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Extracellular-superoxide dismutase (EC-SOD or SOD3), which catalyzes the dismutation of superoxide anions into hydrogen peroxide, plays a key role in vascular protection against reactive oxygen species (ROS). The excess generation of ROS is closely involved in the pathogenesis of diabetic retinopathy (DR); therefore, the maintenance of SOD3 expression at high levels is important for the prevention of DR. In the present study, we showed that caffeic acid phenethyl ester (CAPE) increased the expression of SOD3 through the acetylation of histone within the SOD3 promoter region in human retinal endothelial cells (HRECs). Histone acetylation within its promoter was focused on the inhibition of histone deacetylase (HDAC), and we examined the involvement of myocyte enhancer factor 2 (MEF2) and HDAC1 in CAPE-elicited SOD3 expression. Our results demonstrate that SOD3 silencing in basal HRECs is regulated by HDAC1 composed with MEF2A/2D hetero dimers. Moreover, phosphorylation of threonine 312 in MEF2A and dissociation of HDAC1 from SOD3 promoter play pivotal roles in CAPE-elicited SOD3 expression. Overall, our findings provide that CAPE may be one of the seed compounds that maintain redox homeostasis.

Extracellular-superoxide dismutase (genetic name SOD3) is a secreted anti-oxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. Oxidative stress has been implicated in the pathogenesis of diabetic retinopathy; therefore, increases in extracellular-superoxide dismutase have been suggested to inhibit the progression of diabetic retinopathy. Incretin-based drugs such as glucagon-like peptide-1 receptor agonists are used in the treatment of type 2 diabetes. Glucagon-like peptide-1 receptor agonists are expected to function as extrapancreatic agents because the glucagon-like peptide-1 receptor is expressed not only in pancreatic tissues, but also in many other tissue types. We herein demonstrated that exendin-4, a glucagon-like peptide-1 receptor agonist, induced the expression of extracellular-superoxide dismutase in human retinal microvascular endothelial cells through epigenetic regulation. The results of the present study demonstrated that exendin-4 induced the expression of extracellular-superoxide dismutase through histone H3 acetylation at the SOD3 proximal promoter region. Moreover, plasma extracellular-superoxide dismutase concentrations in diabetic patients were elevated by incretin-based therapies. Therefore, incretin-based therapies may exert direct extrapancreatic effects in order to protect blood vessels by enhancing anti-oxidative activity.

Polyarteritis nodosa (PAN) is a systemic vasculitis in which necrotizing arteritis occurs in medium and/or small arteries [1], and is occasionally associated with viral infection. Haemophilia A is a genetic disorder caused by insufficient clotting factor VIII. Patients are at risk of viral infection because repetitive infusions of clotting factor are necessary for the treatment. Here, we report a case of PAN during a course of haemophilia A.A 33-year-old Japanese man was treated for haemophilia A [...]

Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K+ channels. Many neuromodulators closing leak K+ channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K+ channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso- N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromoguanosine-3′,5′-cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at –70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K+ equilibrium potential ( EK) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K+ current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 μM Rp-8-bromo-β-phenyl-1,N2-ethenoguanosine 3′,5′-cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than EK and close to the reversal potential of Na+-K+ pump current. These observations strongly suggest that NO activates leak K+ channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na+-K+ pump through ATP depletion.

In our previous report, we showed that L-arginine induced depolarization of smooth muscle cells of the rat portal vein with an increased contraction. To clarify the ionic mechanism of the membrane depolarization, the effect of L-arginine on the holding current was studied in freshly isolated smooth muscle cells of the rat portal vein. The whole-cell patch-clamp technique was used, with the membrane potential held at -60 mV. In the presence of Na+ in the perfusate, L-arginine 10 mM induced an inward current in about 50% of the cells. In Na+-deficient perfusate, L-arginine 10 mM increased the amplitude of the inward current in a Na+ concentration-dependent manner. BCH, an inhibitor of the Na+-dependent amino acid transporter, ceased the L-arginine-induced current. These results indicate that L-arginine induces an inward current via Na +-dependent mechanisms in rat portal venous smooth muscle cells.

Clonidine, an alpha2-agonist, has been shown to be useful in the treatment of hepatic portal hypertension in cirrhosis. The mechanism has been attributed to a clonidine-induced decrease in sympathetic activity. While clonidine has been shown to stimulate the alpha2-adrenoceptors of blood vessels, there is limited knowledge of the effects of clonidine on the circular muscle of the hepatic portal vein which regulates its blood flow. To investigate clonidine-induced contraction of the circular muscle of the hepatic portal vein and to clarify the possible role of the endothelium in the contraction, we examined the effects of clonidine on the isometric contraction of endothelium-intact and -removed ring preparations of the rat hepatic portal vein. In endothelium-intact preparations, clonidine caused a concentration-dependent increase in the amplitude of contractions. Inhibition of NO synthesis with Nomega-nitro-L-arginine (L-NNA) elevated the resting tone, and increased the amplitude of the clonidine-induced contractions. Inhibition of cyclooxygenase by diclofenac did not change the amplitude of the clonidine-induced contractions observed both in the presence and absence of L-NNA. Application of a single concentration of clonidine induced a clear increase in amplitude of both twitch and tonic contractions. Twitch and tonic contractions induced by clonidine were inhibited by yohimbine. When the endothelium was damaged by sodium deoxycholate, tonic contractions induced by clonidine were completely suppressed, whereas the increase in twitch contractions was not influenced by chemical damage of the endothelium. Neither SKF-96365, a nonselective cation channel blocker, nor superoxide dismutase, a free radical scavenger, in the presence of catalase, changed the tonic contraction induced by clonidine. These results indicate that stimulation of alpha2-adrenoceptors enhanced twitch contractions and induced tonic contractions in the circular muscle of the rat hepatic portal vein, especially in the absence of NO. The latter, but not the former, occurs through an endothelium-dependent pathway.

Changes in Na + -K + pump activity influence intracellular Na + and K + concentrations. Activation of the electrogenic Na + -K + pump hyperpolarizes plasma membrane and inhibits voltage-dependent Ca 2+ current. Na + -K + pump activity has been shown to be inhibited in the absence of extracellular K + or by cardiac glycosides. Involvement of Na + -K + pump in regulation of cellular functions has been identified by inhibition of responses under inhibition of the Na + -K + pump. In some smooth muscle tissues, responses to β -agonists were inhibited by K + -free medium or ouabain, indicating that responses to β -adrenoceptor agonists are mediated by the Na + -K + pump. However, in other smooth muscle tissues, responses to β -agonists were not inhibited by Na + -K + pump inhibition. The Na + -K + pump plays an important role in the regulation of circulatory function, and the levels of endogenous Na + -K + pump inhibitors have been shown to be elevated in some types of hypertension. Endogenous Na + -K + pump inhibitors possibly affect some of β -adrenoceptor-mediated responses. Regulation of Na + -K + pump may be important in the regulation of smooth muscle activity in normal conditions, as well as under pathophysiological conditions, such as hypertension.

We report a case of cutaneous angiosarcoma occurring on the leg of a 97-year-old Japanese woman. Considering the patient's age and general condition, she was treated with electron beam irradiation, which led to the almost complete disappearance of the tumour. Because cutaneous angiosarcoma is an aggressive tumour with a high propensity for local recurrence and distant metastases, therapy preferably involves a multimodal approach. However, monotherapy with radiation may be effective in some cases of cutaneous angiosarcoma.

Uncoupling protein (UCP) is a transporter family present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. UCP is now recognized as a key molecule in metabolic thermogenesis such as cold- and diet-induced heat production, which is a significant component of energy expenditure, and its dysfunction contributes to the development of obesity. Among the UCP family, UCP-1 is expressed exclusively in brown adipose tissue (BAT), while UCP-2 is present in many organs and UCP-3 is in skeletal muscle. BAT thermogenesis by UCP-1, which has been studied most extensively, is controlled directly by sympathetic nerves principally through the beta-adrenergic action of norepinephrine. Since the beta 3-adrenoceptor is present primarily in adipose tissues, its selective agonists stimulate BAT thermogenesis and also lipid mobilization in white adipose tissue without any noticeable effect on beta 1- and beta 2-adrenoceptos. Therefore, beta 3-adrenoceptor agonists would be promising for the pharmacotherapy of obesity. UCP gene expression is up regulated by ligands for nuclear receptors such as thyroid hormone receptor, peroxisome proliferator-activated receptors (PPAR) and retinoid-X receptor. Long chain fatty acids and some of their metabolites are known to activate PPAR and thereby lead to abundant expression of UCP, which may also contribute to increase in energy expenditure and prevention of obesity. The activity of UCP is suppressed by purine nucleotides but activated by fatty acids. Thus, fatty acids increase UCP-mediated thermogenesis by direct activation of UCP and also by increased gene expression, implying some specific fatty acids or their derivatives as an effective anti-obesity tool.

This essay sketches the changing relationships among the Dutch Colonial Government and among native chiefs and their people in early 19th Century Priangan. This is a time when paddy fields were rapidly spreading to this area.Wet rice cultivation in Priangan started to spread in the middle of the 18th Century, and after the turn of the century, Dutch officials reported construction of various scale irrigation facilities. The Dutch Government began to construct large irrigation canals and dams, limiting its role to planning the works and supplying the necessary funds and goods for the projects. The native chiefs, who had been organizers of irrigation works throughout the 18th Century, undertook the projects. They organized their people's corvee labor, and arranged for native irrigation specialists to supervise the work. Besides these large facilities, many small scale irrigation facilities were constructed; some of them were planned by the chiefs, and others by the people. These small facilities seem to have contributed to the expansion of paddy fields far more than did the Govern ment's large facilities.Although irrigated paddy fields expanded with these facilities, the basic tax system in Priangan didn't change in these decades. Dutch sources show that most of the arable lands irrigated with these facilities were reclaimed by individual settlers who owned the lands. The poll-tax system survived as the main tax system in Priangan at least to the 1820s.During these decades the Government succeeded in expanding coffee cultivation with the people's corvee labor. This was not done by introducing land tax system, but by extending its patronage through the chiefs to the people. The chiefs obeyed the goverment because of their economic dependency. They could'nt manage their finances without the rights and interests given by the Government, which included funds for irrigation works and coffee plantations, concessions of coffee transport and trade, and a coffee production percentage. The people in turn obeyed their chiefs by producing coffee. The reason of their obedience partly because they could get far more profit from wet rice cultivation than from slash and burn. And partly, most of them couldn't run the rice cultivation without agricultural credits given by the chiefs, and part of them couldn't run the cultivation without the facilities constructed by the chiefs.Thus, the relationships between the chiefs and their people in early 19th Century Priangan seemed to be far different from M. C. Hoadley's “Feudal Mode of Production” (1994). On the other hand, this chief to people relationship shows some similar points to these depicted in Y. Breman's “patron-client relationships” (1978, 1982). However, the relationships in early 19th Century are not the same ones as the pre-colonial relationships, but are relationships transmuted under the influence of Dutch colonial rule.

We report a case of hypocomplementaemic urticarial vasculitis with an elevated serum rheumatoid factor level. Hypocomplementaemic urticarial vasculitis is an immune complex-mediated disease characterised by urticarial eruptions. High levels of rheumatoid factor may be associated with hypocomplementaemia due to the consumption of complement, because the rheumatoid factor can form immune complexes with immunoglobulin. It is necessary to pay attention to the amounts of complement in cases of urticarial eruptions with elevated rheumatoid factor level. The eruptions were relieved with a combination of prednisolone and colchicine.

We report a case of cutaneous angiosarcoma occurring on the leg of a 97-year-old Japanese woman. Considering the patient's age and general condition, she was treated with electron beam irradiation, which led to the almost complete disappearance of the tumour. Because cutaneous angiosarcoma is an aggressive tumour with a high propensity for local recurrence and distant metastases, therapy preferably involves a multimodal approach. However, monotherapy with radiation may be effective in some cases of cutaneous angiosarcoma.

Serotonin (5-HT)(1A) receptors play a critical role in the 5-HTergic mechanism associated with fear memory. Previously we showed that adult rats exposed to early postnatal stress, i.e. footshock (FS) stress experienced during the second week (PND 14-18, 2W-FS), exhibited low levels of fear expression. The present study explored whether aversive stress exposure in the second and/or the third week (PND 21-25, 3W-FS) affects the function of cortical 5-HT(1A) receptors, using in vivo and in vitro experiments. A 5-HT(1A) receptor agonist, 8-OH-DPAT (0.5 mg/kg, i.p.), slightly decreased the evoked potential in the mPFC in Non-FS control and 3W-FS group. In contrast, the evoked potential increased after 8-OH-DPAT in the 2W-FS group. The in vitro experiment using patch-clamp recording showed that application of 8-OH-DPAT (10 microM) elicited membrane hyperpolarization of pyramidal neurons in the mPFC in the Non-FS and 3W-FS groups, whereas no changes in membrane potential were observed in the 2W-FS group. These results suggest that synaptic facilitation induced by 8-OH-DPAT resulted from functional changes in cortical 5-HT(1A) receptors. Thus, aversive stress exposure during the second postnatal period appears to cause persistent changes mediated via 5-HT(1A) receptors, presumably involving signal transduction regulating the development of synaptic connectivity underlying fear circuits.

We report a case of bilateral severe bronchial stenosis which was caused by compression by ascending and descending portions of the aorta. Asthma-like symptoms developed 9 years previously and dilation of the ascending aorta was noted 2 years previously. Bronchial obstruction was suspected because of diminishing breath sounds in the left hemithorax. Investigations suggested existence of a vascular ring consisting of the left aortic arch, right descending aorta and possibly the right ligamentum arteriosum. The patient fell in shock during bronchoscopy. Emergency implantations of bronchial stents in the right bronchus and then the left bronchus were made. Because of the patient's poor lung function, there was an extremely high risk for surgical treatment. Although airway stenosis caused by vascular anomaly in elderly patients is very rare, when asthma-like symptoms developed in patients with a right-sided descending aorta, physicians should consider the possibility of such condition.

In an earlier study, we demonstrated that nitric oxide (NO) causes the long-lasting membrane hyperpolarization in the presumed basal forebrain cholinergic (BFC) neurons by cGMP–PKG-dependent activation of leak K+ currents in slice preparations. In the present study, we investigated the ionic mechanisms underlying the long-lasting membrane hyperpolarization with special interest in the pH sensitivity because 8-Br-cGMP–induced K+ current displayed Goldman–Hodgkin–Katz rectification characteristic of TWIK-related acid-sensitive K+ (TASK) channels. When examined with the ramp command pulse depolarizing from −130 to −40 mV, the presumed BFC neurons displayed a pH-sensitive leak K+ current that was larger in response to pH decrease from 8.3 to 7.3 than in response to pH decrease from 7.3 to 6.3. This K+ current was similar to TASK1 current in its pH sensitivity, whereas it was highly sensitive to Ba2+, unlike TASK1 current. The 8-Br-cGMP–induced K+ currents in the presumed BFC neurons were almost completely inhibited by lowering external pH to 6.3 as well as by bath application of 100 μM Ba2+, consistent with the nature of the leak K+ current expressed in the presumed BFC neurons. After 8-Br-cGMP application, the K+ current obtained by pH decrease from 7.3 to 6.3 was larger than that obtained by pH decrease from pH 8.3 to 7.3, contrary to the case seen in the control condition. These observations strongly suggest that 8-Br-cGMP activates a pH- and Ba2+-sensitive leak K+ current expressed in the presumed BFC neurons by modulating its pH sensitivity.

Dietary supplementation of conjugated linoleic acids (CLA) is known to have some beneficial effects such as anti-carcinogenic and anti-obesity effects in several animal species, while it also induces insulin resistance and fatty liver, especially in mice. To explore the possible factors responsible for the CLA-induced insulin resistance, we examined the plasma and mRNA expression levels of several adipocytokines, which are likely involved in the regulation of insulin sensitivity, in normal C5 7BL, mildly obese/diabetic KK and morbidly obese/diabetic KKAy mice. Feeding a diet supplemented with 0.5%, CLA oil consisting of 30.5/% c9, t11-CLA and 28.9% t10, c12-CLA for 4 wk resulted in a decrease in white adipose tissue (WAT), an increase in liver weight with excess accumulation of triglyceride, and insulin resistance associated with hyperglycemia and hyperinsulinemia. The plasma and WAT mRNA levels of leptin were higher in KK and KKAy mice than C57BI. mice, whereas those of adiponectin were higher in C5 7BL mice. CLA-feeding decreased the levels of leptin, adiponectin and resistin, especially in KK and KKAy mice. In contrast, tumor necrosis factor-alpha (TNFalpha) mRNA levels were higher in KK and KKAy mice than C57BL mice, and were increased by CLA feeding. The present results thus indicate that CLA feeding promotes insulin resistance in obese/diabetic mice by at least inverse regulation of leptin and adiponectin, and TNFalpha, adipocytokines known to either ameliorate or deteriorate insulin sensitivity, respectively.

We report a case of hypocomplementaemic urticarial vasculitis with an elevated serum rheumatoid factor level. Hypocomplementaemic urticarial vasculitis is an immune complex-mediated disease characterised by urticarial eruptions. High levels of rheumatoid factor may be associated with hypocomplementaemia due to the consumption of complement, because the rheumatoid factor can form immune complexes with immunoglobulin. It is necessary to pay attention to the amounts of complement in cases of urticarial eruptions with elevated rheumatoid factor level. The eruptions were relieved with a combination of prednisolone and colchicine.

Article, ACTA DERMATO-VENEREOLOGICA.92(1):93-94(2012)

Article, ACTA DERMATO-VENEREOLOGICA.91(4):469(2011)

The newly synthesized araUTP and its derivatives such as ara5-ethyl UTP (1-β-D-arabinofuranosyl-5-ethyluracil triphosphate) and ara5-propyl UTP (l-β-D-arabinofuranosyl-5-propyluracil triphosphate) were tested for inhibition of DNA polymerase γ and of reverse transcriptase. All these three compounds as well as araTTP inhibited the activity of DNA polymerase γ. On the contrary, the activity of reverse transcriptase was inhibited by araUTP, but not by ara5-ethyl UTP and ara5-propyl UTP. The results indicate that there is a distinct difference in function between the active site of DNA polymerase γ and that of reverse transcriptase.

In this paper the author discusses the historical character of the local administration of the Dutch residents in the Priangan area around the year 1820. It is an initial step in her study of the administration of Dutch local officials throughout all of Java during the mid-nineteenth century.In the latter half of the eighteenth century, the Dutch East India Company ruled over the Priangan area through the Commissioner of Native Affairs, a Company employee, who resided at Batavia. His main tasks were purchasing coffee at low prices from native chiefs, and supervising them. He could treat the chiefs rather arbitrarily. He could appoint and dismiss them freely, while he transacted with them and advanced money to them. However, as for the administration, he left the chiefs to control the Priangan area according to traditional custom.Between 1807 and 1816, the system of local rule in Priangan was reorganized by Daendels and Raffles. They introduced into Java the administrative divisions delineated by clear boundaries, which was a peculiar new concept in Indonesia. Priangan became one of these divisions. Moreover, a European administrator was appointed as the new ruler. Nevertheless in practice, the new system was still at a stage of uncertainty during this period.In 1816 the Dutch colonial government regained Java from England, and 3 years after promulgated regulations of local administration, which replaced the system and policy of predecessors. According to the official diary of Priangan residents in 1819-1821, the main feature of control over the Priangan area under these regulations can be described as follows:The Priangan area became a residency delineated by an clear boundery, and was supervised by a resident, who was a Dutch administrative official. Under the tight supervision of the Dutch colonial government, he directly controlled almost all the phases of administration of his residency, the most important of which was the maintenance of public order.He received instructions and orders directly from the colonial government, the director of finance, the high court, and the other superior offices and officials at Batavia, and reported them respectively. In his residency, he was the chief police officer, as well as the prosecutor and judge in the native criminal court of the residency. At the same time, he supervised finance, personnel changes, traveler's affairs, public enterprises, native welfare, and coffee production. In these affairs, he instructed directly not only Dutch subordinates such as an assistant resident, coffee inspectors, warehouse keepers, but also native functionaries such as the chiefs, native prosecutors, and the native police force.Moreover, in order to maintain the coffee production monopoly, which was the staple plant of Priangan, the resident depended upon all of the aforesaid powers. He excluded Europeans and Chinese merchants from his residency, surveyed the residency with native police forces, and arrested coffee smugglers. He also encouraged such public enterprises as construction of roads and bridges to make the government's transportation of coffee more convenient.Thus, the character of the new rule of this resident was quite different from that of the Company's Commissioner before 1807. The new rule had a character similar to the regulation of 1819, which was the framework of the colonial administration in Java in the mid-nineteenth century [Furnivall 1944: 91-2]. Therefore. the resident administration about 1820 can be considered as the earier type of local administration through the Dutch colonial bureaucracy in this area. And since then, it seems to have been taken up by Dutch local officials, who were positively dependent upon their administrative powers to maintain the colonial exploitation.

The optimal condition for the rat DNA polymerase beta activity with (rA)n . (dT)12-18 as a template-primer was determined. The activity was remarkably affected by the concentration of the primer, (dT)12-18' and the mixing ratio of (dT)12-18 to (rA)n. DNA polymerase beta requires higher primer concentration (Km = 11.1 microM with respect to 3'-OH of the primer) than DNA polymerase gamma (Km = 0.04 microM) or oncornaviral DNA polymerase (Km = 0.08 microM) and the enzyme represented the maximum activity in the base ratio of 2:1 with (dT)12-18 and (rA)n suggesting the difference in reaction mechanisms of these enzymes. Under the optimized conditions, the specific activity of the near homogeneous preparation of DNA polymerase beta was 1,000,000 units per mg protein.