Effect of Shear Stress on Platelet Activation via the Glycoprotein VI Receptor

Cardiovascular diseases are the nation\u27s leading cause of death. Such diseases are caused by platelet response to collagen especially in the event of vascular injury leading to thrombosis. One of the platelet receptors known to bind to the collagen ligand is glycoprotein VI (GPVI) with co-receptor Fc receptor γ chain (FcRγ). By stably expressing the GPVI receptor in rat basophilic leukemia cells (RBL-2H3), which abundantly express FcRγ, but endogenously lack GPVI, studies have shown that GPVI-FcRγ is sufficient to confer adhesion as well as signaling responses to collagen as long as the receptor density is equivalent to that found on human platelets. While those investigations confirm that the GPVI receptor mediate binding to collagen under static conditions, they do not provide information on how the GPVI receptor interacts with collagen under dynamic conditions. In the present study we have used the GPVI-expressing RBL-2H3 cells to observe the kinetics of adhesion to collagen under hydrodynamic flow conditions in vitro using a parallel plate flow chamber coupled with video microscopy. We demonstrate that these cells do adhere to the surface at a low shear rate and do so at a greater adherent cell density than wild-type RBL-2H3 (WT-RBL) cells

Reaction of Titanocene Dichloride with Acetylenedicarboxylate

The reaction of Cp2TiCl2 with either the mono- or dipotassium salt of acetylenedicarboxylic acid (ADC) gives high yields of an insoluble orange product. The insoluble compound shows potential semiconductor behavior, as evidenced by an apparent bandgap in the orange region of the visible spectrum. Under N2 ,the compound decomposes at 238° C, eventually losing approximately 46% total mass up to 1350° C. The exothermic decomposition in air, beginning at 235° C, results in the formation of titanium oxides

Elevated Depression Symptoms, Antidepressant Medicine Use, and Risk of Developing Diabetes During the Diabetes Prevention Program

OBJECTIVE—To assess the association between elevated depression symptoms or antidepressant medicine use on entry to the Diabetes Prevention Program (DPP) and during the study and the risk of developing diabetes during the study. RESEARCH DESIGN AND METHODS—DPP participants (n = 3,187) in three treatment arms (intensive lifestyle [ILS], metformin [MET], and placebo [PLB]) completed the Beck Depression Inventory (BDI) and reported their use of antidepressant medication at randomization and throughout the study (average duration in study 3.2 years). RESULTS—When other factors associated with the risk of developing diabetes were controlled, elevated BDI scores at baseline or during the study were not associated with diabetes risk in any arm. Baseline antidepressant use was associated with diabetes risk in the PLB (hazard ratio 2.25 [95% CI 1.38–3.66]) and ILS (3.48 [1.93–6.28]) arms. Continuous antidepressant use during the study (compared with no use) was also associated with diabetes risk in the same arms (PLB 2.60 [1.37–4.94]; ILS 3.39 [1.61–7.13]), as was intermittent antidepressant use during the study in the ILS arm (2.07 [1.18–3.62]). Among MET arm participants, antidepressant use was not associated with developing diabetes. CONCLUSIONS—A strong and statistically significant association between antidepressant use and diabetes risk in the PLB and ILS arms was not accounted for by measured confounders or mediators. If future research finds that antidepressant use independently predicts diabetes risk, efforts to minimize the negative effects of antidepressant agents on glycemic control should be pursued

Ten-year cancer incidence in rescue/recovery workers and civilians exposed to the September 11, 2001 terrorist attacks on the World Trade Center

Background: Cancer incidence in exposed rescue/recovery workers (RRWs) and civilians (non-RRWs) was previously reported through 2008. Methods: We studied occurrence of first primary cancer among World Trade Center Health Registry enrollees through 2011 using adjusted standardized incidence ratios (SIRs), and the WTC-exposure-cancer association, using Cox proportional hazards models. Results: All-cancer SIR was 1.11 (95% confidence interval (CI) 1.03–1.20) in RRWs, and 1.08 (95% CI 1.02–1.15) in non-RRWs. Prostate cancer and skin melanoma were significantly elevated in both populations. Thyroid cancer was significantly elevated only in RRWs while breast cancer and non-Hodgkin's lymphoma were significantly elevated only in non-RRWs. There was a significant exposure dose-response for bladder cancer among RRWs, and for skin melanoma among non-RRWs. Conclusions: We observed excesses of total and specific cancers in both populations, although the strength of the evidence for causal relationships to WTC exposures is somewhat limited. Continued monitoring of this population is indicated

Young and vulnerable: Spatial-temporal trends and risk factors for infant mortality in rural South Africa (Agincourt), 1992-2007

<p>Abstract</p> <p>Background</p> <p>Infant mortality is an important indicator of population health in a country. It is associated with several health determinants, such as maternal health, access to high-quality health care, socioeconomic conditions, and public health policy and practices.</p> <p>Methods</p> <p>A spatial-temporal analysis was performed to assess changes in infant mortality patterns between 1992-2007 and to identify factors associated with infant mortality risk in the Agincourt sub-district, rural northeast South Africa. Period, sex, refugee status, maternal and fertility-related factors, household mortality experience, distance to nearest primary health care facility, and socio-economic status were examined as possible risk factors. All-cause and cause-specific mortality maps were developed to identify high risk areas within the study site. The analysis was carried out by fitting Bayesian hierarchical geostatistical negative binomial autoregressive models using Markov chain Monte Carlo simulation. Simulation-based Bayesian kriging was used to produce maps of all-cause and cause-specific mortality risk.</p> <p>Results</p> <p>Infant mortality increased significantly over the study period, largely due to the impact of the HIV epidemic. There was a high burden of neonatal mortality (especially perinatal) with several hot spots observed in close proximity to health facilities. Significant risk factors for all-cause infant mortality were mother's death in first year (most commonly due to HIV), death of previous sibling and increasing number of household deaths. Being born to a Mozambican mother posed a significant risk for infectious and parasitic deaths, particularly acute diarrhoea and malnutrition.</p> <p>Conclusions</p> <p>This study demonstrates the use of Bayesian geostatistical models in assessing risk factors and producing smooth maps of infant mortality risk in a health and socio-demographic surveillance system. Results showed marked geographical differences in mortality risk across a relatively small area. Prevention of vertical transmission of HIV and survival of mothers during the infants' first year in high prevalence villages needs to be urgently addressed, including expanded antenatal testing, prevention of mother-to-child transmission, and improved access to antiretroviral therapy. There is also need to assess and improve the capacity of district hospitals for emergency obstetric and newborn care. Persisting risk factors, including inadequate provision of clean water and sanitation, are yet to be fully addressed.</p

Protégé: A Tool for Managing and Using Terminology in Radiology Applications

The development of standard terminologies such as RadLex is becoming important in radiology applications, such as structured reporting, teaching file authoring, report indexing, and text mining. The development and maintenance of these terminologies are challenging, however, because there are few specialized tools to help developers to browse, visualize, and edit large taxonomies. Protégé (http://protege.stanford.edu) is an open-source tool that allows developers to create and to manage terminologies and ontologies. It is more than a terminology-editing tool, as it also provides a platform for developers to use the terminologies in end-user applications. There are more than 70,000 registered users of Protégé who are using the system to manage terminologies and ontologies in many different domains. The RadLex project has recently adopted Protégé for managing its radiology terminology. Protégé provides several features particularly useful to managing radiology terminologies: an intuitive graphical user interface for navigating large taxonomies, visualization components for viewing complex term relationships, and a programming interface so developers can create terminology-driven radiology applications. In addition, Protégé has an extensible plug-in architecture, and its large user community has contributed a rich library of components and extensions that provide much additional useful functionalities. In this report, we describe Protégé’s features and its particular advantages in the radiology domain in the creation, maintenance, and use of radiology terminology

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis.

Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.journal articleresearch support, non-u.s. gov'tresearch support, n.i.h., extramural2017 11 062017 10 19importe

Platelet ITAM signaling is critical for vascular integrity in inflammation

Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway

Association Between World Trade Center Exposure and Excess Cancer Risk

Context: The terrorist attacks of September 11, 2001, resulted in the release of known and suspected carcinogens into the environment. There is public concern that exposures may have resulted in increased cancers. Objective: To evaluate cancer incidence among persons enrolled in the World Trade Center Health Registry. Design, Setting, and Participants: Observational study of 55 778 New York State residents enrolled in the World Trade Center Health Registry in 2003-2004, including rescue/recovery workers (n = 21 850) and those not involved in rescue/recovery (n = 33 928), who were followed up from enrollment through December 31, 2008. Within-cohort comparisons using Cox proportional hazards models assessed the relationship between intensity of World Trade Center exposure and selected cancers. Main Outcome Measures: Cases were identified through linkage with 11 state cancer registries. Standardized incidence ratios (SIRs) adjusted for age, race/ethnicity, and sex were computed with 2003-2008 New York State rates as the reference, focusing on cancers diagnosed in 2007-2008 as being most likely to be related to exposure during September 11 and its aftermath. The total and site-specific incidence rate differences (RDs) per 100 000 person-years between the study population and the New York State population in 2007-2008 also were calculated. Results: There were 1187 incident cancers diagnosed, with an accumulated 253 269 person-years (439 cancers among rescue/recovery workers and 748 among those not involved in rescue/recovery). The SIR for all cancer sites combined in 2007-2008 was not significantly elevated (SIR, 1.14 [95% CI, 0.99 to 1.30]; RD, 67 [95% CI, −6 to 126] per 100 000 person-years among rescue/recovery workers vs SIR, 0.92 [95% CI, 0.83 to 1.03]; RD, −45 [95% CI, −106 to 15] per 100 000 person-years among those not involved in rescue/recovery). Among rescue/recovery workers, the SIRs had significantly increased by 2007-2008 for 3 cancer sites and were 1.43 (95% CI, 1.11 to 1.82) for prostate cancer (n = 67; RD, 61 [95% CI, 20 to 91] per 100 000 person-years), 2.02 (95% CI, 1.07 to 3.45) for thyroid cancer (n = 13; RD, 16 [95% CI, 2 to 23] per 100 000 person-years), and 2.85 (95% CI, 1.15 to 5.88) for multiple myeloma (n = 7; RD, 11 [95% CI, 2 to 14] per 100 000 person-years). No increased incidence was observed in 2007-2008 among those not involved in rescue/recovery. Using within-cohort comparisons, the intensity of World Trade Center exposure was not significantly associated with cancer of the lung, prostate, thyroid, non-Hodgkin lymphoma, or hematological cancer in either group. Conclusions: Among persons enrolled in the World Trade Center Health Registry, there was an excess risk for prostate cancer, thyroid cancer, and myeloma in 2007-2008 compared with that for New York State residents; however, these findings were based on a small number of events and multiple comparisons. No significant associations were observed with intensity of World Trade Center exposures. Longer follow-up for typically long-latency cancers and attention to specific cancer sites are needed