Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4

In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-κB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.     

Adhesion/growth-regulatory galectins in the human eye: localization profiles and tissue reactivities as a standard to detect disease-associated alterations

Objectives

To characterize the localization profiles of seven adhesion/growth-regulatory galectins in the normal human eye using immunodetection of endogenous galectins and binding of labeled galectins to sections, useful as a basis to detect disease-associated alterations.

Methods

Non-cross-reactive anti-galectin antibodies and biotinylated galectins were tested on acetone-fixed cryosections of normal human donor eyes. Controls included omission of first-step reagent, testing of an antibody against a galectin specific for rat (galectin-5), and blocking of galectin binding with lactose.

Results

Galectin presence was not restricted to one or few members of this family. Signal occurrence can even include all tested or most proteins (conjunctival or corneal epithelium), whereas choroid positivity is fully accounted for by galectin-9. Regional specificity and characteristic profiles for each protein, immuno- and galectin histochemically, were determined. Differences in tissue reactivity among the galectins were detected.

Conclusions

That the galectins have characteristic localization/reactivity profiles supports the concept of a network with potential for non-overlapping functions. The reported data thus prompt to proceed to the respective analysis of specimens from ocular diseases.     

Nazi indoctrination and anti-Semitic beliefs in Germany

Attempts at modifying public opinions, attitudes, and beliefs range from advertising and schooling to “brainwashing.” Their effectiveness is highly controversial. In this paper, we use survey data on anti-Semitic beliefs and attitudes in a representative sample of Germans surveyed in 1996 and 2006 to show that Nazi indoctrination––with its singular focus on fostering racial hatred––was highly effective. Between 1933 and 1945, young Germans were exposed to anti-Semitic ideology in schools, in the (extracurricular) Hitler Youth, and through radio, print, and film. As a result, Germans who grew up under the Nazi regime are much more anti-Semitic than those born before or after that period: the share of committed anti-Semites, who answer a host of questions about attitudes toward Jews in an extreme fashion, is 2–3 times higher than in the population as a whole. Results also hold for average beliefs, and not just the share of extremists; average views of Jews are much more negative among those born in the 1920s and 1930s. Nazi indoctrination was most effective where it could tap into preexisting prejudices; those born in districts that supported anti-Semitic parties before 1914 show the greatest increases in anti-Jewish attitudes. These findings demonstrate the extent to which beliefs can be modified through policy intervention. We also identify parameters amplifying the effectiveness of such measures, such as preexisting prejudices.Schools, parents, and the media not only communicate information and teach skills, they transmit values and beliefs as well (1). Dictatorships and democracies alike use schooling in particular to influence the outlook of children and young adults––the period of their lives during which humans are most susceptible to outside influences. The efficiency of such interventions, ranging from mild attempts to modify attitudes to “brainwashing,” is highly controversial (2–6). In particular, the effect of schooling has remained doubtful (5–7). Whereas many historians believe that Nazi propaganda and schooling prepared the ground for the Third Reich’s excesses, scientific studies of indoctrination have typically found few systematic effects (8, 9).In this paper, we use modern-day data on anti-Semitic beliefs in Germany to examine the effectiveness of indoctrination. Nazi schooling and extracurricular activities sought to inculcate racial hatred to an extraordinary extent. The entire curriculum––not only biology classes––was used to convince the young of the importance of race and the inferiority of Jews, blacks, etc. In addition to compulsory school attendance, young Germans had to join the Hitler Youth, where indoctrination continued; the official handbook for schooling the Hitler Youth devoted fully 45 out of 105 pages to racial ideology (10). Further, propaganda messages embedded in books and films reinforced indoctrination (11).Germans who grew up under the Nazi regime were therefore exposed to a wide range of indoctrination methods. Using data from the German General Social Survey (ALLBUS), we show that these individuals are still markedly more anti-Semitic today than cohorts born either before or after. They are more inclined to deny Jews equal rights, to resent having them as neighbors or family members, and they believe more often that Jews have too much influence in the world. The creation of additional racial bias varies by location. Where anti-Semitism was already prevalent before World War I (WWI), the Nazi message of racial hatred produced many more zealots than elsewhere. This suggests that indoctrination is particularly effective where it can exploit preexisting stereotypes and beliefs (12), leading to a “magnification effect.”     

Pleural mesothelioma associated with indoor pollution of asbestos

This case report concerns a 46-year-old woman, dying from histologically confirmed diffuse malignant mesothelioma after asbestos exposure, which was only caused by indoor pollution from crocidolite-containing spray asbestos in building materials. There was no other known occupational or environmental asbestos exposure during her life. The lung tissue fibre analysis by light microscopy showed significantly increased concentrations of ferruginous bodies (3162 FB per gram of wet lung tissue). By use of scanning transmission electron microscopy, clearly increased concentrations of amphibole fibres (8.6 x 10(6) fibres longer than 1 microm and 0.6 x 10(6) fibres longer than > or =5 microm per gram dry tissue), mainly classified as crocidolite, were observed. The disease was attributed to indoor exposure to sprayed asbestos, which occurred during her work as a decorator in the studio of a warehouse.     

Immune response to postprimary tuberculosis in mice: Mycobacterium tuberculosis and Miycobacterium bovis bacille Calmette-Guérin induce equal protection

We addressed the question of whether protective immunity induced by natural infection with Mycobacterium tuberculosis and that induced by vaccination with Mycobacterium bovis bacille Calmette-Guerin (BCG) differ in the murine model. We infected mice with M. tuberculosis Erdman, cured them by chemotherapy, and subsequently reinfected them with a low dose of M. tuberculosis H37Rv. The course of tuberculosis was compared with that in mice previously vaccinated with BCG Danish 1331. Protection against postprimary M. tuberculosis infection did not differ significantly between the 2 groups. After challenge infection, numbers of interferon- gamma -positive splenocytes did not differ between mice with primary infection and vaccinated mice. Splenocytes from primary M. tuberculosis-infected mice conferred marginally higher protection than did those from BCG-vaccinated mice. Serum transfer did not protect against reinfection in either group. Our data emphasize that natural infection with M. tuberculosis and vaccination with BCG do not differ in their capacity to induce protective immunity against tuberculosis and support the notions that reinfection contributes to the development of active disease and that any novel vaccine against tuberculosis has to perform better than both vaccination with BCG and immunity evoked by natural infection.     

The R-on-T phenomenon in patients with implantable cardioverter-defibrillators

Cardiac resynchronization therapy (CRT) can improve cardiac function in patients with heart failure and left bundle branch block. To test a new synchrony index derived from mitral annular velocity by color tissue Doppler, 19 subjects were studied: 9 patients with heart failure and left bundle branch block at baseline and at 1, 3 and 6 months after CRT and 10 normal controls. The synchrony index in patients with heart failure was less than that in controls at baseline (r = 0.60 +/- 0.13 vs 0.94 +/- 0.02; p <0.01), but improved at 6 months after CRT (r = 0.77 +/- 0.09; p <0.05 vs baseline).     

Interventionelle Therapie der peripheren arteriellen Verschlusskrankheit

The technical success rate of endovascular interventions in order to improve perfusion in peripheral arterial disease in the lower extremities has been markedly improved in the last decade due to clinical application of new recanalization techniques like application of hydrophil-coated guide wires, implantation of stents or stent grafts. If the-even long-segment-obstruction can be recanalized, the interventional radiologist is able to open the arterial vessel sufficiently. The excellent immediate results are limited in the long term by recurrent stenoses, which appear in different rates according to the vascular region. Whereas recurrent stenoses have nearly no clinical significance in the aortoiliac vascular segment due to the size of the treated vessels and the excellent flow, there is a significant amount of restenoses in the femoropopliteal segment and, even more, in the tibial arteries. This leads to a different indication of endovascular therapy according to the segment treated. However, in an interdisciplinary consensus we offer primary endovascular therapy for treatment of aortoiliac obstruction to all patients, whereas lesions at the femoral bifurcation are a clear primary indication for open surgical treatment. In the femoropopliteal segment, we choose a primary endovascular procedure with respect to the length of the occlusion, patient's risk factors and comorbidities. Yet, longer obstructions are a clear indication for primary surgical treatment. In cases of infrapopliteal disease, we recommend an endovascular treatment as the initial option due to the reduced invasiveness of the predominantly old and multimorbid patient cohort. Further clinical research for the evaluation of endovascular therapeutic measures in peripheral arterial disease urgently requires outcome studies, which include clinically relevant endpoints to better define the clinical value of endovascular therapy compared to traditional surgical bypass procedures. Until new clinical trials will be published, the Transatlantic Consensus document (TASC) of a variety of vascularly specialized scientific societies seems to be a helpful guideline.     

Digital radiogrammetry as a new diagnostic tool for estimation of disease-related osteoporosis in rheumatoid arthritis compared with pQCT

Objectives: To investigate the potential of a new osteogeometric technology based on digital X-ray radiogrammetry (DXR) as a diagnostic tool for quantification of severity-dependent osteoporosis, and to distinguish between inflammation-mediated and corticoid-induced variations of bone mineralisation in patients suffering from rheumatoid arthritis. Methods: Ninety-six patients (duration of disease: <18 months) underwent retrospective calculations of bone mineral density (DXR-BMD) and metacarpal index (MCI) by DXR, which were calculated from plain radiographs of the non-dominant hand. For comparison, pQCT-calculated BMD (total, cortical-subcortical and trabecular partition of bone tissue) was done on the distal radius. Severity was classified using Ratingen Score by two independent radiologists, and divided into three main groups. In addition, the patients were separated into those with corticoid medication (n=44; 5 mg/day over a half year period) and a control group (n=52) without any corticoid therapy. Results: Correlations between DXR-BMD and MCI versus pQCT parameters were all significant (0.36<R<0.71; p<0.01), independent of corticoid therapy. Only in the group without corticoid application, the correlation between DXR-BMD and pQCT-BMD (cortical) showed no significant association. For patients with corticoid therapy, our data revealed the lowest correlation coefficient between DXR parameters and pQCT-BMD (trabecular). Without a difference in comparison to corticoid therapy, the significant relative decrease of BMD estimated by DXR between the highest and lowest score was between 11.1% and 14.3% and for MCI between 15.8% and 17.8%. The also significant relative decrease of trabecular BMD using pQCT varied from 10.3% to 16.9%, whereas no significant results could be verified for pQCT-BMD (cortical and total). Conclusions: Digital radiogrammetry can precisely estimate severity-dependent cortical reduction of bone mineral density in patients suffering from rheumatoid arthritis both with and without corticoid therapy, and seems to be able to distinguish the side effects of antirheumatic treatment from the disease-related periarticular bone loss. The detection and quantification of periarticular osteoporosis by DXR could be an important diagnostic tool in early rheumatoid arthritis.