Search

There is a major gap in our understanding of how childhood social isolation causes adult social dysfunction. To stimulate future developmental mechanistic studies, we present two conceptual models which highlight that isolation can disrupt developmental events that are concurrent (social deprivation model) or subsequent (developmental mismatch model) to adverse experience., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pyridachlometyl is a unique pyridazine fungicide with a novel mode of action. Herein, we describe the pathway for the invention of pyridachlometyl. First, we identified a diphenyl-imidazo[1,2-a]pyrimidine as our proprietary lead with potent fungicidal activity. Then, aiming to simplify the chemical structure, we applied judicious estimations to explore monocyclic heterocycles as pharmacophores. This enabled the identification of a novel class of tetrasubstituted pyridazine compounds with potent fungicidal activity, likely retaining the same mode of action as the aforementioned compounds. The findings indicated bioisosteric similarity between diphenyl-imidazo[1,2-a]pyrimidine and pyridazine. Further structure-activity and mammalian safety investigations of pyridazine compounds resulted in the discovery of pyridachlometyl as a candidate for commercial development., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by Sumitomo Chemical Co. Ltd., and all authors are employees of Sumitomo Chemical Co. Ltd. The patent-claiming substances, including pyridachlometyl, have been applied under PCT application WO2005/121104 and have been issued in certain countries., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic is a major public health concern. Accurate and rapid diagnosis of COVID-19 is critical for disease control. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a nucleic acid amplification assay similar to reverse transcription-polymerase chain reaction (RT-PCR), the former being a simple, low cost, and rapid method., Objectives: This study aimed to compare the RT-LAMP assay with RT-PCR using the Loopamp™ SARS-CoV-2 Detection Kit., Study Design: One hundred and fifty-one nasopharyngeal swab and 88 sputum samples obtained from individuals with suspected or confirmed COVID-19 were examined., Results: RT-LAMP had high specificity (98.5 % (95 % CI: 96.9-100 %)), sensitivity (87.0 % (95 % CI: 82.8-91.3 %)), positive predictive value (97.9 % (95 % CI: 96.1-99.7 %)), negative predictive value (90.2 % (95 % CI: 86.4-94.0 %)), and concordance rate (93.3 % (95 % CI: 90.1-96.5 %)). Nasopharyngeal and sputum samples positive in RT-LAMP contained as few as 10.2 and 23.4 copies per 10 μL, respectively. RT-LAMP showed similar performance to RT-PCR for samples with cycle threshold value below 36., Conclusions: These results indicate that RT-LAMP is a highly reliable and at least equivalent to RT-PCR in utility, and potentially applicable in settings that are more diverse as a point-of-care tool., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Juvenile nasopharyngeal angiofibroma (JNA) is a hypervascular tumor and uncontrolled hemorrhage makes its removal very difficult. Although preoperative intravascular embolization of a feeding artery is recommended, serious complications such as iatrogenic thrombosis in the brain and insufficient decrease in blood flow to the tumor are concerns. Recently, coblation plasma technology has been reported to be useful for tumor removal with minimum hemorrhage under a clear surgical field. Here we report successful removal of advanced JNA without preoperative embolization, using intraoperative ligation of the maxillary artery and coblation plasma technology. The left nasal cavity of a 23-years-old man was closed by a JNA tumor at Radkowski stage IIC, which was 65mm in size and extended from the nasal cavity to the infratemporal fossa. MRA imaging showed the maxillary artery running along the posterior wall of the maxillary sinus. Therefore, the maxillary artery was first clipped using an endoscopic modified medial maxillectomy (EMMM) approach and endoscopic endonasal en bloc resection of the tumor was then completed using coblation technology with no need for blood transfusion. This case illustrates that preoperative embolization is dispensable in JNA surgery even at Stage IIC if the maxillary artery can be ligated during surgery and a coblation device can be utilized., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Here, we report a case of vertebral artery aneurysm causing dysphagia in a 56-year-old man who had no remarkable past history. Two months before the first visit, he developed posterior neck pain followed by difficulty swallowing 1 month later. He was referred to our clinic because of gradually worsening dysphagia. Physical examination showed paralysis of cranial nerves IX, X, and XII; therefore, he was hospitalized. Because enhanced CT and MRI showed a partially thrombosed right vertebral artery aneurysm, he was transferred to the care of the Department of Neurosurgery. Parent artery occlusion of the right vertebral artery aneurysm was performed and it improved his symptoms. After regaining his ability to take in liquid food, he was transferred to another hospital for further rehabilitation. In this case, we attributed the dysphagia to aneurysmal compression of the roots of cranial nerves IX, X, and XII. A partially thrombosed cerebral artery aneurysm may often rupture and cause worsening of neurologic symptoms. The prognosis is generally poor because the rupture rate is extremely high especially with large or giant aneurysms. However, this case had a good clinical course owing to treatment by parent artery occlusion., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

RNA interference therapy utilizes physiological gene silencing that is originally found as a defense function against foreign RNAs. To silence the target gene, short double stranded RNA has to be delivered to cytosol. However, lack of a suitable delivering carrier is the major obstacle to practical usage. In this study, we present a novel complex consisting of β-1,3-glucan and short interference RNA (siRNA) as a solution for the problem. We used a β-1,3-glucan schizophyllan (SPG) and a siRNA (dA-siTNFα) that is designed to suppress tumor necrosis factor alpha (TNF-α), where the sense strand of siRNA has (dA(40)) tail to induce complexation with SPG. The dA-siTNFα/SPG complex showed higher affinity to recombinant dectin-1 than SPG itself, where dectin-1 is a β-1,3-glucan receptor expressed on antigen presenting cells and can be a target for specific delivery. The complex suppressed lipopolysaccharide (LPS)-induced TNF-α secretion by peritoneal macrophages in vitro. When the complex was intravenously injected, the oligonucleotide accumulated in liver; especially distributed into Kupffer cells. The complex significantly decreased the serum TNF-α level for the mouse model of LPS-induced acute hepatitis. This new siRNA delivery system may overcome the problem for RNA interference therapy because of its non-toxicity and high target specificity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The aim of the present study was to characterize the intestinal absorption of ribavirin (1-beta-d-ribofuranosyl-1, 2, 4-trizole-3-carboxamide). We evaluated the contribution of Na(+)-dependent and -independent transport to ribavirin absorption in the rat intestine using an in situ closed loop method. In addition, we performed pharmacokinetic analysis of the uptake of ribavirin in human intestinal epithelial LS180 cells, and also evaluated the effect of extracellular Na(+) concentration and an inhibitor of the Na(+)-independent equilibrative nucleoside transporter, nitrobenzylmercaptopurine ribonucleoside (NBMPR), on the uptake of ribavirin in the cells. In the presence and also absence of Na(+) in rat intestinal loops, more than 80% of the administered dose (50 microg at a concentration of 100 microg/ml=409 microM) of ribavirin was absorbed in 40 min. The absorption of ribavirin in the rat intestine was significantly reduced by coadministration of 10 mg/ml (=37.3 mM) inosine. In LS180 cells, 100 microM ribavirin was taken up time-dependently, and the influx clearance of the drug was similar to the efflux clearance. Five mM inosine and mizoribine reduced the uptake of 100 microM ribavirin in LS180 cells. The absence of extracellular Na(+) decreased the uptake of 100 microM ribavirin only weakly in the cells, whereas the uptake of 100 microM-2 mM ribavirin was markedly decreased by 100 microM NBMPR. These findings suggested that Na(+)-independent nucleoside transport contributes significantly to intestinal absorption of ribavirin at relatively high concentrations (>or=100 microM).

This paper describes a new approach to finding specific dopamine D4 receptor agonists based on pharmacological analysis of the contractile response to ATP in guinea pig vas deferens. A partial cDNA of the dopamine D4 receptor of the vas deferens was identified. In the vas deferens, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis revealed the existence of dopamine D4 receptor mRNA and D4 receptor protein, respectively. ATP (10(-7) M) induced a transient phasic contraction in the presence of prazosin (10(-7) M), an alpha1-adrenoceptor antagonist. This contraction was potentiated by dopamine receptor agonists in a concentration-dependent manner; and was antagonized by 8-Methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (JL-18), a dopamine D4 receptor antagonist, but not by raclopride, a dopamine D2 and D3 receptor antagonist. Assay methods utilizing contractile responses to ATP may be available for identifying novel dopamine D4 receptor agonists.

The ethylene ketal of pyropheophorbides, chlorophylls possessing the 13-keto carbonyl group and lacking the 13(2)-methoxycarbonyl group, reacted with H(2)(18)O (ca. 95% 18O atom) by acidic hydrolysis to give efficiently and regioselectively 13(1)-18O-oxo-labelled compounds (ca. 92% 18O). The resulting 18O-labelled chlorin was modified by several chemical reactions to afford some derivatives with little loss of the 18O atom. Following the same procedures, 3(1),13(1)-doubly-18O-labelled pyrochlorophyll derivatives were also prepared. All the synthetic 18O-labelled compounds were identified by FAB-mass and vibrational spectra. Especially, in the vibrational spectroscopic results including IR and resonance Raman spectra, an about 30 cm(-1) wavenumber down-shift of the 3- and/or 13-C[double bond]O stretching vibrational bands was observed by exchanging 3(1)- or 13(1)-oxo-oxygen atom from 16O to 18O.

We prepared amide compounds which were derived from ferulic acid using various amines, and investigated their stimulatory effects on insulin secretion using rat pancreatic RIN-5F cells. Most of these compounds exhibited significant promotion of the insulin-release at a concentration of 10 microM and in particular, the amides having n-butyl, n-pentyl, pyrrolidine, and piperidine groups showed high activity.

Leptin has been shown to regulate feed intake and energy expenditure. Insulin stimulates leptin secretion in rodents, but its action on leptin secretion is still obscure in ruminants. If insulin stimulates leptin secretion in ruminants, circulating leptin concentrations may change during exposure to cold, because of fluctuating insulin secretion and action in the cold environment. The present experiment was designed to determine whether feeding or exogenous administration of insulin affects circulating leptin levels in sheep exposed to thermoneutral and cold environments. Suffolk rams that were shorn and fed a diet once daily were subjected to a thermoneutral (20 degrees C) or cold (0 degrees C) environment for at least 1 week. Overall mean concentrations of plasma leptin in the feeding experiment were lower (P<0.05) in the cold environment than in the thermoneutral environment. Plasma leptin levels remained relatively unchanged after feeding in both environments, though plasma insulin response to feeding in both environments increased (P<0.01). The euglycemic clamps (insulin infusion rate: 4 mUkgBW(-1)min(-1) for 2 h) increased (P<0.01) circulating leptin concentrations in the thermoneutral, but not in the cold environment. These results suggest that lower circulating leptin levels in ruminants exposed to the cold environment could be partly due to the depressed insulin action on leptin secretion.

We prepared novel polyphenols which were esters composed of two naturally occurring products, ferulic and gallic acids, and investigated their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus (EBV) activation and superoxide (O2-) generation. Most of these compounds exhibited significant EBV activation suppression at a concentration of 20 microM and in particular, the ester 5f having 2-methyl-1-butyl group showed high activity. The suppressive effects on O2- generation were also observed in most of the esters.

This study was carried out to identify subtypes of dopamine D2-like receptors in guinea pig isolated vas deferens. Dopamine had no effect on the muscle tone in the presence of prazosin, an alpha1-adrenoceptor antagonist. However, contractile responses to adenosine triphosphate (ATP), noradrenaline and acetylcholine were potentiated in a concentration dependent manner by dopamine in the presence of prazosin. This potentiation was not inhibited by raclopride, an antagonist for dopamine D2 and D3 receptors. However, the potentiation of ATP- and noradrenaline-induced contraction was inhibited by clozapine and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3b][1,4]benzodiazepine (JL-18), dopamine D4 receptor antagonists. Further, the potentiation of noradrenaline- and acetylcholine-induced contraction was also inhibited by spiperone, an antagonist for dopamine D2, D3 and D4 receptors. These results suggest that the dopamine D4 receptor is located on the postsynaptic site of guinea pig vas deferens and that activation of the dopamine D4 receptor enhances contractile responses to agonists without affecting muscle tone.

Effects of dopamine and (+/-)-2-(N-phenylethyl-N-propyl)amino-5-hydroxy-tetralin hydrochloride (N-0434), a dopamine D2 receptor agonist, in the presence of prazosin on the ATP- and acetylcholine-induced contraction were investigated in the guinea-pig vas deferens in order to test for the existence of postsynaptic dopamine receptors. The contraction induced by ATP was potentiated by dopamine and N-0434. This potentiation was antagonized by spiperone, a dopamine D2 receptor antagonist, but not by a dopamine D1 receptor antagonist and an alpha2-adrenoceptor antagonist. Similar results were also observed by acetylcholine as well as ATP. The contraction induced by transmural nerve stimulation in the presence of alpha-adrenoceptor antagonists was also potentiated by N-0434, and this potentiation was antagonized by spiperone. The results suggest that dopamine D2 receptors are located on the postsynaptic site of guinea-pig vas deferens and that the contractile responses to ATP and acetylcholine are potentiated via activation of dopamine D2 receptor.

The effects of selective dopamine receptor agonists and antagonists on sympathetic neuromuscular transmission were investigated in the guinea-pig vas deferens in order to test for the presence of presynaptic dopamine receptors. A single-pulse field stimulus induced a rapid monophasic contraction which was strongly inhibited by alpha,beta-methylene ATP, a P2X purinoceptor desensitizing agent. The contraction was also inhibited by 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304), a selective alpha2-adrenoceptor agonist. This inhibition was antagonized by idazoxan, an alpha2-adrenoceptor antagonist, but not by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride (SCH-23390), a dopamine D1 receptor antagonist. Furthermore, the contractions were inhibited in a dose-dependent manner by R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) and (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF-82958), dopamine D1 receptor agonists, and the inhibition was antagonized by both SCH-23390 and idazoxan, but not by spiperone, a dopamine D2 receptor antagonist. The results suggest that dopamine D1 receptors are located on the sympathetic nerve endings of guinea-pig vas deferens.

Electrical stimulation produced a contraction in the isolated guinea-pig vas deferens. This response was blocked by tetrodotoxin, guanethidine and bretylium but not by atropine. The magnitude of the contractile response to electrical stimulation depended on the concentration of the external calcium. Sulfur-containing amino acids and GABA inhibited the electrically induced contraction but not that caused by noradrenaline and ATP. The order of potency for inhibition of the contraction at a concentration of 10(-4) M being GABA greater than or equal to cysteine greater than methionine greater than cysteic acid greater than taurine. The contractile response to electrical stimulation was also inhibited by EGTA, this inhibition being similar to that by cysteic acid and taurine but weaker than that by methionine, cysteine and GABA at a concentration of 10(-4) M. The inhibitory action of sulfur-containing amino acids and GABA was abolished by increasing the calcium concentration in the medium. The results suggest that sulfur-containing amino acids and GABA reduce transmitter release from the sympathetic nerve terminals by inhibiting calcium availability for the transmitter secretion process.

We performed transurethral resection for prostatic hypertrophy on 128 patients, and encountered 6 causes of postoperative urethral stricture. As they occurred during a short period, we investigated the causes. An electrical check revealed electrical resistance of more than 10,000 omega in the electric cord of a resectoscope. When an unused loop was connected with three used cords (No. 1, 2 and 3) and a new cord, the resistances were 2,000, 5,000, 0.9 and 0.5 omega, respectively. Moreover, the respective resistances were 15,000, 1,150,000, 1.3 and 0.9 omega when a used loop was tested. These findings suggested that the excessive resistance resulted from the use of a worn cord and that the used loop caused the postoperative urethral stricture.

ATP, noradrenaline and KCl induced contractions of the isolated guinea-pig vas deferens. The ATP-induced contraction was potentiated by decreasing the external calcium concentration and was reduced by increasing the external calcium concentration. The maximum potentiation was obtained at a low calcium concentration (0.8 mM), the dose-response curve for ATP was shifted to the left in a parallel fashion at this concentration. Calcium antagonists, such as verapamil and diltiazem and MnCl2, induced a similar potentiation. On the other hand, the noradrenaline- and KCl-induced contractions were reduced by calcium antagonists and by decreasing the external calcium concentration. The ATP- and KCl-induced contractions were slightly potentiated by the removal of Mg ions from the medium, but the contractile response to ATP was not potentiated by pretreatment with difluorodinitrobenzene, an ecto-ATPase inhibitor. These results suggest that the affinity of P2-purinoceptors for ATP may be regulated by calcium sites to which calcium and calcium antagonists can bind.