In a placebo-controlled trial, treatment with the preferential phosphodiesterase 4B inhibitor BI 1015550 prevented a decrease in lung function over a 12-week period in patients with idiopathic ...pulmonary fibrosis.
Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology ...and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon ...laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.
The radiative cooling of highly excited carbon cluster cations of sizes N = 8, 10, 13–16 has been studied in an electrostatic storage ring. The cooling rate constants vary with cluster size from a ...maximum at N = 8 of 2.6 × 104 s−1 and a minimum at N = 13 of 4.4 × 103 s−1. The high rates indicate that photon emission takes place from electronically excited ions, providing a strong stabilizing cooling of the molecules.
The Northern Hemisphere experienced dramatic changes during the last glacial, featuring vast ice sheets and abrupt climate events, while high northern latitudes during the last interglacial (Eemian) ...were warmer than today. Here we use high-resolution aerosol records from the Greenland NEEM ice core to reconstruct the environmental alterations in aerosol source regions accompanying these changes. Separating source and transport effects, we find strongly reduced terrestrial biogenic emissions during glacial times reflecting net loss of vegetated area in North America. Rapid climate changes during the glacial have little effect on terrestrial biogenic aerosol emissions. A strong increase in terrestrial dust emissions during the coldest intervals indicates higher aridity and dust storm activity in East Asian deserts. Glacial sea salt aerosol emissions in the North Atlantic region increase only moderately (50%), likely due to sea ice expansion. Lower aerosol concentrations in Eemian ice compared to the Holocene are mainly due to shortened atmospheric residence time, while emissions changed little.
There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing ...chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC).
Patients with a malignant solid tumor who would receive HEC containing 50 mg/m2 or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2–4) and aprepitant (125 mg on day 1 and 80 mg on days 2–3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0–120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea).
Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0–120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0–24 h) period, while at the delayed (24–120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0–120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369).
The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point.
UMIN000004863.
Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to ...the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 ± 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 ± 250 metres, reaching surface elevations 122,000 years ago of 130 ± 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future.
Aim
To investigate the relationship between apical periodontitis and atherosclerosis in rats by lipid profile and carotid artery intima tunic measurement, and histological and histometric evaluation ...of periapical lesions.
Methodology
Forty male Wistar rats were allocated into four groups: control (C), with apical periodontitis (AP), with atherosclerosis (AT) and with AP and AT (AP + AT). Atherosclerosis was induced using a high‐lipid diet associated with a surgical ligature in the carotid artery and a super dosage of vitamin D3. AP was induced via pulp exposure to the oral environment. At 45 and 75 days, serum levels of total cholesterol (TC), triglycerides (TG), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) were measured. The maxillary and mandibular jaws and carotid artery were collected and processed for histological analysis. The Kruskal–Wallis or Mann–Whitney test was performed for nonparametric data, and the Tukey’s or Student’s t‐test was performed for parametric data (P < 0.05).
Results
In nonatherosclerotic animals, the induction of apical periodontitis increased TG levels significantly, from 63.1 ± 11.4 mg dL−1 in group C to 88.2 ± 7.9 mg dL−1 in the AP group (P < 0.05). The induction of AP was associated with a trend for higher TC and LDL‐C levels in atherosclerotic animals (P > 0.05); however, it only significantly increased TG levels, from 93.2 ± 18.0 mg dL−1 in AT group to 121.9 ± 14.5 mg dL−1 in the AP + AT group (P < 0.05). Animals in the AP + AT group had a 36.5% increase in the thickness of the carotid intima tunic when compared with the AT group (P < 0.05). The intensity of the inflammatory infiltrate was significantly larger in the AP + AT group when compared with AP group (P < 0.05). The AP + AT group exhibited significantly greater alveolar bone loss, with a periapical lesion size of 206.4 ± 56.3 × 104 μm2, compared with 151.4 ± 49.1 × 104 μm2 in the AP group (P < 0.05).
Conclusion
Apical periodontitis influenced triglyceride levels, increasing them even in the absence of atherosclerosis, and influenced the increase in the thickness of the carotid artery intima tunic in the presence of atherosclerosis. Atherosclerosis intensified the inflammatory reaction and increased bone resorption in periapical lesions.
1. To investigate whether the role of symbiotic fungi in lignin degradation and food provision differs among fungus-growing termites (four species of Macrotermes, three species of Odontotermes, ...Hypotermes makhamensis, Ancistrotermes pakistanicus and Pseudacanthotermes militaris), the chemical composition of fungus combs of different ages and the chitinolytic activity in the gut of termites were analysed. In addition, the carbon stable isotope ratios (δ13C) in old combs, worker termite tissues and fungal nodules (aggregated conidia) were compared. 2. In Macrotermes spp., the carbohydrate: lignin ratio of the combs increased with increased comb age, but it decreased or remained the same in Odontotermes spp., H. makhamensis, A. pakistanicus and P. militaris. In contrast, the chitin: carbohydrate ratio and ash content increased more over time in the combs of Odontotermes spp., H. makhamensis, A. pakistanicus and P. militaris than in the combs of Macrotermes spp. 3. Chitinolytic activity in the gut of workers was higher in O. takensis, H. makhamensis and A. pakistanicus than in M. annandalei. 4. In all species examined, the δ13C value increased in the sequence: old combs < termites < fungal nodules. Based on a two-source model of δ13C, the contribution of fungi to termite nutrition was considered higher in Odontotermes spp., H. makhamensis, A. pakistanicus and P. militaris than in Macrotermes spp. 5. These results suggest that symbiotic fungi play different roles among fungus-growing termites. In Macrotermes spp., the main role of symbiotic fungi is to degrade lignin, so that the termites can utilize cellulose more efficiently, whereas in Odontotermes spp., H. makhamensis, A. pakistanicus and P. militaris, it is to serve as a food source.
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