An extremely energetic cosmic ray observed by a surface detector array.

Cosmic rays are energetic charged particles from extraterrestrial sources, with the highest-energy events thought to come from extragalactic sources. Their arrival is infrequent, so detection requires instruments with large collecting areas. In this work, we report the detection of an extremely energetic particle recorded by the surface detector array of the Telescope Array experiment. We calculate the particle's energy as [Formula: see text] (~40 joules). Its arrival direction points back to a void in the large-scale structure of the Universe. Possible explanations include a large deflection by the foreground magnetic field, an unidentified source in the local extragalactic neighborhood, or an incomplete knowledge of particle physics.

Glibenclamide attenuates brain edema associated with microglia activation after intracerebral hemorrhage.

OBJECTIVE: Glibenclamide, Sulfonylurea receptor 1 antagonist, reduces brain edema after cerebral hemorrhage. However, the effects of glibenclamide on microglial activation and inflammatory cell infiltration after cerebral hemorrhage are unclear. The present study investigated the effect of glibenclamide on microglial activation and inflammatory cell infiltration in a rat cerebral hemorrhage model. METHODS: A collagenase intracerebral injection model was used to cause cerebral hemorrhage in rats. After injury, glibenclamide was continuously administered at 1.0µL/h for 24hours. We evaluated hematoma volume, brain edema, expression of ABCC8, galectin-3 and CD11b, and anti-Iba-1 antibody staining. RESULTS: Glibenclamide significantly reduced water content. Meanwhile, glibenclamide significantly reduced expression of galectin-3 and CD11b in the cerebral cortex and putamen on the bleeding side. Immunohistochemical staining confirmed that glibenclamide attenuated activation of microglia around the hematoma. CONCLUSIONS: Glibenclamide reduced microglial activation and infiltration of inflammatory cells, resulting in amelioration of cerebral edema.

Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation.

Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated ApcΔ716 Trp53LSL•R270H villin-CreER compound mice, in which mutant p53R270H was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53R270H, but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in ApcΔ716 Trp53R270H/R270H homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in ApcΔ716 Trp53+/R270H heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted ApcΔ716 Trp53R270H/R270H organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear-accumulated mutant p53R270H induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53R270H, which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53R270H induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53R270H is a potential therapeutic target for the treatment of advanced CRCs.

TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells.

Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-α) is a proinflammatory cytokine, and polymorphism in the TNF-α gene increases the risk of gastric cancer. We herein investigated the role of TNF-α in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-α (Tnf) or TNF-α receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf-/- Gan and Tnfrsf1a-/- Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf-/- Gan mice and Tnfrsf1a-/- Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf+/+ or Tnfrsf1a+/+ Gan mice. These results indicate that TNF-α signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-α expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-α-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-α/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-α/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.

Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells.

Inflammation has an important role in cancer development through various mechanisms. It has been shown that dysregulation of microRNAs (miRNAs) that function as oncogenes or tumor suppressors contributes to tumorigenesis. However, the relationship between inflammation and cancer-related miRNA expression in tumorigenesis has not yet been fully understood. Using K19-C2mE and Gan mouse models that develop gastritis and gastritis-associated tumors, respectively, we found that 21 miRNAs were upregulated, and that 29 miRNAs were downregulated in gastric tumors in an inflammation-dependent manner. Among these miRNAs, the expression of miR-7, a possible tumor suppressor, significantly decreased in both gastritis and gastric tumors. Moreover, the expression of miR-7 in human gastric cancer was inversely correlated with the levels of interleukin-1ß and tumor necrosis factor-α, suggesting that miR-7 downregulation is related to the severity of inflammatory responses. In the normal mouse stomach, miR-7 expression was at a basal level in undifferentiated gastric epithelial cells, and was induced during differentiation. Moreover, transfection of a miR-7 precursor into gastric cancer cells suppressed cell proliferation and soft agar colony formation. These results suggest that suppression of miR-7 expression is important for maintaining the undifferentiated status of gastric epithelial cells, and thus contributes to gastric tumorigenesis. Although epigenetic changes were not found in the CpG islands around miR-7-1 of gastritis and gastric tumor cells, we found that activated macrophage-derived small molecule(s) (<3 kDa) are responsible for miR-7 repression in gastric cancer cells. Furthermore, the miR-7 expression level significantly decreased in the inflamed gastric mucosa of Helicobacter-infected mice, whereas it increased in the stomach of germfree K19-C2mE and Gan mice wherein inflammatory responses were suppressed. Taken together, these results indicate that downregulation of tumor suppressor miR-7 is a novel mechanism by which the inflammatory response promotes gastric tumorigenesis.

The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic ß-cell function.

AIM: AS1535907, a small molecule agonist of GPR119, was assessed for its glucose-stimulated insulin secretory activity and pancreatic ß-cell function in type 2 diabetes. METHODS: Both in vitro and in vivo tests were conducted using NIT-1 and HEK293 cell lines, male normal and db/db mice and isolated perfused rat pancreas preparations. RESULTS: AS1535907 had an EC50 value of 1.5 µM for human GPR119 transfected in HEK293 cells. AS1535907 enhanced insulin secretion in NIT-1 cells and in the perfused rat pancreas. A transient increase in the human insulin promoter activity was also observed in NIT-1 cells. First-phase insulin secretion was particularly more evident in the AS1535907-treated perfused rat pancreas than that in the nateglinide or glibenclamide-treated group. Oral glucose tolerance improved following a single dose of AS1535907 in normal and db/db mice. Subsequently, 2 weeks of multiple dosing significantly increased plasma insulin levels and decreased blood glucose levels in db/db mice. After 3 weeks of treatment in db/db mice, the numbers of insulin and proliferation cell nuclear antigen-positive cells and the islet area were significantly higher than those in the vehicle-treated mice. As compared with the vehicle, gene expression analysis revealed that AS1535907 significantly upregulated transcription factors (Nkx 2.2, Nkx 6.1, NeuroD and activin A), responsible for ß-cell regulation and prohormone-converting enzyme 1 responsible for insulin biosynthesis. CONCLUSION: These results suggest that AS1535907 can potentially regulate first-phase insulin secretion and exert a protective effect on pancreatic ß-cell function via regulation of transcription factors.

Fracture resistance of root filled molar teeth restored with glass fibre bundles.

AIM: To evaluate the effect of unidirectional or woven glass fibre tapes inserted into MOD cavity preparations on the fracture resistance of root filled molar teeth. METHODOLOGY: Extracted human molar teeth were randomly divided into six groups (n = 15) : G1 - sound teeth, control; G2 - MOD cavity preparation; G3 - MOD + root canal treatment (Endo); G4 - MOD + Endo + composite resin restoration (Resin); G5 - MOD + Endo + unidirectional fibre (UF) + Resin; G6 - MOD + ;Endo + woven fibre (WF) + Resin. The teeth were subjected to a compressive fracture test in a universal testing machine. After testing, two failure modes were classified: pulp chamber floor or cusp. RESULTS: The highest and the lowest mean fracture strengths were found in sound teeth (G1) (4960N) and MOD + root canal treatment (G3) (612.84N), respectively, with significant differences from the other groups (P < 0.05). The remaining groups had statistically similar means. In G5 and G6, there was a tendency for fracture to occur in the pulp chamber floor compromising tooth integrity. CONCLUSIONS: The insertion of glass fibres into MOD cavity preparations and restoring them with composite resin was not different than molar teeth filled with composite resin only in terms of fracture resistance. Fibres placed into MOD cavities do not reinforce teeth.

Changes in hardness and surface topography of tissue conditioners submitted to chemical disinfection.

AIM: The aim of this study was to evaluate the longitudinal effect of chemical disinfection on Shore A hardness, surface roughness (Ra) and morphology of two tissue conditioners (Dura Conditioner [DC] and Softone [SO]). METHODS: Twenty-four specimens (2 mm-thick) were made of each material and randomly divided into three groups (N.=8): control (no disinfection), 10 000 ppm chloride solution (sodium hypochlorite) and Corega Tabs solution (peroxide solution). Soaking was performed daily for 15 min, and Shore A hardness and Ra were measured at baseline and 3, 7, 10, and 14 days. Data were analyzed by repeated measures ANOVA and Bonferroni's test (alfa= 0.05). RESULTS: Chemical disinfection for 14 days with sodium hypochlorite and Corega Tabs affected differently the tested materials. Hardness varied from 8 to 20 for DC and from 8 to 23 for SO with significant interaction (P<0.05) between material and disinfection treatment up to day 7. Ra values (in microm) varied from 1.51 to 4.35 for DC and from 2.08 to 4.15 for SO; there was a significant difference between disinfection treatments (P=0.043) but not between materials (P=0.119). Sodium hypochlorite groups displayed smaller Ra values than the control groups, but did not differ from Corega Tabs groups. Scanning electron microscopy showed different pattern of degradation for each material. CONCLUSIONS: The results suggest that the effect of chemical disinfection on degradation of tissue conditioners is material-specific, but hardness is less affected than surface topography. The overall results support the use of the tested materials for up to three days, independently from the disinfection treatment.

Influence of storage solution and curing method on a microhybrid composite microhardness.

AIM: The purpose of this study is to evaluate and compare the Vickers microhardness of one microhybrid composite polymerized with different sources and stored in different solutions for up to 14 days. METHODS: Using a bipartite PTFE mould with 6 mm inner diameter and 3 mm high, 30 samples were manufactured with Charisma B1 shade for each polymerization procedures (halogen light, LED and halogen light and postcure cycles) stored in tree types of storage solution. RESULTS: The postcuring method tended to improve the microhardness, but was not statistically different from halogen or LED curing methods (P>0.05). The storage solutions interfered in surface hardness, with the samples eluted in red wine showing the lowest hardness values (P<0.05). After seven days, the hardness values were higher than the first day, but statistically equal to 14 days (P<0.05). CONCLUSION: On accordance with the findings of this study, different storage solutions can change the surface microhardness of a composite resin. An alcoholic solution seems most harmful to the composite. Samples postcured in autoclave had an improved mean value, however, without differing from those of the LED and halogen photo polymerized specimens.

Magnetic behavior in an ordered Co nanorod array.

The magnetization reversal process of an ordered Co nanorod array is shown using the images obtained from successive in-field magnetic force microscope (MFM) measurements. The magnetization reversal model is discussed according to local and whole magnetization reversal properties measured by the polar magneto-optical Kerr effect (PMOKE) and an alternating gradient magnetometer (AGM), respectively. Additionally, the dipolar field was probed using in-field MFM measurements. By removing the effect of the dipolar field, an intrinsic switching field distribution (SFD) is shown in a map with a hexagonal array. A detailed study of the dipolar field in ordered nanorod arrays with various diameters and pitches was carried out by numerical calculations.

Portal blood flow regulates volume recovery of the rat liver after partial hepatectomy: molecular evaluation.

BACKGROUND/AIM: Liver regeneration is a finely tuned process that is closely regulated by multiple cell cycle steps. Although the portal blood flow affects liver regeneration, the molecular mechanism by which the blood flow regulates gene expression and liver function is largely unknown. The aim of this study was to investigate the molecular effect of portal blood flow on hepatocyte proliferation and gene regulation during liver regeneration. MATERIALS AND METHODS: We developed a simple surgical rat model to investigate the relation between portal blood flow and liver regeneration by partially ligating the portal trunk with 8-0 Proline sutures under microscopy to reduce the blood flow by 40%. We investigated recovery of liver volume, DNA synthesis, and gene expression associated with cell cycle regulators, comparing partially hepatectomized (PH) rats without (PH group; n = 30) and with partial portal ligation (PHPL group; n = 30) for 7 days after the operation. RESULTS: The hepatic tissue blood flow and the recovery ratio between liver weight and body weight in the PHPL group were significantly lower than in the PH group after hepatectomy. The peak 5-bromo-2'-deoxyuridine labeling index in the PHPL group was delayed and weak compared with the PH group. The expression of CT-1 and cyclin D, E, and B mRNAs indicated that the liver regeneration in the PHPL group was delayed and weak. In addition, there was reciprocal expression of C/EBPalpha and C/EBPbeta mRNAs, an observation supported by their nuclear protein levels. Furthermore, the cytochrome P-450 protein level in the PHPL group was higher than that in the PH group 1 day after hepatectomy. CONCLUSION: The portal blood flow regulates the activity of liver regeneration and the gene expression associated with cell cycle regulators, while the functions are maintained.

Influencia de la polimerización adicional en las propiedades de una resina Ormocer® / Influencie of post-curing in Ormocer® mechanical properties

Los objetivos de este estudio fueron evaluar y comparar la influencia de la polimerización adicional con calor y presión de vapor o calor y nitrógeno presurizado en la resistencia a la compresión, módulo de elasticidad y microdureza Vickers de una resina compuesta Ormocer®. Para esto, se confeccionaron 45 muestras cilíndricas con 3 mm de diámetro y 6 mm de altura en una matriz de PTFE. La resina compuesta Admira (Voco,Cuxhaven, Germany) fue introducida gradualmente y fotopolimerizada por 40 s con el aparato XL-1500 (3MESPE, St. Paul, MN, EUA). Seguidamente, las muestras fueron almacenadas en un horno a 37ºC por 24 horas y divididas aleatoriamente en tres grupos. Las muestras del grupo I (control) fueron testadas inmediatamente después del período de almacenamiento. En el grupo II, las muestras fueron sometidas a 120ºC bajo presión de vapor de agua por 20 min y, en el grupo III, las muestras fueron polimerizadas adicionalmente a 140°C con presión de 60 lbs. de nitrógeno durante 10 minutos. Inmediatamente, las muestras fueron testadas en una máquina de ensayo universal (Emic DL 2000, São José dos Pinhais, Paraná, Brazil) a 0,5 mm/min hasta quese fracturaron. Los valores de resistencia a la compresión (MPa), módulo de elasticidad (GPa) y microdureza Vickers (VHN) fueron tratados estadísticamente con ANOVA/Tukey (p < 0,05). Los valores de resistencia (MPa,DP) fueron: grupo I (control) 114,25b (±34,74); grupo II 127,64b (±33,27); grupo III 167,97a (±40,15). Módulo de elasticidad (GPa, DP): grupo I (control) 6,11b (±0,35); grupo II 8,45ab (±0,33); grupo III 11,31a (±0,47). Microdureza Vickers (VHN, DP): grupo I (control) 47,26b (6,32); grupo II 58,63a (13,92); grupo III 63,69a (8,86). Se puede concluir entonces, que el método de polimerización adicional a 140°C bajo presión de 60 lbs de nitrógeno aumentó significativamente la resistencia a la compresión, y ambos métodos adicionales de cura aumentaron significativamente el módulo de elasticidad y microdureza Vickers de la resina compuesta Admira (p < 0,05) (AU)

The purposes of this study were evaluate and compare the influence of post-curing with heat and steam pressure or heat and nitrogen pressure in the compressive strength, elastic modulus and Vickers microhardness of an Ormocer® composite resin. Forty-five cylindrical samples with 3 mm diameter and 6 mm high were manufacture using a PTFE mould. The composite resin Admira (Voco, Cuxhaven, Germany) was inserted incrementally and cured for 40 s with XL-1500 (3M ESPE, St. Paul, MN, EUA). After that, the samples were stored in a stove at 37ºC for 24 hours and randomly divided in three groups. The samples of group I (control) were tested just after the stored period. In group II, the samples were submitted to 120ºC with water steam for 20 min, and for group III, the samples was post-cured at 140°C under 60 lbs of nitrogen for 10 min. The samples were tested with universal testing machine (Emic DL 2000, São José dos Pinhais, Paraná, Brazil) at 0.5 mm/min until fracture. Data of compressive strength (MPa), elastic modulus (GPa), and Vickers microhardness (VHN) were statistically evaluated with ANOVA/Tukey (p < 0.05). The mean values of compressive ;;strength (SD) were: group I (control) 114.25b (±34.74); group II 127.64b (±33.27); group III 167.97a (±40.15); elastic modulus (SD): group I (control) 6.11b(±3.5); group II 8.45ab (±3.34); group III 11.31a(±4.7); Vickers microhardness (SD): group I (control) 47.26b (2.7); group II 58.63a (2.3) and group III 63.69a (3.5). It is possible to conclude that the post-curing method at 140°C under 60 lbs of nitrogen improved significantly the compressive strength, and both methods improved the elastic modulus and microhardness (p < 0.05) (AU)

Seasonal variations of acute massive submacular haemorrhage associated with age-related macular degeneration.

AIMS: To determine whether there is a seasonal variation in the onset of acute, massive submacular haemorrhage associated with age-related macular degeneration. METHODS: Sixty eyes of 59 patients diagnosed between April 1998 and March 2005, were studied retrospectively. For each patient, the month and season of onset of the submacular haemorrhage and the mean monthly ambient temperature in Nagoya were analysed. Any history of systemic hypertension was also recorded, and the seasonal variations were also investigated in hypertensive and non-hypertensive groups. RESULTS: The number of cases peaked in winter with a trough in summer, and this seasonal variation was significant (Roger's R = 12.03, p<0.01). The monthly incidence was inversely correlated with the temperature (Spearman's rank correlation coefficient r = 0.89, p<0.01). The seasonal variations were significant in the hypertensive group but not in the non-hypertensive group. CONCLUSION: The considerable seasonal variations suggests that the mechanism for the haemorrhage is strongly correlated with the systemic blood pressure.

[Aortic valve replacement for the small aortic annulus].

Aortic valve surgery for the small aortic annulus is still challenging for surgeons. Recently, the new types of high performance prosthesis have been developed and the chance of an aortic root enlargement (ARE) is decreasing. In this study, we propose the ideal strategy of the aortic surgery for the small aortic annulus. We analyzed the clinical records of 158 patients who underwent aortic valve replacement from August 1999 to October 2005 in our institution. The small aortic annulus was observed in 38 patients (24%). Fourteen patients of this group underwent ARE. Patient-prosthesis mismatch (PPM) was less frequently observed in patients with ARE compared to those without ARE. The additional time required for ARE was not considerable, and neither ischemic time nor cardiopulmonary bypass time was significantly prolonged by ARE. In conclusion, we have to select a prosthesis with sufficient orifice area to avoid PPM, otherwise we should choose an option of ARE. For this consideration, we definitely need the chart that demonstrates the relationship between the nominal size of various types of prostheses and the size of a patient's annulus that those prostheses actually fit.

Feed-forward control of post-stroke movement disorders by on-demand type stimulation of the thalamus and motor cortex.

Deep brain stimulation (DBS) of the thalamus (Vo/Vim) has become popular as a means of controlling involuntary movements, including post-stroke movement disorders. We have also found that post-stroke movement disorders and motor weakness can sometimes be controlled by motor cortex stimulation (MCS). In some forms of movement disorders, motor dysfunction becomes evident only when patients intend to move their body. We have developed an on-demand type stimulation system which triggers stimulation by detecting intrinsic signals of intention to move. Such a system represents feed-forward control (FFC) of involuntary movements. We report here our experience of DBS and MCS for controlling post-stroke movement disorders, and discuss the value of FFC. Excellent control of post-stroke movement disorders was achieved by conventional DBS and/or MCS in 20 of 28 patients with hemichoreoathetosis, hemiballism tremor, and motor weakness. FFC was tested in 6 patients who demonstrated excellent control of post-stroke postural tremor or motor weakness by conventional DBS or MCS. The on-demand stimulation provided satisfactory FFC in 4 of 4 patients with postural tremor and 2 of 2 patients with motor weakness, when the activity of muscles involved in posturing or intention to move was fed into the system. These findings justify further clinical studies on DBS and MCS in patients with post-stroke movement disorders. The on-demand type stimulation system may also be useful for overcoming various post-stroke movement disorders.

Pallidal high-frequency deep brain stimulation for camptocormia: an experience of three cases.

INTRODUCTION: The term "camptocormia" describes a forward-flexed posture. It is a condition characterized by severe frontal flexion of the trunk. Recently, camptocormia has been regarded as a form of abdominal segmental dystonia. Deep brain stimulation (DBS) is a promising therapeutic approach to various types of movement disorders. The authors report the neurological effects of DBS to the bilateral globus pallidum (GPi) in three cases of disabling camptocormia. METHODS: Of the 36 patients with dystonia, three had symptoms similar to that of camptocormia, and all of these patients underwent GPi-DBS. The site of DBS electrode placement was verified by magnetic resonance imaging (MRI). The Burke Fahn and Marsden dystonia rating scale (BFMDRS) was employed to evaluate the severity of dystonic symptoms preoperatively and postoperatively. RESULTS: Significant functional improvement following GPi-DBS was noted in the majority of dystonia cases. At a follow-up observation after more than six months, the overall improvement rate was 71.2 +/- 27.0%, in all dystonia cases who underwent the GPi-DBS. In contrast, the improvement rate of the three camptocormia cases was 92.2 +/- 5.3%. It was confirmed that the improvement rate for camptocormia was much higher than for other types of dystonia. CONCLUSION: According to our experience, a patient with a forward-bent dystonic posture indicative of camptocormia is a good candidate for GPi-DBS. The findings of this study add further support to GPi-DBS as an effective treatment for dystonia, and provide the information on predictors of a good outcome.

Detection of boundaries of subthalamic nucleus by multiple-cell spike density analysis in deep brain stimulation for Parkinson's disease.

When microelectrode recording of single cell activity is employed for targeting the subthalamic nucleus (STN), multiple sampling of single cells is needed to determine whether the electrode has passed through the ventral boundaries of the STN. In contrast, stepwise recording of multiple cell activities by a semimicroelectrode reveals robust changes in such activities at the dorsal and ventral boundaries. We attempted to quantify changes in multiple cell activities by computing multiple-cell spike density (MSD). We analyzed MSD in 60 sides of 30 patients with Parkinson's disease. Neural noise level was defined as the lowest cut-off level at which neural noise is separated from larger amplitude spikes. MSD was analyzed at cut-off levels ranging from 1.2 to 2.0-fold the neural noise level in the white matter in each trajectory. Both the dorsal and ventral boundaries were clearly identified by an increase and a decrease (p < 0.0001) in MSD, respectively, in all the 60 sides. The cut-off level of 1.2-fold showed the clearest change in MSD between the STN and the pars reticulata of substantia nigra. MSD analysis by semimicroelectrode recording represents the most practical means of identifying the boundaries of STN.

Tyrosinase induction and inactivation in normal cultured human melanocytes by endothelin-1.

Since endothelin was found to be expressed in epithelial cells as well as in vascular endothelial cells, the functional regulation of melanocytes with endothelin has been actively investigated. In particular, it has been suggested that endothelin may influence pigmentation and depigmentation, which are mediated by melanocytes. In the present study, we investigated the regulation of melanocyte function and tyrosinase expression by endothelin from the point of view of tyrosinase protein expression and enzyme activity. The influence of endothelins on melanocyte function was assessed. Melanocytes showed a dose-dependent increase in cell proliferation with the addition of endothelin-1. When the confluence of melanocytes was cultured with endothelin-1 for 72 h, tyrosinase activity in melanocytes was significantly and dose-dependently decreased. In contrast, there was no significant change with endothelin-3. However, tyrosinase protein expression of melanocytes was significantly and dose-dependently increased by endothelin-1, but endothelin-3 had no effect. Both the suppression of enzyme activity and the enhanced protein expression were regulated by the ETA receptor antagonist, BQ123. In view of these observations, we conclude that endothelin-1-induced tyrosinase is mediated by ETA receptors. However, the reason for the decrease in the specific activity of tyrosinase remains unknown, and our results suggest that another mechanism underlying the activation of tyrosinase is present in addition to the inductive action of endothelin-1 on tyrosinase.