Everolimus-associated interstitial pneumonia in a renal transplant patient: a case report

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DOWNSIZING E ESTRESSE

This work aims to analyze the relationship between downsizing and stress during the year 2002 in an aeronautic sector company in Rio de Janeiro, and its effects on the organization and the remaining employees, who are called “survivors”. Through qualitative analyses of forty-five interviews out of the remaining staff, it was concluded that downsizing is related to the survivors’ stress, due to not only the increase of work amount and responsibilities, but also insecurity regarding maintenance of jobs. It was noticeable that this restructuring process in the Company, due to its broadness, has changed psychological contract of most survivors. As an advice to other organizations, it should be pointed out the role of human resources to planning and implementing downsizing, and the importance of communication process in the Company to diminishing unwanted effects of downsizing and assuring the whole staff has been informed on the reasons for downsizing in order to avoid misunderstandings.O propósito deste trabalho é analisar a relação existente entre downsizing e estresse a partir da redução de pessoal ocorrida no ano de 2002 em uma empresa do setor aeronáutico situada no estado do Rio de Janeiro, e seus efeitos na Organização e nos empregados que foram mantidos, aos quais denominamos de “sobreviventes”. A partir da análise qualitativa de quarenta e cinco entrevistas deste grupo de funcionários que permaneceram na Empresa, concluímos que a prática do downsizing está relacionada ao estresse provocado nos sobreviventes, tendo como causa não apenas o aumento do volume de trabalho e do grau de responsabilidades assumidas, mas também a insegurança quanto à manutenção do emprego. Foi possível perceber também que este processo de reestruturação vivenciado pela Empresa, dada a sua abrangência, tangibilizou uma mudança no contrato psicológico da maioria dos sobreviventes. Como recomendação a outras organizações, destacamos o papel da área de Recursos Humanos que foi fundamental para o sucesso do planejamento e da implementação do downsizing, e a importância do processo de comunicação da Empresa como forma de diminuir os efeitos não desejados do downsizing garantindo que todos os funcionários recebessem a informação, evitando distorções de entendimento quanto às razões que levaram a decisão pela redução de pessoal

Monoclonal antibody therapy and renal transplantation: focus on adverse effects.

A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications

In vitro identification of new transcriptomic and miRNomic profiles associated with pulmonary fibrosis induced by high doses everolimus: Looking for new pathogenetic markers and therapeutic targets

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) of airway cells. To improve our knowledge, primary bronchial epithelial cells (BE63/3) were treated with EVE (5 and 100 nM) for 24 h. EMT markers (α-SMA, vimentin, fibronectin) were measured by RT-PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. mRNA and microRNA profiling were performed by Illumina and Agilent kit, respectively. Only high dose EVE increased EMT markers and reduced the transepithelial resistance of BE63/3. Bioinformatics showed 125 de-regulated genes that, according to enrichment analysis, were implicated in collagen synthesis/metabolism. Connective tissue growth factor (CTGF) was one of the higher up-regulated mRNA. Five nM EVE was ineffective on the pro-fibrotic machinery. Additionally, 3 miRNAs resulted hyper-expressed after 100 nM EVE and able to regulate 31 of the genes selected by the transcriptomic analysis (including CTGF). RT-PCR and western blot for MMP12 and CTGF validated high-throughput results. Our results revealed a complex biological network implicated in EVE-related pulmonary fibrosis and underlined new potential disease biomarkers and therapeutic targets

Detection of the BRAF(V600E) Mutation in Fine Needle Aspiration Cytology of Thyroid Papillary Microcarcinoma Cells Selected by Manual Macrodissection: An Easy Tool to Improve the Preoperative Diagnosis.

Background: Papillary carcinomas with diameters that are less than or equal to 1 cm (thyroid papillary microcarcinoma [mPTC]) are quite common but can carry more risk than previously thought. The proper treatment and management of these lesions is still being debated. Even though fine needle aspiration cytology (FNAC) is considered the best method for the diagnosis of thyroid nodules, its efficacy is still questioned for mPTC. We investigated the role of BRAF gene status in preoperative cytological samples, using manual macrodissection as an additional tool to improve the diagnostic accuracy of mPTC. Methods: DNA was extracted directly from stained FNAC smears of 95 patients including 85 with histological diagnoses of papillary thyroid carcinoma (PTC) ≤1 cm and 10 with goiters. The cytological diagnoses of the 95 cases included the following: 42 samples were suspicious for papillary carcinoma, 38 were PTCs, and 15 were indeterminate lesions. DNA was then extracted from the FNAC slides after performing a "manual macrodissection" procedure. The BRAF(V600E) mutational status was determined by sequence analysis in all the patients. Results: In this study, we showed that the BRAF(V600E) mutation was present with a high frequency in patients with mPTC (74%). The presence of the mutation was independent of the size of the tumor. In our study, the combination of the cytological diagnosis and the molecular analysis was able to identify 82% of all cases of mPTC, with an increase of 37% compared with a morphological diagnosis alone. The morpho-molecular analysis was able to reduce the number of suspicious cases by >70%. All of the goiters had a wild-type BRAF status. Conclusions: The analysis of BRAF mutational status in FNAC obtained from papillary microcarcinomas demonstrates that molecular pathology, combined with morphology and molecular biology is a powerful tool for cytological diagnosis of mPTC. Our results also confirm the data supporting the biological relevance of PTCs with diameters that are ≤1 cm and the importance of "manual macrodissection" in the molecular analysis of cytological material

Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in "Omics" Medicine.

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients' quality of life. Significant improvements in one-year renal allograft and patients' survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%-5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, "omics" techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient's genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies

Mitochondria: a new therapeutic target in chronic kidney disease.

Cellular metabolic changes during chronic kidney disease (CKD) may induce higher production of oxygen radicals that play a significant role in the progression of renal damage and in the onset of important comorbidities. This condition seems to be in part related to dysfunctional mitochondria that cause an increased electron "leakage" from the respiratory chain during oxidative phosphorylation with a consequent generation of reactive oxygen species (ROS). ROS are highly active molecules that may oxidize proteins, lipids and nucleic acids with a consequent damage of cells and tissues. To mitigate this mitochondria-related functional impairment, a variety of agents (including endogenous and food derived antioxidants, natural plants extracts, mitochondria-targeted molecules) combined with conventional therapies could be employed. However, although the anti-oxidant properties of these substances are well known, their use in clinical practice has been only partially investigated. Additionally, for their correct utilization is extremely important to understand their effects, to identify the correct target of intervention and to minimize adverse effects. Therefore, in this manuscript, we reviewed the characteristics of the available mitochondria-targeted anti-oxidant compounds that could be employed routinely in our nephrology, internal medicine and renal transplant centers. Nevertheless, large clinical trials are needed to provide more definitive information about their use and to assess their overall efficacy or toxicity

Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats

<p>Abstract</p> <p>Background</p> <p>The steroid hormone testosterone has been found to be greatly reduced by opioids in different experimental and clinical conditions. The purpose of this study on male rats was to determine the effects of a single injection of morphine (5 mg/Kg) on persistent pain (formalin test) and the single or combined effects on p450-aromatase and 5-alpha reductase type 1 mRNA expression in the brain, liver and testis. Testosterone was determined in the plasma and in the brain, morphine was assayed in the plasma.</p> <p>Results</p> <p>In the morphine-treated rats, there were increases of 5-alpha reductase mRNA expression in the liver and aromatase mRNA expression in the brain and gonads. Morphine was detected in the blood of all morphine-treated rats even though there were no clear analgesic affects in the formalin-treated animals three hours after treatment. Testosterone was greatly reduced in the plasma and brain in morphine-treated subjects.</p> <p>Conclusions</p> <p>It appears that morphine administration can induce long-lasting genomic effects in different body areas which contribute to the strong central and peripheral testosterone levels. These changes were not always accompanied by behavioral modifications.</p

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

The mammalian target of rapamycin inhibitors (mTOR-I), sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications

CORRELACIONANDO TIPOS DE CULTURA ORGANIZACIONAL COM ESTRATÉGIAS DE REMUNERAÇÃO UTILIZANDO A TIPOLOGIA DE CHARLES HANDY

This study identified the correlations between compensation strategies and the organizational culture typology proposed by Handy (2003), based on the degree of formalization and centralization that identifies the culture: Zeus (power), Apollo (roles), Athena (task) and Dionysus (person). A survey was performed of compensation managers at 76 companies associated with the Salary Information Exchange Group (GRUPISA), and the questionnaires with a construct composed of twelve organizational compensation components were analyzed using Pearson’s correlation coefficient and multiple regression We concluded that the compensation variables were correlated in a different fashion with each of the culture types: (i) “Zeus” organizations should emphasize behavioral factors in all spheres of the compensation system; (ii) in the case of “Apollo” organizations the emphasis should be on growth and development opportunities; (iii) in “Athena” organizations the focus should be on financial rewards, and, “Dionysus” organizations should place emphasis on the quality of compensation.Esta investigación identificó las correlaciones entre las estrategias de remuneración y la topología de cultura organizacional propuesta por Handy (2003) basada en las dimensiones del grado de formalización y centralización que identifica la cultura: Zeus (poder), Apolo (papeles), Atena (tarea) y Dionisio (persona). La investigación fue aplicada en gestores de remuneración de 76 empresas asociadas al Grupo de Permuta de Informaciones Salariales (Grupisa), y los cuestionarios con un constructo compuesto por doce componentes de la remuneración organizacional fueron analizadas utilizando Correlación de Pearson y Regresión Múltipla. Concluimos que las variables de remuneración se correlacionan de manera distinta con cada uno de los tipos de cultura: (1) organizaciones “Zeus” deben enfatizar los factores de comportamiento en todas las esferas del sistema de remuneración; (ii) para las organizaciones “Apolo” el énfasis debe ser aplicada en las oportunidades de crecimiento y desarrollo, (iii) en las organizaciones “Atena” el foco debe ser en las recompensas financieras y (iv) organizaciones “Dionisio” deben dar énfasis a la calidad de la remuneración.Este estudo identificou as correlações entre as estratégias de remuneração e a tipologia de cultura organizacional proposta por Handy (2003) baseada nas dimensões do grau de formalização e centralização que identifica a cultura: Zeus (poder), Apolo (papéis), Atena (tarefa), e Dionísio (pessoa). A pesquisa foi aplicada a gestores de remuneração de 76 empresas associadas ao Grupo de Permuta de Informações Salariais (Grupisa), e os questionários com um construto composto por doze componentes da remuneração organizacional foram analisados utilizando Correlação de Pearson e Regressão Múltipla. Concluímos que as variáveis de remuneração se correlacionam de forma diferente com cada um dos tipos de cultura: (i) organizações “Zeus” devem enfatizar os fatores comportamentais em todas as esferas do sistema de remuneração; (ii) para as organizações “Apolo” a ênfase deve ser aplicada nas oportunidades de crescimento e desenvolvimento, (iii) nas organizações “Atena” o foco deve ser nas recompensas financeiras, e, (iv) organizações “Dionísio” devem dar ênfase à qualidade da remuneração