Regional connectivity in continental ASEAN

This chapter examines the issue on Mekong region’s connectivity on quantitative base through the analysis of the gravity trade model and its modified fragmentation model. The main findings are as follows: First, the evolution of international production networks (IPNs) between Thailand and Vietnam as well as the other advanced ASEAN could be identified in terms of their two-way trade integration of machinery parts and components beyond the gravity trade standard. Second, the trade intensity of machinery parts and components, in particular, the one between Thailand and Vietnam, could be partly explained by the fragmentation factors, i.e. their gaps in per capita GDP and the relatively lower service-link costs in Vietnam, through the fragmentation-model estimation. Third, the trade disintegration of machinery parts and components between Thailand and Mekong latecomers, such as Cambodia and Myanmar, could be explained by their higher service-link costs also through the fragmentation-model estimation. This chapter also investigates the border area development in Mekong region, which is a crucial issue for the connectivity in a continental area. Since the border areas have their own area-advantages called “border bonuses”: “complementary factor endowment” and “cross-border infrastructure services”, the areas might be the real gateways for IPN penetration across the countries in Mekong region, if their development were carefully designed. This was proved by the success stories of forerunners: the Maquila case at US-Mexico border and the Savannakhet SEZ at Thai-Lao PDR border. Considering their lessons, the strategies for border area development should be careful designing of institutional frameworks for Special Economic, enhancing outer-link connectivity from borders to central cities, and securing labor forces with skill developments

Regional connectivity in continental ASEAN

This chapter examines the issue on Mekong region’s connectivity on quantitative base through the analysis of the gravity trade model and its modified fragmentation model. The main findings are as follows: First, the evolution of international production networks (IPNs) between Thailand and Vietnam as well as the other advanced ASEAN could be identified in terms of their two-way trade integration of machinery parts and components beyond the gravity trade standard. Second, the trade intensity of machinery parts and components, in particular, the one between Thailand and Vietnam, could be partly explained by the fragmentation factors, i.e. their gaps in per capita GDP and the relatively lower service-link costs in Vietnam, through the fragmentation-model estimation. Third, the trade disintegration of machinery parts and components between Thailand and Mekong latecomers, such as Cambodia and Myanmar, could be explained by their higher service-link costs also through the fragmentation-model estimation. This chapter also investigates the border area development in Mekong region, which is a crucial issue for the connectivity in a continental area. Since the border areas have their own area-advantages called “border bonuses”: “complementary factor endowment” and “cross-border infrastructure services”, the areas might be the real gateways for IPN penetration across the countries in Mekong region, if their development were carefully designed. This was proved by the success stories of forerunners: the Maquila case at US-Mexico border and the Savannakhet SEZ at Thai-Lao PDR border. Considering their lessons, the strategies for border area development should be careful designing of institutional frameworks for Special Economic, enhancing outer-link connectivity from borders to central cities, and securing labor forces with skill developments

Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells.

Statins exert atheroprotective effects through the induction of specific transcriptional factors in multiple organs. In endothelial cells, statin-dependent atheroprotective gene up-regulation is mediated by Kruppel-like factor (KLF) family transcription factors. To dissect the mechanism of gene regulation, we sought to determine molecular targets by performing microarray analyses of human umbilical vein endothelial cells (HUVECs) treated with pitavastatin, and KLF4 was determined to be the most highly induced gene. In addition, it was revealed that the atheroprotective genes induced with pitavastatin, such as nitric oxide synthase 3 (NOS3) and thrombomodulin (THBD), were suppressed by KLF4 knockdown. Myocyte enhancer factor-2 (MEF2) family activation is reported to be involved in pitavastatin-dependent KLF4 induction. We focused on MEF2C among the MEF2 family members and identified a novel functional MEF2C binding site 148 kb upstream of the KLF4 gene by chromatin immunoprecipitation along with deep sequencing (ChIP-seq) followed by luciferase assay. By applying whole genome and quantitative chromatin conformation analysis {chromatin interaction analysis with paired end tag sequencing (ChIA-PET), and real time chromosome conformation capture (3C) assay}, we observed that the MEF2C-bound enhancer and transcription start site (TSS) of KLF4 came into closer spatial proximity by pitavastatin treatment. 3D-Fluorescence in situ hybridization (FISH) imaging supported the conformational change in individual cells. Taken together, dynamic chromatin conformation change was shown to mediate pitavastatin-responsive gene induction in endothelial cells

Antiallodynic Effect of Pregabalin in Rat Models of Sympathetically Maintained and Sympathetic Independent Neuropathic Pain

Pregabalin binds to the voltage-dependent calcium channel α2δ subunit and modulates the release of neurotransmitters, resulting in analgesic effects on neuropathic pain. Neuropathic pain has both sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) components. We studied the antiallodynic effects of pregabalin on tactile allodynia (TA) and cold allodynia (CA) in SMP-and SIP-dominant neuropathic pain models. Allodynia was induced by ligation of the L5 & L6 spinal nerves (SMP model) or by transection of the tibial and sural nerves (SIP model) in rats. For intrathecal drug administration, a PE-10 catheter was implanted through the atlantooccipital membrane to the lumbar enlargement. Pregabalin was administered either intraperitoneally (IP) or intrathecally (IT) and dosed up incrementally until an antiallodynic effect without sedation or motor impairment was apparent. TA was assessed using von Frey filaments, and CA was assessed using acetone drops. IP-administered pregabalin dose-dependently attenuated TA in both models and CA in the SMP model, but not CA in the SIP model. IT-administered pregabalin dose-dependently attenuated both TA and CA in both models. However, the dose response curve of IT-administered pregabalin in SMP was shifted to left from that of SIP and the ED50 of IT-administered pregabalin for CA in SMP was about 900 times less than that in SIP. These findings suggest that pregabalin exerts its antiallodynic effect mainly by acting at the spinal cord, and that IT-administered pregabalin has more potent antiallodynic effects in SMP. The α2δ subunit might be less involved in the CA in SIP

Tetrodotoxin (TTX) as a Therapeutic Agent for Pain

Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed

Accumulation of Pericardial Fat Correlates with Left Ventricular Diastolic Dysfunction in Patients with Normal Ejection Fraction

Background Left ventricular diastolic dysfunction (LVDD) plays an important role inheart failure with normal left ventricular ejection fraction (LVEF). Obesity is one ofthe major comorbid conditions of LVDD. Pericardial fat (PF) is an ectopic fat depotwith possible paracrine or mechanical effects on the coronary circulation and35 myocardial function.Methods We measured PF volume on 64 slice computed tomography and analyzedechocardiographic parameters to confirm LVDD in 229 consecutive patients suspectedof coronary artery disease with LVEF of more than 50% and no symptomatic heartfailure (59% men, 67±12 years). LVDD was defined as the ratio of transmitral40 Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity(E/e’) >10.Results PF volume correlated significantly with E/e’ (r=0.21, p<0.01), left ventricularmass index (r=0.23, p<0.001), and left atrial diameter (r=0.32, p<0.001). The mean PFvolume was significantly greater in patients with LVDD (184±61 cm3, n=141) than in45 those without LVDD (154±58, n=88, p<0.001). Multivariate logistic regressionanalysis indicated that PF volume correlated significantly with the presence of LVDD(odds ratio: 2.00 per 100 cm3 increase in PF volume, p=0.02) independent of age,gender, abdominal obesity, hypertension, and diabetes.Conclusions PF volumes are significantly associated with LVDD, independent of50 other factors such as hypertension or diabetes. PF may be implicated in the pathogenesis of LVDD in patients with normal LVEF

Low-dose of olanzapine has ameliorating effects on cancer-related anorexia

Hideki Okamoto,1 Koyo Shono,2 Natsuko Nozaki-Taguchi2 1Department of Kampo Medicine (Japanese Traditional Medicine), School of Medicine, International University of Health and Welfare, Tokyo, Japan; 2Palliative Care Center, Chiba University Hospital, Chiba, Japan Background: Olanzapine (OLZ) has become well-known for its antiemetic effects on chemotherapy-induced nausea and vomiting. However, it remains unclear whether OLZ also has efficacy for treating cancer-related anorexia. This study, therefore, retrospectively examined whether or not OLZ administration affects the food intake in anorexic cancer patients who exhibit neither nausea nor vomiting. Methods: Eighty patients prescribed OLZ were extracted from 951 inpatients who consulted with our palliative care team at Chiba University Hospital from April 2008 to March 2016. Their food intake described on a nursing record was compared before and after OLZ administration. The observation period was 3 days before and after the start of OLZ treatment, because most inpatients whose food intake increased were discharged in 3 days. Results: In those 80 patients, the average dose of OLZ for 3 days was 2.28&plusmn;0.87 (mean&plusmn;SD) mg/day. First, the food intake in 80 patients was significantly higher after than before starting OLZ, and the relative change in food intake was 149% on average (P&lt;0.0001, Student&rsquo;s paired t-test). Second, OLZ increased the food intake even in 40 out of 80 patients without nausea or vomiting, and the relative change in food intake was 143% on average (P&lt;0.001, Student&rsquo;s paired t-test). Third, the average food intake increased in 13 out of 40 patients who were prescribed 1.5 mg/day of OLZ, and the relative change in food intake was 124% on average (P&lt;0.01, Student&rsquo;s paired t-test). There was no significant difference in food intake between a dose of 1.5 mg/day and a dose of &gt;1.5 mg/day of OLZ (P=0.18, Welch&rsquo;s unpaired t-test). Conclusion: We have herein reported OLZ&rsquo;s ameliorating efficacy in cancer-related anorexia at the low dose of 1.5 mg/day. Although our study has many limitations, low-dose OLZ can be a promising treatment for cancer-related anorexia. Keywords: chemotherapy, nausea, cachexia, appetite, end-of-life care, tranquilize