Patients with paroxysmal nocturnal hemoglobinuria demonstrate a prothrombotic clotting phenotype which is improved by complement inhibition with eculizumab

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement-mediated intravascular hemolysis and thrombosis. The increased incidence of PNH-driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement-mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti-thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in-part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure.     

Fracture Strength of Roots Instrumented with Self-Adjusting File and the ProTaper Rotary Systems

Introduction

The purpose of this study was to evaluate the fracture strength of roots instrumented with the Self-Adjusting File (SAF; ReDent-Nova, Ra’anana, Israel) and the ProTaper system (Dentsply Maillefer, Ballaigues, Switzerland) and filled with the cold lateral compaction technique.

Methods

In total, 50 mandibular premolar teeth were sectioned at or below the cementoenamel junction to obtain roots 13 mm in length. The roots were balanced with respect to buccolingual-mesiodistal diameters and weight. They were distributed into 4 experimental groups and 1 control group (n = 10): no instrumentation (control group), instrumentation with ProTaper rotary files but no filling (PT), instrumentation with ProTaper rotary files and filling with cold lateral compaction (PT filling), instrumentation with SAF but no filling (SAF), and instrumentation with SAF and filling with cold lateral compaction (SAF filling). AH Plus sealer (Dentsply DeTrey, Konstanz, Germany) was used along with gutta-percha points. One week later, a vertical load was applied to the specimen’s canal until fracture occurred. Data were statistically analyzed using 1-way analysis of variance (P = .05).

Results

The mean fracture load was 244 ± 51 N for the control group, 226 ± 21 N for the PT, 242 ± 45 N for PT filling, 233 ± 14 N for the SAF, and 271 ± 44 N for SAF filling. However, the differences were not statistically significant (P > .05).

Conclusions

Instrumentation with the SAF or the ProTaper rotary system did not change the fracture strength of standardized roots with respect to cross-sectional diameter and weight.     

Relationship Between Measures of Cerebrovascular Reactivity and Intracranial Lesion Progression in Acute TBI Patients: an Exploratory Analysis

Neurocritical Care - Failure of cerebral autoregulation and progression of intracranial lesion have both been shown to contribute to poor outcome in patients with acute traumatic brain injury...     

Incat disability score: A critical analysis of its measurement properties

Background: The INCAT (Inflammatory Neuropathy Cause and Treatment) disability score is a measure of activity limitation. It is used frequently as a primary endpoint in inflammatory polyneuropathy clinical trials. A comprehensive critical analysis of its measurement properties has not been performed. Methods: Critical analysis of measurement properties. Results: The INCAT disability score was derived based on items from Guy's Neurological Disability Scale (GNDS), a disability measure intended for application in multiple sclerosis. Strengths of the INCAT score include evaluation of upper and lower limb dysfunction, ease of administration (feasibility), high face validity, and high reliability. Weaknesses of the scale include concerns about methodological quality of validation studies; failure to properly capture activity limitations due to proximal arm weakness, or fatigue; heavy individual item weighting; and poor sensitivity for detection of clinically important change. Conclusions: Although the INCAT scale has been an effective tool in inflammatory polyneuropathy studies, its limitations may warrant development of new scales. Muscle Nerve 50:164–169, 2014