Rivaroxaban attenuates neutrophil maturation in the bone marrow niche.

Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte-monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor.

Essentials Successful outcome of platelet transfusion depends on specific antiplatelet therapy in use. We assessed if ticagrelor, clopidogrel or prasugrel impacts on donor platelet activity ex vivo. Ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets. This might compromise the effectiveness of platelet transfusion therapy. SUMMARY: Background Platelet transfusion is the conventional approach to restore platelet function during acute bleeds or surgery, but successful outcome depends on the specific antiplatelet therapy. Notably ticagrelor is associated with inadequate recovery of platelet function after platelet transfusion. We examined whether plasma and/or platelets from ticagrelor-treated patients influence donor platelet function, in comparison with clopidogrel and prasugrel. Methods Platelet transfusion was mimicked ex vivo by mixing naïve donor platelet-rich plasma (PRP) or gel-filtered platelets (GFP) in defined proportions with PRP, plasma or GFP from cardiovascular patients receiving standard care including medication with prasugrel, clopidogrel or ticagrelor (n = 20 each). Blood was taken 4 h after the previous dose. HLA2/HLA28 haplotyping let us distinguish net (all platelet) and individual patient/donor platelet reactivity in mixtures of patient/donor platelets, measured by flow cytometry analysis of ADP-induced fibrinogen binding and CD62P expression. Results ADP responsiveness of donor platelets was dramatically reduced by even low (10%) concentrations of PRP or plasma from ticagrelor-treated patients. Clopidogrel and prasugrel were associated with more modest donor platelet inhibition. GFP from ticagrelor-treated patients but not patients receiving clopidogrel or prasugrel also suppressed donor GFP function upon mixing, suggesting the transfer of ticagrelor from patient platelets to donor platelets. This transfer did not lead to recovery of ADP responsiveness of patient's platelets. Conclusion Collectively, these observations support the concept that ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets, which might compromise the effectiveness of platelet transfusion therapy.

Ultrafast-laser inscription of a three dimensional fan-out device for multicore fiber coupling applications.

A fan-out device has been fabricated using ultrafast-laser waveguide-inscription that enables each core of a multicore optical fiber (MCF) to be addressed by a single mode fiber held in a fiber V-groove array (FVA). By utilizing the unique three-dimensional fabrication capability of this technique we demonstrate coupling between an FVA consisting of a one-dimensional array of fibers and an MCF consisting of a two-dimensional array of cores. When coupled to all cores of the MCF simultaneously, the average insertion loss per core was 5.0 dB in the 1.55 mum spectral region. Furthermore, the fan-out exhibited low cross-talk and low polarization dependent loss.

Vascular access by physician assistants: evaluation of an implantable peripheral port system in cancer patients.

PURPOSE: To determine the ability of a physician assistant (PA) to insert, in an ambulatory setting, a peripheral subcutaneous implanted vascular-access device (VAD) and to evaluate the ability to transfer this training to a second PA. We also evaluated the performance and complications associated with this new device. PATIENTS AND METHODS: The Peripheral Access System (PAS) Port catheter system (Sims-Deltec Inc, St Paul, MN) was inserted in patients who required long-term (> 3 months) vascular access for infusion therapy. RESULTS: The first PA (PA-1) successfully inserted 57 of 62 devices (92%) after gaining experience with the technique in 10 patients (success rate, five of 10 [50%]; P = .003). The second PA (PA-2) was successful in eight of 10 initial attempts (80%) and 25 of 30 overall (83%). Complications were few and limited to phlebitis, thrombosis, and a low infection rate (0.2 per 1,000 catheter days). CONCLUSION: PAs can be taught to insert a peripheral subcutaneous implanted VAD. This technique is transferable from one PA to another, and the device studied is appropriate for outpatient VAD programs.

Reference values of indices of spontaneous baroreceptor reflex sensitivity.

Spontaneous baroreceptor reflex sensitivity (BRS) is a well established method for determining baroreflex function, which can be used to assess the potential impact on survival after myocardial infarction, to detect autonomic dysfunction in diabetic patients and in human essential hypertension. The assessment of impaired spontaneous baroreflex function in individual patients contains important clinical information, but age-dependent reference values are still lacking. In the present study we evaluated spontaneous BRS in healthy human controls to determine reference values as a function of age. Two hundred and sixty-two healthy volunteers divided into six age groups (I: <20 years, f = 11, m = 9, II: 20-29 years, f = 42, m = 37, III: 30-39 years, f = 23, m = 37, IV: 40-49 years, f = 27, m = 22, V: 50-59 years, f = 19, m = 17, VI: 60-69 years, f = 5, m = 13). Electrocardiograms (ECG) and finger arterial BP were measured with each subject in the supine position (sup, 7 min) and during deep breathing (dB, 6/min, 15 cycles). BRS was assessed using the sequence technique and the alpha coefficients as obtained from a power spectrum density estimate. Due to the normal logarithmic distribution of the BRS, the limits for impaired baroreflex function at rest were defined from logarithmic data. The limits for the BRS at rest (P = .025) were calculated as (-0.0283 x age) + 2.5198 for the sequence technique. We did not find significant differences in BRS among the female and male healthy volunteers. Our analysis of the six age groups showed the expected significant decrease in BRS, which was most prominent at the transition from group III (<40 years) to group IV (<50 years). BRS at rest and during deep breathing as well as sequential and spectral BRS indices did differ significantly. The results underline the necessity of reference values to evaluate impaired baroreflex function in individual patients.

The cerebellum is necessary for rabbit classical eyeblink conditioning with a non-somatosensory (photic) unconditioned stimulus.

The present research investigated the acquisition of classically conditioned eyeblinks in rabbits using a light flash unconditioned stimulus (US), as well as the contribution of deep cerebellar nuclei to such an association. Two independent groups of animals experienced three phases of training: (1) pre-lesion delay conditioning using either a light- (Group 1) or an air puff-US (Group 2), (2) post-lesion testing of response performance, and (3) post-lesion acquisition to the opposite US. During the initial acquisition (720 trials), the groups did not differ with regard to their rate of learning or their overall level of responding. To assess the contribution of the cerebellum to the maintenance of responding, the interpositus nucleus was electrolytically lesioned and animals were given 8 days of additional training. Both groups exhibited a profound reduction in conditioned responding (CR) and showed no signs of recovery over the remainder of this phase (480 trials). Animals were then shifted to the opposite US (same eye) and given 12 days of training to assess the effect of interpositus lesions on the acquisition of CRs to a novel US. No learning was observed during this phase, regardless of whether animals experienced the light- or air puff-US. These results demonstrate: (1) the ability of a non-somatosensory stimulus to serve as a US during classical eyeblink conditioning; and (2) a common reliance on deep cerebellar nuclei for both somatosensory- and non-somatosensory-based reflexive motor learning. The findings are discussed in reference to the processing of conditioning stimuli within the brainstem-cerebellar circuitry that underlies eyeblink conditioning.

Long-term survival after chest-wall reconstruction with musculocutaneous flaps.

Reconstruction of chest-wall defects with musculocutaneous flaps permits resection of advanced chest-wall tumors and of tissues severely damaged by radiotherapy in patients who in a previous era were not surgically treatable. To determine the long-term outcome from this surgery, the records of 96 patients who had undergone chest-wall resection with musculocutaneous flap reconstruction were reviewed. Median survival for the entire group was 20.5 months, but a more accurate prediction of outcome could be obtained by dividing the patients into three groups. In group I, patients free of known malignancy and undergoing resection of radionecrotic tissues, median survival was 60.0 months. In group II, patients with resectable disease and free of tumor following surgery, median survival was 31.1 months. In group III, patients incompletely resected or known to have metastatic disease following surgery, median survival was only 12.5 months. Even in group III, however, some individuals achieved prolonged survival and lasting benefits from the surgery, so these data should not be used to exclude patients from undergoing necessary palliative procedures.

An investigation of the radiation doses to the lower legs and feet of staff undertaking interventional procedures.

OBJECTIVE: Occupational radiation doses from fluoroscopic procedures are some of the highest doses of exposure amongst medical staff using radiography. Protective equipment and dose monitoring are used to minimize and control the risk from these occupational doses. Other studies have considered the effectiveness of this protection, but this study further considers whether protection is adequate for the lower leg and foot and the extent to which these doses can be reduced. METHODS: Scatter air kerma profiles at toe level were measured with an ionization chamber. Thermoluminescent dosemeters and lower extremity phantoms were used to estimate the dose variation with the height of patient couch. A 7-week period of in situ toe dose monitoring of four radiologists was also undertaken. RESULTS: The use of protective curtains effectively reduced the exposure to most of the lower extremities. Toe doses were found to be high and increased with increase in couch height. In situ monitoring indicated annual toe doses of 110 mSv for two of the four radiologists monitored. CONCLUSION: Protective curtains should be used, but they might have limitations with respect to toe doses. Annual toe doses approaching the classification threshold of 150 mSv were measured for two radiologists. Caution should be exercised when there is a gap below curtains and, when possible, staff should step back from the couch. Lower legs and toes should be included in local radiation protection programmes. ADVANCES IN KNOWLEDGE: Toe doses in interventional radiology may be higher than expected and may have to be included in radiation protection programmes.

Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer.

BACKGROUND: Hospitalization and intravenous (IV) broad-spectrum antibiotics are the standard of care for all febrile neutropenic patients with cancer. Recent work suggests that a low-risk population exists who might benefit from an alternate approach. METHODS: A prospective randomized clinical trial was performed comparing oral ciprofloxacin 750 mg plus clindamycin 600 mg every 8 hours with IV aztreonam 2 g plus clindamycin 600 mg every 8 hours for the empiric outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer. RESULTS: The oral regimen cured 35 of 40 episodes (88% response rate), whereas the IV regimen cured 41 of 43 episodes (95% response rate, P = 0.19). Although the cost of the oral regimen was significantly less than that of the IV regimen (P < 0.0001), it was associated with significant renal toxicity (P < 0.05), which led to early termination of the study. Overall, combining its safety and efficacy, the IV regimen was superior (P = 0.03). CONCLUSIONS: This prospective study suggested that outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer is safe and effective. Better oral regimens are needed.