New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schönlein purpura)

Immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, is the most common form of childhood vasculitis. The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. Symptoms can resolve without intervention, but some patients develop glomerulonephritis with features similar to IgA nephropathy that include hematuria, proteinuria and IgA deposition in the glomerulus. Ultimately, this can lead to end-stage renal disease. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Although Gd-IgA1 complexes are also present in patients with IgAV with nephritis, their role in IgAV is disputed. Alternatively, it has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells. We anticipate that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV. In this Review, we discuss the putative role of IgA, IgA receptors, neutrophils and other factors such as infections, genetics and the complement system in the pathogenesis of IgA vasculitis.     

Interaction of CD154 with different receptors and its role in bidirectional signals

In addition to its classical receptor, CD40, it is now well established that CD154 also binds αIIbβ3, α5β1, and αMβ2 integrins. Although these integrins are all members of the same family, they bind CD154 differently. The current investigation aims to analyze the interaction of CD154 with α5β1 and αMβ2 and investigate its role in bidirectional signals in various human cell lines. Results obtained herein indicate that the CD154 residues involved in the interaction with α5β1 are N151 and Q166, whereas those involved in αMβ2 binding are common to residues required for CD40, namely Y145 and R203. Soluble CD40/CD154 or αMβ2/CD154 complexes do not interfere with the binding of CD154 to α5β1‐positive cells, but inhibit the binding of CD154 to CD40‐ or αMβ2‐positive cells, respectively. Ligation of CD154 on CD154‐positive cells with soluble CD40, αIIbβ3, α5β1, or αMβ2 stimulates intracellular signaling, including MAPK phosphorylation. Given that CD154 exists as a trimer, our data strongly suggest that CD154 may bind concomitantly to two receptors of the same or different family, and biologically activate cells expressing both receptors. The characterization of CD154/receptor interactions helps the identification of new therapeutic targets for the prevention and/or treatment of CD154‐associated autoimmune and inflammatory diseases.     

Patient activation with respect to advanced heart failure therapy in patients over age 65 years

Background

Clinical and ethical issues persist in determining candidacy for advanced heart failure (HF) therapies in elderly patients. Selection takes many factors into account, including “activation” (engagement and ability to self-manage).

Effects of ouabain on calcium-45 flux in guinea pig cardiac tissue

Intact heart fragments (mince) from guinea pig were prepared by a mechanical chopper. Calcium-45 uptake in control and ouabain-treated tissue was measured after post-incubation of the tissue in a calcium-free medium containing lanthanum. After 30 min, ouabain significantly increased tissue calcium-45.In guinea pig heart mince loaded with calcium-45, the appearance of calcium-45 in the medium revealed an energy of activation of 8.2 kcal/mol; ouabain reduced this value 50%. Washout of calcium-45 in the presence or absence of ouabain was measured at 25°C. A portion of the washout appeared to be affected by ouabain; the $\text{T}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ for retention of tissue calcium-45 for this phase was increased 1.5 times. These results may bear on the mechanism of cardiac glycoside effects on the sodium gradient and its relationship to calcium movements.     

Cell Tracking Using Nanoparticles

Tracking cells in regenerative medicine is becoming increasingly important for basic cell therapy science, for cell delivery optimization and for accurate biodistribution studies. This report describes nanoparticles that utilize stable-isotope metal labels for multiple detection technologies in preclinical studies. Cells labeled with nanoparticles can be imaged by electron microscopy, fluorescence, and magnetic resonance. The nanoparticle-labeled cells can be quantified by neutron activation, thereby allowing, with the use of standard curves, the determination of the number of labeled cells in tissue samples from in vivo sources. This report describes the characteristics of these nanoparticles and methods for using these nanoparticles to label and track cells. Suggested reviewers: Timothy Henry, Anthony DeMaria, Bernard Gersh     

Unifying Family A GPCR Theories of Activation

Several new pairs of active and inactive GPCR structures have recently been solved enabling detailed structural insight into the activation process, not only of rhodopsin but now also of the β₂ adrenergic, M₂ muscarinic and adenosine A_2A receptors. Combined with structural analyses they have enabled us to examine the different recent theories proposed for GPCR activation and show that they are all indeed parts of the same process, and are intrinsically related through their effect on the central hydrophobic core of GPCRs. This new unifying general process of activation is consistent with the identification of known constitutively active mutants and an in-depth conservational analysis of significant residues implicated in the process.     

缺血性结肠炎的临床特点以及血小板功能的研究

背景:近年缺血性结肠炎(IC)的发病率明显增加,尤其是重症IC,早期无特殊表现,可引起结肠坏死、穿孔,甚至死亡。目的:探讨IC患者的临床特点以及血小板功能的变化。方法:将2009年1月～2012年1月同济大学附属第十人民医院87例IC患者分成重症IC组和轻症IC组,并选取30名健康者作为正常对照。分析轻症IC和重症IC的临床特点,并检测血小板激活复合物(PAC)-1和血小板α-颗粒膜糖蛋白(CD62P)、血小板平均体积(MPV)、血小板分布宽度(PDW)和血小板计数(PLT)。结果:与轻症IC组相比,重症IC组右半结肠发病率显著升高(P<0.05),左半结肠发病率显著降低(P<0.05),死亡率显著升高(P<0.05),腹痛、腹泻、便血、全结肠发病率无明显差异(P>0.05)。IC组PAC-1和CD62P、MPV、PDW均显著高于正常对照组(P<0.05),PLT无明显差异(P>0.05)。重症IC组PAC-1、CD62P、MPV、PDW显著高于轻症IC组(P<0.05),PLT显著低于轻症IC组(P<0.05)。结论:右半结肠病变、血小板活化以及参数的变化可能与重症IC患者密切相关,作为危险因素早期应引起临床医师的高度重视。     

Alcohol Abuse, Alcoholism, and Damage to the Immune System—A Review

Chronic alcohol abuse exacts a major social and medical toll in the United States and other Western countries. One of the least appreciated medical complications of alcohol abuse is altered immune regulation leading to immunodeficiency and autoimmunity. The consequences of the immunodeficiency include increased susceptibility to bacterial pneumonia, tuberculosis, and other infectious diseases. In addition, the chronic alcoholic often has circulating autoantibodies, and recent investigations indicate that the most destructive complications of alcoholism, such as liver disease and liver failure, may have a component of autoimmunity. Current research on altered cytokine balance produced by alcohol is leading to new insights on the regulation of the immune system in the chronic alcoholic. There is also recent development of exciting new techniques designed to improve or restore immune function by manipulation of cytokine balance. Although much remains to be learned, both in the abnormalities produced by alcohol and in the techniques to reverse those abnormalities, current progress reflects a rapidly improving understanding of the basic immune disorders of the alcoholic.     

A novel high molecular weight metalloproteinase cleaves fragment F1 of activated human prothrombin.

A hemorrhagic proteinase, jerdohagin, was purified from Trimeresurus jerdonii venom by gel filtration and ion-exchange chromatographies. It was a single chain polypeptide with an apparent molecular weight of 96 kDa as estimated by SDS-PAGE under the non-reducing and reducing conditions. Internal peptide sequencing indicated that it consisted of metalloproteinase, disintegrin-like and cysteine-rich domains and belonged to the class III snake venom metalloproteinases (class P-III SVMPs). Like other typical metalloproteinases, hemorrhagic activities of jerdohagin were completely inhibited by EDTA, but not by PMSF. Jerdohagin preferentially degraded alpha-chain of human fibrinogen. Interestingly, jerdohagin did not activate human prothrombin, whereas it cleaved human prothrombin and fragment F1 of activated human prothrombin.     

Caffeine effects on resting-state arousal.

OBJECTIVE: This study examined the use of caffeine to manipulate arousal level without the confounds associated with task-related activation. From previous work in our laboratory, an increase in skin conductance level (SCL) and EEG alpha frequency, together with a global decrease in alpha power, were used as markers of arousal increase, and we sought to identify these effects with caffeine ingestion. METHODS: We examined the effect of a single oral dose of caffeine (250 mg) in a randomised double-blind placebo-controlled repeated-measures cross-over study. Eighteen healthy university students (mean age 21 years; 13/18 females) participated in two sessions 1 week apart. EEG and autonomic data (SCL, heart rate, systolic and diastolic blood pressure, and respiration rate) from a 2 min eyes-closed epoch, commencing approximately 30 min after ingestion of caffeine or placebo, were examined. RESULTS: Caffeine was associated with increased SCL, a global reduction in EEG power in the alpha band, and a global increase in alpha frequency. There were no cardiovascular effects. CONCLUSIONS: The positive results are consistent with recent electrodermal and EEG studies of arousal and suggest that caffeine may be utilised as a task-free means of manipulating arousal in future investigations. Further work is necessary to clarify the absence of cardiovascular effects, and to integrate those data with emerging conceptualisations of arousal and activation. SIGNIFICANCE: The present data support the use of caffeine as a simple tool to explore the role of arousal in both normal and atypical functioning, and this may be useful in determining the validity and importance of supposed hyper- or hypo-arousal in such syndromes as attention-deficit/hyperactivity disorder (AD/HD).