Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells. Over the past several years, a number of clinical trials have demonstrated the clinical activity of alemtuzumab in treating patients with chronic lymphocytic leukemia, T-cell malignancies such as T-prolymphocytic leukemia and cutaneous T-cell lymphoma, as well as in the prevention and therapy of graft-versus-host disease in the setting of allogeneic stem cell transplantation. Its application in a number of autoimmune disorders is currently under investigation. The most significant side effect of alemtuzumab is predisposition to infections related to the associated profound lymphopenia. Despite this, and with appropriate and more effective antibiotic prophylaxis, it is likely that we will witness an expansion of the role of alemtuzumab in the future.     

Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B

Background  

HBV infection is a serious global heath problem. It is crucial to monitor this disease more closely with a non-invasive marker in clinical trials. We aimed to evaluate the predictive value of serum hyaluronate for the presence of extensive liver fibrosis and inflammation.     

Dual angiotensin-converting enzyme/neutral endopeptidase inhibition on cardiac and renal fibrosis and inflammation in DOCA-salt hypertensive rats

OBJECTIVES: The relative roles of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on cardiac and renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats were studied. METHODS: The ACE/NEP inhibitor omapatrilat (40 mg/kg per day), the ACE inhibitor enalapril (10 mg/kg per day) and the NEP inhibitor CGS 25462(100 mg/kg per day) were administrated for 3 weeks to DOCA rats. Collagen was stained with Sirius red, and mediators of inflammation were identified by immunolabeling (vascular cell adhesion molecule, nuclear factor-kappaB, infiltrating ED-1-positive macrophages and monocyte chemotactic protein-1) or by western blot (platelet-endothelial cell adhesion molecule-1). RESULTS: Elevated systolic blood pressure of DOCA rats was significantly reduced (P < 0.05) by omapatrilat and CGS 25462. Omapatrilat and CGS 25462 significantly (P < 0.05) decreased interstitial collagen density in the left ventricle of DOCA rats compared with untreated DOCA rats. Enalapril only decreased the subepicardial collagen of DOCA rats. Omapatrilat significantly (P < 0.05) decreased renal mesangial collagen deposition in DOCA rats. Cardiac and renal expression of surface adhesion molecules, nuclear factor-kappaB, monocyte chemotactic protein and ED-1-positive cells were decreased in omapatrilat-treated DOCA rats compared with untreated DOCA rats. Enalapril and CGS 25462 did not alter mesangial collagen of DOCA rats. CONCLUSIONS: Dual ACE/NEP inhibition was more effective than ACE or NEP inhibition in decreasing inflammatory mediators, and improving cardiac and renal fibrosis. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.     

Infections associated with purine analogs and monoclonal antibodies

Nucleoside analogs and monoclonal antibodies are commonly used to treat lymphoproliferative disorders and have become established as the treatment of choice in chronic lymphocytic leukemia, hairy cell leukemia, and follicular lymphomas, as well as a number of other malignant lymphoid neoplasms. When used in standard doses, these agents have a low incidence of extramedullary side effects resulting in their inclusion in a number of combination regimens. The most important complications associated with these drugs are myelosuppression, immunosuppression and infections. This is further accentuated when they are used in combination with other drugs such as alkylating agents. Several investigators have attempted to delineate the risk factors predicting the risk of infections associated with these agents. Furthermore, risk-based strategies to decrease the incidence of these infectious complications have been proposed.     

Pretransplant cardiac investigations in the Irish renal transplant population--the effectiveness of our current screening techniques in predicting cardiac events

BACKGROUND: Coronary artery disease (CAD) is prevalent among endstage renal failure patients and remains the major cause of mortality following renal transplantation. Death with a functioning transplant institute remains the most common cause of kidney graft failure. In this study we attempt to evaluate the effectiveness of the clinical history and current screening techniques available in predicting posttransplant CAD and also assess the role of coronary angiography as a pretransplant screening technique. METHODS: Clinical data of 190 renal transplant patients was analyzed. Any clinical history of cardiac disease and all preoperative cardiac screening data was recorded for each patient. The study endpoints were the subsequent development of myocardial infarction (MI), undergoing coronary artery bypass graft (CABG) or death. RESULTS: Factors that were significantly associated with reaching a study endpoint included: age at transplant [Hazard Ratio (HR) 1.91, P<0.001], history of heart failure (HR 8.22, P<0.001), presence of CAD on coronary angiography (HR 5.55, P=0.033), anterior Q wave on electrocardiograph (ECG) (HR 8.6, P<0.001), carotid artery disease (HR 3.74, P=0.030) and history of a cerebrovascular accident (HR of 4.32, P=0.008). The screening techniques of exercise stress testing and echocardiography were not conclusive as predictive variables of outcome. CONCLUSION: Clinical history and ECG results are good, practical and low-cost screening methods. In our study exercise stress testing and echocardiography were found to be of limited value. Coronary angiography is appropriate in certain high-risk groups but not necessary as part of screening in all potential renal transplant recipients.     

Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated upregulation of p27

Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 microM) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 microM) or geranylgeranyl pyrophosphate (5 microM) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H2O2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H2O2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.