Effect of bivalirudin compared with unfractionated heparin plus abciximab on infarct size and myocardial recovery after primary percutaneous coronary intervention: the horizons-AMI CMRI substudy

Background : Myocardial infarct size is a strong independent predictor of mortality in patients with ST‐elevation myocardial infarction (STEMI). In the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS‐AMI) trial, bivalirudin compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor reduced cardiac mortality in STEMI patients, which was attributed to reduced major bleeding. Whether a possible reduction in infarct size with bivalirudin may have contributed to the enhanced survival with this agent is unknown. Methods : Cardiac magnetic resonance imaging was performed within 7 days and after 6 months in 51 randomized patients from a single center in HORIZONS‐AMI trial (N = 28 bivalirudin, N = 23 heparin plus abciximab). Infarct size, microvascular obstruction (MVO), left ventricular ejection fraction (LVEF), and LV end‐diastolic and end‐systolic volume indices were evaluated. Results : Infarct size was not significantly different after treatment with bivalirudin compared with heparin plus abciximab either within 7 days (median 9.3% [interquartile range 4.9%, 26.6%] vs. 20.0% [5.9%, 28.2%], P = 0.28) or at 6 months 6.7% [3.8%, 20.0%] vs. 8.2% [1.8%, 16.5%], P = 0.73). MVO was present in 28.6% versus 34.8% of patients respectively (P = 0.63). LVEF and LV volume indices also did not significantly differ between the two groups at either time period, nor were differences in myocardial recovery evident. Conclusions : In conclusion, in the HORIZONS‐AMI Cardiac magnetic resonance imaging (CMRI) substudy, cardiac magnetic resonance imaging within 7 days and at 6 months after primary percutaneous coronary intervention (PCI) did not demonstrate significant differences in infarct size, MVO, LVEF, or LV volume indices in patients treated with bivalirudin compared with unfractionated heparin plus abciximab. © 2011 Wiley Periodicals, Inc.     

Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry

Aims

We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke.

Methods

The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke.

Results

At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA₂DS₂-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA₂DS₂-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01].

Conclusion

At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge.

Clinical trial registration

NCT02306824.

     

Pre‐programmed robotic osteotomies for fibula free flap mandible reconstruction: A preclinical investigation

Bony free flap reconstruction of the facial skeleton remains a challenging area of reconstructive surgery. Despite technological advances that have aided planning and execution of these procedures, surgical inaccuracy is not insignificant. One source of error that has not been wholly addressed is that attributable to a human operator. In this study, we investigate the feasibility and accuracy of performing osteotomies robotically in pre‐programmed fashion for fibula free flap mandible reconstruction as a method to reduce inaccuracies related to human error. A mandibular defect and corresponding free fibula flap reconstruction requiring six osteotomies were designed on a CAD platform. A methodology was developed to translate this virtual surgical plan data to a robot (KUKA, Augsburgs, Germany), which then executed osteotomies on three‐dimensional (3D) printed fibula flaps with the aid of dynamic stereotactic navigation. Using high‐resolution computed tomography, the osteotomized segments were compared to the virtually planned segments in order to measure linear and angular accuracy. A total of 18 robotic osteotomies were performed on three 3D printed fibulas. Compared to the virtual preoperative plan, the average linear variation of the osteotomized segments was 1.3 ± 0.4 mm, and the average angular variation was 4.2 ± 1.7°. This preclinical study demonstrates the feasibility of pre‐programmed robotic osteotomies for free fibula flap mandible reconstruction. Preliminarily, this method exhibits high degrees of linear and angular accuracy, and may be of utility in the development of techniques to further improve surgical accuracy. © 2015 Wiley Periodicals, Inc. Microsurgery 36:246–249, 2016.     

The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells

Multiple signal transduction cascades, consisting of multiple interacting proteins, are activated following stimulation through most cell surface receptors, including the immunoglobulin receptor of B lymphocytes. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, resulting in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a lipid kinase that consists of an 85-kD regulatory subunit, bound to a 110-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that contains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 120-kD protein that is expressed in early B-lineage cells and in myeloid cells and is phosphorylated on tyrosine following receptor-mediated signaling in T and B lymphocytes. We demonstrate here that phosphorylated c-cbl complexes with CD19 and with PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active PI3K in anti-Ig- stimulated cells. Although we cannot differentiate between a three- component, c-cbl/CD19/p85 complex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct signal transduction pathways.     

Protein-tyrosine kinase p72syk in Fc gamma RI receptor signaling

In this report we show that gamma-interferon (IFN) induces the expression of the nonreceptor protein tyrosine kinase, p72syk, and that cross-linking the Fc gamma RI receptor in IFN-differentiated U937 cells (U937IF cells) results in the activation of syk kinase. We show that syk is tyrosine phosphorylated (12-fold increase) after Fc gamma RI cross-linking. In vitro kinase assays demonstrate that the specific kinase activity of syk increased eightfold after Fc gamma RI cross- linking. The activation of signal transduction through the Fc gamma RI receptor, as measured by the respiratory burst, is associated with the tyrosine phosphorylation and catalytic activation of the syk kinase. We show that syk coprecipitates with the gamma subunit of the Fc gamma RI, Fc gamma RI gamma. The data suggest that p72syk is involved in signal transduction through the Fc gamma RI receptor, involving the Fc gamma RI gamma subunit.     

Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection

Maternally administered recombinant human granulocyte colony- stimulating factor (rhG-CSF) has been shown to cross the placenta and induce a peripheral neutrophilia and increases in the marrow and spleen neutrophil storage pools in fetal and newborn rats. In the present study, we have used this model system to investigate the efficacy of prenatally administered rhG-CSF on neonatal defense to a lethal challenge with Group B-beta hemolytic Streptococcus (GBS). Pregnant rats were injected with rhG-CSF twice daily beginning 6 days before parturition. At birth, all pups were infected with a dose of GBS that is lethal for 90% of infected pups (LD90). Survival was monitored daily for 5 days. Survival of infected pups from saline-treated mothers beyond 60 hours after infection was 10%. No difference in survival was observed among pups from mothers treated 2 and 4 days before parturition. In contrast, we determined that survival was 82.5% among infected pups from mothers treated for 6 days before parturition with rhG-CSF. Our results demonstrate that maternal administration of rhG- CSF augments neonatal defenses against a lethal bacterial challenge.