Tissue coverage and neointimal hyperplasia in overlap versus nonoverlap segments of drug-eluting stents 9 to 13 months after implantation: in vivo assessment with optical coherence tomography

BACKGROUND Histologic experimental studies have reported incomplete neointimal healing in overlapping with respect to nonoverlapping segments in drug-eluting stents (DESs), but these observations have not been confirmed in human coronary arteries hitherto. On the contrary, angiographic and optical coherence tomography studies suggest that DES overlap elicits rather an exaggerated than an incomplete neointimal reaction. METHODS Optical coherence tomography studies from 2 randomized trials including sirolimus-eluting, biolimus-eluting, everolimus-eluting, and zotarolimus-eluting stents were analyzed at 9- to 13-month follow-up. Coverage in overlapping segments was compared versus the corresponding nonoverlapping segments of the same stents, using statistical pooled analysis. RESULTS Forty-two overlaps were found in 31 patients: 11 in sirolimus-eluting stents, 3 in biolimus-eluting stents, 17 in everolimus-eluting stents, and 11 in zotarolimus-eluting stents. The risk ratio of incomplete coverage was 2.35 (95% CI 1.86-2.98) in overlapping versus nonoverlapping segments. Thickness of coverage in overlaps was only 85% (95% CI 81%-90%) of the thickness in nonoverlaps. Significant heterogeneity of the effect was observed, especially pronounced in the comparison of thickness of coverage (I(2) = 90.31). CONCLUSIONS The effect of overlapping DES on neointimal inhibition is markedly heterogeneous: on average, DES overlap is associated with more incomplete and thinner coverage, but in some cases, the overlap elicits an exaggerated neointimal reaction, thicker than in the corresponding nonoverlapping segments. These results might help to understand why overlapping DES is associated with worse clinical outcomes, both in terms of thrombotic phenomena and in terms of restenosis and revascularization.

Diagnosis and management of chronic obstructive pulmonary disease: the Swiss guidelines. Official guidelines of the Swiss Respiratory Society

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration.

Defining the role of IL-15 trans-presentation by distinct cell-types during the development and homeostasis of Natural Killer and invariant Natural Killer T cells

The immuno-regulatory functions displayed by NK and iNKT cells have highlighted their importance as key lymphocytes involved in innate and adaptive immunity. Therefore, understanding the dynamics influencing the generation of NK and iNKT cells is extremely important. IL-15 has been shown to provide a critical signal throughout the development and homeostasis of NK and iNKT cells; however, the cellular source of IL-15 has remained unclear. In this investigation, I provide evidence that the cell-type providing IL-15 to NK and iNKT cells via trans-presentation is determined by the tissue site and the maturation status of NK and iNKT cells. For NK cells, I revealed the non-hematopoietic compartment provides IL-15 to NK cells in the early stages of development while hematopoietic cells were crucial for the generation and maintenance of mature NK cells. Regarding iNKT cells in the thymus, IL-15 trans-presentation by non-hematopoietic cells was crucial for the survival of mature iNKT cells. In the liver, both hematopoietic and non-hematopoietic compartments provided IL-15 to both immature and mature iNKT cells. This IL-15 signal helped mediate the survival and proliferation of both NK and iNKT cells as well as induce the functional maturation of mature iNKT cells via enhanced T-bet expression. In conclusion, my work illustrates an important notion that the immunological niche of NK and iNKT cells is tightly regulated and that this regulation is meticulously influenced by the tissue microenvironment.

ROLE OF GSH METABOLISM IN MEDIATING STROMAL-LEUKEMIA INTERACTION AND PROMOTING CELL SURVIVAL AND DRUG RESISTANCE IN CHRONIC LYMPHOCYTIC LEUKEMIA

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries. The interaction between CLL cells and the bone marrow stromal environment is thought to play a major role in promoting the leukemia cell survival and drug resistance. My dissertation works proved a novel biochemical mechanism by which the bone marrow stromal cells exert a profound influence on the redox status of primary CLL cells and enhance their ability to sustain oxidative stress and drug treatment. Fresh leukemia cells isolated from the peripheral blood of CLL patients exhibited two major redox alterations when they were cultured alone: a significant decrease in cellular glutathione (GSH) and an increase in basal ROS levels. However, when cultured in the presence of bone marrow stromal cells, CLL cells restored their redox balance with an increased synthesis of GSH, a decrease in spontaneous apoptosis, and an improved cell survival. Further study showed that CLL cells were under intrinsic ROS stress and highly dependent on GSH for survival, and that the bone marrow stromal cells promoted GSH synthesis in CLL cells through a novel biochemical mechanism. Cysteine is a limiting substrate for GSH synthesis and is chemically unstable. Cells normally obtain cysteine by uptaking the more stable and abundant precursor cystine from the tissue environment and convert it to cysteine intracellularly. I showed that CLL cells had limited ability to take up extracellular cystine for GSH synthesis due to their low expression of the transporter Xc-, but had normal ability to uptake cysteine. In the co-culture system, the bone marrow stromal cells effectively took up cystine and reduced it to cysteine for secretion into the tissue microenvironment to be taken up by CLL cells for GSH synthesis. The elevated GSH in CLL cells in the presence of bone marrow stromal cells significantly protected the leukemia cells from stress-induced apoptosis, and rendered them resistant to standard therapeutic agents such as fludarabine and oxaliplatin. Importantly, disabling of this protective mechanism by depletion of cellular GSH using a pharmacological approach potently sensitized CLL cells to drug treatment, and effectively enhanced the cytotoxic action of fludarabine and oxaliplatin against CLL in the presence of stromal cells. This study reveals a key biochemical mechanism of leukemia-stromal cells interaction, and identifies a new therapeutic strategy to overcome drug resistance in vivo.

Stratigraphic Variation Within Polar Firn Caused by Differential Accumulation and Ice Flow: Interpretation of a 400 Mhz Short-Pulse Radar Profile from West Antarctica

We investigate causes of the stratigraphic variation revealed in a 177 km, 400 MHz short-pulse radar profile of firn from West Antarctica. The profile covers 56 m depth, and its direction was close to those of the ice flow and mean wind. The average, near-surface accumulation rates calculated from the time delays of one radar horizon consistently show minima on leeward slopes and maxima on windward slopes, confirming an earlier study based on stake observations. The stratigraphic variation includes up to 30 m depth variation in individual horizons over tens of km, fold limbs that become progressively steeper with depth, and fold-hinge loci that change direction or propagate down-ice with depth over distances far less than predicted by the ice speeds. We use an accumulation rate model to show how local rate anomalies and the effect of ice speed upon a periodic variation in accumulation rate cause these phenomena, and we reproduce two key features seen in the stratigraphic variations. We conclude that the model provides an explanation of changes in spatial stratigraphy and local measures of accumulation history given the constraints of surface topography, ice and wind velocities, and a general accumulation rate for an area.

CHARACTERIZATION OF DIFFERENTIATION AND PROGNOSTIC BIOMARKERS ON CD8+ TUMOR-INFILTRATING LYMPHOCYTES IN METASTATIC MELANOMA

CD8+ cytotoxic T lymphocytes (CTL) frequently infiltrate tumors, yet most melanoma patients fail to undergo tumor regression. We studied the differentiation of the CD8+ tumor-infiltrating lymphocytes (TIL) from 44 metastatic melanoma patients using known T-cell differentiation markers. We also compared CD8+ TIL against the T cells from matched melanoma patients’ peripheral blood. We discovered a novel subset of CD8+ TIL co-expressing early-differentiation markers, CD27, CD28, and a late/senescent CTL differentiation marker, CD57. This CD8+CD57+ TIL expressed a cytolytic enzyme, granzyme B (GB), yet did not express another cytolytic pore-forming molecule, perforin (Perf). In contrast, the CD8+CD57+ T cells in the periphery were CD27-CD28-, and GBHi and PerfHi. We found this TIL subset was not senescent and could be induced to proliferate and differentiate into CD27-CD57+, perforinHi, mature CTL. This further differentiation was arrested by TGF-β1, an immunosuppressive cytokine known to be produced by many different kinds of tumors. Therefore, we have identified a novel subset of incompletely differentiated CD8+ TIL that resembled those found in patients with uncontrolled chronic viral infections. In a related study, we explored prognostic biomarkers in metastatic melanoma patients treated in a Phase II Adoptive Cell Therapy (ACT) trial, in which autologous TIL were expanded ex vivo with IL-2 and infused into lymphodepleted patients. We unexpectedly found a significant positive clinical association with the infused CD8+ TIL expressing B- and T- lymphocyte attentuator (BTLA), an inhibitory T-cell receptor. We found that CD8+BTLA+ TIL had a superior proliferative response to IL-2, and were more capable of autocrine IL-2 production in response to TCR stimulation compared to the CD8+BTLA- TIL. The CD8+BTLA+ TIL were less differentiated and resembled the incompletely differentiated CD8+ TIL described above. In contrast, CD8+BTLA- TIL were poorly proliferative, expressed CD45RA and killer-cell immunoglobulin-like receptors (KIRs), and exhibited a gene expression signature of T cell deletion. Surprisingly, ligation of BTLA by its cognate receptor, HVEM, enhanced the survival of CD8+BTLA+ TIL by activating Akt/PKB. Our studies provide a comprehensive characterization of CD8+ TIL differentiation in melanoma, and revealed BTLA as a novel T-cell differentiation marker along with its role in promoting T cell survival.

Carbonate and Aluminium accumulation in the central equatorial Pacific Ocean

We examined the flux of Al to sediment accumulating beneath the zone of elevated productivity in the central equatorial Pacific Ocean, along a surface sediment transect at 135°W as well as downcore for a 650 kyr record at 1.3°N, 133.6°W. Across the surface transect, a pronounced, broadly equatorially symmetric increase in Al accumulation is observed, relative to Ti, with Al/Ti ratios reaching values 3-4 times that of potential detrital sources. The profile parallels biogenic accumulation and the modeled flux of particulate 234Th, suggesting rapid and preferential adsorptive removal of Al from seawater by settling biogenic particles. Normative calculations confirm that most Al is unsupported by the terrigenous fraction. The observed distributions are consistent with previous observations of the relative and absolute behavior of Al and Ti in seawater, and we can construct a reasonable mass balance between the amount of seawater-sourced Al retained in the sediment and the amount of seawater Al available in the overlying column. The close tie between Al/Ti and biogenic accumulation (as opposed to concentration) emphasizes that biogenic sedimentary Al/Ti responds to removal-transport phenomena and not bulk sediment composition. Thus, in these sediments dominated by the biogenic component, the bulk Al/Ti ratio reflects biogenic particle flux, and by extension, productivity of the overlying seawater. The downcore profile of Al/Ti at 1.3°N displays marked increases during glacial episodes, similar to that observed across the surface transect, from a background value near Al/Ti of average upper crust. The excursions in Al/Ti are stratigraphically coincident with maxima in both bulk and CaCO3 accumulation and the excess Al appears to not be preferentially affiliated with opaline or organic phases. Consistent with the similar behavioral removal of Al and 234Th, the latter of which responds to the total particle flux, the Al flux reflects carbonate accumulation only because carbonate comprises the dominant flux in these particular deposits. These results collectively indicate that (1) Al in biogenic sediment and settling biogenic particles is strongly affected by a component adsorbed from seawater. Therefore, the common tenet that Al is dominantly associated with terrestrial particulate matter, and the subsequent use of Al distributions to calculate the abundance and flux of terrestrial material in settling particles and sediment, needs to be reevaluated. (2) The Al/Ti ratio in biogenic sediment can be used to trace the productivity of the overlying water, providing a powerful new paleochemical tool to investigate oceanic response to climatic variation. (3) The close correlation between the Al/Ti productivity signal and carbonate maxima downcore at 1.3°N suggests that the sedimentary carbonate maxima in the central equatorial Pacific Ocean record increased productivity during glacial episodes.

Faunal analysis and Mg/Ca records of planktic foraminifera in sediment core SO189/2_039KL

Climate phenomena like the monsoon system, El Niño Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD) are interconnected via various feedback mechanisms and control the climate of the Indian Ocean and its surrounding continents on various timescales. The eastern tropical Indian Ocean is a key area for the interplay of these phenomena and for reconstructing their past changes and forcing mechanisms. Here we present records of upper ocean thermal gradient, thermocline temperatures (TT) and relative abundances of planktic foraminifera in core SO 189-39KL taken off western Sumatra (0°47.400' S, 99°54.510' E) for the last 8 ka that we use as proxies for changes in upper ocean structure. The records suggest a deeper thermocline between 8 ka and ca 3 ka compared to the late Holocene. We find a shoaling of the thermocline after 3 ka, most likely indicating an increased occurrence of upwelling during the late Holocene compared to the mid-Holocene which might represent changes in the IOD-like mean state of the Indian Ocean with a more negative IOD-like mean state during the mid-Holocene and a more positive IOD-like mean state during the past 3 ka. This interpretation is supported by a transient Holocene climate model simulation in which an IOD-like mode is identified that involves an insolation-forced long-term trend of increasing anomalous surface easterlies over the equatorial eastern Indian Ocean.

Comparison of experimental and numerical sloshing loads in partially filled tanks

Sloshing describes the movement of liquids inside partially filled tanks, generating dynamic loads on the tank structure. The resulting impact pressures are of great importance in assessing structural strength, and their correct evaluation still represents a challenge for the designer due to the high level of nonlinearities involved, with complex free surface deformations, violent impact phenomena and influence of air trapping. In the present paper, a set of two-dimensional cases, for which experimental results are available, is considered to assess the merits and shortcomings of different numerical methods for sloshing evaluation, namely two commercial RANS solvers (FLOW-3D and LS-DYNA), and two academic software (Smoothed Particle Hydrodynamics and RANS). Impact pressures at various critical locations and global moment induced by water motion in a partially filled rectangular tank, subject to a simple harmonic rolling motion, are evaluated and predictions are compared with experimental measurements. 2012 Copyright Taylor and Francis Group, LLC.

The genetics of pain and pain inhibition.

The present review summarizes the current state of knowledge about the genetics of pain-related phenomena and illustrates the scope and power of genetic approaches to the study of pain. We focus on work performed in our laboratories in Jastrzebiec, Poland; Portland, OR; and Los Angeles, which we feel demonstrates the continuing usefulness of classical genetic approaches, especially when used in combination with newly available molecular genetic techniques.

The debt, the stock market and the state-owned enterprises. The sources of chaos on the Chinese financial markets. OSW Commentary NUMBER 201/16.03.2016

The government’s extensive programme for stimulating the economy has enabled China to maintain high economic growth after the global financial crisis in 2008. However, this success has come at the price of a number of negative economic phenomena and the consequences they have had are the major challenge for the government today. The vast programme of investments in infrastructure, construction and fixed assets, which has been the main source of economic growth over the past few years, has caused a rapid increase in China’s debt from 158% of GDP in 2007 to 282% in 2014. Along with the local governments in charge of implementing the programme, the Chinese sector of state-owned enterprises (SOEs) has been heavily burdened by the stimulation policy. The sector’s profitability has fallen, its indebtedness has increased and management problems have been revealed.

The Foreign commerce and navigation of the United States for the year ending ... /

Prepared by the Foreign Trade Division, 1941-

Rules and regulations ... and National Labor Relations Act /

Some numbers also in amended editions.

Rules, policy, organization, and acts

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Eating disorders and oral health: A review of the literature

This article is a review of the recent literature pertaining to the oral sequelae of eating disorders (EDs). Dentists are recognized as being some of the first health care professionals to whom a previously undiagnosed eating disorder patient (EDP) may present. However, despite the prevalence (up to 4 per cent) of such conditions in teenage girls and young adult females, there is relatively little published in the recent literature regarding the oral sequelae of EDs. This compares unfavourably with the attention given recently in the dental literature to conditions such as diabetes mellitus, which have a similar prevalence in the adult population. The incidence of EDs is increasing and it would be expected that dentists who treat patients in the affected age groups would encounter more individuals exhibiting EDs. Most of the reports in the literature concentrate on the obvious clinical features of dental destruction (perimolysis), parotid swelling and biochemical abnormalities particularly related to salivary and pancreatic amylase. However, there is no consistency in explanation of the oral phenomena and epiphenomena seen in EDs. Many EDPs are nutritionally challenged; there is a relative lack of information pertaining to non-dental, oral lesions associated with nutritional deficiencies.