Heavy Ion Irradiation Reduces Vulnerability to Atrial Tachyarrhythmias　- Gap Junction and Sympathetic Neural Remodeling.

BACKGROUND: Low-invasive stereotactic body radiation therapy is a novel anti-arrhythmic strategy. The mechanisms underlying its effects against ventricular tachycardia/fibrillation (VT/VF) are gradually becoming clear, whereas those underlying atrial tachycardia/fibrillation (AT/AF) remain unknown. This study investigated the effects of carbon ion beam on gap junction expression and sympathetic innervation.Methods and Results: Atrial and ventricular tachyarrhythmia models was established in 26 hypercholesterolemic (HC) 3-year-old New Zealand white rabbits; 12 rabbits were irradiated with a single 15-Gy carbon ion beam (targeted heavy ion irradiation [THIR]) and 14 were not (HC group). Eight 3-month-old rabbits (Young) were used as a reference group. In vivo induction frequencies in the Young, HC, and HC+THIR groups were 0%, 9.9%, and 1.2%, respectively, for AT/AF and 0%, 7.8%, and 1.2%, respectively, for VT/VF (P<0.01). The conduction velocity of the atria and ventricles on optical mapping was significantly reduced in the HC group; this was reversed in the HC+THIR group. Connexin-40 immunolabelling in the atria was 66.1-78.7% lower in the HC than Young group; this downregulation was less pronounced in the HC+THIR group (by 23.1-44.4%; P<0.01). Similar results were obtained for ventricular connexin-43. Sympathetic nerve densities in the atria and ventricles increased by 41.9-65.3% in the HC vs. Young group; this increase was reversed in the HC+THIR group. CONCLUSIONS: Heavy ion radiation reduced vulnerability to AT/AF and VT/VF in HC elderly rabbits and improved cardiac conductivity. The results suggest involvement of connexin-40/43 upregulation and suppression of sympathetic nerve sprouting.

Hypofractionated Stereotactic Radiotherapy with CyberKnife for Large Arteriovenous Malformations and Arteriovenous Malformations Located in Eloquent Areas.

Literature has yet to establish an appropriate treatment strategy for large arteriovenous malformations (AVMs) and AVMs located in eloquent areas. In this study, the treatment outcomes of hypofractionated stereotactic radiotherapy (HSRT) with CyberKnife (CK) for large AVMs and AVMs in eloquent areas were evaluated. This study retrospectively evaluated 38 consecutive patients with AVMs treated with HSRT in the Japanese Red Cross Medical Center between August 2010 and July 2015. Obliteration rates and hemorrhage rates at 3- and 5-years of follow-up were calculated. Factors for hemorrhage and obliteration were analyzed with logistic regression analysis. Fourteen (36.8%) patients had a history of hemorrhage. Twenty (52.6%) AVMs were larger than 10 mL, and 34 (89.5%) AVMs were located in eloquent areas. The majority of the AVMs (84.2%) were classified into high grades (grades 3, 4, and 5) using the Spetzler-Martin grading scale. The median modified radiosurgery-based AVM score was 2.05, and the median Virginia Radiosurgery AVM Score was 3. The mean marginal dose was 24.5 ± 2.5 Gy. Twenty-three and 15 patients received three- and five-fraction stereotactic radiotherapy, respectively. At 3 and 5 years posttreatment, two (2.0%/year) and six (6.7%/year) patients had hemorrhage with obliteration rates of 15.2% and 16.7%, respectively. AVM localization in eloquent areas was a risk factor for obliteration failure. This study revealed that HSRT with CK for large AVMs and AVMs located in eloquent areas contributed to hemorrhage risk reduction and obliteration, at least in the early stages.

Revisitation of imaging features of skull base chondrosarcoma in comparison to chordoma.

PURPOSE: Pre-surgical diagnosis of skull base chondrosarcoma (SBC) is often challenging due to the resemblance to chordoma. The goal of this study was to develop an optimal method for predicting SBC diagnosis. METHODS: This retrospective study included patients with histologically diagnosed SBC and skull base chordoma. Their clinical and radiologic features were compared, and the predictive factors of SBC were examined. RESULTS: Forty-one patients with SBC and 41 with chordoma were included. Most SBCs exhibited hypointensity (25, 64.1%) or isointensity (12, 30.8%) on T1-weighted images, and hyperintensity (34, 87.1%) or mixed intensity (5, 12.8%) on T2-weighted images. MRI contrast enhancement was usually avid or fair (89.7%) with "arabesque"-like pattern (41.0%). The lateral/paramidline location was more common in SBC than in chordoma (85.4% vs. 9.8%; P < 0.01), while midline SBCs (14.6%) were also possible. Multivariate analysis demonstrated that higher apparent diffusion coefficient (ADC) value (unit odds ratio 1.01; 95% confidence interval 1.00-1.02; P < 0.01) was associated with an SBC diagnosis. An ADC value of ≥ 1750 × 10-6 mm2/s demonstrated a strong association with an SBC diagnosis (odds ratio 5.89 × 102; 95% confidence interval 51.0-6.80 × 103; P < 0.01) and yielded a sensitivity of 93.9%, specificity of 97.4%, positive predictive value of 96.9%, and negative predictive value of 95.0%. CONCLUSION: The ADC-based method is helpful in distinguishing SBC from chordoma and readily applicable in clinical practice. The prediction accuracy increases when other characteristics of SBC, such as non-midline location and arabesque-like enhancement, are considered together.

Accurate Preoperative Identification of Motor Speech Area as Termination of Arcuate Fasciculus Depicted by Q-Ball Imaging Tractography.

BACKGROUND: Tractography is one way to predict the distribution of cortical functional domains preoperatively. Diffusion tensor tractography (DTT) is commonly used in clinical practice, but is known to have limitations in delineating crossed fibers, which can be overcome by Q-ball imaging tractography (QBT). We aimed to compare the reliability of these 2 methods based on the spatial correlation between the arcuate fasciculus depicted by tractography and direct cortical stimulation during awake surgery. METHODS: In this study, 15 patients with glioma underwent awake surgery with direct cortical stimulation. Tractography was depicted in a three-dimensional computer graphic model preoperatively, which was integrated with a photograph of the actual brain cortex using our novel mixed-reality technology. The termination of the arcuate fasciculus depicted by either DTT or QBT and the results of direct cortical stimulation were compared, and sensitivity and specificity were calculated in speech-associated brain gyri: pars triangularis, pars opercularis, ventral precentral gyrus, and middle frontal gyrus. RESULTS: QBT had significantly better sensitivity and lower false-positive rate than DTT in the pars opercularis. The same trend was noted for the other gyri. CONCLUSIONS: QBT is more reliable than DTT in identification of the motor speech area and may be clinically useful in brain tumor surgery.

Symptomatic Change of an Intracranial Neuroepithelial Cyst 7 Years After Its Incidental Finding.

A natural course of asymptomatic neuroepithelial cysts (NECs) is poorly understood due to its rarity. Herein we report a 23-year-old female patient of an asymptomatic NEC which grew in size from 1 cm to 5 cm and caused progressive symptoms seven years after its incidental finding. Partial resection of the cyst was performed for decompression and pathological examination and effectively achieved symptoms alleviation and regression of the cyst. Our case showed the importance of regular follow-up because NECs may show symptomatic change even in the late phase.

Nonrheumatoid Retro-Odontoid Pseudotumors: Characteristics, Surgical Outcomes, and Time-Dependent Regression After Posterior Fixation.

OBJECTIVE: Although a retro-odontoid pseudotumor associated with rheumatoid arthritis is a well-known clinical entity, little is known about retro-odontoid pseudotumors not associated with rheumatoid arthritis due to their rarity. METHODS: Between 2006 and 2019, consecutive patients with nonrheumatoid pseudotumors were included and retrospectively compared with patients with rheumatoid pseudotumors. RESULTS: Nineteen patients had nonrheumatoid pseudotumors (mean age, 73 ± 6 years; male, 53%). All had cervical lesions including ossified anterior and posterior longitudinal ligaments with a history of cervical surgery in 5. The mean thickness of the pseudotumors at diagnosis was 8.1 mm (range, 4.2-17.2 mm). Pseudotumor thickness had a significant negative correlation with the atlantodental interval (p = 0.008) and the subaxial range of motion (p = 0.049). In comparison with 7 rheumatoid pseudotumor patients, nonrheumatoid pseudotumor patients were older (p = 0.042), had a higher proportion of males (p = 0.023), had a smaller atlantodental interval (p = 0.007), and had larger pseudotumors at diagnosis (p = 0.030). Of the 19 patients, 18 received posterior fixation with or without C1 laminectomy, while the other received C1 laminectomy alone. The percent pseudotumor thickness at follow-up to those at diagnosis was 91%, 77%, 68%, 46%, 58%, and 49% at 1, 3, 6, 12, 24, and 36 months after surgery, respectively. CONCLUSION: This study revealed markedly clinical and radiological differences between nonrheumatoid and rheumatoid pseudotumors. The main etiology for nonrheumatoid pseudotumors was subaxial cervical degeneration and ossified lesions. There were good outcomes following posterior fixation and time-dependent pseudotumor regression within 12 months.

Rapid intracranial pressure drop as a cause for posterior reversible encephalopathy syndrome: Two case reports.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized by reversible edematous lesions on radiological examinations as well as symptoms of altered consciousness and seizures. To date, the underlying mechanism remains largely unknown. CASE DESCRIPTIONS: Case 1 is a 72-year-old man with a history of hypertension presented with a subarachnoid hemorrhage. Fourteen days after the successful clipping of a ruptured aneurysm; he experienced inadvertent overdrainage via the intraventricular drain. Nine hours later, he started to have seizures followed by disturbances in consciousness. An emergency magnetic resonance imaging showed multiple high-intensity lesions in the frontal, temporal, parietal, and occipital lobes, basal ganglia, brainstem, and cerebellar hemispheres bilaterally, which are compatible with typical magnetic resonance findings in PRES patients. He was treated conservatively and recovered well. Case 2 is a 68-year-old woman with a mild history of hypertension and a ventriculo-peritoneal shunt for obstructive hydrocephalus, who underwent a cysto-peritoneal shunt placement because of an enlarging symptomatic arachnoid cyst. Immediately following surgery, she experienced disturbances in consciousness and developed status epilepticus. Radiological examinations revealed remarkable shrinkage of the arachnoid cyst and multiple edematous lesions, which led us to strongly suspect PRES. With conservative treatment, her symptoms and the radiological abnormalities disappeared. CONCLUSION: Based on the previous literature and our cases, we believe that the association between rapid reduction of intracranial pressure (ICP) and the development of PRES should be recognized because most neurosurgical procedures such as craniotomy or cerebrospinal fluid diversion present a potential risk of rapid reduction of ICP.

Partial IK1 blockade destabilizes spiral wave rotation center without inducing wave breakup and facilitates termination of reentrant arrhythmias in ventricles.

It has been reported that blockade of the inward rectifier K(+) current (IK1) facilitates termination of ventricular fibrillation. We hypothesized that partial IK1 blockade destabilizes spiral wave (SW) re-entry, leading to its termination. Optical action potential (AP) signals were recorded from left ventricles of Langendorff-perfused rabbit hearts with endocardial cryoablation. The dynamics of SW re-entry were analyzed during ventricular tachycardia (VT), induced by cross-field stimulation. Intercellular electrical coupling in the myocardial tissue was evaluated by the space constant. In separate experiments, AP recordings were made using the microelectrode technique from right ventricular papillary muscles of rabbit hearts. Ba(2+) (10-50 µM) caused a dose-dependent prolongation of VT cycle length and facilitated termination of VT in perfused hearts. Baseline VT was maintained by a stable rotor, where an SW rotated around an I-shaped functional block line (FBL). Ba(2+) at 10 µM prolonged I-shaped FBL and phase-singularity trajectory, whereas Ba(2+) at 50 µM transformed the SW rotation dynamics from a stable linear pattern to unstable circular/cycloidal meandering. The SW destabilization was not accompanied by SW breakup. Under constant pacing, Ba(2+) caused a dose-dependent prolongation of APs, and Ba(2+) at 50 µM decreased conduction velocity. In papillary muscles, Ba(2+) at 50 µM depolarized the resting membrane potential. The space constant was increased by 50 µM Ba(2+) Partial IK1 blockade destabilizes SW rotation dynamics through a combination of prolongation of the wave length, reduction of excitability, and enhancement of electrotonic interactions, which facilitates termination of ventricular tachyarrhythmias.

Differential action of chlorinated polycyclic aromatic hydrocarbons on aryl hydrocarbon receptor-mediated signaling in breast cancer cells.

Chlorinated polycyclic aromatic hydrocarbons (ClPAHs), which are a series of halogenated aromatic hydrocarbons, have been found in the environment. The primary step in their metabolic activation seems to be associated with aryl hydrocarbon receptor (AhR)-mediated induction of the cytochrome P450 (CYP) 1 family, although the evidence remains unclear. In this study, we first investigated the effects of five ClPAHs with three to five rings and the corresponding parent PAHs on the expression of CYP1A1 and 1B1 in human breast cancer MCF-7 cells. For the targeted ClPAHs, Western blot analysis of ClPAH-induced CYP1A1 and 1B1 showed an enhancement in activities in comparison with induction by the corresponding parent PAHs, and the effects of chlorination were especially prominent in phenanthrene. In a further study, using 6-chlorobenzo[a]pyrene (6-ClBaP), cotreatment with 17beta-estradiol showed an increase in the expression of CYP1B1 mRNA but not CYP1A1 mRNA. Since the AhR ligand has been reported to induce formation of an AhR-estrogen receptor (ER) complex, which stimulates transcription of ER target genes, the effects of ClPAHs in MCF-7 cells transfected with estrogen response elements-regulated green fluorescent protein (GFP) reporter genes were also investigated in this study. 6-ClBaP induced a dose-dependent increase in GFP expression related to ER signaling through AhR activation in the cells, but 3,9,10-trichlorophenanthrene (3,9,10-Cl(3)ClPhe) did not, despite its ability to activate AhR. Furthermore, we investigated the effect of ClPAHs on the expression of the endogenous ER-responsive genes, cathepsin D, in MCF-7 cells. 6-ClBaP stimulated expression of the ER-responsive genes but 3,9,10-Cl(3)ClPhe did not, as in the GFP expression system. These results suggest that estrogenic action mediated ER signaling through AhR activation does not necessarily occur for every ligand that can activate AhR.

Molecular determinants of hERG channel block by terfenadine and cisapride.

Block of cardiac hERG K+ channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160-3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.

Estrogenic activity of the chlorinated derivatives of estrogens and flavonoids using a GFP expression system.

Estrogenic chemicals are widely reported to be present in the environment. Their chlorinated derivatives are considered to be produced through the chlorination process in water purification and sewage treatment plants. In this study, several chlorinated derivatives of estrogens and flavonoids, including phytoestrogens, were synthesized by the reaction with hypochlorous acid, and their estrogenic activities were investigated using a devised GFP expression system in human breast carcinoma MCF7 cells. The chlorinated derivatives were less estrogenic than the parent compounds. The EC(50) ranking of estrogen-related compounds was 17ß-estradiol (E2)>4-ClE2>estrone (E1)>4-ClE1>10-Cl-1,4-estradiene-3,17-dione (10-Cl-3,17-dione)>2-ClE2>2-ClE1. 2,4-diClE2, 2,4-diClE1, and 2,4,16,16-tetraClE1 showed lower or no estrogenic activity. Genistein and daidzein are well known as phytoestrogens. 6,8-diCl-genistein, 3',8-diCl-daidzein, (+)-6,8-diCl-naringenin, and 6,8-diCl-apigenin showed lower estrogenic activity than their parent compounds. 3',5',8-triCl-daidzein exhibited no estrogenic activity. No activity was detected in chrysin, (+)-catechin, and their chlorinated derivatives. Similar results were obtained in a cell proliferation assay using MCF7 cells.

Molecular determinants of HERG channel block.

Drug-induced block of cardiac hERG K+ channels causes acquired long QT syndrome. Here, we characterized the molecular mechanism of hERG block by two low-potency drugs (Nifekalant and bepridil) and two high-potency drugs 1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine (E-4031) and dofetilide). Channels were expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. All four drugs progressively reduced hERG current during a 20-s depolarization to 0 mV after a 10-min pulse-free period, consistent with the preferential block of open channels. Recovery from block in response to pulses to -160 mV was observed for D540K hERG channels but not for wild-type hERG channels, suggesting that all four drugs are trapped in the central cavity by closure of the activation gate. The molecular determinants of hERG channel block were defined by using a site-directed mutagenesis approach. Mutation to alanine of three residues near the pore helix (Thr623, Ser624, and Val625) and four residues in Ser6 (Gly648, Tyr652, Phe656, and Val659) reduced channel sensitivity to block by dofetilide and E-4031, effects identical with those reported previously for two other methanesulfonanilides, (+)- N -[1' -(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H -1-benzopyran-2,4' -piperidin)-6-yl]-methanesulfonamide] monohydrochloride (MK-499) and ibutilide. The effect of nifekalant on mutant channels was similar, except that V659A retained normal sensitivity and I655A channels were less sensitive. Finally, mutation of the three residues near the pore helix and Phe656 in the Ser6 domain reduced channel block by bepridil. We conclude that the binding site is not identical for all drugs that preferentially block hERG in the open state.

1,25-Dihydroxyvitamin D3 suppresses gene expression of eukaryotic translation initiation factor 2 in human promyelocytic leukemia HL-60 cells.

The physiologically active metabolite of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (DVD), is a potent inducer of cell differentiation in human myeloid leukemia cells. In the present study, we examined changes in gene expression during DVD-induced cell differentiation of promyelocytic HL-60 cells employing a DNA microarray technique. The results identified 7 up-regulated and 9 down-regulated genes with a change greater than 1.5-fold after the DVD-treatment for both 2 and 6 days. Seven of these genes were further examined by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that findings obtained from the DNA microarray analysis and RT-PCR are generally comparable with each other. Gene expression of the subunits of eukaryotic translation initiation factor 2 was then examined by methods including RT-PCR and real-time PCR. The results indicated the suppression of these genes, suggesting a linkage to differentiation-associated growth inhibition of these cells.

DPPH radical-scavenging compounds from dou-chi, a soybean fermented food.

Dou-chi, a traditional soybean food fermented with Aspergillus sp., is usually used as a seasoning in Chinese food, and has also been used as a folk medicine in China and Taiwan. As 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavengers, four phenol compounds, one isoflavanone, eight isoflavones and one 4-pyrone have been isolated from dou-chi. Among these fourteen compounds, 3'-hydroxydaidzein, dihydrodaidzein and a 4-pyrone compound have not yet been isolated from soybean miso. The structure of the novel 4-pyrone compound, 3-((E)-2-carboxyethenyl)-5-(4-hydroxyphenyl)-4-pyrone-2-carboxylic acid was elucidated by using the same compound as that obtained from the biotransformation of daidzein. 3'-Hydroxydaidzein showed as high DPPH radical-scavenging activity as that of alpha-tocopherol, and 6-hydroxydaidzein had mushroom tyrosinase inhibitory activity with an IC(50) value of 10 muM. The order of estrogenic activity is as follows: genistein > daidzein >> 3'-hydroxydaidzein > 8-hydroxygenistein, using a green fluorescent protein expression system. Furthermore, the contents of isoflavones in the fermentation process of dou-chi were measured.

Identification of estrogenic activity of chlorinated bisphenol A using a GFP expression system.

A green fluorescent protein (GFP)-reporter vector regulated by an estrogen response element (ERE) was constructed and transfected into human breast carcinoma MCF7 cells. Stable transfectants were selected and their GFP fluorescence intensity was measured using a quantitative fluorescent imaging system. 17ß-estradiol (E(2)) and bisphenol A (BPA) induced a dose-dependent increase in GFP intensity in the cells, reaching maximum response at 5×10(-10) and 10(-5) M, respectively. Using this GFP expression system, we examined the estrogenicity of mono-, di-, tri-, and tetra-chlorinated BPAs, which were detected in wastewater from waste-paper recycling plants using sodium hypochlorite as a bleaching agent. 3-ClBPA and 3,3'-diClBPA showed similar estrogenicities, effective at lower concentrations than parent BPA. On the other hand, the maximum activities of BPA and 3,3',5-triClBPA, whose EC(50) were similar, were higher than other chlorinated BPAs. This is the first demonstration of the estrogenicity of chlorinated BPAs. Since polychlorinated BPAs were not easily biodegraded, chlorinated BPAs might be more severe endocrine disruptors than BPA.