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1.
J Thromb Haemost ; 16(10): 2083-2096, 2018 10.
Article in English | MEDLINE | ID: mdl-30007118

ABSTRACT

Essentials Reactive oxygen species (ROS) generation by NOX2 plays a critical role in platelet activation. Rac1 regulation of NOX2 is important for ROS generation. Small molecule inhibitor of the Rac1-p67phox interaction prevents platelet activation. Pharmacologic targeting of Rac1-NOX2 axis can be a viable approach for antithrombotic therapy. SUMMARY: Background Platelets from patients with X-linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX2 exhibit diminished reactive oxygen species (ROS) generation and platelet activation. Binding of Rac1 GTPase to p67phox plays a critical role in NOX2 activation by facilitating the assembly of the NOX2 enzyme complex. Objective We tested the hypothesis that Phox-I, a rationally designed small molecule inhibitor of Rac-p67phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Results Collagen-related peptide (CRP) induced ROS generation in a time-dependent manner. Platelets from Rac1-/- mice or human platelets treated with NSC23766, a specific Rac inhibitor, produced significantly less ROS in response to CRP. Treatment of platelets with Phox-I inhibited diverse CRP-induced responses, including: (i) ROS generation; (ii) release of P-selectin; (iii) secretion of ATP; (iv) platelet aggregation; and (v) phosphorylation of Akt. Similarly, incubation of platelets with Phox-I inhibited thrombin-induced: (i) secretion of ATP; (ii) platelet aggregation; (iii) rise in cytosolic calcium; and (iv) phosphorylation of Akt. In mouse models, intraperitoneal administration of Phox-I inhibited: (i) collagen-induced platelet aggregation without affecting the tail bleeding time and (ii) in vivo platelet adhesion/accumulation at the laser injury sites on the saphenous vein without affecting the time for complete cessation of blood loss. Conclusions Small molecule targeting of the Rac1-p67phox interaction may present an antithrombosis regimen by preventing GPVI- and non-GPVI-mediated NOX2 activation, ROS generation and platelet function without affecting the bleeding time.


Subject(s)
Blood Platelets/drug effects , Enzyme Inhibitors/pharmacology , Fibrinolytic Agents/pharmacology , NADPH Oxidase 2/antagonists & inhibitors , Neuropeptides/antagonists & inhibitors , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Reactive Oxygen Species/blood , rac1 GTP-Binding Protein/antagonists & inhibitors , Animals , Blood Platelets/enzymology , Calcium Signaling/drug effects , Carrier Proteins/pharmacology , Humans , Mice, Knockout , NADPH Oxidase 2/blood , Neuropeptides/blood , Neuropeptides/genetics , Peptides/pharmacology , Platelet Membrane Glycoproteins/metabolism , Thrombin/pharmacology , rac1 GTP-Binding Protein/blood , rac1 GTP-Binding Protein/genetics
2.
Phys Rev Lett ; 120(12): 125001, 2018 Mar 23.
Article in English | MEDLINE | ID: mdl-29694102

ABSTRACT

Multiple self-emission x-ray images are used to measure tomographically target modes 1, 2, and 3 up to the end of the target acceleration in direct-drive implosions on OMEGA. Results show that the modes consist of two components: the first varies linearly with the laser beam-energy balance and the second is static and results from physical effects including beam mistiming, mispointing, and uncertainty in beam energies. This is used to reduce the target low modes of low-adiabat implosions from 2.2% to 0.8% by adjusting the beam-energy balance to compensate these static modes.

3.
Phys Rev E ; 95(5-1): 051202, 2017 May.
Article in English | MEDLINE | ID: mdl-28618558

ABSTRACT

A series of direct-drive implosions performed on OMEGA were used to isolate the effect of an adiabat on the in-flight shell thickness. The maximum in-flight shell thickness was measured to decrease from 75±2 to 60±2µm when the adiabat of the shell was reduced from 6 to 4.5, but when decreasing the adiabat further (1.8), the shell thickness increased to 75±2µm due to the growth of the Rayleigh-Taylor instability. Hydrodynamic simulations suggest that a laser imprint is the dominant seed for these nonuniformities.

4.
Rev Sci Instrum ; 87(11): 11E340, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27910667

ABSTRACT

As hydrodynamics codes develop to increase understanding of three-dimensional (3-D) effects in inertial confinement fusion implosions, diagnostics must adapt to evaluate their predictive accuracy. A 3-D radiation postprocessor was developed to investigate the use of soft x-ray self-emission images of an imploding target to measure the size of nonuniformities on the target surface. Synthetic self-emission images calculated from 3-D simulations showed a narrow ring of emission outside the ablation surface of the target. Nonuniformities growing in directions perpendicular to the diagnostic axis were measured through angular variations in the radius of the steepest intensity gradient on the inside of the ring and through changes in the peak x-ray intensity in the ring as a function of angle. The technique was applied to an implosion to measure large 3-D nonuniformities resulting from two dropped laser beam quads at the National Ignition Facility.

5.
Transpl Immunol ; 39: 30-33, 2016 11.
Article in English | MEDLINE | ID: mdl-27663090

ABSTRACT

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.


Subject(s)
ABO Blood-Group System/immunology , Cystic Fibrosis/therapy , Graft Rejection/immunology , Isoantigens/immunology , Kidney Failure, Chronic/therapy , Kidney Transplantation , Lung Transplantation , Sepsis/therapy , Acute Disease , Adult , Disease-Free Survival , Female , Graft Rejection/drug therapy , HLA Antigens/immunology , Humans , Living Donors , Middle Aged , Mothers , Mycophenolic Acid/therapeutic use , Plasmapheresis , Prednisolone/therapeutic use , Tacrolimus/therapeutic use , Withholding Treatment
6.
J Thromb Haemost ; 14(11): 2253-2260, 2016 11.
Article in English | MEDLINE | ID: mdl-27601054

ABSTRACT

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.


Subject(s)
Blood Platelets/cytology , Extracorporeal Membrane Oxygenation , Heart-Assist Devices , Platelet Glycoprotein GPIb-IX Complex/chemistry , Platelet Membrane Glycoproteins/chemistry , Adolescent , Adult , Aged , Aortic Valve Stenosis/physiopathology , Blood Platelets/metabolism , Cohort Studies , Female , Heart Failure/complications , Hemorrhage/complications , Heparin/therapeutic use , Humans , Male , Middle Aged , Platelet Activation , Stress, Mechanical , Thrombosis , Warfarin/therapeutic use , Young Adult , von Willebrand Factor/chemistry
8.
Phys Rev Lett ; 117(2): 025001, 2016 Jul 08.
Article in English | MEDLINE | ID: mdl-27447511

ABSTRACT

A record fuel hot-spot pressure P_{hs}=56±7 Gbar was inferred from x-ray and nuclear diagnostics for direct-drive inertial confinement fusion cryogenic, layered deuterium-tritium implosions on the 60-beam, 30-kJ, 351-nm OMEGA Laser System. When hydrodynamically scaled to the energy of the National Ignition Facility, these implosions achieved a Lawson parameter ∼60% of the value required for ignition [A. Bose et al., Phys. Rev. E 93, 011201(R) (2016)], similar to indirect-drive implosions [R. Betti et al., Phys. Rev. Lett. 114, 255003 (2015)], and nearly half of the direct-drive ignition-threshold pressure. Relative to symmetric, one-dimensional simulations, the inferred hot-spot pressure is approximately 40% lower. Three-dimensional simulations suggest that low-mode distortion of the hot spot seeded by laser-drive nonuniformity and target-positioning error reduces target performance.

12.
Phys Rev Lett ; 114(15): 155002, 2015 Apr 17.
Article in English | MEDLINE | ID: mdl-25933317

ABSTRACT

Measurements of the conduction-zone length (110±20 µm at t=2.8 ns), the averaged mass ablation rate of the deuterated plastic (7.95±0.3 µg/ns), shell trajectory, and laser absorption are made in direct-drive cryogenic implosions and are used to quantify the electron thermal transport through the conduction zone. Hydrodynamic simulations that use nonlocal thermal transport and cross-beam energy transfer models reproduce these experimental observables. Hydrodynamic simulations that use a time-dependent flux-limited model reproduce the measured shell trajectory and the laser absorption but underestimate the mass ablation rate by ∼10% and the length of the conduction zone by nearly a factor of 2.

13.
Rev Sci Instrum ; 85(11): 11D616, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25430192

ABSTRACT

A technique to measure the mass ablation rate in direct-drive inertial confinement fusion implosions using a pinhole x-ray framing camera is presented. In target designs consisting of two layers of different materials, two x-ray self-emission peaks from the coronal plasma were measured once the laser burned through the higher-Z outer layer. The location of the inner peak is related to the position of the ablation front and the location of the outer peak corresponds to the position of the interface of the two layers in the plasma. The emergence of the second peak was used to measure the burnthrough time of the outer layer, giving the average mass ablation rate of the material and instantaneous mass remaining. By varying the thickness of the outer layer, the mass ablation rate can be obtained as a function of time. Simulations were used to validate the methods and verify that the measurement techniques are not sensitive to perturbation growth at the ablation surface.

14.
Physiol Biochem Zool ; 87(5): 719-28, 2014.
Article in English | MEDLINE | ID: mdl-25244383

ABSTRACT

Long-distance migrations are energetically expensive for many animals, including migratory songbirds. During these demanding journeys, birds likely face limitations in allocating resources to different physiological functions, including lipid reserves needed to fuel the migration and costly immune defense against pathogens. We sampled three species of long-distance migratory songbirds during their fall migration through coastal Georgia and quantified their body condition, subcutaneous fat reserves, and infection status with blood parasites (Hemoproteus and Plasmodium). We also quantified cellular immunity, on the basis of total and differential white blood cell counts, and estimated individual stress levels, using the heterophil∶lymphocyte (H∶L) ratio. We tested whether birds infected with blood parasites had decreased fat measures, poorer body condition, or increased stress levels (as reflected by H∶L ratios). We also examined relationships between immune cell profiles and the following variables: body condition, subcutaneous fat, infection status, age, and species. Infected birds did not show greater H∶L ratios, poorer body condition, or lower fat measures, but in one species infected individuals showed significantly elevated leukocyte counts. Although we found little evidence for negative relationships between immune cell counts and body condition or fat measures, as might reflect underlying trade-offs in resource allocation, our results concerning hemoparasites are consistent with past work and suggest that chronic hemoparasite infections might have minimal effects on the outcome of long-distance migratory flight.


Subject(s)
Adipose Tissue , Animal Migration , Bird Diseases/parasitology , Immunity, Innate , Protozoan Infections, Animal/parasitology , Songbirds , Animals , Bird Diseases/immunology , Bird Diseases/physiopathology , Female , Georgia , Haemosporida/isolation & purification , Leukocytes/metabolism , Malaria, Avian/immunology , Malaria, Avian/parasitology , Malaria, Avian/physiopathology , Male , Plasmodium/isolation & purification , Polymerase Chain Reaction/veterinary , Protozoan Infections, Animal/immunology , Protozoan Infections, Animal/physiopathology , Species Specificity , Stress, Physiological
15.
Haemophilia ; 19(6): 847-52, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23738855

ABSTRACT

In Australia prior to 1992, many patients with bleeding disorders were exposed to hepatitis C through blood products. However, the incidence, complications and response to treatment of chronic hepatitis C (CHC) in this population are poorly characterized. The aim of this study was to examine the prevalence of CHC and response to treatment in an Australian bleeding disorders population. Demographic data, virological data and liver disease status from these 700 patients with inherited bleeding disorders were analysed. Of these 700 patients, 424 (61%) had been tested for CHC infection and 219 (52%) were hepatitis C antibody positive, with the prevalence approaching 100% in patients with severe bleeding disorders. Of 219 patients, 73 (33%) had received treatment for their infection with a response rate of 33/73 (45%) across all genotypes. Of 219 patients, 34 (16%) had spontaneous viral clearance. When measured with transient elastography, 44/98 (45%) patients with CHC had significant liver fibrosis and 15/98 (15%) had liver cirrhosis. Of 130 patients, 38 (29%) with CHC infection had no evidence of follow-up with an appropriate clinician in the past 2 years. This study demonstrates that testing for CHC in this population is incomplete and treatment rates are low. Given the substantial morbidity and mortality associated with CHC and new therapeutic options becoming available, it seems important to reengage patients to diagnose, offer treatment and monitor this infection.


Subject(s)
Blood Coagulation Disorders/complications , Hepatitis C, Chronic/epidemiology , Transfusion Reaction , Adolescent , Adult , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , Australia , Blood Transfusion/statistics & numerical data , Drug Therapy, Combination , Female , HIV Infections/complications , HIV Infections/epidemiology , Hepacivirus/genetics , Hepatitis C Antibodies/blood , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Humans , Interferon-alpha/therapeutic use , Liver Cirrhosis/epidemiology , Male , Middle Aged , Polyethylene Glycols/therapeutic use , Prevalence , Recombinant Proteins/therapeutic use , Retrospective Studies , Ribavirin/therapeutic use , Young Adult
16.
Vox Sang ; 105(2): 159-66, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23600799

ABSTRACT

OBJECTIVES: Errors in administration of blood products can lead to poor patient outcomes including fatal ABO incompatible transfusions. This pilot study sought to establish whether the use of two-dimensional (2D) barcode technology combined with patient identification software designed to assist in blood administration improves the bedside administration of transfusions in an Australian tertiary hospital. STUDY DESIGN AND METHODS: The study was conducted in a Haematology/Oncology Day Clinic of a major metropolitan hospital, to evaluate the use of 2D barcode technology and patient safety-software and hand-held PDAs to assist nursing staff in patient identification and blood administration. Comparative audits were conducted before and after the technology's implementation. RESULTS: The preimplementation transfusion practice audits demonstrated a poor understanding of the blood checking process, with focus on the product rather than patient identification. Following the implementation of 2D barcode technology and patient safety-software, there was significant improvement in administration practice. Positive, verbal patient identification improved from 57% (51/90) to 94% (75/80). Similarly, the cross-referencing of the patient's identification with the patient's wristband improved from 36% (32/90) to 94% (75/80), and the cross-referencing of patient ID on the compatibility tag to wristbands improved from 48% (43/90) to 99% (79/80). Importantly, the 2D barcode technology and patient safety-software saw 100% (80/80) of checks being conducted at the patient bedside, compared with 76% (68/90) in the preimplementation audits. CONCLUSION: This pilot study demonstrates that 2D barcode technology and patient safety-software significantly improves the bedside check of patient and blood product identification in an Australian setting.


Subject(s)
Blood Group Incompatibility/prevention & control , Blood Transfusion , Medical Records Systems, Computerized/instrumentation , Patient Safety , Software , Tertiary Care Centers , Australia , Clinical Audit , Female , Humans , Male , Pilot Projects
17.
Br Dent J ; 213(4): E6, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22918373

ABSTRACT

OBJECTIVE: The National Institute for Health and Clinical Excellence (NICE) introduced the antibiotic prophylaxis guideline in 2008 for cardiac patients in the UK, which has led to a decrease in national prescription levels for antibiotic prophylaxis. Despite the introduction of the guideline there is still a discrepancy in levels of compliance among the dental community. The aims of this study were to determine the understanding of the NICE clinical guideline on antimicrobial prophylaxis against infective endocarditis (IE) and the difference in antibiotic prescription for high risk cardiac patients (HRCP) between dental trainers and trainees. METHODS: A proforma was designed and distributed among dental trainers and trainees attending a conference at the London deanery. The trainers were GDPs responsible for training dental trainees allocated to them over a 12 month period based in a general dental practice. Dental trainees were recent graduates about to commence their vocational dental training. Eighty-five vocational dental trainees and 70 trainers completed the proforma on a voluntary basis. RESULTS: The results of the study confirm that most trainers (95.7%) and trainees (94.1%) are aware of this guideline but only 62% of trainers and 69.7% of trainees have read the guideline. Compliancy with the guideline was low among trainers (55.7%) and trainees (77.6%). Compliance was high among those who had read the guideline. Trainers were more likely to prescribe prophylaxis antibiotics for HRCP. The majority (74-76%) would prescribe antibiotics on a specialist's request. Some trainers (54.9%) and trainees (48.2%) would want antibiotics themselves if they were HRCP. CONCLUSION: This study concludes that much needs to be done to improve the understanding and practice of NICE guideline among the dental trainers and trainees.


Subject(s)
Antibiotic Prophylaxis , Dental Care for Chronically Ill , Education, Dental , General Practice, Dental/education , Guideline Adherence , Heart Diseases , Internship and Residency , Practice Guidelines as Topic , Adult , Amoxicillin/therapeutic use , Anti-Bacterial Agents/therapeutic use , Attitude of Health Personnel , Dentists/psychology , Education, Dental, Graduate , Endocarditis, Bacterial/prevention & control , Female , Humans , Male , Middle Aged , Prescription Drugs , United Kingdom
18.
J Thromb Haemost ; 10(6): 1133-41, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22489915

ABSTRACT

BACKGROUND: Ligation of the platelet-specific collagen receptor, GPVI/FcRγ, causes rapid, transient disulfide-dependent homodimerization, and the production of intracellular reactive oxygen species (ROS) generated by the NADPH oxidase, linked to GPVI via TRAF4. OBJECTIVES: The aim of this study was to evaluate the role of early signaling events in ROS generation following engagement of either GPVI/FcRγ or a second immunoreceptor tyrosine-based activation motif (ITAM)-containing receptor on platelets, FcγRIIa. METHODS AND RESULTS: Using an H(2) DCF-DA-based flow cytometric assay to measure intracellular ROS, we show that treatment of platelets with either the GPVI agonists, collagen-related peptide (CRP) or convulxin (Cvx), or the FcγRIIa agonist 14A2, increased intraplatelet ROS; other platelet agonists such as ADP and TRAP did not. Basal ROS in platelet-rich plasma from 14 healthy donors displayed little inter-individual variability. CRP, Cvx or 14A2 induced an initial burst of ROS within 2 min followed by additional ROS reaching a plateau after 15-20 min. The Syk inhibitor BAY61-3606, which blocks ITAM-dependent signaling, had no effect on the initial ROS burst, but completely inhibited the second phase. CONCLUSIONS: Together, these results show for the first time that ROS generation downstream of GPVI or FcγRIIa consists of two distinct phases: an initial Syk-independent burst followed by additional Syk-dependent generation.


Subject(s)
Blood Platelets/enzymology , Intracellular Signaling Peptides and Proteins/metabolism , Platelet Membrane Glycoproteins/metabolism , Protein-Tyrosine Kinases/metabolism , Reactive Oxygen Species/metabolism , Receptors, IgG/metabolism , Signal Transduction , Amino Acid Motifs , Blood Platelets/drug effects , Carrier Proteins/pharmacology , Crotalid Venoms/pharmacology , Enzyme Activation , Female , Flow Cytometry , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lectins, C-Type , Male , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Peptides/pharmacology , Platelet Membrane Glycoproteins/agonists , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Receptors, IgG/agonists , Signal Transduction/drug effects , Syk Kinase , Time Factors
20.
Acad Med ; 73(9): 935-42, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9759094

ABSTRACT

The Interdisciplinary Generalist Curriculum Project (IGC) was funded in 1993 by the Health Resources and Services Administration with the goal of developing innovative preclinical generalist curricula in ten of the nation's medical and osteopathic schools. The IGC successfully completed two competitive cycles in which ten schools were awarded three-year contracts. Although the long-term goal of the project is to increase the proportion of medical students choosing generalist careers, much has been learned thus far about the processes of curricular change and interdisciplinary cooperation. Drawing on information from school reports, site visits, external evaluations, academic presentations, and annual project meetings, this report presents the emerging lessons learned in the key areas of interdisciplinary collaboration, recruitment and retention of community preceptors, faculty development, and integration of generalist-related components into the four-year medical school curriculum. These lessons should prove useful for other schools embarking upon significant curricular innovations.


Subject(s)
Curriculum , Family Practice/education , Interprofessional Relations , Career Choice , Community-Institutional Relations , Faculty, Medical , Personnel Selection , Preceptorship , United States
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