Numerical Simulation of Magnetic Resonance Angiographies of an Anatomically Realistic Stenotic Carotid Bifurcation

Magnetic Resonance Angiography (MRA) has become a routine imaging modality for the clinical evaluation of obstructive vascular disease. However, complex circulatory flow patterns, which redistribute the Magnetic Resonance (MR) signal in a complicated way, may generate flow artifacts and impair image quality. Numerical simulation of MRAs is a useful tool to study the mechanisms of artifactual signal production. The present study proposes a new approach to perform such simulations, applicable to complex anatomically realistic vascular geometries. Both the Navier-Stokes and the Bloch equations are solved on the same mesh to obtain the distribution of modulus and phase of the magnetization. The simulated angiography is subsequently constructed by a simple geometric procedure mapping the physical plane into the MRA image plane. Steady bidimensional numerical simulations of MRAs of an anatomically realistic severely stenotic carotid artery bifurcation are presented, for both time-of-flight and contrast-enhanced imaging modalities. These simulations are validated by qualitative comparison with flow phantom experiments performed under comparable conditions.     

Visualization of melatonin's multiple mitochondrial levels of protection against mitochondrial Ca2+-mediated permeability transition and beyond in rat brain astrocytes

Abstract: Melatonin protects cells against various types of oxidative stress‐induced apoptosis due primarily to its ability to effectively scavenge pathological and disease condition‐augmented generation of mitochondrial reactive oxygen species (mROS). Once produced, mROS indiscriminately damage mitochondrial components and more importantly they crucially activate directly the mitochondrial permeability transition (MPT), one of the critical mechanisms for initiating post mitochondrial apoptotic signaling. Whether or not melatonin targets directly the MPT, however, remains inconclusive, particularly during oxidative stress. This study, thus, investigated this possibility of an ‘oxidation free Ca²⁺ stress’ in the presence of vitamin E after ionomycin exposure as a sole Ca²⁺‐mediated MPT in order to exclude melatonin’s primary antioxidative effects as well as Ca²⁺‐mediated oxidative stress. The studies were carried out using cultured rat brain astrocytes RBA‐1. With the application of laser scanning multiple fluorescence imaging microscopy, we visualized for the first time multiple mitochondrial protective effects provided by melatonin during Ca²⁺ stress. First, melatonin, due to its primary antioxidative actions, completely prevented mCa²⁺‐induced mROS formation during ionomycin exposure. Secondly, when melatonin^’s antioxidative effects were prevented due to the addition of vitamin E, melatonin significantly prevented mCa²⁺‐mediated MPT and apoptosis suggesting its direct targeting of the MPT. Surprisingly, in the presence of cyclosporin A, a MPT inhibitor, melatonin reduced further mCa²⁺‐mediated apoptosis during ionomycin exposure also suggesting its targeting beyond the MPT. As astrocytes are actively involve in regulating synaptic transmission and neurovascular coupling in the CNS, these multiple mitochondrial layers of protection provided by melatonin against mCa²⁺‐and/or mROS‐mediated apoptosis in astrocytes may be crucial for future therapeutic prevention and treatment of astrocyte‐mediated neurodegenerative diseases in the CNS.     

Identification of Oncogenic Point Mutations and Hyperphosphorylation of Anaplastic Lymphoma Kinase in Lung Cancer

The oncogenic property of anaplastic lymphoma kinase (ALK) plays an essential role in the pathogenesis of various cancers and serves as an important therapeutic target. In this study, we identified frequent intragenic loss of heterozygosity and six novel driver mutations within ALK in lung adenocarcinomas. Overexpression of H694R or E1384K mutant ALK leads to hyperphosphorylation of ALK, and activation of its downstream mediators STAT3, AKT, and ERK resulted in enhanced cell proliferation, colony formation, cell migration, and tumor growth in xenograft models. Furthermore, the activated phospho-Y1604 ALK was increasingly detected in 13 human lung cancer cell lines and 263 lung cancer specimens regardless of tumor stages and types. Treatment of two different ALK inhibitors, WHI-P154 and NVP-TAE684, resulted in the down-regulation of aberrant ALK signaling, shrinkage of tumor, and suppression of metastasis and significantly improved survival of ALK mutant-bearing mice. Together, we identified that novel ALK point mutations possessed tumorigenic effects mainly through hyperphosphorylation of Y1604 and activation of downstream oncogenic signaling. The upregulated phospho-Y1604 ALK could serve as a diagnostic biomarker for lung cancer. Furthermore, targeting oncogenic mutant ALKs with inhibitors could be a promising strategy to improve the therapeutic efficacy of fatal lung cancers.     

Polymorphic locus in the 5'-flanking region of human insulin gene and non-insulin-dependent diabetes mellitus

The etiology of non-insulin-dependent diabetes mellitus (NIDDM) is still unclear, but appears to involve some genetic factors. There have been disputes over the association between DNA sequences flanking the insulin gene and NIDDM. In order to characterize insulin gene polymorphism in the Chinese population and elucidate its association with NIDDM, 100 unrelated Chinese subjects living in Taiwan were observed for polymorphism of this hypervariable region. Most of them were descendants of immigrants from the southern part of mainland China. Among them, 52 were nondiabetic controls, and 48 were subjects with NIDDM. Insulin gene polymorphism was classified into classes 1, 2 and 3 alleles according to Bell et al. Neither the class 2 allele nor the genotype for the homozygous class 3 allele was not observed in this study. The allelic frequencies of class 1 and 3 genes were 97% and 3% in the nondiabetic subjects, and 99% and 1% in the NIDDM group, respectively. The frequencies of genotypes 1/1 and 1/3 were 94% and 6% in nondiabetics and 98% and 2% in the NIDDM group, respectively. No significant association was found between insulin gene polymorphism and NIDDM. It is concluded that DNA marker flanking the insulin gene may not be associated with the development of NIDDM in Chinese subjects.     

Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders

A retrospective study was conducted to assess the effectiveness and tolerability of atomoxetine in children and adolescents with pervasive developmental disorders (PDD). An outpatient clinic registry of individuals with PDD was used to identify all children and adolescents who received atomoxetine over a period of 12 months. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI) based on the Conners Parent Rating Scale (CPRS) routinely completed by primary caretakers and other clinical information available in the registry. Twenty patients were identified, including 16 males and 4 females (age, 11.5 years; standard deviation, 3.5). Most patients (80%) were taking at least 1 concomitant medication. Treatment dose was 43.3 mg (standard deviation, 18.1) and duration was 19.5 weeks (standard deviation, 10.5). Twelve patients were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Differences between baseline and the end of the trial period were observed in the following CPRS subscales: Conduct, hyperactivity, inattention, and learning. No differences were noted in the anxiety and psychosomatic subscales. One patient discontinued atomoxetine because of severe mood swings. Atomoxetine may be beneficial for treating secondary symptoms of PDD, and prospective open-label or double-blind, placebo-controlled studies are needed to assess its efficacy and safety.     

Hyponatremia from oxcarbazepine and carbamazepine

The authors examined sodium concentrations from 97 oxcarbazepine-treated (OXC) and 451 carbamazepine-treated (CBZ) patients with epilepsy using cross-section and follow-up studies. The frequency of hyponatremia (Na+ < or = 134 mEq/L) was 29.9% among OXC-treated patients and 13.5% among CBZ-treated patients (p < 0.0001). Hyponatremia (Na+ < or = 128 mEq/L) was severe: 12.4% of OXC-treated patients and 2.8% of CBZ-treated patients (p < 0.001). Advanced age was a risk factor for hyponatremia. Hyponatremia, once present, persisted in both groups.     

Endodontic working width: current concepts and techniques

Root canal morphology is a critically important part of conventional and surgical endodontics (root canal therapy). Many in vitro studies have recorded the scales and average sizes of root canals, but there have been few clinical attempts to determine the working width. In the absence of a study that defines what the original width and optimally prepared horizontal dimensions of canals are, clinicians are making treatment decision without any support of scientific evidence. This article provides definitions and perspectives on the current concepts and techniques to handle working width-the horizontal dimension of the root canal system-and its clinical implications.     

Clustering of minimal deleted regions reveals distinct genetic pathways of human hepatocellular carcinoma

Systematic scan and statistical analysis of loss of heterozygosity (LOH) has been widely used to define chromosomal aberrations in various cancers for cloning of tumor suppressor genes and for development of prognostic markers. However, the establishment of novel strategies is needed, so that the nonrandom but heterogeneous chromosomal aberration data could provide significant insights into our understanding of molecular pathogenesis of cancers. After comprehensive allelotyping of recurrent allelic losses with 441 highly informative microsatellite markers and overlapping LOH regions on human hepatocellular carcinoma (HCC) chromosomes, 33 minimal deleted regions (MDRs) were revealed. Five and 15 of the 33 MDRs have physical intervals in less than 5 and 10 Mb, respectively, with the smallest MDR9p1 of 2.2 Mb located at 9p21.3-p21.2. Statistical and Kaplan-Meier survival analysis revealed a significant association between the loss of MDR15q1 (15q21.1-q22.2) and the HCC patient survival (adjusted P = 0.033). After cluster analysis of 33 MDRs that represented LOH profiles of each HCC tissue based on clinicopathological features and p53 mutations, two major genetic pathways, low-stage and advanced-stage HCC, were uncovered based on high concordance of MDR clusters. We propose that the definition of genome-wide MDRs on the cancer genome not only narrows down the location of existing tumor suppressor genes to facilitate positional candidate cloning and develop potential prognostic markers after statistical association of MDRs with clinicopathological features but also dissects genetic interactions and pathways of chromosomal aberrations in tumorigenesis.