MRI intensity inhomogeneity correction by combining intensity and spatial information

We propose a novel fully automated method for retrospective correction of intensity inhomogeneity, which is an undesired phenomenon in many automatic image analysis tasks, especially if quantitative analysis is the final goal. Besides most commonly used intensity features, additional spatial image features are incorporated to improve inhomogeneity correction and to make it more dynamic, so that local intensity variations can be corrected more efficiently. The proposed method is a four-step iterative procedure in which a non-parametric inhomogeneity correction is conducted. First, the probability distribution of image intensities and corresponding second derivatives is obtained. Second, intensity correction forces, condensing the probability distribution along the intensity feature, are computed for each voxel. Third, the inhomogeneity correction field is estimated by regularization of all voxel forces, and fourth, the corresponding partial inhomogeneity correction is performed. The degree of inhomogeneity correction dynamics is determined by the size of regularization kernel. The method was qualitatively and quantitatively evaluated on simulated and real MR brain images. The obtained results show that the proposed method does not corrupt inhomogeneity-free images and successfully corrects intensity inhomogeneity artefacts even if these are more dynamic.     

Isolation,biochemical characterization and anti-bacterial activity of BPIFA2 protein

Objective

Human BPIFA2 (parotid secretory protein) is a ubiquitous soluble salivary protein, which belongs to the PLUNC family of proteins. Having sequence similarity to bactericidal/permeability-increasing protein and lipopolysaccharide-binding protein, PLUNC proteins are probably involved in local antibacterial response at mucosal sites, such as oral cavity. The aim of the study was to isolate and characterize human BPIFA2.

Design

In this paper, we report one-step affinity chromatography method for BPIFA2 purification from whole human saliva. The isolated BPIFA2 was identified by trypsin mass fingerprinting and characterized by electrophoretic methods. Antibacterial activity of BPIFA2 against model microorganism Pseudomonas aeruginosa was shown in minimum inhibitory concentration and time kill study assays.

Results

The protein showed microheterogeneity, both in molecular weight and pI value. BPIFA2 inhibited the growth of P. aeruginosa in microgram concentration range determined by minimum inhibitory concentration assay. In the time kill study, 32 μg/mL BPIFA2 showed clear bactericidal activity and did not cause any aggregation of bacteria.

Conclusion

Affinity chromatography is well suited for isolation of functional BPIFA2 with a potent bactericidal activity against P. aeruginosa.     

Antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold in two rat venous thrombosis models

The antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amidoxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.     

Identification of novel genes with somatic frameshift mutations within coding mononucleotide repeats in colorectal tumors with high microsatellite instability

We have systematically retrieved genes with coding mononucleotide repeats from sequence databases and analyzed them for mutations in tumors with high levels of microsatellite instability (MSI-H). We found somatic frameshift mutations in 7/13 genes previously not analyzed in MSI-H tumors. According to the frequency of mutations in MSI-H tumors, these genes could be divided into genes with high coding mononucleotide repeat instability (CMRI-H) and genes with low coding mononucleotide instability (CMRI-L). CMR-H genes were mutated in more than 9/38 and CMRI-L in less than 4/38 of MSI-H tumors. Four genes in our study were CMRI-H and could thus possibly play a role in the development of MSI-H tumors: TFE3 (9/38), TEF4 (12/38), RGS12 (11/38), and TCF1 (12/38). Our results suggest that systematic identification of genes with CMR in the sequence databases and determination of mutation frequency in MSI-H tumors might be a powerful tool for identification of new molecular targets in the development of MSI-H tumors.     

Cardiac resynchronization therapy for the failing Fontan patient

Myocardial dysfunction is the leading cause of death in single-ventricle patients. Heart transplantation has traditionally been reserved for Fontan patients with end-stage myocardial dysfunction. Cardiac resynchronization therapy with multisite pacing was found to improve the myocardial performance in Fontan patients in acute postoperative settings; however, its role is unclear in chronic Fontan patients with progressive myocardial dysfunction. We present a case in which cardiac resynchronization therapy improved both hemodynamics and clinical condition in a Fontan patient with advanced myocardial dysfunction.     

Neurotoxicity of ammodytoxin a in the envenoming bites of Vipera ammodytes ammodytes

Envenoming bites by Vipera ammodytes ammodytes (the long-nosed viper) can cause life-threatening neurotoxicity, particularly in children. We investigated the mechanisms of the neurotoxicity of ammodytoxin A, the principal toxin in the venom of these snakes, in isolated nerve-muscle preparations from mice. The toxin was bound selectively to the neuromuscular junction, and at concentrations similar to those likely to be found in the circulation of young bite victims, it blocked the response of the muscle to indirect but not direct stimulation. Electron microscopy showed that the toxin induced a small but insignificant depletion of synaptic vesicles from motor nerve terminals; nerve terminal mitochondria were swollen and damaged, but plasma membranes of terminal boutons were undamaged. Exposure to the toxin did not affect postjunctional acetylcholine receptors or cause structural damage to preterminal motor axons or muscle fibers. Spontaneous transmitter release was similarly unaffected. Taken together, these results indicate that ammodytoxin A is the principal agent involved in the neurotoxic activity of the venom of V ammodytes ammodytes and that the underlying cause of the failure of transmission may be the deenergization of the nerve terminal resulting from mitochondrial degeneration and subsequent impairment of coupling between the action-potential-induced depolarization of the nerve terminal and the evoked transmitter release.