Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis

Francisella tularensis is a highly infectious gram-negative coccobacillus that causes the zoonosis tularemia. This bacterial pathogen causes a plague-like disease in humans after exposure to as few as 10 cells. Many of the mechanisms by which the innate immune system fights Francisella are unknown. Here we show that wild-type Francisella, which reach the cytosol, but not Francisella mutants that remain localized to the vacuole, induced a host defense response in macrophages, which is dependent on caspase-1 and the death-fold containing adaptor protein ASC. Caspase-1 and ASC signaling resulted in host cell death and the release of the proinflammatory cytokines interleukin (IL)-1beta and IL-18. F. tularensis-infected caspase-1- and ASC-deficient mice showed markedly increased bacterial burdens and mortality as compared with wild-type mice, demonstrating a key role for caspase-1 and ASC in innate defense against infection by this pathogen.     

Management of patellofemoral pain syndrome

Patellofemoral pain syndrome (PFPS) is the most common cause of knee pain in the outpatient setting. It is caused by imbalances in the forces controlling patellar tracking during knee flexion and extension, particularly with overloading of the joint. Risk factors include overuse, trauma, muscle dysfunction, tight lateral restraints, patellar hypermobility, and poor quadriceps flexibility. Typical symptoms include pain behind or around the patella that is increased with running and activities that involve knee flexion. Findings in patients with PFPS range from limited patellar mobility to a hypermobile patella. To confirm the diagnosis, an examination of the knee focusing on the patella and surrounding structures is essential. For many patients with the clinical diagnosis of PFPS, imaging studies are not necessary before beginning treatment. Radiography is recommended in patients with a history of trauma or surgery, those with an effusion, those older than 50 years (to rule out osteoarthritis), and those whose pain does not improve with treatment. Recent research has shown that physical therapy is effective in treating PFPS. There is little evidence to support the routine use of knee braces or nonsteroidal anti-inflammatory drugs. Surgery should be considered only after failure of a comprehensive rehabilitation program. Educating patients about modification of risk factors is important in preventing recurrence.     

Antisense-mediated reduction in thrombospondin reverses the malignant phenotype of a human squamous carcinoma.

Thrombospondin (TSP) is a trimeric glycoprotein which is synthesized and incorporated into the extracellular matrix by a wide variety of cells. TSP is involved in a number of cellular processes which govern tumor cell behavior including mitogenesis, attachment, migration, and differentiation. To directly assess the role of TSP in tumor cell growth and spread, a human squamous carcinoma cell line, with high TSP production and an invasive phenotype, was transfected with a TSP cDNA antisense expression vector. Five unique transfected clones were obtained with reduced TSP production. Expression of the transfected antisense sequence in these clones was verified by a ribonuclease protection assay. These clones demonstrated reduced growth rates in vitro when compared with a vector transfected control. After subcutaneous inoculation into athymic mice, the antisense clones formed either no tumors or tumors that were slow growing and highly differentiated. This contrasted with the vector-transfected clone which produced poorly differentiated, rapidly growing, invasive tumors. Our results argue in favor of a direct role for TSP in determining the malignant phenotype of certain human tumors.     

Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation

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Meta-analysis: the impact of diabetes mellitus on the immunological response to hepatitis B virus vaccine in dialysis patients

Aliment Pharmacol Ther 2011; 33: 815–821

Summary

Background Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non‐uraemic population. A variety of inherited or acquired factors have been implicated in this diminished response. It is well known that patients with diabetes mellitus have a compromised immune system, and diabetic nephropathy is an important cause of chronic kidney disease. However, the impact of diabetes mellitus on the immune response to HBV vaccine in patients receiving long‐term dialysis remains unclear. Aim To evaluate the influence of diabetes mellitus on the immune response to HBV vaccine in dialysis population by performing a systematic review of the literature with a meta‐analysis of clinical studies. Methods We used the random effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end‐point of interest was the rate of patients showing seroprotective antibody against hepatitis B surface antigen at completion of vaccine schedule in the diabetic vs. the nondiabetic dialysis individuals. Results We identified 12 studies involving 1002 unique patients on long‐term dialysis. Aggregation of study results showed a significant decrease in response rates among the diabetic vs. the nondiabetic patients [pooled odds ratio = 0.52 (95% CI 0.38–0.71)]. The P‐value was 0.29 for our test of study heterogeneity. Stratified analysis in various subgroups of interest did not meaningfully change our results. Conclusions Our meta‐analysis showed a clear association between diabetes mellitus and impaired response to hepatitis B virus vaccine in individuals on long‐term dialysis. Such a relationship is biologically plausible. Vaccination schedules with adapted vaccine doses and frequent serum testing for loss of immunity against hepatitis B virus should be considered in patients on maintenance dialysis with diabetes mellitus.     

仙茅:对健康有众多益处的黑金

仙茅(石蒜科)是一种濒临灭绝的多年生草本植物,是印度本土药,作为强有力的适应原和春药在印度传统药物中占有重要位置.它也是多种印度传统药物处方的重要组成部分,被认为具有促进性欲、刺激免疫、保护肝脏、抗氧化、抗癌和治疗糖尿病等作用.已有报道,从仙茅中提取出多种化学成分,如植物黏胶,酚苷、皂苷和脂肪族化合物等.仙茅也是中医和日本汉方医学中各种草药处方的重要成分.本文对仙茅的多种生物活性和其不同化学成分的作用进行了综述.     

Peroxynitrite-induced modification of H2A histone presents epitopes which are strongly bound by human anti-DNA autoantibodies: role of peroxynitrite-modified-H2A in SLE induction and progression

Peroxynitrite is a potent oxidant and nitrating agent and has in vivo existence. It is a powerful proinflammatory substance and may increase vascular permeability in inflamed tissues. Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease of unknown etiology. Since its discovery, numerous self- and non-self, nuclear, and cytoplasmic antigens have been suggested as stimuli for SLE initiation, but the exact trigger is yet to be identified. In this study, an attempt has been made to investigate the binding characteristics of SLE anti-DNA autoantibodies to native DNA and native and peroxynitrite-modified H2A histone to explore the possible role of modified protein antigen(s) in SLE initiation and progression. The nuclear protein (H2A histone) was modified by peroxynitrite synthesized in our laboratory. The peroxynitrite-modified H2A revealed generation of nitrotyrosine, dityrosine, and carbonyls when subjected to investigation by physicochemical methods. Binding characteristics and specificity of SLE anti-DNA antibodies were analyzed by direct binding and inhibition enzyme-linked immunosorbent assay. The data show preferential binding of SLE autoantibodies to peroxynitrite-modified H2A histone in comparison with native H2A histone or native DNA. A band shift assay further substantiated the enhanced recognition of peroxynitirite-modified H2A histone by anti-DNA autoantibodies. The results suggest that peroxynitrite modification of self-antigen(s) can generate neoepitopes capable of inducing SLE characteristic autoantibodies. The preferential binding of peroxynitrite-modified H2A histone by SLE anti-DNA antibodies points out the likely role of oxidatively modified and nitrated H2A histone in the initiation/progression of SLE. Moreover, oxidatively modified and nitrated nuclear protein antigen, rather than nucleic acid antigens, appear to be more suitable as a trigger for SLE.     

Acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in mice: effects of exposure to stress and modulation by mecamylamine

Nicotinic acetylcholine receptors mediate some of the rewarding and motivational effects of ethanol, including relapses. Relapses are common in drug addicts during abstinence when exposure to any stressor ensues. However, the role of nicotinic acetylcholine receptors in the ethanol- and stress-induced reinstatement of ethanol-induced conditioned place preference has not yet been explored. Therefore, the present study investigated the influence of mecamylamine, a nicotinic acetylcholine receptors antagonist on acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in adult male Swiss mice. The results revealed that mecamylamine (0.1-10 μg/mouse, intracerebroventricularly) dose dependently prevented the development, expression, and reinstatement of ethanol-induced conditioned place preference. Further, acute treatment with mecamylamine blocked the restraint stress and forced swim stress-induced reinstatement of ethanol-induced conditioned place preference. All of these treatments had no influence on the locomotor activity. Therefore, it is concluded that mecamylamine blocks the acquisition, expression and reinstatement of conditioned reinforcing effects of ethanol without per se reinforcing or aversive influence. This ability of mecamylamine might be a potential advantage in the treatment of alcoholism.     

Ascending aortic aneurysms in unicommissural aortic valve disease

BackgroundAneurysms of the ascending aorta occur as result of intrinsic changes in the aortic wall and have been well documented in patients with bicuspid aortic valve (BAV). In few reported clinical studies, documenting aneurysmal dilatation in unicommissural aortic valves (UAV); there have been no comments on the aortic wall pathology. This study presents the pathological findings of the ascending aorta in patients with UAV.Materials and MethodsThe clinical data from 39 patients with concomitant excision of the UAV and aneurysmal aortic tissue were reviewed. In all cases, the gross features of the valve and aortic segments were noted and submitted for histology. The sections of the aorta were semi-quantitatively graded for the extent of medionecrosis, cystic medial change, fibrosis, and elastic tissue changes (fragmentation/ loss) in the media. The medial alterations were correlated with patient age, gender, and valvular dysfunction, and compared to aneurysmal disease in BAV and three-cuspid aortic valves (TAV) excised over a 3-year period.ResultsAmong 39 patients studied, a majority were males (92.3%), with a mean age at surgery of 39.92 years. Only three patients (7.69%) were above the age of 50 years. Eighteen patients (46.1%) had aortic stenosis with regurgitation. Ascending aorta diameters ranged from 4 to 5.5 cm. The overall pattern of medial changes was nearly the same in all cases of UAV, irrespective of age and nature of valvular dysfunction. Most cases showed mild histological changes, with medionecrosis and fibrosis being the more common and consistent features. However, varying grades of change affected different portions of the media and/or the aortic wall in the same patient. The changes in UAV aortae were comparable to the changes seen in the TAV and BAV, but these differed with the age of onset.ConclusionsThis study demonstrates the presence of medial changes in the ascending aortic tissue in all patients of UAV with aneurysms. These changes, while mild to moderate in degree, likely have a similar pathogenetic mechanism as those seen in BAV disease. The significant difference in age, at the time of surgery, suggests a more rapid progression of the aortic changes.