Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity.

Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa-mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa-directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX-dependent fibrinolysis and plasmin generation by tissue plasminogen activator. BACKGROUND: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaß and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaß and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin, and the persistent FXaß enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. METHODS: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. RESULTS: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaß. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaß, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. CONCLUSION: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaß in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.

Fatty acid binding protein 4 is expressed in distinct endothelial and non-endothelial cell populations in glioblastoma.

AIMS: Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults. Angiogenesis and vasculogenesis play key roles in progression of GBMs. Fatty acid binding protein 4 (FABP4) is an intracellular chaperone for free fatty acids. FABP4 is detected in microvascular endothelial cells (ECs) in several normal tissues and promotes proliferation of ECs. The goal of this study was to characterize the tissue distribution pattern of FABP4 in GBMs. METHODS: Immunohistochemistry for FABP4 was performed on paraffin-embedded tumour sections and the intensity and distribution of FABP4 immunoreactivity were analysed. Double immunofluorescence was employed for detailed characterization of FABP4-positive cells. RESULTS: FABP4 immunoreactivity was absent in normal brain tissue sections. FABP4-positive cells were detected in 33%, 43%, 64% and 89% of Grade I, Grade II, Grade III and Grade IV glial tumours, respectively. Thus, the percentage of FABP4-positive cells in GBMs was significantly higher than lower-grade gliomas. In general, FABP4-expressing cells were distributed in a non-homogenous pattern, as 'hot spots' in glial tumours. FABP4 expression was detected in a subset of vascular ECs as well as some non-ECs. CONCLUSION: FABP4 is expressed in a significantly higher percentage of GBMs in comparison to both normal brain tissues and lower-grade glial tumours. FABP4 is expressed in some tumour ECs as well as non-ECs in glial tumours. As FABP4 promotes proliferation of ECs, detection of FABP4 in GBM-ECs, but not normal brain ECs suggests that FABP4 may play a role in the robust angiogenesis associated with GBMs.

Efficacy and safety of morphine-6-glucuronide (M6G) for postoperative pain relief: a randomized, double-blind study.

AIMS: The aim of the study was to assess analgesia and safety effects of a range of intravenous doses of M6G (10, 20 and 30 mg/70 kg), compared to placebo, in postoperative patients. METHODS: In a randomized, multicentre, double-blind study, patients undergoing knee replacement surgery under spinal anaesthesia were administered one of three doses of M6G, or placebo, 150 min after spinal nerve block. Morphine rescue medication was available via a PCA pump. The key index of analgesic activity was determined as the amount of morphine consumed by the patient over 12 and 24 h after M6G administration. Time to first use of rescue medication, VAS and global pain assessment scales were also recorded. Safety was assessed by monitoring supine blood pressure, heart rate, respiratory rate and body temperature and typical opioid side-effects of PONV and sedation. RESULTS: A total of 170 patients were dosed with study medication. M6G induced a dose-related reduction in morphine use over 24-h that reached statistical significance compared to placebo at M6G 30 mg/70 kg. There was no clear relationship between M6G dose and time to first use of PCA morphine. Pain relief was similar in all groups. M6G showed small, but inconsistent effects on the cardiovascular system and on sedation and no effects were observed on respiration or PONV. CONCLUSION: M6G induced long-lasting dose-related analgesic effects in postoperative patients with limited effects on cardiorespiratory systems or of opioid-like side-effects. M6G is an effective opioid for the treatment of moderate to severe postoperative pain.

Posterior sternoclavicular joint dislocation in children-role of spiral computed tomography.

Traumatic posterior dislocation of the sternoclavicular joint is an uncommon injury in children. It is not normally well seen on plain films. We report 2 cases where spiral computed tomography with intravenous contrast confirmed the clinical suspicion of sternoclavicular joint dislocation and also allowed assessment of the adjacent mediastinum for possible complications. Emergency physicians should be aware that the use of spiral computed tomography is the procedure of choice in posterior sternoclavicular joint dislocation. This is particularly helpful in allowing multiplanar reconstruction to show complications arising in the mediastinum.

Triplane fractures of the distal tibia requiring open reduction and internal fixation. Pre-operative planning using computed tomography.

Computed tomography (CT) of triplane fractures provides useful information not available on conventional radiographs. Knowledge of the size and position of displaced fragments, the location of the intra-articular fracture and any associated articular incongruency is useful when undertaking pre-operative planning.A postal survey of surgeons revealed only 38% always requested CT scans before undertaking open reduction and internal fixation of displaced triplane fractures. Examples of the usefulness of CT scans in pre-operative planning is presented in two cases.

Market age live weight, carcass yield, and liver characteristics of broiler offspring from breeder hens fed diets differing in fat and energy contents.

The effects of energy level, fat type, and fat level in breeder hen diets on subsequent offspring market age live BW, carcass yield, and liver characteristics from breeder hens at 29 and 36 wk of age were evaluated. At 22 wk of age, six dietary treatments were imposed. Dietary treatments contained: 1) 3.0%, added poultry fat (PF) and 467 (high energy) kcal/hen per day at peak production (CPP), 2) no added fat and high energy, 3) 3.0% added PF and 430 (low energy) CPP, 4) no added fat and low energy, 5) 1.5% added PF and 449 (moderate energy) CPP, and 6) 3.0% added corn oil (CO) and moderate energy. Breeder age influenced Day 43 broiler live BW, percentage total carcass and front-half yields, and liver moisture contents. Furthermore, wet and dry liver weights were higher in female broilers compared to those of male broilers from 29-wk-old breeder hens. Live BW was higher in broilers from hens fed low-energy diets compared with moderate-energy diets and 3.0% compared to 1.5% PF diets. Percentage liver DM was higher in females compared to male broilers from hens fed 3.0% CO and moderate energy and was highest in male and female broilers from hens fed 1.5% PF and moderate energy. Percentage wet liver weight and liver DM were higher and liver moisture content was lower in broilers from hens fed 1.5% compared to 3.0% PF diets. Overall, energy and fat levels in breeder diets had subsequent influences on market age weight and liver characteristics of broilers.

Functional evaluation of the modified Elmslie-Trillat procedure for patello-femoral dysfunction.

A series of 28 knees in 27 patients were evaluated at an average of 36 months following surgical treatment for patella dislocation, patello-femoral pain, or a combination of both. All cases were treated by the modified Elmslie-Trillat procedure, which involves a lateral retinacular release and medialisation of the tibial tubercle on a distal pedicle. The evaluation included subjective, objective (Fulkerson and Kujala functional knee scores) and radiographic assessments. Subjectively, eight knees (28%) had excellent results, nine knees (33%) good results and seven knees (25%) fair results, accounting for an overall improvement of 86% over the preoperative status. All the knees in patients with a primary symptom of patella dislocation had an excellent or good subjective result, whilst only four knees (40%) in those patients with a primary symptom of pain and four knees (44%) in those with both pain and dislocation had a good or excellent result. The mean objective knee score was excellent for patients with dislocation only, and fair for those with only pain or both pain and dislocation. There have been no further episodes of dislocation in all patients. Six knees (21%) required later screw removal. The modified Elmslie-Trillat procedure produces a favourable outcome in patients with patella dislocation.

Subacute diencephalic angioencephalopathy: biopsy diagnosis and radiological features of a rare entity.

Subacute diencephalic angioencephalopathy (SDAE) is a rare and fatal disease of unknown etiology that involves the thalami bilaterally. To date, there have been four cases reported, in which the diagnosis was established only after post mortem examination of the brain. We report two male patients, ages 69 and 41 years, who presented with progressive dementia and somnolence. Radiological evaluation revealed enhancing lesions involving both thalami. The differential diagnosis included a number of neoplastic, inflammatory and vascular processes. In both cases, pathological evaluation of biopsy specimens suggested the diagnosis of SDAE. Despite supportive care, the disease progressed rapidly and both patients died within weeks after initial presentation. The diagnosis was confirmed at autopsy in both cases. SDAE is a rare cause of bithalamic disease that can be mistaken for a neoplasm as well as a number of conditions that necessitate different treatment choices. The histopathological findings can establish the diagnosis when combined with radiological and clinical information. This report emphasizes the utility of stereotactic biopsy in early diagnosis of SDAE.

Absence of hippocampal sclerosis in children with multiple daily seizures since infancy.

We report a series of nine children with multiple daily seizures since infancy who underwent functional hemispherectomy that included en bloc resection of the hippocampus and the temporal neocortex. In all cases, the hippocampi were normal by conventional histology despite the fact that these patients had suffered from recurrent seizures over a long period of time. This observation suggests that extremely frequent seizures in childhood are not invariably associated with the development of hippocampal sclerosis.

Distinguishing narcissism and hostility: similarities and differences in interpersonal circumplex and five-factor correlates.

Narcissism and hostility are both characterized by dysfunctional social interactions, including tendencies to perceive slights, experience anger, and behave aggressively. The aim of this study was to examine the similarities and differences of narcissism and hostility, using 2 conceptual tools-the interpersonal circumplex and the Five-factor model. In a sample of 292 undergraduate men and women, composite measures of hostility (i.e., Buss-Perry Aggression Questionnaire [Buss & Perry, 1992] and Cook-Medley Hostility [Cook & Medley, 1954] total scores) were inversely correlated with affiliation and unrelated to dominance. In contrast, composite narcissism scores (i.e., Narcissistic Personality Inventory) were positively correlated with dominance and inversely correlated with affiliation. Examination of components of these traits revealed additional similarities and differences, as did associations with other dimensions of the Five-factor model. These findings suggest that the traits of narcissism and hostility are distinguishable by their interpersonal referents, as are their components.

Inter-laboratory comparison of DNA preservation in archival paraffin-embedded human brain tissue from participating centres on four continents.

DNA extracted from formalin-fixed and paraffin-embedded brain tissue is known to contain as yet ill-characterized inhibitors of the PCR process. As part of a project that aims to clarify the role of mitochondrial DNA sequence variation in human neurodegenerative diseases using DNA from various ethnic backgrounds, we have investigated factors that influence the preservation of archival DNA and its suitability for PCR. In this study, neuropathological tissue samples were analysed that had been routinely processed in 18 international centres on four continents. Following DNA extraction, PCR amplification of mitochondrial and nuclear DNA sequences was performed with and without additional purification of the template DNA. In addition, the DNA used for PCR was analysed by HPLC. Phosphate-buffered formalin proved to be a superior fixative compared with unbuffered aldehyde: DNA extraction resulted in greater yields, the molecular weight of the isolated DNA was higher and PCR was more successful. PCR inhibitors were identified as (1) high concentrations of small (<300 bp) DNA fragments that competitively compete with template DNA and (2) contaminants of the DNA template solution including denatured protein that cannot be completely removed by phenolic extraction. HPLC analysis did not reveal significant qualitative differences between DNA isolated from fresh-frozen tissue samples and DNA recovered from formalin-fixed, paraffin-embedded brain tissue. The fact that DNA could be amplified from the majority of tissue specimens in this study suggests that rare diseases and diseases where ethnic background plays an important role can be sampled for genetic polymorphism analysis on a global scale using archival neuropathological collections.