Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly.

Aging immune deterioration and Epstein-Barr (EBV) intrinsic mechanisms play an essential role in EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV + DLBCLe) pathogenesis, through the expression of viral proteins, interaction with host molecules and epigenetic regulation, such as miR-155, required for induction of M1 phenotype of macrophages. This study aims to evaluate the relationship between macrophage polarization pattern in the tumor microenvironment and relative expression of miR-155 in EBV + DLBCLe and EBV-negative DLBCL patients. We studied 28 EBV + DLBCLe and 65 EBV-negative DLBCL patients. Tumor-associated macrophages (TAM) were evaluated by expression of CD68, CD163 and CD163/CD68 ratio (degree of M2 polarization), using tissue microarray. RNA was extracted from paraffin-embedded tumor samples for miR-155 relative expression study. We found a significantly higher CD163/CD68 ratio in EBV + DLBCLe compared to EBV-negative DLBCL. In EBV-negative DLBCL, CD163/CD68 ratio was higher among advanced-staged/high-tumor burden disease and overexpression of miR-155 was associated with decreased polarization to the M2 phenotype of macrophages. The opposite was observed in EBV + DLBCLe patients: we found a positive association between miR-155 relative expression and CD163/CD68 ratio, which was not significant after outlier exclusion. We believe that the higher CD163/CD68 ratio in this group is probably due to the presence of the EBV since it directly affects macrophage polarization towards M2 phenotype through cytokine secretion in the tumor microenvironment. Therapeutic strategies modulating miR-155 expression or preventing immuno-regulatory and pro-tumor macrophage polarization could be adjuvants in EBV + DLBCLe therapy since this entity has a rich infiltration of M2 macrophages in its tumor microenvironment.

[Causes of death after revascularization of the lower limbs through surgery and angioplasty in the State of Rio de Janeiro, Brazil, between 2006 and 2011]. / Causas de Morte após Revascularização dos Membros Inferiores por Cirurgia e Angioplastia no Estado do Rio de Janeiro - Brasil, de 2006 a 2011.

INTRODUCTION: The underlying cause of death is the single diagnosis to which the cause of death is attributed. Other diagnostic codes written in the death certificate are the multiple causes. The study of the multiple causes allows the identification of the diseases present in the death. OBJECTIVE: To analyze the underlying and multiple causes of death after revascularization of the lower limbs using open surgery or angioplasty. METHODS: Two databases of the Public Health System of Rio de Janeiro were used: Authorizations for Hospitalizations 2006/10, and Statements of Deaths 2006/11. Probabilistic linkage of records between databases was performed using the Stata program. RESULTS: The most frequent underlying and multiple cause of death was Diabetes mellitus. The second was the systemic atherosclerotic disease represented by peripheral arterial disease, ischemic coronary disease and cerebrovascular disease. The analysis of multiple causes revealed septicemia, iatrogenic and complications after surgery, as well as renal failure after angio- plasty. Patients submitted to lower limb revascularization procedures had a higher overall mortality rate than the population of the State of Rio de Janeiro over 50 years of age, for all causes and specific ones. CONCLUSION: The period of highest risk of death was up to 30 days after hospital discharge, demonstrating the need to improve medical and hospital care before, during and after procedures. The study of multiple causes revealed adverse events and complications that were not chosen as the underlying cause.

Objetivos: A causa básica de morte é o diagnóstico único ao qual se atribui a causa da morte. Outros códigos de diag- nóstico anotados na declaração de óbito, são as causas múltiplas. O estudo das causas múltiplas permite identificar as doenças presentes no óbito. Objetivo: Conhecer as causas básica e múltiplas de morte após revascularização dos membros inferiores por cirurgia aberta ou angioplastia. Métodos: Foram utilizadas duas bases de dados do Sistema Único de Saúde do Estado do Rio de Janeiro: Autorizações de Internação Hospitalar de 2006-10 e as Declarações de Óbito do Sistema de Informação de Mortalidade de 2006-11. Foi realizada vinculação probabilístico de registros entre os bancos de dados, com programa estatístico Stata. Resultados: A causa básica e múltipla de óbito mais freqüente foi o Diabetes mellitus. Em segundo lugar a doença ate- rosclerótica sistêmica representada pela doença arterial periférica, doença isquêmica coronariana e doença cérebro vascular. A análise das causas múltiplas revelou septicemia, iatrogenia e complicações após cirurgia, e insuficiência renal após angioplastia. Os pacientes submetidos aos procedimentos de revascularização de membros inferiores apresentaram mortalidade geral mais elevada do que a população do Estado do Rio de Janeiro acima de 50 anos, por todas as causas e pelas específicas. Conclusão: O período de maior risco de morte foi até 30 dias após a alta hospitalar revelando a necessidade de melhorar os cuidados antes, durante e após os procedimentos. O estudo das causas múltiplas revelou eventos adversos e complicações que não foram escolhidas como causa básica.

[Hospital Lethality Following Lower Limbs Revascularization in the State of Rio de Janeiro, Brasil, 2006/10]. / Letalidade Hospitalar após Revascularização dos Membros Inferiores no Estado Rio de Janeiro - Brasil - 2006/10.

INTRODUCTION: Ischemic peripheral arterial disease is a form of presentation of systemic atherosclerosis and can be treated by angioplasty or open vascular surgery Objective: To find in-hospital lethality after revascularization according to sex, age, procedures and hospitalization conditions. METHOD: The data comes from authorizations to hospitalize from The State of Rio De Janeiro´s Public Healthcare System from the years 2006/10. We performed a search using the International Code of Diseases tenth revision (ICD-10) to identify codes of revascularization by angioplasty or open vascular surgery. The statistical analysis was done with Stata Program of statistics. RESULTS: The procedures were performed in 41 hospitals, public, private and university medical facilities. We identified 1558 registrations, 900 (57.8%) men and 658 women (42.2%). There were 68 hospital deaths and in-hospital mortality was 3.7% for men and 5.1% for women.The lethality was 2.6% under 50 years old, 4.1% between 50-69 years and 5.3% above 70 years. We identified 846 (46.6%) open surgeries and 968 (53.4%) angioplasties with a lethality of 2.0% in angioplasties (16/809) and 7.0% (52/748) with open surgeries. Elective procedures had 4.6 % of lethality and 4.1% in urgent/emergency procedures. Elective angioplasties had a mortality of 2.6%, and 1.4% in urgent/emergency. Open surgeries had the mortality of 6.5% and 7.5%, respectively. CONCLUSION: Hospital lethality showed high levels in open vascular surgery and angioplasties. A very sensitive aspect is the mortality of angioplasties in elective patients. These results are similar to those observed in myocardial revascularization from atherosclerosis. Public hospitals had lower lethality.

[Survival analysis after open vascular surgery and angioplasty in lower limbs vascularization in Rio de Janeiro, Brazil 2006-2013]. / Sobrevida Após Cirurgia Aberta Ou Angioplastia Para Revascularização dos Membros Inferiores No Estado Do Rio De Janeiro - Brasil, 2006-13.

Objective -The aim of this study is survival analysis after lower limb revascularization according to sex, age and procedures. METHOD: Were analysed in-hospital administrative database coming from the Public Health System of Rio de Janeiro (SUS-RJ) from 2006 through 2010 and the Public Registers of death of Rio de Janeiro (SIM-RJ) from 2006 through 2013. Both groups of information had linkaged using the Stata program of statistics. Three groups of age were studied: 50 years old or less, 50 to 79 and over 70 years old. RESULTS: More than half of patients received angioplasty as procedures during the study. In both procedures, men were more frequent, except in angioplasty after 70 years of age. In the period of 30 days after discharge in both procedures the survival had an abrupt reduction and it continue reducing until 180 days after open surgery. After these the survival curves run in parallel until the fourth year and then they had the same performance. CONCLUSION: The greatest reduction in survival was registered in the first thirty days after discharge, mainly in women after open surgery. It is necessary to improve in-hospital care in order to improve the survival index on the first thirty days after discharge..

Perceptions of power-assist devices: interviews with manual wheelchair users.

PURPOSE: The study had three main objectives. (1) To investigate the perceived impact of power-assist devices (PADs) on manual wheelchair (MWC) user mobility. (2) To compare perceptions about different types of PADs. (3) To identify preferred features and design characteristics of PADs. METHODS: Semi-structured interviews were conducted with community-dwelling MWC users aged 31 years and older, with at least 2.5 years of experience using an MWC independently (n = 16). Data were thematically analysed using an inductive approach. RESULTS: Two main themes related to participants' perceptions about the effects of PAD use were identified: (1) "Expanding my world", which illustrated the perceived benefits of using PADs (e.g., gaining a sense of autonomy and access to new environments, maintaining physical health) and (2) "Falling short", which described challenges with PADs (e.g., safety, reliability and portability issues). Participants also identified strengths and limitations of different types of PADs that were mainly related to specific user-device and device-environment interactions as well as various functional characteristics. Moreover, participants outlined their priorities for future PAD design, including improving controllability, customizability and affordability of these devices. CONCLUSIONS: Participants' perceptions about PADs varied across different types of devices and in different contexts. However, PADs were generally perceived as enhancing the capabilities of MWCs. Our findings provide insight into the factors that can be considered when selecting a PAD and can inform the development of future PADs that are better equipped to overcome challenges that MWC users frequently encounter.Implications for RehabilitationPower-assist devices (PADs) for manual wheelchairs (MWCs) have the potential to improve the mobility, community participation and well-being of users.Some of the existing PADs have safety and reliability issues that affect their performance and limit their use by MWC users.The three types of PADs (front-mounted attachments, rear-mounted attachments, powered wheels) offer different types of assistance that can benefit users with various capabilities.

JAK2V617F mutation in patients with splanchnic vein thrombosis.

BACKGROUND: Splanchnic vein thrombosis can be the presenting manifestation of myeloproliferative neoplasms. However, the diagnosis of a myeloproliferative neoplasm in these patients is often problematic, and more objective criteria are needed. AIM: To determine the frequency of the mutation JAK2V617F in patients with splanchnic vein thromboses. METHODS: A consecutive series of 108 adult patients with portal vein thrombosis (n = 77) and Budd-Chiari syndrome (n = 31) referred for hemostasis evaluation was retrospectively studied, with a median follow-up of 51 months (1-104). RESULTS: One or more prothrombotic risk factors were present in 63% of the patients. Twenty-four (22%) out of the 108 patients presented the JAK2V617F, including 2 cirrhotic patients. Most had a low mutated allele burden (median 16.5%). JAK2V617F was present in all four patients with a previous diagnosis of a myeloproliferative neoplasm. In nine JAK2V617F-positive patients, the diagnosis of a myeloproliferative neoplasm was made at the thrombosis work-up, during follow-up or after JAK2V617F detection. Among the other 11 patients carrying the mutation, 2 patients have died, 4 had no evidence suggesting a myeloproliferative neoplasm, 1 had a normal bone marrow biopsy, and the other 4 could not be persuaded to undergo a biopsy. Among the patients without an overt myeloproliferative neoplasm, 15 out of 99 (15%) presented the JAK2V617F mutation. None of the JAK2V617F-negative patients have developed signs of a myeloproliferative neoplasm during follow-up. CONCLUSIONS: Our findings suggest that JAK2V617F occurs in a high proportion of patients with splanchnic vein thrombosis, and reinforces the diagnostic utility of JAK2V617F testing in this setting.

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines.

INTRODUCTION: Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR). METHODS: We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors. RESULTS: For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload. CONCLUSION: Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

Transcriptome Analysis of Mesenchymal Stem Cells from Multiple Myeloma Patients Reveals Downregulation of Genes Involved in Cell Cycle Progression, Immune Response, and Bone Metabolism.

A growing body of evidence suggests a key role of tumor microenvironment, especially for bone marrow mesenchymal stem cells (MSC), in the maintenance and progression of multiple myeloma (MM), through direct and indirect interactions with tumor plasma cells. Thus, this study aimed to investigate the gene expression and functional alterations of MSC from MM patients (MM-MSC) in comparison with their normal counterparts from normal donors (ND-MSC). Gene expression analysis (Affymetrix) was performed in MM-MSC and ND-MSC after in vitro expansion. To validate these findings, some genes were selected to be evaluated by quantitative real time PCR (RT-qPCR), and also functional in vitro analyses were performed. We demonstrated that MM-MSC have a distinct gene expression profile than ND-MSC, with 485 differentially expressed genes (DEG) - 280 upregulated and 205 downregulated. Bioinformatics analyses revealed that the main enriched functions among downregulated DEG were related to cell cycle progression, immune response activation and bone metabolism. Four genes were validated by qPCR - ZNF521 and SEMA3A, which are involved in bone metabolism, and HLA-DRA and CHIRL1, which are implicated in the activation of immune response. Taken together, our results suggest that MM-MSC have constitutive abnormalities that remain present even in the absence of tumors cells. The alterations found in cell cycle progression, immune system activation, and osteoblastogenesis suggest, respectively, that MM-MSC are permanently dependent of tumor cells, might contribute to immune evasion and play an essential role in bone lesions frequently found in MM patients.

Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients.

JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells.

Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma.

HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed ∼60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed ∼60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.

Avaliaçäo multiprofissional de digitadores do I.B.G.E. com queixas de dores nos membros superiores

O trabalho objetiva o diagnóstico multiprofissional (médico, psicológico, social e institucional) através da avaliaçäo de 51 digitadores que compareceram ao Serviço Médico do IBGE-SEDE (RJ), no período de julho de 1986 a fevereiro de 1987, queixando-se de dores nos membros superiores, relacionando-as as exercício profissional. Estes digitadores foram submetidos a avaliaçäo, psicológica e social, tendo sido analisadas as características do ambiente de trabalho, procurando-se compreender globalmente as diversas situaçöes que interferem no desempenho de sua profissäo