Association of G-33A polymorphism in the thrombomodulin gene with myocardial infarction in Koreans.

Thrombomodulin (TM), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the TM gene (G-33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which stenosis was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more stenosis on angiography. In addition, 102 controls (CONT) who had no significant stenosis were employed. The number of AA/GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p=0.004 by chi2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the TM promoter activity. These results indicated that G-33A polymorphism in TM might be a genetic risk factor for myocardial infarction.     

Successful application of burst spinal cord stimulation for refractory upper limb pain: a case series

Spinal cord stimulation (SCS) has been used to treat sustained pain that is intractable despite various types of treatment. However, conventional tonic waveform SCS has not shown promising outcomes for spinal cord injury (SCI) or postamputation pain. The pain signal mechanisms of burst waveforms are different to those of conventional tonic waveforms, but few reports have presented the therapeutic potential of burst waveforms for the abovementioned indications. This current case report describes two patients with refractory upper limb pain after SCI and upper limb amputation that were treated with burst waveform SCS. While the patients could not obtain sufficient therapeutic effect with conventional tonic waveforms, the burst waveforms provided better pain reduction with less discomfort. However, further studies are necessary to better clarify the mechanisms and efficacy of burst waveform SCS in patients with intractable pain.     

Optimizing tissue clearing and imaging methods for human brain tissue

ObjectivesTo identify optimum sample conditions for human brains, we compared the clearing efficiency, antibody staining efficiency, and artifacts between fresh and cadaver samples.MethodsFresh and cadaver samples were cleared using X-CLARITY™. Clearing efficiency and artifact levels were calculated using ImageJ, and antibody staining efficiency was evaluated after confocal microscopy imaging. Three staining methods were compared: 4-day staining (4DS), 11-day staining (11DS), and 4-day staining with a commercial kit (4DS-C). The optimum staining method was then selected by evaluating staining time, depth, method complexity, contamination, and cost.ResultsFresh samples outperformed cadaver samples in terms of the time and quality of clearing, artifacts, and 4′,6-diamidino-2-phenylindole (DAPI) staining efficiency, but had a glial fibrillary acidic protein (GFAP) staining efficiency that was similar to that of cadaver samples. The penetration depth and DAPI staining improved in fresh samples as the incubation period lengthened. 4DS-C was the best method, with the deepest penetration. Human brain images containing blood vessels, cell nuclei, and astrocytes were visualized three-dimensionally. The chemical dye staining depth reached 800 µm and immunostaining depth exceeded 200 µm in 4 days.ConclusionsWe present optimized sample preparation and staining protocols for the visualization of three-dimensional macrostructure in the human brain.     

Hypofractionated radiotherapy with Tomotherapy for patients with hepatic oligometastases: retrospective analysis of two institutions

To evaluate the efficacy and toxicity for patients with hepatic oligometastases, receiving hypofractionated radiotherapy with Tomotherapy to the liver. A total of 42 patients with 54 hepatic lesions, who had been treated from 2007 to 2011 at two institutions, were retrospectively reviewed for this study. All the patients received radical resections of the primary tumor, and had been presented with one to two hepatic lesions. The radiation dose of 40–75 Gy in 10–20 fractions (median, 50 Gy in 10 fractions) was delivered for the planning target volume. At a median follow-up time of 15 months, 1- and 2-year local control (LC) rates were 59.9 and 49.0 %, respectively. The 1- and 2-year overall survival (OS) rates were 60.0 and 44.0 %, respectively. Maximal tumor diameter of <3 cm and biologically effective dose (BED) of ≥100 Gy_α/β=10 were significantly associated with higher LC and OS. Primary colorectal cancer tended to be associated with higher LC (P = 0.075), and was significantly associated with higher OS (P = 0.037). 12 (28.6 %) of the 42 patients had grade 1–2 toxicities, and grade 3 or higher toxicity did not occur. Hypofractionated radiotherapy with Tomotherapy was safe for patients with hepatic oligometastases. The maximal tumor diameter of <3 cm and BED of ≥100 Gy_α/β=10 were significant prognostic factors for higher local control and survival, and primary colorectal cancer patients had statistically higher overall survival than the others.     

Interference with Ca2+ release activated Ca2+ (CRAC) channel function delays T‐cell arrest in vivo

Entry of lymphocytes into secondary lymphoid organs (SLOs) involves intravascular arrest and intracellular calcium ion ([Ca²⁺]_i) elevation. TCR activation triggers increased [Ca²⁺]_i and can arrest T‐cell motility in vitro. However, the requirement for [Ca²⁺]_i elevation in arresting T cells in vivo has not been tested. Here, we have manipulated the Ca²⁺ release‐activated Ca²⁺ (CRAC) channel pathway required for [Ca²⁺]_i elevation in T cells through genetic deletion of stromal interaction molecule (STIM) 1 or by expression of a dominant‐negative ORAI1 channel subunit (ORAI1‐DN). Interestingly, the absence of CRAC did not interfere with homing of naïve CD4⁺ T cells to SLOs and only moderately reduced crawling speeds in vivo. T cells expressing ORAI1‐DN lacked TCR activation induced [Ca²⁺]_i elevation, yet arrested motility similar to control T cells in vitro. In contrast, antigen‐specific ORAI1‐DN T cells had a twofold delayed onset of arrest following injection of OVA peptide in vivo. CRAC channel function is not required for homing to SLOs, but enhances spatiotemporal coordination of TCR signaling and motility arrest.     

Layer- and cell-type-specific tonic GABAergic inhibition of pyramidal neurons in the rat visual cortex

Tonic inhibition mediated by persistent activation of γ-aminobutyric acid_A (GABA_A) receptors by ambient GABA plays a crucial role in the regulation of network excitability and neuronal signal processing. Varying degrees in the strength of tonic inhibition were detected across different cell types throughout the brain. Since sensory information flows through cortical layers in a specific order, the characteristics of tonic inhibition in different cortical layers are of interest. Therefore, we examined the properties of tonic inhibition in pyramidal neurons (PyNs) throughout the rat visual cortex. Layer 2/3 PyNs and burst-spiking PyNs in layers 5 and 6 showed prominent tonic GABA_A currents. Tonic GABA_A currents in layer 4 star PyNs and regular-spiking PyNs in layers 5 and 6 were much weaker. The magnitude of tonic currents correlated well with the inhibition of spike generation. The amplitude of tonic GABA_A currents measured with bicuculline and gabazine, the two different GABA_A receptor blockers, did not differ. The differences in the expression levels of extrasynaptic GABA_A receptors might be the major contributor to the differences in tonic GABA_A currents among cell types. Furthermore, α5 subunits might contribute significantly to tonic currents in infragranular burst-spiking PyNs, especially in layer 5. These results suggest that ambient GABA might exert differential effects on the neuronal integration in a layer- and cell-type-specific manner and thus contribute to the processing of sensory properties by selectively tuning the signals flowing through the visual cortex.     

Lack of association between hepatitis B virus pre‐S mutations and recurrence after surgical resection in hepatocellular carcinoma

Pre‐S mutation of hepatitis B virus (HBV) is known to be a risk factor for hepatocarcinogenesis. A previous study suggested that pre‐S mutation(s) may associate with increased recurrence after surgical resection. In the present study, 64 patients with HBV‐related hepatocellular carcinoma (HCC) were categorized into two groups according to the presence or absence of pre‐S mutation(s). The clinicopathological variables of the two groups were analyzed to assess the relationship between pre‐S mutations and postoperative recurrence. Nineteen patients (29.7%) had pre‐S mutations;13 had a pre‐S deletion, three had a pre‐S2 start codon mutation, two patients had both a pre‐S deletion, and a pre‐S2 start codon mutation, and one patient had a pre‐S2 insertion. The two groups did not differ in terms of baseline clinicopathological parameters. Cirrhosis and satellite lesion(s) were predictive factors for postoperative recurrence and poor overall survival. Recurrence‐free survival (P = 0.320) and overall survival (P = 0.238) did not differ significantly when pre‐S mutations were present. In conclusion, this study did not find evidence supporting the notion that pre‐S mutation(s) are associated with postoperative recurrence after surgical resection. J. Med. Virol. 85:589–596, 2013. © 2013 Wiley Periodicals, Inc.     

Predictors of relapse in patients with major depressive disorder in a 52-week,fixed dose,double blind,randomized trial of selegiline transdermal system (STS)

Objective

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment.

Method

After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse.

Results

For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis.

Conclusions

While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD.     

The Extent of Late Gadolinium Enhancement Can Predict Adverse Cardiac Outcomes in Patients with Non-Ischemic Cardiomyopathy with Reduced Left Ventricular Ejection Fraction: A Prospective Observational Study

ObjectiveThe clinical course of an individual patient with heart failure is unpredictable with left ventricle ejection fraction (LVEF) only. We aimed to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived myocardial fibrosis extent and to determine the cutoff value for event-free survival in patients with non-ischemic cardiomyopathy (NICM) who had severely reduced LVEF.Materials and MethodsOur prospective cohort study included 78 NICM patients with significantly reduced LV systolic function (LVEF < 35%). CMR images were analyzed for the presence and extent of late gadolinium enhancement (LGE). The primary outcome was major adverse cardiac events (MACEs), defined as a composite of cardiac death, heart transplantation, implantable cardioverter-defibrillator discharge for major arrhythmia, and hospitalization for congestive heart failure within 5 years after enrollment.ResultsA total of 80.8% (n = 63) of enrolled patients had LGE, with the median LVEF of 25.4% (19.8–32.4%). The extent of myocardial scarring was significantly higher in patients who experienced MACE than in those without any cardiac events (22.0 [5.5–46.1] %LV vs. 6.7 [0–17.1] %LV, respectively, p = 0.008). During follow-up, 51.4% of patients with LGE ≥ 12.0 %LV experienced MACE, along with 20.9% of those with LGE ≤ 12.0 %LV (log-rank p = 0.001). According to multivariate analysis, LGE extent more than 12.0 %LV was independently associated with MACE (adjusted hazard ratio, 6.71; 95% confidence interval, 2.54–17.74; p < 0.001).ConclusionIn NICM patients with significantly reduced LV systolic function, the extent of LGE is a strong predictor for long-term adverse cardiac outcomes. Event-free survival was well discriminated with an LGE cutoff value of 12.0 %LV in these patients.     

Precommissural Fornix in the Human Brain: A Diffusion Tensor Tractography Study

Purpose

Other than a single case report, no diffusion tensor tractography (DTT) studies of the precommissural fornix in the human brain have been conducted. In the current study, we attempted to visualize the precommissural fornix in the human brain using DTT.

Materials and Methods

We recruited 36 healthy volunteers for this study. Diffusion tensor images were scanned using a 1.5-T scanner, and the precommissural fornix was analyzed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) software. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of the precommissural fornix were measured.

Results

The precommissural fornix originated from the hippocampal formation on each hemisphere as a crus; both crura were then joined to the body of the fornix. The body of the fornix continued anteriorly to the level just superior to the anterior commissure, where it divided into each column of the precommissural fornix. Each column descended anteriorly to the anterior commissure and terminated in the septal nuclei. Values of FA, MD, and tract volumes of the precommissural fornix did not differ between the right and left hemispheres (p>0.05).

Conclusion

We believe that the methodology and results of this study would be helpful to future research on the precommissural fornix and in the elucidation of the pathology of diseases involving the precommissural fornix.