Magnetic resonance venography and liver transplant complications

Hepatic vein stenosis is a rare but serious complication following liver transplantation.Multiple modalities can be utilized to image the hepatic vasculature.Magnetic resonance venography(MRV)provides certain advantages over ultrasound,computed tomography angiography and digital subtraction venography.MRV utilizes the same imaging principles of magnetic resonance angiography in order to image the venous system.Blood pool contrast agents,specifically gadofosveset trisodium,allow for steady state imaging up to 1 h following injection,with improved visualisation of vital venous structures by utilising delayed steady state imaging.Additionally,the inherent physics properties of magnetic resonance imaging also provide excellent soft tissue detail and thus help define the extent of complications that often plague the post-liver transplant patient.This case report describes the use of gadofosveset trisodium in a patient with hepatic venous stenosis following liver transplantation.Initial venography failed to outline the stenoses and thus MRV using a blood pool contrast agent was utilised in order to delineate the anatomy and plan a therapeutic endovascular procedure.     

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia

AIM: To examine the association of genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)A/G TNFR2 with the development of primary open angle glaucoma (POAG) among people in Central Russia. METHODS: The study sample included 443 individuals, of which 252 patients with POAG and 191 individuals in the control group. Genotyping of (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)A/G TNFR2 was performed using polymerase chain reaction. The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables and χ2 with the Yates’s correction for continuity and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Allele (-308)G TNFα (Р=0.01, OR=1.78, 95%CI 1.12-2.85) was identified as a risk factor for POAG. Homozygotes (-308) AA TNFα are at a lowest risk for development of the disease (Р=0.01, OR=0.0005). The following combination of genetic variants of cytokines were associated with a reduced risk of POAG: (+1663)A TNFR2 and (+250)G Ltα (OR=0.34) CONCLUSION: Genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+1663)A/G TNFR2 associated with the development of POAG in the population of Central Russia.     

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.     

Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability

Alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)), we studied the role of alphaCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus-dependent spatial learning in the Morris water maze. Wild-type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild-type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning-specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, alphaCaMKII(T286A) mice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild-type controls after water-maze training. Notably, both trained and swim-control groups of alphaCaMKII(T286A) mutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal alphaCaMKII function. This result demonstrates dissociation of alphaCaMKII-independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitability per se are not perfectly correlated with learning. Our findings suggest that alphaCaMKII signaling may function to suppress learning-unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.     

The evolving practice of intrauterine cervix brachytherapy in Canada: A medical physics perspective

PurposeTo determine the current equipment, technology, and treatment planning methods used in Canadian cancer centers for intrauterine cervix brachytherapy.Methods and MaterialsA questionnaire was developed to survey medical physicists in Canada regarding technical aspects of intrauterine cervix brachytherapy. A response was obtained from one physicist at each radiotherapy facility in Canada.ResultsA total of 32 of the 41 Canadian radiotherapy facilities perform intrauterine brachytherapy. Most (88%) use high-dose-rate brachytherapy. Images used for treatment planning are two-dimensional (2D) X-rays (63%), CT (66%), MRI (13%), and cone beam CT (9%). Patients are moved to another room to obtain images at 66% of the centers. Dose is prescribed to a volume at 28% of centers, and dose–volume histogram information is used in evaluating dose to the organs at risk (47%) and target (31%). Manual optimization was the most common optimization method (81%). A total of 69% of the institutions made significant changes within the past 5 years, and 66% plan major changes within the next 2 years.ConclusionsIntrauterine brachytherapy treatment for cervical cancer is rapidly evolving in Canada, with centers moving toward 3D image-based methods. Often these imaging modalities are not located in the brachytherapy room, so studies on immobilization and verification would be useful. Access to MRI is increasing, but remains low, correlating with a low adoption of volume-based parameters for evaluating target coverage. National treatment guidelines would be useful for centers making the transition from 2D to 3D methods and for encouraging access to MRI.     

Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02–4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel–Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups.