Cardiovascular changes after pulmonary embolism from injecting calcium phosphate cement

Concerns have been raised that the use of calcium phosphate (CaP) cements for the augmentation of fractured, osteoporotic bones may aggravate cardiovascular deterioration in the event of pulmonary cement embolism by stimulating coagulation. The aim of the present study was therefore to investigate the cardiovascular changes after pulmonary embolism of CaP cement using an animal model. In 14 sheep, 2.0 mL CaP or polymethylmethacrylate cement were injected intravenously. Cardiovascular parameters and antithrombin levels were monitored until 60 min postinjection. Postmortem, lungs were subjected to CT scanning, and 3D reconstruction of the cement was performed. Intravenous injection of CaP cement resulted in a more severe increase in pulmonary arterial pressure and decrease in arterial blood pressure. Disintegration of the CaP cement seemed to be the reason for the more severe reaction. There was no evidence of thromboembolism. Disintegration of CaP cement in circulating blood does not only compromise the mechanical properties, but also represents a risk of cardiovascular complications. Reliable cohesion of CaP cements in an aqueous environment is essential for clinical applications such as osteoporotic bone augmentation.     

CD2 and TCR synergize for the activation of phospholipase Cgamma1/calcium pathway at the immunological synapse

Upon conjugation with cognate antigen-presenting cells (APCs), T lymphocytes undergo a sustained [Ca(2+)](i) increase resulting from the engagement of TCR and of accessory molecules with ligands expressed on the surface of APCs. We investigated the contribution of the accessory molecule CD2 to the activation of phospholipase Cgamma1 (PLCgamma1)/calcium pathway in antigen-stimulated T cells. We show that CD2 binding with its ligand CD58 expressed on the surface of APCs augments and sustains antigen-induced [Ca(2+)](i) increase in individual T cells interacting with APCs. We also show that in conditions in which CD2-CD58 interaction is impeded, the recruitment of PLCgamma1 to the immunological synapse (IS) is reduced. Interestingly, in these conditions PLCgamma1 phosphorylation in the regulatory tyrosine 783 is also defective. Our results indicate that TCR- and CD2-derived signals converge for the recruitment and activation of PLCgamma1 at the IS and shed new light on the accessory function of CD2 in T cell activation by specific antigen.     

Endemic human monkeypox, Democratic Republic of Congo, 2001-2004

By analyzing vesicle fluids and crusted scabs from 136 persons with suspected monkeypox, we identified 51 cases of monkeypox by PCR, sequenced the hemagglutinin gene, and confirmed 94% of cases by virus culture. PCR demonstrated chickenpox in 61 patients. Coinfection with both viruses was found in 1 additional patient.     

Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors.

Combinations of tests comprising alpha2-macroglobulin, haptoglobin, apolipoprotein Al, gamma-glutamyltransferase, total bilirubin (Fibrotest) and alanine aminotransferase (Actitest) are being developed as alternatives to liver biopsy in patients with chronic hepatitis C. The aim of this study was to assess in the same laboratory the impact of parameter assay variations on Fibrotest and Actitest results and intra-patient reproducibility of the two tests. The stability of the samples for each test was studied after storage at -80 degrees C and -20 degrees C. Within-run, between-run and total imprecision for each parameter assay, and for Fibrotest and Actitest results, were determined. Transferability of assay results between different analyzers was studied. Intra-patient reproducibility was assessed in 55 hospitalized patients. Fibrotest and Actitest reference ranges were determined in 300 blood donors (reference group). The stability of the parameters was affected by serum storage at -20 degrees C only. The impact of parameter analytical variability on Fibrotest and Actitest results was less than 10% and intra-patient reproducibility was acceptable (p > 0.05). The transferability between different analyzers of results of assays performed under the same standardized and calibration conditions was excellent. Fibrotest and Actitest reference ranges in blood donors were (mean+/-SE) 0.075+/-0.004 and 0.068+/-0.004, respectively. The low intra-laboratory and intra-patient variability in Fibrotest and Actitest results confirm Fibrotest and Actitest reliability.     

Tetracycline use in the community may promote decreased susceptibility to quinolones in <Emphasis Type="Italic">Escherichia coli</Emphasis> isolates

We previously found that the hospital use of tetracyclines is associated with quinolone resistance in hospital isolates of Enterobacteriaceae. Tetracyclines are heavily used in the community. Our aim was to assess whether their use in the community favors quinolone resistance in community isolates of Escherichia coli. Monthly data of community antibiotics use and E. coli quinolone resistance in a 1.3 million inhabitant French area were obtained from 2009 to 2014, and were analyzed with autoregressive integrated moving average (ARIMA) models. Quinolone use decreased from 10.1% of the total antibiotic use in 2009 to 9.3% in 2014 (trend, ? 0.016; p-value < 0.0001), while tetracycline use increased from 16.5% in 2009 to 17.1% in 2014 (trend, 0.016; p < 0.0001). The mean (95% confidence interval) monthly proportions of isolates that were non-susceptible to nalidixic acid and ciprofloxacin were 14.8% (14.2%–15.5%) and 9.5% (8.8%–10.1%), respectively, with no significant temporal trend. After adjusting on quinolone use, tetracycline use in the preceding month was significantly associated with nalidixic acid non-susceptibility (estimate [SD], 0.01 [0.007]; p-value, 0.04), but not with ciprofloxacin non-susceptibility (estimate [SD], 0.01 [0.009]; p-value, 0.23). Tetracycline use in the community may promote quinolone non-susceptibility in E. coli. Decreasing both tetracycline and quinolone use may be necessary to fight against the worldwide growth of quinolone resistance.     

A coupled human–natural system analysis of freshwater security under climate and population change

Limited water availability, population growth, and climate change have resulted in freshwater crises in many countries. Jordan’s situation is emblematic, compounded by conflict-induced population shocks. Integrating knowledge across hydrology, climatology, agriculture, political science, geography, and economics, we present the Jordan Water Model, a nationwide coupled human–natural-engineered systems model that is used to evaluate Jordan’s freshwater security under climate and socioeconomic changes. The complex systems model simulates the trajectory of Jordan’s water system, representing dynamic interactions between a hierarchy of actors and the natural and engineered water environment. A multiagent modeling approach enables the quantification of impacts at the level of thousands of representative agents across sectors, allowing for the evaluation of both systemwide and distributional outcomes translated into a suite of water-security metrics (vulnerability, equity, shortage duration, and economic well-being). Model results indicate severe, potentially destabilizing, declines in freshwater security. Per capita water availability decreases by approximately 50% by the end of the century. Without intervening measures, >90% of the low-income household population experiences critical insecurity by the end of the century, receiving <40 L per capita per day. Widening disparity in freshwater use, lengthening shortage durations, and declining economic welfare are prevalent across narratives. To gain a foothold on its freshwater future, Jordan must enact a sweeping portfolio of ambitious interventions that include large-scale desalinization and comprehensive water sector reform, with model results revealing exponential improvements in water security through the coordination of supply- and demand-side measures.

Jordan, a nearly land-locked nation, has a tenuous freshwater future. The country’s water challenges stem from having extremely limited natural water availability with few alternatives for generating new supply and dependence on transboundary rivers and groundwater (Fig. 1A). Flows in the lower Jordan River, which marks Jordan’s western border with Israel and the West Bank, are estimated to have declined by nearly 90% since predevelopment conditions (1), mostly due to the diversion of the upper Jordan River into the National Water Carrier by Israel (2). The Yarmouk River tributary, currently Jordan’s primary surface-water source, is also largely captured by upstream Syria (3–6). Throughout the country, groundwater is being rapidly depleted, with observed groundwater-level declines of 0.9 to 3.5 m/y since 1995 in the country’s most highly productive aquifer (7, 8). To the south, Jordan competes with Saudi Arabia for shared groundwater from the fossil Disi regional aquifer (9). Jordan has long sought construction of the Red Sea–Dead Sea conveyance project, which would desalinate Red Sea water, transport the freshwater north to Amman, and dispose of the saline brine to the Dead Sea. Although first conceived of in the 1960s, project costs and fragile international cooperation have stood in the way.Open in a separate windowFig. 1.Map of Jordan and conceptual model. (A) Jordan relies on surface-water sources (primarily the Yarmouk River) and groundwater wells for water supply. The most recent record of total freshwater use from Jordan’s MWI is 1,054 MCM for 2017, with groundwater contributing 59% of the total supply, surface water 27%, and treated wastewater 14%. The domestic sector uses 45% of all water, agriculture 52%, and industry 3%. Groundwater is the primary source for the domestic sector, constituting over 70% of its supply. For the agricultural sector, groundwater constitutes 46% of the supply for irrigation, surface water 28%, and treated wastewater 26%. (B) The JWM consists of two types of modules: human modules (white rectangles) and biophysical modules (gray rectangles) of natural and engineered physical phenomena. The systems model includes interactions between modules, distinguished by endogenous human decisions (blue lines), endogenous physical flows and production (green lines), and exogenous scenarios (pink lines) and human interventions (yellow lines).Climate change and population growth further threaten Jordan’s tenuous situation (10). Rainfall decline in Jordan is already evident over the past century (11, 12), while climate models predict further increased temperatures with doubling in the frequency, duration, and intensity of droughts by 2100 (13). Jordan’s growing population has been punctuated by sudden, large refugee influxes (10, 14). In 2010, Jordan’s population was 7.2 million, growing to over 10.8 million by 2020, a period when at least 1.1 million Syrian refugees fled Syria’s 2011 war to Jordan (2, 15). In response to water shortage, Jordan has implemented significant water-supply efficiencies. In Amman, the largest city and capital, over 95% of wastewater is treated and recycled. However, Jordan’s water-distribution system is inefficient and intermittent. Approximately 50% of Jordan’s piped supply is lost as “nonrevenue water” (NRW), due to either physical factors (e.g., pipeline leaks) or administrative issues (e.g., water theft, incorrect meter readings, or underbilling). On average, households in the capital of Amman receive piped water for only 36 h per week (16), with lower-income neighborhoods receiving as low as 24 h of municipal supply, while higher-income households receive up to 5 d of uninterrupted supply per week (17). As a result, urban users purchase expensive water delivered by tanker trucks that obtain water from private agricultural wells through both formal and informal tanker-water markets (17, 18). Ecological impacts related to both groundwater and surface-water withdrawals by Jordan and upstream riparian nations in the Jordan River Basin have been severe, with notable examples including the drying of the Azraq Oasis, a Ramsar wetland (19, 20), and the shrinking of the Dead Sea, whose shoreline is receding by ∼1 m/y (21).The situation in Jordan is emblematic of water crises around the world, in which rapid population growth, intensifying water use, sudden demographic shocks, climate change, transboundary water competition, and institutional challenges pose serious threats to freshwater security (22–28). In the face of such global changes, an overarching sustainability goal is the long-term provision of freshwater as formalized in the 2015 Sustainable Development Goals (29). Given the complex and interacting physical and socioeconomic facets of such a challenge, there has been a growing call for analytic frameworks to evaluate freshwater systems that account for both the physical processes that govern freshwater supply and the human institutions and behaviors that influence the management, allocation, and consumption of water (30–36). Here, we present such a coupled human–natural-engineered system framework to explore the long-term impacts of a suite of policy interventions aimed at achieving freshwater security in Jordan in the face of anticipated changes in climate, population, and the economy.     

A Phase 2 study of L‐asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL‐SA2‐2008 study

Purpose : The GRASPALL/GRAALL‐SA2‐2008 Phase II trial evaluated the safety and efficacy of L‐asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome‐negative acute lymphoblastic leukemia. Findings : Thirty patients received escalating doses of GRASPA^® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti‐asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L‐asparaginase activity. Complete remission rate was 70%. With a median follow‐up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. Conclusions : The addition of GRASPA^®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. ( clinicaltrials.gov identifier NCT01523782). Am. J. Hematol. 90:811–818, 2015. © 2015 Wiley Periodicals, Inc.     

Histological validation of ICDAS II and radiological assessment of occlusal carious lesions in permanent teeth

The International Caries Detection and Assessment System (ICDAS) was introduced for a detailed evaluation of dental caries. The aim of the present study was to compare the ICDAS scores and radiologically evaluated caries depths to the histologically evaluated carious lesions in permanent teeth. 84 freshly extracted human teeth were included. Visual examination and scoring of the occlusal aspect were performed according to the ICDAS II criteria after completing a respective e-learning programme to support training in the use of ICDAS. Bucco-lingual digital X-ray images of the teeth were taken. Specimens were then fixed in formalin and embedded in a photocuring one-component methacrylate-based resin. Longitudinal sections were cut and stained with rhodamine B, fuchsin and acetic light green dye to assess the caries extension by light microscopic analysis. Assessing ICDAS II scores and histological findings, a rank correlation coefficient of r = 0.890 could be found. ICDAS II/radiology and histology/radiology showed correlation coefficients of r = 0.658 and 0.661, respectively. Evaluating receiver operating characteristic (ROC) curves, no exact predictability could be found for caries lesions in enamel for both ICDAS II and radiological evaluation. Focussing on deep dentin lesions, values of 0.940 (ICDAS II) and 0.845 (radiology) showed high predictability with respect to the histologically observed caries extension. The present study indicates an acceptable validity of the ICDAS II criteria when applied to permanent teeth. Especially, dentin lesions can be reliably detected. Thus, ICDAS assessment provides the possibility of reducing X-ray exposure for caries detection.     

Preserved regulation of renal perfusion pressure by small and intermediate conductance K<Subscript>Ca</Subscript> channels in hypertensive mice with or without renal failure

The purpose of this study was to assess, in the murine kidney, the mechanisms underlying the endothelium-dependent control of vascular tone and whether or not, in a severe model of hypertension and renal failure, K_Ca channels contribute to its regulation. Wild-type (BL) and double-transgenic female mice expressing human angiotensinogen and renin (AR) genes received either control or a high-salt diet associated to a nitric oxide (NO) synthase inhibitor treatment (BLSL and ARSL). Changes in renal perfusion pressure (RPP) were measured in isolated perfused kidneys. BLSL and AR were moderately hypertensive without kidney disease while ARSL developed severe hypertension and renal failure. In the four groups, methacholine induced biphasic endothelium-dependent responses, a transient decrease in RPP followed by a cyclooxygenase-dependent increase in RPP. In the presence or not of indomethacin, the vasodilatations were poorly sensitive to NO synthase inhibition. However, in the presence of cyclooxygenase and NO synthase inhibitors, apamin, and/or TRAM-34, blockers of K_Ca2.3 and K_Ca3.1, respectively, abolished the decrease in RPP in response to either methacholine or the two activators of K_Ca2.3/K_Ca3.1, NS309, and SKA-31. Thus, K_Ca2/3 channels play a major role in the regulation of murine kidney perfusion and this mechanism is maintained in hypertension, even when severe and associated with kidney damage.