Aspiration toxicology of hydrocarbons and lamp oils studied by in vitro technology

Medical literature regularly reports on accidental poisoning in children after aspiration of combustibles such as lamp oils which usually contain hydrocarbons or rape methyl esters (RMEs). We aimed to analyze the toxic potential of alkanes and different combustible classes in vitro with regard to biologic responses and mechanisms mediating toxicity. Two different in vitro models were used, i.e. (i) a captive bubble surfactometer (CBS) to assess direct influence of combustibles on biophysical properties of surfactant film and (ii) cell cultures (BEAS-2B and R3/1 cells, primary macrophages, re-differentiated epithelia) closely mimicking the inner lung surface. Biological endpoints included cell viability, cytotoxicity and inflammatory mediator release. CBS measurements demonstrate that combustibles affect film dynamics, i.e. the surface tension/area characteristics during compression and expansion, in a dose and molecular chain length dependent manner. Cell culture results confirm the dose dependent toxicity. Generally, cytotoxicity and cytokine release are higher in short-chained alkanes and hydrocarbon-based combustibles than in long-chained substances, e.g. highest inducible cytotoxicity in BEAS-2B was for hexane 84.6%, decane 74% and hexadecane 30.8%. Effects of RME-based combustibles differed between the cell models. Our results confirm data from animal experiments and give new insights into the mechanisms underlying the adverse health effects observed.

Migration of immature mouse DC across resting endothelium is mediated by ICAM-2 but independent of beta2-integrins and murine DC-SIGN homologues

Immature dendritic cells (DC) reside in tissues where they initiate immune responses by taking up foreign antigens. Since DC have a limited tissue half-life, the DC pool in tissues has to be replenished constantly. This implies that precursor/immature DC must be able to cross non-activated endothelium using as yet unknown mechanisms. Here we show that immature, but not mature bone marrow-derived murine DC migrate across resting endothelial monolayers in vitro. We find that endothelial intercellular adhesion molecule-2 (ICAM-2) is a major player in transendothelial migration (TEM) of immature DC, accounting for at least 41% of TEM. Surprisingly, the ICAM-2-mediated TEM was independent of beta2-integrins, the known ICAM-2 ligands, since neither blocking of beta2-integrins with antibodies nor the use of CD18-deficient DC affected the ICAM-2-specific TEM. In humans, the C-type lectin DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) was shown to interact with ICAM-2, suggesting a similar role in mice. However, we find that none of the murine DC-SIGN homologues mDC-SIGN, murine DC-SIGN-related molecule-1 (mSIGN-R1) and mSIGN-R3 is expressed on the surface of bone marrow-derived mouse DC. Taken together, this study shows that ICAM-2 strongly supports transmigration of immature DC across resting endothelium by interacting with ligands that are distinct from beta2-integrins and DC-SIGN homologues.

Evaluation of cavitations in proximal caries lesions at various magnification levels in vitro

OBJECTIVES: The aim of this study was to evaluate the cavitation rate of proximal caries using different magnification aids in vitro. METHODS: Radiographs of 285 extracted teeth were taken and the proximal surfaces were graded to the criteria R0 (no radiolucency), R1 (radiolucency confined to the outer half of enamel), R2 (inner half of enamel) and R3 (outer half of dentin). Subsequently, the proximal surfaces were checked for the presence of cavitations with the naked eye (NE), and by using 4.3 x magnification eyeglasses (ME), a stereo microscope (SM, 10x), or a scanning electron microscope (SEM, up to 2000 x magnification). RESULTS: In surfaces with R3 caries, cavitations were visible in 56 of 59 cases with the naked eye. When using SEM, all surfaces revealed cavitations (100%). Regarding the surfaces with R2 lesion, 36 of 46 cases showed cavitations (NE); the corresponding values were 39/46 (ME), 41/46 (SM), and 46/46 (SEM); in the latter, in most cases deep defects could be observed. With regard to R1 lesions, 36/60 (NE), 43/60 (ME), 45/60 (SM), and 58/60 (SEM) cases revealed cavitations. A breakdown of radiographically sound surfaces (R0) was present in some 10% of the examined surfaces (24/261, NE; 33/261, SEM). CONCLUSIONS: Cavitations (defined as breakdown of the surface) are present in significantly more cases than previously reported. This might be an explanation why even small radiolucencies tend to progress, albeit slowly. Thus, close follow-ups should strongly be recommended when considering a preventive treatment regimen with small radiolucencies.

Late Holocene summer temperatures in the central Andes reconstructed from the sediments of high-elevatin Laguna Chepical, Chile (32° S)

High-resolution reconstructions of climate variability that cover the past millennia are necessary to improve the understanding of natural and anthropogenic climate change across the globe. Although numerous records are available for the mid- and high-latitudes of the Northern Hemisphere, global assessments are still compromised by the scarcity of data from the Southern Hemisphere. This is particularly the case for the tropical and subtropical areas. In addition, high elevation sites in the South American Andes may provide insight into the vertical structure of climate change in the mid-troposphere. This study presents a 3000 yr-long austral summer (November to February) temperature reconstruction derived from the 210Pb- and 14C-dated organic sediments of Laguna Chepical (32°16' S, 70°30' W, 3050 m a.s.l.), a high-elevation glacial lake in the subtropical Andes of central Chile. Scanning reflectance spectroscopy in the visible light range provided the spectral index R570/R630, which reflects the clay mineral content in lake sediments. For the calibration period (AD 1901–2006), the R570/R630 data were regressed against monthly meteorological reanalysis data, showing that this proxy was strongly and significantly correlated with mean summer (NDJF) temperatures (R3 yr = −0.63, padj = 0.01). This calibration model was used to make a quantitative temperature reconstruction back to 1000 BC. The reconstruction (with a model error RMSEPboot of 0.33 °C) shows that the warmest decades of the past 3000 yr occurred during the calibration period. The 19th century (end of the Little Ice Age (LIA)) was cool. The prominent warmth reconstructed for the 18th century, which was also observed in other records from this area, seems systematic for subtropical and southern South America but remains difficult to explain. Except for this warm period, the LIA was generally characterized by cool summers. Back to AD 1400, the results from this study compare remarkably well to low altitude records from the Chilean Central Valley and southern South America. However, the reconstruction from Laguna Chepical does not show a warm Medieval Climate Anomaly during the 12–13th century, which is consistent with records from tropical South America. The Chepical record also indicates substantial cooling prior to 800 BC. This coincides with well-known regional as well as global glacier advances which have been attributed to a grand solar minimum. This study thus provides insight into the climatic drivers and temperature patterns in a region for which currently very few data are available. It also shows that since ca. AD 1400, long-term temperature patterns were generally similar at low and high altitudes in central Chile.

Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery

INTRODUCTION Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. AIMS AND METHODS Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. RESULTS The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. CONCLUSION This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.

State Capture from Below? The Contradictory Effects of Decentralisation on Public Spending

This study analyses the contradictory effects of decentralisation on public spending. We distinguish three dimensions of decentralisation and analyse their joint and separate effects on public spending in the Swiss cantons over 20 years. We find that overall decentralisation has a strong, significant and negative effect on the size of the public sector, thus confirming the Leviathan hypothesis. The same holds for fiscal and institutional decentralisation. However, the extent to which political processes and actors are organised locally rather than centrally actually increases central and decreases local spending. This suggests that actors behave strategically when dealing with the centre by offloading the more costly policies. The wider implication of our study is that the balance between self-rule and shared rule has implications also for the size of the overall political system.