisciplinary collaboration are discussed. The study of leukocyte adhesion deficiency-associated periodontitis has revealed that the connection of neutrophils with destructive inflammation may involve mechanisms beyond the typical bystander injury dogma. In this regard, neutrophils are required for important immunomodulatory functions and their absence from the periodontium leads to dysregulated overproduction of interleukin-17, which drives inflammatory bone loss. We have also discovered that both the production of neutrophils in the bone marrow and their recruitment to peripheral tissues, including the periodontium, are homeostatically regulated by a secreted protein designated developmental endothelial locus-1. However, developmental endothelial locus-1 expression, and hence developmental endothelial locus-1-dependent homeostasis, declines considerably with aging and contributes to an increased susceptibility to periodontitis in old age. Moreover, our work has mechanistically supported the concept that periodontitis is a dysbiotic disease and we have shown that neutrophils become targets of immune subversion by periodontal bacteria in a manner that promotes dysbiosis. The mechanism involves microbial exploitation of key neutrophil receptors (complement C5a receptor-1 and toll-like receptor-2), leading to crosstalk signaling that uncouples neutrophil-mediated killing (which is impaired) from neutrophil-induced inflammation (which is enhanced). These studies have collectively established new mechanisms governing the protective and destructive functions of neutrophils in periodontitis and offered targeted host-modulation approaches for the treatment of periodontal diseases.


Assuntos
Transtornos Leucocíticos , Periodontite , Humanos , Inflamação , Neutrófilos , Periodonto
3.
J Biomed Sci ; 26(1): 64, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472685

RESUMO

Terminally differentiated B cell, the plasma cell, is the sole cell type capable of producing antibodies in our body. Over the past 30 years, the identification of many key molecules controlling B cell activation and differentiation has elucidated the molecular pathways for generating antibody-producing plasma cells. Several types of regulation modulating the functions of the important key molecules in B cell activation and differentiation add other layers of complexity in shaping B cell responses following antigen exposure in the absence or presence of T cell help. Further understanding of the mechanisms contributing to the proper activation and differentiation of B cells into antibody-secreting plasma cells may enable us to develop new strategies for managing antibody humoral responses during health and disease. Herein, we reviewed the effect of different types of regulation, including transcriptional regulation, post-transcriptional regulation and epigenetic regulation, on B cell activation, and on mounting memory B cell and antibody responses. We also discussed the link between the dysregulation of the abovementioned regulatory mechanisms and B cell-related disorders.


Assuntos
Linfócitos B/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Transtornos Leucocíticos/fisiopatologia , Animais , Humanos , Transtornos Leucocíticos/genética
4.
Immunohorizons ; 3(9): 440-446, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533951

RESUMO

Endotoxin shock is induced by LPS, one of the most potent virulence factors of the Gram-negative bacteria that cause sepsis. It remains unknown if either proinflammatory stress-responsive transcription factors (SRTFs), ferried to nucleus by importin α5, or lipid-regulating sterol regulatory element binding proteins (SREBPs), transported to the nucleus by importin ß1, mediate endotoxin shock. A novel cell-penetrating peptide targeting importin α5 while sparing importin ß1 protected 80% of animals from death in response to a high dose of LPS. This peptide suppresses inflammatory mediators, liver glycogen depletion, endothelial injury, neutrophil trafficking, and apoptosis caused by LPS. In d-galactosamine-pretreated mice challenged by 700-times lower dose of LPS, rapid death through massive apoptosis and hemorrhagic necrosis of the liver was also averted by the importin α5-selective peptide. Thus, using a new tool for selective suppression of nuclear transport, we demonstrate that SRTFs, rather than SREBPs, mediate endotoxin shock.


Assuntos
Inflamação/tratamento farmacológico , Fígado/patologia , Macrófagos/imunologia , Peptídeos/uso terapêutico , Choque Séptico/tratamento farmacológico , alfa Carioferinas/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Humanos , Doenças do Sistema Imunitário , Transtornos Leucocíticos , Lipopolissacarídeos/imunologia , Camundongos , NF-kappa B/metabolismo , Necrose , Células RAW 264.7 , Transdução de Sinais , alfa Carioferinas/genética , beta Carioferinas/metabolismo
5.
Int J Gynecol Cancer ; 29(8): 1258-1263, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31320488

RESUMO

OBJECTIVE: The objective of this study was to investigate the relationship between pre-treatment absolute neutrophil count and clinical outcomes in patients with uterine carcinosarcoma. METHODS: In an Institutional Review Board approved, retrospective cohort study of 103 patients with uterine carcinosarcoma, the pre-treatment absolute neutrophil count data were obtained from the medical records, along with clinical, pathologic, treatment, and outcome data. Kaplan-Meier survival estimates were calculated and compared by the log rank test. Univariable and multivariable Cox proportional hazard regression models were used to examine the relationship of pre-treatment absolute neutrophil count with progression-free survival and overall survival. RESULTS: Uterine carcinosarcoma patients in the highest quartile of pre-treatment absolute neutrophil count had significantly reduced progression-free survival (p<0.001, log rank test), and overall survival (p<0.001, log rank test), compared with patients in the lower absolute neutrophil count quartiles. On multivariable analysis, high absolute neutrophil count was an independent poor prognostic factor for disease recurrence, HR 2.97 (95% CI 1.35 to 6.53, p=0.007) for highest versus lowest quartile absolute neutrophil count, and for mortality, HR 4.43 (95% CI 1.64 to 12.00, p= 0.003). CONCLUSIONS: High pre-treatment absolute neutrophil count is an independent poor prognostic factor in patients with uterine carcinosarcoma and may be useful as a potential biomarker in clinical trials. The mechanistic relationship of neutrophilia and uterine carcinosarcoma progression merits further investigation.


Assuntos
Carcinossarcoma/sangue , Carcinossarcoma/mortalidade , Transtornos Leucocíticos/sangue , Transtornos Leucocíticos/mortalidade , Neoplasias Uterinas/sangue , Neoplasias Uterinas/mortalidade , Idoso , Alabama/epidemiologia , Carcinossarcoma/patologia , Feminino , Humanos , Contagem de Leucócitos , Transtornos Leucocíticos/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Uterinas/patologia
6.
J Eur Acad Dermatol Venereol ; 33(11): 2179-2187, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31166045

RESUMO

BACKGROUND: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. OBJECTIVES: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. METHODS: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). RESULTS: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease. CONCLUSIONS: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.


Assuntos
Transtornos Leucocíticos/diagnóstico , Neutrófilos , Dermatopatias/diagnóstico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Dermatopatias/classificação , Dermatopatias/imunologia
7.
Blood ; 133(12): 1271-1272, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898774
8.
Nutrients ; 11(2)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699901

RESUMO

Studies devoted to evaluating the outcome of different doses of probiotics are very limited, especially for multistrain formulations. In this context, we performed an intervention study that aimed to compare the effect of the administration of two doses (7 billion and 70 billion bacterial cells) of a multistrain probiotic formulation on the persistence of the four probiotic strains that were present in the product in the fecal samples collected from healthy subjects. The overall persistence of the probiotic strains was significantly higher for the 70 billion formulation than for the 7 billion formulation. Furthermore, probiotic strains were detected earlier and for longer for the 70 billion formulation compared to those for the 7 billion formulation. All probiotic strains were recovered alive from the 70 billion preparation, whereas recovery was not possible in a few fecal samples upon administration of the 7 billion preparation. In addition, the overall number of viable probiotic cells recovered on day 14 (i.e., the last day of consumption) was significantly higher for the 70 billion formulation than that for the 7 billion formulation. Finally, we found that the viability of the probiotic cells was stable over the course of the trial independent of volunteers' handling, demonstrating good manufacturing of the product. In conclusion, this study demonstrated that strains belonging to different taxa may coexist in the human gastrointestinal tract upon ingestion of a multispecies probiotic formulation. Moreover, this study suggests that higher doses of bacterial cells in probiotic formulations may permit a higher, earlier, and longer recovery of the probiotics in the feces of healthy adults.


Assuntos
Bifidobacterium/fisiologia , Lactobacillus/fisiologia , Probióticos/administração & dosagem , Sobrevivência Celular , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Fezes/microbiologia , Trato Gastrointestinal , Humanos , Lactoferrina/deficiência , Transtornos Leucocíticos
10.
J Immunol ; 202(1): 207-217, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30504419

RESUMO

Acute inflammation recruits neutrophils with a band-shaped nucleus to the circulation. This neutrophil population was recently shown to have superior antibacterial capacity. Early recruitment of banded neutrophils to an infection site will likely improve the outcome of the immune response, yet it critically depends on efficient migration. However, the current dogma states that the segmentation of the mature neutrophil nucleus has evolved to favor migration through narrow pores as found between endothelial cells and in the interstitium. Therefore, we hypothesized that banded neutrophils migrate less efficiently than neutrophils with segmented nuclei, whereas recently described neutrophils with hypersegmented nuclei would in turn migrate more efficiently. Acute inflammation was evoked in a human model of experimental endotoxemia to recruit neutrophil subsets with different nuclear segmentation to the circulation. To simulate migration toward an infection site, migration of the subsets was studied in in vitro models of transendothelial migration or interstitial chemokinesis and chemotaxis. In both models, nuclear segmentation did not increase migration speed. In dense collagen matrices, the speed of the hypersegmented neutrophils was even reduced compared with the banded neutrophils. Fluorescence microscopy suggested that the hypersegmented neutrophils displayed reduced rear release and deposited more membrane vesicles. Vice versa, migration through narrow pores did not induce nuclear segmentation in the neutrophils. In conclusion, like neutrophils with a segmented nucleus, the banded subset exhibited efficient migration through narrow pores. These findings suggest that the nucleus does not preclude the banded subset from reaching an infection site.


Assuntos
Núcleo Celular/fisiologia , Células Endoteliais/fisiologia , Endotoxemia/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Doença Aguda , Adolescente , Adulto , Idoso , Diferenciação Celular , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Doenças do Sistema Imunitário , Transtornos Leucocíticos , Masculino , Pessoa de Meia-Idade , Migração Transendotelial e Transepitelial , Adulto Jovem
13.
Mucosal Immunol ; 12(1): 247-257, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279514

RESUMO

Gram-positive pathogens, including Staphylococcus aureus, cause necrotizing pneumonia. The central feature of S. aureus pneumonia is toxin-induced necroptosis of immune and resident cells, which impedes host defense. However, the role of the NLRC4 in the lung following S. aureus infection remains elusive. Here, we demonstrate that S. aureus activates the NLRC4 to drive necroptosis and IL-18 production, which impaired IL-17A-dependent neutrophil-mediated host susceptibility. In particular, Nlrc4-/- mice exhibit reduced necroptosis, enhanced neutrophil influx into the lungs, decreased bacterial burden, and improved host survival. Loss of NLRC4 signaling in both hematopoietic and non-hematopoietic cells contributes to the host protection against S. aureus pneumonia. Secretion of IL-17A by γδ T cells is essential for neutrophil recruitment into the lungs of Nlrc4-/- mice following infection. Moreover, treatment of wild-type mice with necroptosis inhibitors or genetic ablation of MLKL and IL-18 improves host defense against S. aureus infection, which is associated with increased IL-17A+γδ T cells and neutrophils. Taken together, these novel findings reveal that S. aureus activates the NLRC4 to dampen IL-17A-dependent neutrophil accumulation through induction of necroptosis and IL-18. Thus, modulating the function of the NLRC4 may be an attractive therapeutic approach for treating S. aureus infections.


Assuntos
Pulmão/imunologia , Neutrófilos/imunologia , Pneumonia Estafilocócica/imunologia , Staphylococcus aureus/imunologia , Linfócitos T/imunologia , Animais , Apoptose , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Humanos , Doenças do Sistema Imunitário , Interleucina-18/genética , Interleucina-18/metabolismo , Transtornos Leucocíticos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Proteínas Quinases/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Transdução de Sinais , Regulação para Cima
15.
Chin J Integr Med ; 25(5): 354-359, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29500545

RESUMO

OBJECTIVE: To explore the effect of Qinghuang Powder (QHP,()combined with Bupi Yishen Decoction (BPYS, ) on myelodysplastic syndromes (MDS) patients with refractory cytopenia with multilineage dysplasia (RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. METHODS: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count (ANC), hemoglobin (Hb), platelets (PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation. Gene Ontology (GO) and Pathway analysis were applied to analyze the methylation data. RESULTS: The overall MDS response rate to QHP was 61.68% (190/360) including hematologic improvement-neutrophil (HI-N) or hematologic improvement-erythroid (HI-E) or hematologic improvement-platelet (HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia (55.88% vs 31.54% or 55.88% vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. CONCLUSIONS: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement (HI-N, HI-P or HI-E) and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.


Assuntos
Arsenicais/uso terapêutico , Linhagem da Célula , Metilação de DNA/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos Leucocíticos/tratamento farmacológico , Transtornos Leucocíticos/genética , Arsenicais/administração & dosagem , Arsenicais/farmacologia , Linhagem da Célula/efeitos dos fármacos , Desmetilação , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Pós , Resultado do Tratamento
16.
PLoS One ; 13(10): e0204490, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30304046

RESUMO

OBJECTIVE: To study the prognostic value of baseline leukocytosis or neutrophiliain two retrospective cohorts of stage III Non-Small Cell Lung Cancer (NSCLC) patients. MATERIALS AND METHODS: Clinical records of consecutive previously untreated NSCLC patients in our Institution between June 2001 and September 2016 for stage III NSCLC were collected. The prognostic value of pretreatment leucocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophil count exceeding 10 and 7 G/L, respectively. RESULTS: We identified 238 patients, displaying baseline leukocytosis or neutrophilia in 39% and 40% respectively. Most were diagnosed with adenocarcinoma (48%), and stage IIIB NSCLC (58%). 3-year actuarial overall survival (OS) and progression-free survival (PFS) were 35% and 27% respectively. Local relapses were reported in 100 patients (42%), and distant metastases in 132 patients (55%). In multivariate analysis, leukocytosis, neutrophilia, and induction chemotherapy regimen based on carboplatin/paclitaxel were associated with worse OS and PFS (p<0.05). Neutrophilia independently decreased Locoregional Control (LRC) (HR = 2.5, p<0.001) and Distant Metastasis Control (DMC) (HR = 2.1, p<0.001). Neutrophilia was significantly associated with worse brain metastasis control (p = 0.004), mostly in adenocarcinoma patients (p<0.001). CONCLUSION: In stage III NSCLC patients, treated with concurrent cisplatin-based chemoradiation, baseline leukocytosis and neutrophilia were associated with worse OS, PFS, LRC, and DMC. In addition with previously available markers, this independent cost-effective biomarker could help to stratify stage III NSCLC population with more accuracy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Transtornos Leucocíticos/diagnóstico , Neoplasias Pulmonares/sangue , Neutrófilos , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Estudos de Coortes , Feminino , Humanos , Contagem de Leucócitos , Transtornos Leucocíticos/complicações , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
17.
Thromb Haemost ; 118(10): 1790-1802, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30235485

RESUMO

Pulmonary arterial hypertension (PAH) is a rare disease characterized by increased pulmonary pressure and vascular remodelling as a consequence of smooth muscle cell proliferation, endothelial cell dysfunction and inflammatory infiltrates. Meprin α is a metalloproteinase whose substrates include adhesion and cell-cell contact molecules involved in the process of immune cell extravasation. In this study, we aimed to unravel the role of meprin α in PAH-induced vascular remodelling. Our results showed that meprin α was present in the apical membrane of endothelial cells in the lungs and pulmonary arteries of donors and idiopathic PAH (IPAH) patients. Elevated circulating meprin α levels were detected in the plasma of IPAH patients. In vitro binding assays and electron microscopy confirmed binding of meprin α to the glycocalyx of human pulmonary artery endothelial cells (hPAECs). Enzymatic and genetic approaches identified heparan sulphate (HS) as an important determinant of the meprin α binding capacity to hPAEC. Meprin α treatment protected from excessive neutrophil infiltration and the protective effect observed in the presence of neutrophils was partially reversed by removal of HS from hPAEC. Importantly, HS levels in pulmonary arteries were decreased in IPAH patients and binding of meprin α to HS was impaired in IPAH hPAEC. In summary, our results suggest a role of HS in docking meprin α to the endothelium and thus in the modulation of inflammatory cell extravasation. In IPAH, the decreased endothelial HS results in the reduction of meprin α binding which might contribute to enhanced inflammatory cell extravasation and potentially to pathological vascular remodelling.


Assuntos
Endotélio Vascular/metabolismo , Heparitina Sulfato/metabolismo , Hipertensão Pulmonar/imunologia , Inflamação/imunologia , Pulmão/metabolismo , Metaloendopeptidases/metabolismo , Artéria Pulmonar/patologia , Animais , Células Cultivadas , Endotélio Vascular/patologia , Humanos , Doenças do Sistema Imunitário , Transtornos Leucocíticos , Pulmão/patologia , Masculino , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Remodelação Vascular
18.
Anticancer Res ; 38(8): 4731-4734, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061242

RESUMO

BACKGROUND/AIM: In chronic lymphocytic leukemia (CLL) the absolute neutrophil count (ANC) has generally been reported to be within normal limits and leukocytosis is due to absolute lymphocytosis. However, other cell types such as neutrophils and monocytes may also exceed the normal range in this disorder. The aim of this retrospective study was to evaluate the frequency and prognostic value of neutrophilia defined as an ANC>7×109/l and monocytosis- an absolute monocyte count (AMC)>1×109/l in 113 patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: We analyzed clinical and laboratory data from the records of patients with CLL followed in the Hematology unit of a tertiary hospital in Israel. Patients were categorized according to their ANC and AMC before treatment and their data compared. RESULTS: In 24 (21%) patients, neutrophilia was present at diagnosis while 40 (35%) had monocytosis. We identified that 9% of cases had neutrophilia with normal AMC. This subgroup of patients had a better prognosis with lower mortality rate, longer time-to-treatment interval and a higher rate of complete or partial response to treatment compared to patients without neutrophilia or monocytosis. CONCLUSION: The presence of neutrophilia without monocytosis before treatment appears to be associated with a more favorable prognosis in CLL. These observations still need to be confirmed and validated in a larger cohort of patients.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Transtornos Leucocíticos/congênito , Idoso , Feminino , Humanos , Israel , Contagem de Leucócitos/métodos , Transtornos Leucocíticos/patologia , Leucocitose/patologia , Masculino , Monócitos/patologia , Neutrófilos/patologia , Prognóstico , Estudos Retrospectivos
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