Status of and problems concerning neonatal resuscitation in Japan in 2015.

BACKGROUND: The International Liaison Committee on Resuscitation (ILCOR) published Consensus 2015 in October 2015. Thereafter, the Japanese version of neonatal cardiopulmonary resuscitation programs was revised. Prior to the revision, we re-conducted questionnaire surveys in three types of medical facilities in January 2015. METHODS: Targeted groups included (i) 277 training hospitals authorized by the Japanese Society of Perinatal/Neonatal Medicine for training of physicians specialized in perinatal care (neonatology) in January 2015 (training hospitals; response rate, 70.8%); (ii) 459 obstetric hospitals/clinics (response rate, 63.6%); and (iii) 453 midwife clinics (response rate, 60.9%). The survey included systems of neonatal resuscitation, medical equipment and practices, and education systems. The results were compared with that of similar surveys conducted in 2005, 2010 and 2013. RESULTS: Almost all results were generally improved compared with past surveys. In training hospitals, however, the use of oxygen blenders or manometers was not widespread. Only 35% of institutions used continuous positive airway pressure systems frequently, and expert neonatal resuscitation doctors attended all deliveries in only 6% of training centers. In addition, only 71% of training hospitals had brain therapeutic hypothermia facilities. Not all obstetric hospitals/clinics prepared pulse oximeters, and only a few used manometers frequently. Some midwife clinics did not keep warming equipment, and few midwife clinics were equipped with pulse oximeters. In addition, some midwife clinics did not prepare ventilation bags (masks). CONCLUSIONS: The equipment in Japanese delivery rooms is variable. Further efforts need to be made in the distribution of neonatal resuscitation devices and the dissemination of techniques.

[Successful treatment with chloramphenicol in four pediatric cases of intractable bacterial meningitis].

Chloramphenicol (CP) is recently one of the rarely-used antibiotics. In this study, we present four patients with intractable bacterial meningitis, who were successfully treated with CP and discuss the therapeutic indications of CP in these pediatric cases. The patients were diagnosed as bacterial meningitis at the ages ranging from 2 months to 1 year and 4 months. The causative organisms found in three of the patients were H. influenzae and in the fourth patient, S. pneumoniae. According to the microbial sensitivity tests, these organisms were highly sensitive to antibiotics including ceftriaxone, meropenem and/or panipenem/betamipron. Treatment with these antibiotics was initially effective; however, recurrences of meningitis appeared in all patients. Administration of CP (100 mg/kg/day) started between the 11th and the 58th days, and was continued for 9 days up to 19 days. Their fever had disappeared within four days after the administration of CP, and it was confirmed that all patients completely recovered from meningitis. Two of the patients developed a mild degree of anemia, but soon recovered after the discontinuation of CP. None of them had neurological sequela. We recommend CP as one of the choices for the treatment of intractable bacterial meningitis.

Down-regulation of chondroitin 4-O-sulfotransferase-1 by Wnt signaling triggers diffusion of Wnt-3a.

During metazoan development, Wnt molecules are secreted from Wnt-producing cells, diffuse to target cells, and determine cell fates; therefore, Wnt secretion is tightly regulated. However, the molecular mechanisms controlling Wnt diffusion are not fully elucidated. The specific chondroitin sulfate (CS) structure synthesized by chondroitin-4-O-sulfotransferase-1 (C4ST-1) binds to Wnt-3a with high affinity (Nadanaka, S., Ishida, M., Ikegami, M., and Kitagawa, H. (2008) J. Biol. Chem. 283, 27333-27343). In this study we tested whether Wnt signaling regulates sulfation patterns of cell-associated CS chains by suppressing expression of C4ST-1 to trigger release of Wnt molecules from Wnt-producing cells. C4ST-1 expression was dramatically reduced in L cells that stably expressed Wnt-3a (L-Wnt-3a cells) and had CS with low affinity for Wnt-3a. Forced expression of C4ST-1 in L-Wnt-3a cells inhibited diffusion of Wnt-3a due to structural alterations in CS chains mediated by C4ST-1. Furthermore, sustained Wnt signaling negatively regulated C4ST-1 expression in a cell-autonomous and non-cell autonomous fashion. These results demonstrated that C4ST-1 is a key downstream target of Wnt signaling that regulates Wnt diffusion from Wnt-producing cells.

Effects of second generation of histamine H1 antagonists, cetirizine and ebastine, on the antitussive and rewarding effects of dihydrocodeine in mice.

RATIONALE: Little information is available about the interaction between dihydrocodeine and second-generation antihistamine drugs such as cetirizine and ebastine, with particular reference to the rewarding effect of dihydrocodeine. OBJECTIVE: The effects of second generation histamine H(1) antagonists, such as cetirizine and ebastine on the antitussive and rewarding effect of dihydrocodeine were examined in mice. METHODS: Mice were exposed to a nebulized solution of capsaicin (30 micromol/l) under conscious and identical conditions, using a body plethysmograph. The coughs produced during a 3-min exposure period were counted. Effects of H(1) antagonists on the reinforcing effect of dihydrocodeine were assessed by using the conditioned place preference procedure in mice. RESULTS: The antitussive effect of dihydrocodeine was enhanced by the simultaneous administration of either cetirizine or ebastine. There was no statistical difference between the ED(50) of dihydrocodeine in combination with ebastine and that of dihydrocodeine in combination with cetirizine. Concurrent dosing of dihydrocodeine and ebastine produced a significant place preference. This behavioral potentiation was antagonized by SCH23390, a dopamine D(1) antagonist. Moreover, ebastine enhanced the central dopamine turnover ratio, but cetirizine could not, in this study. CONCLUSION: Taken together, the potentiation of place preference of dihydrocodeine with ebastine may be due, at least in part, to stimulation of the central dopaminergic system via D(1) receptors. However, combination of dihydrocodeine with cetirizine does not potentiate place preference at all, nor does it potentiate the central dopaminergic system. Thus, it is likely that cetirizine may be a useful constituent in opioid-containing, antitussive preparations that would not potentiate the development of psychological dependence.

Modification of the fenvalerate-induced nociceptive response in mice by diabetes.

We examined the effect of diabetes on the fenvalerate-induced nociceptive response in mice. The intrathecal (i.t.) or intraplantar (i.pl.) injection of fenvalerate, a sodium channel activator, induced a characteristic behavioral syndrome mainly consisting of reciprocal hind limb scratching directed towards caudal parts of the body and biting or licking of the hind legs in both non-diabetic and diabetic mice. However, the intensity of such fenvalerate-induced nociceptive responses was significantly greater in diabetic mice than in non-diabetic mice. Calphostin C (3 pmol, i.t.), a selective protein kinase C inhibitor, significantly inhibited intrathecal fenvalerate-induced nociceptive behavior with a rightward shift of the dose-response curve for fenvalerate-induced nociceptive behavior to the level those observed in non-diabetic mice. On the other hand, when non-diabetic mice were pretreated with phorbol-12, 13-dibutyrate (50 pmol, i.t.), the dose-response curve for intrathecal fenvalerate-induced nociceptive behavior was shifted leftward to the level those observed in diabetic mice. These results suggest that the sensitization of sodium channels, probably tetrodotoxin-resistant (TTX-R) sodium channels, by the long-term activation of protein kinase C may play an important role in the enhancement of the duration of fenvalerate-induced nociceptive behavior in diabetic mice.

Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist.

Several lines of evidence indicate that the opioid and cannabinoid systems produce synergistic interactions. The present study examined the opioid receptors involved in the antitussive effect of WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity cannabinoid receptor agonist, in mice. WIN 55212-2, at doses of 0.3-3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT receptor antagonist, or naloxone (1 mg/kg ip), an opioid receptor antagonist. Furthermore, pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a cannabinoid CB(1) receptor antagonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of mu-opioid receptors by pretreatment with beta-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a kappa-opioid receptor antagonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a mu(1)-opioid receptor antagonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of cannabinoid CB(1) receptors and mu(2) (naloxonazine-insensitive)-opioid receptors, but not mu(1) (naloxonazine-sensitive)- or kappa-opioid receptors.

The antitussive effects of endomorphin-1 and endomorphin-2 in mice.

The antitussive effects of endomorphin-1 and endomorphin-2, endogenous mu-opioid receptor agonists, on capsaicin-induced coughs were examined in mice. Endomorphin-2, at doses of 3, 10 and 30 microg, i.c.v., dose-dependently inhibited the number of capsaicin-induced coughs. However, the same doses (3, 10 and 30 microg) of endomorphin-1 injected with i.c.v. had no significant effects on the number of capsaicin-induced coughs. The antitussive effect of endomorphin-2 was significantly reduced by beta-funaltrexamine, a mu(1)/mu(2)-opioid receptor antagonist, but not naloxonazine, a selective mu(1)-opioid receptor antagonist. Furthermore, the antitussive effect of endomorphin-2 was also partially but significantly reduced by nor-binaltorphimine, a selective kappa-opioid receptor antagonist. These results indicate that the administration of the endogenous mu-opioid ligand endomorphin-2, but not endomorphin-1, into the brain produces an antitussive effect via mainly naloxonazine-insensitive mu-opioid receptors, namely mu(2)-opioid receptors and partially kappa-opioid receptors.

Effects of T-82, a novel acetylcholinesterase inhibitor, on impaired learning and memory in passive avoidance task in rats.

Effects of 2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumarate (T-82), a new quinoline derivative, on drug- and basal forebrain lesion-induced amnesia models were examined in rats. Scopolamine (0.5 mg/kg, i.p.) and cycloheximide (1.5 mg/kg, s.c.) shortened the step-through latency in the passive avoidance task. T-82 significantly ameliorated amnesia induced by scopolamine or cycloheximide at the dose of 0.03, 0.1 and 0.3 mg/kg, p.o., and 0.3 and 1.0 mg/kg, p.o., respectively. Basal forebrain lesions with ibotenic acid shortened the step-through latency in passive avoidance task. An acute (0.1 and 0.3 mg/kg, p.o.) or subacute (0.03-0.3 mg/kg, p.o., for 7 days) treatment of T-82 significantly reversed the shortened latency. These results suggest that T-82 may ameliorate the impairment of memory induced by acetylcholinergic dysfunction.

Prazosin inhibits spontaneous locomotor activity in diabetic mice.

We examined the effect of prazosin, a selective alpha1-adrenergic receptor antagonist, on the enhanced spontaneous locomotor activity in streptozotocin-induced diabetic mice. Spontaneous locomotor activity in diabetic mice was significantly greater than that in nondiabetic mice. Pretreatment with either intracerebroventricular (5, 10 nmol) or intraperitoneal (0.5, 1.0 mg/kg) injection of prazosin dose-dependently reduced the spontaneous locomotor activity in diabetic mice, but not in nondiabetic mice. Furthermore, the enhanced dopamine turnover ratio in the limbic forebrain in diabetic mice was reduced to the same level as that in nondiabetic mice after the administration of prazosin. Thus, these results suggest that alpha1-adrenergic receptors might play an important role in the enhanced spontaneous locomotor activity in diabetic mice. Furthermore, alpha1-adrenoceptor antagonism might have an inhibitory effect on presynaptic dopaminergic neurotransmission in the limbic forebrain in diabetic mice.

Effects of selective serotonin reuptake inhibitors on immobility time in the tail suspension test in streptozotocin-induced diabetic mice.

We examined the effects of fluoxetine and fluvoxamine, selective serotonin reuptake inhibitors (SSRIs), and desipramine, a selective noradrenaline (NA) reuptake inhibitor, given alone or in combination with diazepam on immobility time in the tail suspension test in diabetic mice. Immobility time was significantly longer in diabetic than in nondiabetic mice. Diazepam (0.1 and 0.3 mg/kg s.c.) dose-dependently decreased immobility time in diabetic mice to the level observed in saline-treated nondiabetic mice. However, diazepam had no significant effect on immobility time in nondiabetic mice. Fluoxetine (3-56 mg/kg i.p.) and desipramine (1-30 mg/kg i.p.) produced marked, dose-dependent suppression of immobility time in both nondiabetic and diabetic mice. However, anti-immobility effects of fluoxetine and desipramine in diabetic mice were less than those in nondiabetic mice. Fluvoxamine (3-30 mg/kg i.p.) produced a dose-dependent suppression of immobility time in nondiabetic mice but not in diabetic mice. The anti-immobility effects of fluoxetine, fluvoxamine and desipramine in nondiabetic mice were antagonized by pretreatment with diazepam (0.3 mg/kg s.c.). Furthermore, fluoxetine, fluvoxamine and desipramine had no effect on the immobility time in diazepam (0.3 mg/kg s.c.)-treated diabetic mice. These results indicate that the anti-immobility effects of SSRIs and desipramine are less in diabetic mice than in nondiabetic mice in the tail suspension test. Furthermore, in diabetic mice, SSRIs and selective NA reuptake inhibitors did not affect immobility time even though the prolonged duration of immobility was suppressed by pretreatment with diazepam.

Synthesis of heparan sulfate tetrasaccharide as a substrate for human heparanase.

Regiospecifically sulfated heparan sulfate tetrasaccharide, GlcAß-GlcN(NS6S)α-GlcAß-GlcN(NS6S)α was first synthesized as an octyl glycoside. Total synthesis was achieved effectively by coupling the corresponding disaccharide units in short steps.

Anti-arthritic activity of synthesized chondroitin sulfate E hexasaccharide.

The purpose of this study was to investigate the anti-arthritic effects of synthesized chondroitin sulfate E hexasaccharide (sCSE-6, CAS 866407-73-0), using a type II collagen-induced arthritis model in mice. sCSE-6 was administered subcutaneously on a daily basis to type II collagen (CII)-sensitized mice from day 0 to day 55. The severity of arthritis, as well as the immunohistological features of the arthritic mice, were analyzed. sCSE-6 inhibited the course of arthritis and restored the body weight loss of CII-immunized mice. An immunohistological analysis showed that bone/cartilage destruction in the arthritic mice was significantly attenuated by sCSE-6 treatment, with a marginal inhibition of synovial inflammation also observed. The beneficial effect of sCSE-6 on bone destruction, which is the most important factor in preventing arthritis, is particularly noteworthy. In summary, sCSE-6 inhibited arthritis and helped to prevent bone and cartilage destruction in a type II collagen-induced arthritis model in mice. The findings indicated that CSE oligosaccharides might be a novel potential therapeutic tool for rheumatoid arthritis.

Inhaled pinacidil, an ATP-sensitive K+ channel opener, and moguisteine have potent antitussive effects in guinea pigs.

We investigated whether inhaled pinacidil and moguisteine inhibit capsaicin-induced coughs in guinea pigs. Inhaled pinacidil (15 - 60 microg/ml), an ATP-sensitive K+ channel opener, and moguisteine (15 - 60 microg/ml) each dose-dependently inhibited the number of capsaicin-induced coughs. The antitussive effects of pinacidil and moguisteine were significantly antagonized by pretreatment with glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel blocker. However, pretreatment with naloxone methiodide (10 mg/kg, s.c.) had no significant effect on the antitussive effects of either pinacidil or moguisteine. On the other hand, inhaled dihydrocodeine (15 - 60 microg/ml) also dose-dependently suppressed the number of capsaicin-induced coughs. The antitussive effect of inhaled dihydrocodeine was significantly antagonized by pretreatment with naloxone methiodide (10 mg/kg, s.c.), but not by glibenclamide (10 mg/kg, i.p.). These results indicate that inhaled pinacidil and moguisteine both attenuate capsaicin-induced coughs. Pinacidil and moguisteine may exert their antitussive effects through the activation of ATP-sensitive K+ channels in the tracheobronchial tract. Furthermore, it is possible that ATP-sensitive K+ channels may be involved in the antitussive effects of peripherally acting non-narcotic antitussive drugs.