Top-down brain circuits for operant bradycardia.

Heart rate (HR) can be voluntarily regulated when individuals receive real-time feedback. In a rat model of HR biofeedback, the neocortex and medial forebrain bundle were stimulated as feedback and reward, respectively. The rats reduced their HR within 30 minutes, achieving a reduction of approximately 50% after 5 days of 3-hour feedback. The reduced HR persisted for at least 10 days after training while the rats exhibited anxiolytic behavior and an elevation in blood erythrocyte count. This bradycardia was prevented by inactivating anterior cingulate cortical (ACC) neurons projecting to the ventromedial thalamic nucleus (VMT). Theta-rhythm stimulation of the ACC-to-VMT pathway replicated the bradycardia. VMT neurons projected to the dorsomedial hypothalamus (DMH) and DMH neurons projected to the nucleus ambiguus, which innervates parasympathetic neurons in the heart.

Sampling bag-based emission chamber for measuring volatile organic compounds from household materials using solid-phase extraction-type collection device.

A simple screening analytical method for determining the emission of volatile organic compounds (VOCs) from household materials was developed using a solid-phase extraction (SPE)-type collection device and a gas sampling bag. The VOCs emitted from the sample material placed in the gas sampling bag with a volume of 20 L were extracted on the SPE-type collection device. In this study, complete sampling mode was developed in addition to a conventional flow sampling mode. The extracted VOCs were then eluted with 8 mL of acetone and measured using gas chromatography-mass spectrometry. The proposed method does not require a stainless-steel chamber and a thermal desorption system; therefore, VOC emission from household materials could be easily evaluated with an affordable cost, suggesting that the method is suitable for the screening technique for evaluating VOC emission from solid materials.

Clinical Outcomes of Intraoperative Radiotherapy, Postoperative Radiotherapy, and Definitive Radiotherapy for Non-metastatic Pancreatic Cancer.

OBJECTIVE: The aim of this study is to evaluate the utility of adjuvant radiotherapy (intraoperative radiotherapy, IORT; postoperative radiotherapy, PORT), and definitive radiotherapy for non-metastatic pancreatic cancer. METHODS: Ninety-nine patients were analyzed. Thirty patients underwent IORT with surgery, 31 underwent PORT after surgery, and 38 underwent definitive radiotherapy. Tumor stage [Union for International Cancer Control (UICC) 2009] was as follows: Stage I, 7; IIA, 16; IIB, 31; III, 45. The doses for IORT, PORT, and definitive radio therapy were 20 to 30, 40 to 64.6, and 50.4 to 61.2 Gy, respectively. Associations between clinical parameters including age, gender, tumor site, stage, performance status, surgical margin, and use of chemotherapy and local control (LC) or overall survival (OS) were analyzed. RESULTS: Follow-up periods for all patients were 1.1-145 months (median, 11). OS rate in the IORT, PORT, and definitive radiotherapy groups was 22%, 16%, and 6%, respectively, at 2 years. The 5-year OS rate was 13%, 3.2%, and 0%, respectively. Local control rate at 2 years was 33%, 35%, and 0%, respectively. No Grade ≥ 3 tox icities were observed. Distant metastasis was less common in the IORT group. Stage and surgical margin were sig nificant factors for OS after IORT. Performance status and chemotherapy were significant factors for OS after PORT and definitive radiotherapy. CONCLUSIONS: The present study showed the safety of the three treatment modalities, but the outcomes were not satisfactory. More intensive strategies including radiotherapy should be investigated.

Importance of beating rate control for the analysis of drug effects on contractility in human induced pluripotent stem cell-derived cardiomyocytes.

Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical cardiotoxicity predictive model. Most studies on this were conducted under spontaneous beating conditions and involved video-based analyses. Cardiac contractility is known to be influenced by beating rates; accordingly, beating rate control is recommended to accurately analyze the effects of drugs on cardiac contractility. Therefore, we investigated the relationship between contraction parameters and beating rates of cardiac cell sheet tissues by directly measuring the contraction force and compared the effects of ion channel drugs (mexiletine, ranolazine, and dofetilide) on contraction parameters under spontaneous beating conditions with those under pacing (1 Hz) conditions. To characterize the contraction/relaxation kinetics, we introduced a novel analysis tool, called a "C-V loop," a plot of contraction force versus force-changing rate ("velocity"). When we increased the beating rate, the contraction force, force-changing rate, and relaxation time markedly decreased. The occurrence frequencies of beating arrest and irregular beats at high concentration ranges of mexiletine and ranolazine were more suppressed in paced samples than in spontaneously beating ones. We also found that relaxation time increased by treatment with dofetilide and contraction amplitude decreased in a concentration-dependent manner by mexiletine treatment only in the samples under pacing. These drug responses were consistent with the previous reports using human samples. These results indicated that beating rate control is necessary to stably evaluate the effects of drugs on contractility and that tests under 1-Hz pacing are more relevant to clinical settings.

Radiotherapy alone for stage IE ocular adnexal mucosa-associated lymphoid tissue lymphomas: long-term results.

BACKGROUND: To evaluate the long-term efficacy and toxicity of radiation therapy in patients with Stage IE primary ocular adnexal mucosa-associated lymphoid tissue lymphoma. METHODS: We designed a retrospective analysis to evaluate 81 patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma treated with radiation therapy between 2006 and 2016. The median radiation dose was 30 Gy (range, 30-36 Gy in 15-18 fractions). Local control, progression-free survival, overall survival, and cumulative incidence of Grade 3 cataract were calculated by using the Kaplan-Meier method. RESULT: The median follow-up time was 74 months (range, 4-157 months). The 5-year local control was 100%. Although local relapse was suspected in 3 patients after radiation therapy, 2 patients were pathologically diagnosed as IgG4-related inflammation and in 1 patient as intense inflammatory cell infiltration. The 5-year progression-free survival was 94.4%. Five patients had relapse at distant sites. The 5-year overall survival was 98.8%. Twenty patients had Grade 3 cataract. The 5-year cumulative incidences of Grade ≥ 3 and Grade ≥ 2 cataract for 58 patients treated without a lens shield were 38 and 40%, respectively. The incidence of Grade ≥ 3 cataract was 42% for 50 patients treated with 6-MV X-rays (estimated lens dose: 29 Gy) and 17% for 8 patients treated with 9-MeV electrons (estimated lens dose: 24 Gy). CONCLUSIONS: Radiation therapy alone yielded excellent local control and long-term survival in Stage IE ocular adnexal mucosa-associated lymphoid tissue lymphoma. Long-term observation with careful attention to relapse at distant sites is necessary. In the case of suspected local relapse, IgG4-related disease should be carefully ruled out.

Quantitative sensory testing with Electronic von Frey Anesthesiometer and von Frey filaments in nonpainful cats: a pilot study.

OBJECTIVE: Measurement of sensory thresholds could represent a complementary tool to behavioural pain scores in cats. The aim of this study was to investigate the feasibility of quantitative sensory testing (QST) with the Electronic von Frey Anesthesiometer (EVF) and von Frey filaments (VFF) in healthy cats, and to assess the limits of agreement (LOA) between the two devices. STUDY DESIGN: Prospective clinical study. ANIMALS: A total of 15 client-owned healthy cats. METHODS: Two investigators (A and B) carried out the measurements independently. The EVF and the VFF were applied on the upper lip and at the level of the medial aspect of the stifle. A 1-hour interval was allowed between the sets of measurements taken by investigators A and B; each investigator repeated the entire session of measurements after 24 hours. The LOA between the EVF and the VFF were analysed with the intraclass correlation coefficient (ICC), and with the Bland Altman method. RESULTS: QST with both the EVF and the VFF was feasible in healthy cats; however, the willingness of the cats to cooperate was negatively affected by the repetition of the measurements on the second day. The presence of the cat owners seemed to facilitate the trial. There was a fair agreement between the EVF and the VFF (ICC = 0.49; 95% confidence interval: 0.13-0.70). CONCLUSIONS: and clinical relevance Our findings indicate that both EVF and VFF may be used for QST in cats. Further trials will be needed to verify the usefulness of QST with EVF and VFF in feline patients suffering from actual chronic pain.

Chemoradiotherapy for localized extranodal natural killer/T-cell lymphoma, nasal type, using a shrinking-field radiation strategy: multi-institutional experience.

PURPOSES: The prognosis of localized extranodal natural killer/T-cell lymphoma, nasal type (ENKTL), has improved with the development of chemoradiotherapy. However, conventional extended-field radiotherapy may cause optic disorders. Our group has employed smaller radiation fields in an attempt to avoid toxicity. The efficacy and toxicity of treatments were evaluated. MATERIALS AND METHODS: Chemoradiotherapy was delivered with a shrinking-field radiotherapy strategy. The endpoints of this study were overall survival (OS), local control (LC), progression-free survival (PFS), and toxicity. RESULTS: Fifteen patients with localized ENKTL were treated. After irradiation (median, 40 Gy) to the tumor plus a prophylactic volume, a reduced treatment volume to the tumor was boosted (median, 10 Gy). Twelve patients underwent chemoradiotherapy and 3 patients received radiotherapy alone. A complete response was achieved in 12 and a partial response in 3 patients. The 5-year OS, PFS, and LC rates were 80, 67, and 93 %, respectively. Distant recurrence occurred in 4 patients and locoregional and distant recurrence in 1 patient. Cataract (grade 3) and dry eye (grade 2) were observed as late adverse events in 1 patient each. CONCLUSIONS: Sufficiently high OS and LC were achieved with acceptable toxicities. Appropriate target volumes may be smaller with newer chemotherapy regimens.

The effect of fast eating on the thermic effect of food in young Japanese women.

The relationship between eating speed and the thermic effect of food (TEF) remains unclear. We investigated the difference in the TEF when meals containing the same amount of energy were eaten in 5 min (fast eating) or 15 min (regular eating). Subjects were nine non-obese young women. Following a 350 kcal (1464 kJ) meal, energy expenditure and autonomic nervous system activity were measured. The frequency of mastication was also calculated. The TEF for the 15-min period after the start of eating with fast eating was significantly lower than with regular eating (p < 0.01). There was a significant positive correlation between the low-frequency/high-frequency ratio and TEF at 5-min intervals up to 20 min after the start of eating and between total mastication frequency and TEF during ingestion. Fast eating may reduce the TEF, potentially because a decrease in mastication frequency decreases sympathetic nervous system activity.

Concurrent chemoradiotherapy with a novel fluoropyrimidine, S-1, and cisplatin for locally advanced esophageal cancer: long-term results of a phase II trial.

OBJECTIVES: A phase II study was performed to investigate the safety and efficacy of concurrent chemoradiotherapy (CCRT) combined with an orally active fluoropyrimidine, S-1, plus cisplatin for locally advanced esophageal cancer (LAEC). METHODS: CCRT comprised 2 courses, a 30-Gy radiotherapy over 3 weeks plus daily oral S-1 (80 mg/m(2)/day) for 2 weeks and a 24-hour cisplatin infusion (70 mg/m(2)) on day 8, and an identical course administered after a 2-week break. RESULTS: One hundred and sixteen patients, 12 with stage II, 71 with stage III, and 33 with stage IVa LAEC participated, and 106 of them (91.4%) completed the CCRT course. The most serious toxicity was myelosuppression: grade 3 and 4 neutropenia occurred in 28.4 and 9.5% of patients, respectively. Nonhematologic toxicity was moderate. Complete response rates in patients with stage II, III, and IVa LAEC were 91.7, 67.6, and 36.4%, respectively. The overall median survival time was 2.3 years and that of patients with stage II, III, and IVa cancer was 7.0, 2.6, and 1.3 years, respectively. CONCLUSIONS: CCRT combined with S-1 plus cisplatin showed promising safety and efficacy. Potentially, this combination therapy could become a baseline medication for patients with LAEC.

Arabidopsis RPT2a, 19S proteasome subunit, regulates gene silencing via DNA methylation.

The ubiquitin/proteasome pathway plays a crucial role in many biological processes. Here we report a novel role for the Arabidopsis 19S proteasome subunit RPT2a in regulating gene activity at the transcriptional level via DNA methylation. Knockout mutation of the RPT2a gene did not alter global protein levels; however, the transcriptional activities of reporter transgenes were severely reduced compared to those in the wild type. This transcriptional gene silencing (TGS) was observed for transgenes under control of either the constitutive CaMV 35S promoter or the cold-inducible RD29A promoter. Bisulfite sequencing analysis revealed that both the transgene and endogenous RD29A promoter regions were hypermethylated at CG and non-CG contexts in the rpt2a mutant. Moreover, the TGS of transgenes driven by the CaMV 35S promoters was released by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine, but not by application of the inhibitor of histone deacetylase Trichostatin A. Genetic crosses with the DNA methyltransferase met1 single or drm1drm2cmt3 triple mutants also resulted in a release of CaMV 35S transgene TGS in the rpt2a mutant background. Increased methylation was also found at transposon sequences, suggesting that the 19S proteasome containing AtRPT2a negatively regulates TGS at transgenes and at specific endogenous genes through DNA methylation.

Dedifferentiation and progression of an intracranial solitary fibrous tumor: autopsy case of a Japanese woman with a history of radiation therapy of the head during infancy.

Solitary fibrous tumor (SFT) is usually an indolent neoplasm with a low rate of local recurrence and metastasis. Although dedifferentiation of low-grade sarcoma is well documented, the concept of dedifferentiated SFT was not recognized until recently. A case of intracranial SFT with seven recurrences within 5 years, showing progression and dedifferentiation during the course of disease, is reported here. A 51-year-old woman with a history of irradiation during infancy presented with a SFT in the right posterior fossa. Because of the close proximity to the brain stem, the tumor could not be removed completely. The tumor recurred 12, 16, and 28 months after the initial operation. With the repeated recurrences, cellularity, mitotic count, and Ki-67 (MIB-1) index increased gradually. The histology suddenly changed at the fourth recurrence, which occurred 16 months after postoperative radiation therapy for the third recurrence. The tumor revealed a fibrosarcoma-like appearance with necrosis and markedly increased mitotic activity. The tumor further recurred 50, 52, and 55 months after the initial operation with the same fibrosarcoma-like histology. The patient died of uncontrolled tumor 58 months after the initial operation. In this case radiation may have played some role in the tumorigenesis, progression, and dedifferentiation of the SFT.

Primary central nervous system lymphoma in Japan: changes in clinical features, treatment, and prognosis during 1985-2004.

We have conducted nationwide surveys of primary central nervous system lymphoma (PCNSL) treated since 1985. In the present study, we newly collected data between 2000 and 2004 and investigated changes in clinical features and outcome over time. A total of 739 patients with histologically proven PCNSL under going radiotherapy were analyzed. Seventeen institutions were surveyed, and data on 131 patients were collected. These data were compared with updated data that were previously obtained for 466 patients treated during 1985-1994 and 142 patients treated during 1995-1999. Recent trends toward decrease in male/female ratio, increase in aged patients, and increase in patients with multiple lesions were seen. Regarding treatment, decrease in attempts at surgical tumor removal and increases in use of systemic chemotherapy and methotrexate (MTX)-containing regimens were observed. The median survival time was 18, 29, and 24 months for patients seen during 1985-1994, 1995-1999, and 2000-2004, respectively, and the respective 5-year survival rates were 15%, 30%, and 30%. In groups seen during 1995-1999 and during 2000-2004, patients who received systemic or MTX-containing chemotherapy had better prognosis than those who did not. Multivariate analysis of all patients seen during 1985-2004 suggested the usefulness of MTX-containing chemotherapy as well as the importance of age, lactate dehydrogenase level, and tumor multiplicity as prognostic factors. Thus, this study revealed several notable changes in clinical features of PCNSL patients. The prognosis improved during the last 10 years. Advantage of radiation plus chemotherapy, especially MTX-containing chemotherapy, over radiation alone was suggested.

Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s.

PURPOSE: Results of radiation therapy for primary central nervous system lymphoma (PCNSL) were poor in the 1970-1980s, with most reported 5-year survival rates being less than 10%. To investigate whether the prognosis of PCNSL patients treated by radiation alone remains still poor, we investigated the results of radiation monotherapy in the 1990s. METHODS AND MATERIALS: We collected data on 132 patients with histologically proven PCNSL treated by radiation alone in the 1990s from three nationwide or regional multiinstitutional studies conducted by the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) Lymphoma Study Group or the Chubu Radiation Oncology Group. Follow-up data were updated as far as possible. Eleven patients who did not complete planned radiotherapy were included. The data were analyzed in relation to patient and tumor characteristics. The median patient age was 63 years, and the World Health Organization performance status (PS) was 3 or 4 in 40% of the patients. Multiple tumors were seen in 34%. Whole-brain irradiation with or without focal boost was used in 92%. The median radiation dose to the tumor site was 50 Gy (range, 8-74 Gy). RESULTS: For all 132 patients, the median survival time was 18 months and the 5-year survival rate was 18.0%. For 62 patients with PS 0-3 and aged 16-65 years (i.e., those eligible for the European Organization for Research and Treatment of Cancer 20962 study), the median survival was 26 months and 5-year survival was 24%. The 5-year survival was 25% for patients 63 years old or younger, and 9.8% for those older than 63 years (p = 0.0005). The 5-year survival was 22% for patients with PS 0-2 and 13% for those with PS 3 or 4 (p = 0.0040). Multivariate analysis confirmed the negative influence of higher age on patient prognosis. CONCLUSIONS: The results of radiation monotherapy for PCNSL appear to have improved as compared with those reported previously. The results of new treatment should be evaluated in light of this finding. Since most prospective studies on the combined treatment exclude poor PS and high-age patients, the 5-year survival rate of 30% may not be regarded as a marked improvement over radiation alone.

Esophageal cancer with colonic metastasis successfully treated by chemoradiotherapy followed by chemotherapy with S-1 and cisplatin.

A 51-year-old man was hospitalized for evaluation of dysphagia and bloody stool. Gastrointestinal endoscopy showed esophageal cancer invading the gastric fundus. A metastatic lesion was demonstrated in the sigmoid colon. The patient agreed to have concurrent chemoradiotherapy for the primary lesion, followed by additional chemotherapy. The first course included 30 Gy of radiotherapy given over 3 weeks, together with daily oral administration of S-1 (80 mg/m2 per day) for 2 weeks, and a 24-h infusion of cisplatin (70 mg/m2) on day 8. After a second course of chemoradiotherapy, four additional courses of chemotherapy with S-1 and cisplatin were administered, at 4-week intervals. After the additional chemotherapy, gastroscopy and colonoscopy showed disappearance of both the primary and the metastatic lesions. One year after his initial hospitalization, no recurrence of either the primary or the metastatic tumor lesions is evident.

[A case of advanced cervical and upper thoracic esophageal carcinoma completely responding to chemoradiotherapy with TS-1 and cisplatin].

A 52-year-old man was hospitalized for evaluation of dysphagia. Esophagography depicted an irregular narrowing extending 7 cm from the cervical esophagus to the upper thoracic esophagus. Esophagoscopy with biopsy showed cervical esophageal cancer narrowing the lumen. Surgery was contraindicated because of a previous cardiac infarction. The patient selected concurrent chemoradiotherapy with TS-1 and cisplatin. The first course included 30 Gy of radiotherapy given over 3 weeks, together with daily oral administration of TS-1 (120 mg/day) for 2 weeks, and a 24-h infusion of cisplatin (70 mg/m2) on day 8. After a second course of chemoradiotherapy, 4 courses of chemotherapy with TS-1 and cisplatin were administered at 4-week intervals. After additional chemotherapy, esophagoscopy and cervical CT showed that the primary lesion had disappeared. Two years after initial hospitalization, no recurrence has been detected.

Oxidative stress induces GSTP1 and CYP3A4 expression in the human erythroleukemia cell line, K562.

To explore the effects of oxidative stress on metabolizing enzymes in blood cells, we examined the effect of hydrogen peroxide (H(2)O(2)) on glutathione S-transferase (GST) and cytochrome P450 (CYP) expression in a human erythroleukemic cell line, K562. After adding H(2)O(2) (up to 100 microM) to the culture medium of K562 cells, the expression levels of GST and CYP enzymes were monitored by RT-PCR. The expression of GSTP1 and CYP3A4 was induced by oxidative stress. Quantitative PCR and immunoblot analysis revealed a 3- to 4-fold increase in GSTP1 and CYP3A4 mRNA, and a 2- to 3-fold increase in GSTP1 and CYP3A4 protein levels, 3 d after the addition of 100 microM H(2)O(2). Induction was H(2)O(2) dose-dependent and also depended on the length of culture. Our results suggest that oxidative stress may affect GST and/or CYP expression in human blood cells, which may alter the metabolism of drugs and xenobiotics and thus, the toxicity of these compounds to the blood cells.

Concurrent chemoradiotherapy for locally advanced and metastatic esophageal cancer: longterm results of a phase II study of UFT/CDDP with radiotherapy.

BACKGROUND: No effective treatment for advanced esophageal cancer extending to adjacent organs or associated with distant metastasis is known. We prospectively analyzed the efficacy of concurrent chemoradiotherapy with uracil plus tegafur (UFT) and cisplatin (CDDP) for such cases of advanced esophageal cancer. METHODS: Patients with advanced cancers received 60 to 70 Gy of radiotherapy given during a period of 7 weeks, concurrently with daily oral UFT (200 mg/m(2) per day), and a 24-h infusion of CDDP (70 mg/m(2)) on days 8 and 36. After chemoradiotherapy, UFT (250 mg/m(2)/per day) was administered daily for 1 year, while CDDP (80 mg/m(2)) was administered twice every 4 weeks. RESULTS: Patients with stage III disease numbered 31, while 24 had stage IV disease according to the tumor-node-metastasis (TNM) staging. Including all patients, complete response (CR) occurred in 20% and partial response (PR) in 51%. In stage III patients, CR, PR, and CR+PR rates were 29%, 48%, and 77%, respectively. In stage IV patients, CR, PR, and CR+PR rates were 8%, 54%, and 63%. Grade 4 leukocytopenia occurred in 22% of patients, and grade 3 pain, nausea/vomiting, and oral mucositis occurred in 7%, 9%, and 4% of patients respectively, but resolved after the reduction or discontinuation of chemoradiotherapy. Median survival in stage III patients was 415 days (range, 3 to 3046 days), and in stage IV patients, it was 187 days (range, 75 to 764 days). The 2-year survival rate in stage III patients was 25% and it was 4% in stage IV patients. The 5-year survival rate in stage III patients was 7%, while in stage IV patients it was 0%. CONCLUSION: This combined treatment may be a promising nonsurgical management option for locally advanced esophageal cancer, and can achieve good palliative effects in patients with distant metastasis.