The Effect of p38 Mitogen-Activated Protein Kinase Activation on Inflammatory Liver Damage following Hemorrhagic Shock in Rats

Hemorrhagic shock is a frequent cause of liver failure and often leads to a fatal outcome. Several studies have revealed that p38 MAPK is a key mediator in hemorrhagic damage of the primary organs through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. However, the precise role of these factors in liver damage following hemorrhagic shock is unclear. In this study, we used FR167653, a specific inhibitor of p38 MAPK phosphorylation, to examine the role of p38 MAPK in liver damage occurring up to 5 hours after a hemorrhagic episode in a rat model. Activation of p38 MAPK in the liver as well as an increase in hepatic mRNA expression and serum concentrations of TNF-α and IL-1β occurred during the early phase after hemorrhage. Increased serum levels of hepatic enzymes, as well as histological damage and activated neutrophil accumulation in the liver, were observed in the late phase following hemorrhagic shock. FR167653 inhibited the inflammation-related hepatic injury following hemorrhagic shock. Bacterial lipopolysaccharide (LPS) derived from the gut appeared to have little effects on the hepatic damage. These results demonstrate that p38 MAPK activation is induced by hepatic ischemia during hemorrhagic shock and plays an important role both in the hepatic expression of proinflammatory cytokines and in the development of inflammation-related liver damage

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Efeitos do alongamento muscular e condicionamento físico no tratamento fisioterápico de pacientes com fibromialgia Effects of muscle stretching and physical conditioning as physical therapy treatment for patients with fibromyalgia

OBJETIVO: Verificar os efeitos de exercícios de alongamento muscular e condicionamento físico no tratamento fisioterápico da fibromialgia (FM). CASUÍSTICA E MÉTODOS: Foram avaliadas 15 mulheres com diagnóstico de FM, segundo os critérios do Colégio Americano de Reumatologia, divididas em dois grupos: Grupo 1 (G1) com oito pacientes, realizou tratamento por meio de alongamentos musculares e Grupo 2 (G2), sete pacientes, condicionamento físico. Foram avaliados qualidade do sono, fatores de piora e melhora da dor, sintomas associados e medicamentos utilizados. Além disso, foi aplicado o Fibromyalgia Impact Questionnaire (FIQ), para avaliar o impacto da FM. O tratamento durou oito semanas, sendo uma sessão semanal com duração de 40 a 45 minutos. As variáveis do FIQ antes e depois dos tratamentos foram comparadas pelo teste t para amostras dependentes (alfa< 0,05) e as demais foram analisadas descritivamente. RESULTADOS: A maioria das pacientes apresentava sono não reparador (86,67%), piora da dor com serviços domésticos (40%), nenhum fator de melhora da dor (28,57%), distúrbios do sono como sintomas associados (100%) e utilizava antidepressivos (69,23%). Em relação às variáveis do FIQ, observaram-se diferenças estatisticamente significantes no sono (p= 0,0428) e rigidez matinal (p= 0,0130) nas pacientes do G1. Já no G2, não foram observadas diferenças significantes após o tratamento. CONCLUSÕES: Sugere-se que os alongamentos musculares realizados podem gerar impacto positivo na FM, promovendo melhora do sono e rigidez matinal das pacientes avaliadas.<br>OBJECTIVE: To investigate the effects of muscle stretching exercises and physical conditioning as physical therapy treatment for fibromyalgia. METHODS: Fifteen women with a diagnosis of fibromyalgia in accordance with the criteria of the American College of Rheumatology were evaluated and divided into two groups: Group 1 (G1, eight patients) underwent treatment consisting of muscle stretching and Group 2 (G2, seven patients), participated in a physical conditioning program. Sleep quality, pain-modulating factors, associated symptoms and medications used were evaluated. Furthermore, the Fibromyalgia Impact Questionnaire (FIQ) was applied to evaluate the impact of fibromyalgia. The treatment lasted for eight weeks, with one session per week of 40 to 45 minutes in duration. The FIQ data obtained before and after treatment were analyzed by means of Student’s t test for dependent samples (alpha< 0.05) and other variables were analyzed descriptively. RESULTS: Most of the patients presented poor quality of sleep (86.67%). Many presented worsening of their pain when doing domestic tasks (40%) and there were no factors that relieved their pain (28.57%). All presented sleep disorders with associated symptoms (100%) and most used antidepressives (69.23%). For the FIQ data, statistically significant differences were observed in morning tiredness (p= 0.0428) and stiffness (p= 0.0130) among the G1 patients. Conversely, no difference was observed in G2 after the treatment. CONCLUSIONS: It is suggested that the muscle stretching may have had a positive impact on fibromyalgia, with reductions in morning tiredness and stiffness among the patients evaluated

Depressão e qualidade de vida em pacientes com fibromialgia Depression and quality of life among patients with fibromyalgia

CONTEXTO: Fibromialgia é uma síndrome reumática caracterizada por dor musculoesquelética difusa e crônica, e sítios dolorosos específicos à palpação (tender points). Freqüentemente é associada à fadiga generalizada, distúrbios do sono, rigidez matinal, dispnéia, ansiedade, alterações no humor que podem evoluir para um quadro de depressão. Sendo assim, afeta negativamente a qualidade de vida das pessoas. No entanto, ainda não se sabe o poder de discriminação dos instrumentos de avaliação da depressão e qualidade de vida. O objetivo desse estudo foi avaliar a depressão e a qualidade de vida de pacientes com fibromialgia e avaliar o poder de discriminação de instrumentos relacionados a esses aspectos. MÉTODO: Para avaliar a qualidade de vida foram utilizados dois instrumentos: um específico, o Fibromyalgia Impact Questionnaire (FIQ) e outro genérico, o Medical Outcomes Study 36-item Short-Form Healthy Survey (SF-36); para avaliar a depressão, a Escala de Depressão de Beck (BDS). Participaram do estudo 40 mulheres sendo 20 com fibromialgia - Grupo teste e 20 saudáveis - Grupo controle. Os três protocolos foram aplicados aos indivíduos dos dois grupos em uma única sessão de avaliação. Toda a análise estatística foi realizada utilizando-se o teste "t" Student, com significância alfa = 0,05. RESULTADOS: Houve diferença estatisticamente significante entre os grupos controle e teste em todos os questionários (p<0,05). Os três questionários têm bom poder discriminatório para diferenciar os dois grupos, porém o FIQ é o que tem maior poder de discriminação e o BDS o menor. CONCLUSÃO: O grupo de pacientes com fibromialgia tem pior qualidade de vida quando comparado com o grupo controle. Comparando os três questionários todos são eficientes não somente para avaliar a qualidade de vida mas também para avaliar a depressão. Entretanto, como o FIQ é um instrumento específico é o que melhor discrimina o grupo teste do grupo controle, fato este mostrado através dos valores estatisticamente significantes mais altos.<br>BACKGROUND: Fibromyalgia is a rheumatic syndrome characterized by widespread chronic musculoskeletal pain and specific palpable tender points. It is often associated with generalized fatigue, sleep disturbances, morning stiffness, dyspnea, anxiety and mood disturbances that may evolve into depression. Thus, such individuals' quality of life is negatively affected. However, the discriminating power of quality-of-life and depression assessment instruments is still unknown. OBJECTIVE: To assess depression and quality of life among patients with fibromyalgia, and the discriminating power of such instruments. METHOD: Quality of life was assessed by one specific instrument, the Fibromyalgia Impact Questionnaire (FIQ), and another generic one, the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). The Beck Depression Scale (BDS) was used to assess depression. Forty women participated: 20 with fibromyalgia (test group) and 20 healthy women (control group). The three protocols were applied to all individuals in both groups in a single evaluation session. All statistical analyses were performed using Student's t-test, with alpha = 0.05. RESULTS: Statistically significant differences between test and control groups were found via all questionnaires (p<0.05). The three questionnaires had good discriminatory power for differentiating between the two groups, but FIQ had the greatest and BDS least. CONCLUSION: Patients with fibromyalgia presented poor quality of life, compared with the control group. Comparing the three questionnaires, they were all efficient for both quality-of-life and depression assessments. However, since FIQ is a specific instrument, this gave the best discrimination between test and control groups, and this was shown through higher, statistically significant values