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Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 polyunsaturated fatty acids (PUFAs), and are abundant in fish oil. These n-3 PUFAs have been reported to improve the lower gastrointestinal (LGI) disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effect of n-3 PUFAs on motility of the LGI tract, such as the ileum and colon, the parts frequently affected by these inflammatory disorders. To elucidate the effects of DHA and EPA on the LGI tract motility, we performed comparative evaluation of their effects and linoleic acid (LA), an n-6 PUFA, on contractions in the ileal and colonic longitudinal smooth muscles (LSMs) isolated from guinea pigs. In the ileal and colonic LSMs, DHA and EPA (3 × 10-5 M each) significantly inhibited contractions induced by acetylcholine (ACh), histamine, and prostaglandin (PG) F2α (vs. control), and these effects are stronger than that of LA (3 × 10-5 M). In the colonic LSMs, DHA and EPA also significantly inhibited contractions induced by PGD2 (vs. control). In addition, DHA and EPA significantly inhibited CaCl2-induced ileal and colonic LSM contractions in Ca2+-free 80 mM-KCl solution (vs. control). Any ileal and colonic LSM contractions induced by ACh, histamine, PGF2α, and CaCl2 were completely suppressed by verapamil (10-5 M), a voltage-gated/dependent Ca2+ channel (VGCC/VDCC) inhibitor. These findings suggest that DHA and EPA could improve the abnormal contractile functions of the LGI tract associated with inflammatory diseases, partly through inhibition of VGCC/VDCC-dependent ileal and colonic LSM contractions.

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10-5 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.

The inhibitory effects of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and linoleic acid (LA) on the contractions induced by five prostanoids and U46619 (a TP receptor agonist) were examined in guinea pig gastric fundus smooth muscle (GFSM). Tension changes were isometrically measured, and the mRNA expression of prostanoid receptors was measured by RT-qPCR. DHA and EPA significantly inhibited contractions induced by the prostanoids and U46619, whereas LA inhibited those induced by prostaglandin D

Summary Aim Previous experiments using our in vivo tissue engineering chamber (TEC) model demonstrated that adipose flap was spontaneously generated without the need for adipocyte or stem cell implantation. The purposes of the present study are to clarify 1) the reproducibility of this method to create adipose flaps, 2) the time-course of adipogenesis, and 3) the long-term stability of the adipose flap generated. Methods The chambers that afforded a protected space for tissue growth were implanted into the groins of rabbits. A vascular pedicle as the vascular source of newly formed tissue, a collagen sponge as a scaffold, and platelet-rich plasma (PRP) and fibroblast growth factor (bFGF) as growth factors were contained within the chamber. There were three experimental groups according to the implantation period of the chamber; Group 4 w, Group 8 w, and Group 12 w (n = 5 in each group). Results The percent volumes of the combined adipose/pedicle tissue compared with the total volume of the generated tissue were 14.8% (0.437 cm3/2.96 cm3), 47% (0.87 cm3/1.85 cm3) and 80% (1.82 cm3/2.27 cm3) in Groups 4 w, 8 w, and 12 w, respectively. When a 12-week adipose flap was transferred outside the chamber on its vascular pedicle and retained for a further five months, it became more like mature adipose tissue and had increased fat density. Conclusion Adipose flaps were spontaneously generated in vivo in TECs at 12 weeks with reproducibility and showed long-term stability outside the chamber following pedicle transfer. The tissue-engineered adipose flap will contribute to breast reconstruction and augmentation without donor-site morbidity.

In this study, we investigated the effects of platelet-activating factor (PAF) on the basal tone and spontaneous contractile activities of guinea pig (GP) and mouse urinary bladder (UB) smooth muscle (UBSM) tissues to determine whether PAF could induce UBSM tissue contraction. In addition, we examined the mRNA expression of the PAF receptor, PAF-synthesizing enzyme (lysophosphatidylcholine acyltransferase, LPCAT), and PAF-degrading enzyme (PAF acetylhydrolase, PAF-AH) in GP and mouse UB tissues using RT-qPCR. PAF (10−9–10−6 M) strongly enhanced the basal tone and spontaneous contractile activities (amplitude and frequency) of GP and mouse UBSM tissues in a concentration-dependent manner. The enhancing effects of PAF (10−6 M) on both GP and mouse UBSM contractile activities were strongly suppressed by pretreatment with apafant (a PAF receptor antagonist, GP: 10−5 M; mouse: 3 × 10−5 M). The PAF receptor (Ptafr), LPCAT (Lpcat1, Lpcat2), and PAF-AH (Pafah1b3, Pafah2) mRNAs were detected in GP and mouse UB tissues. These findings reveal that PAF strongly enhances the contractile mechanical activities of UBSM tissues through its receptor and suggest that the PAF-synthesizing and -degrading system exists in UBSM tissues. PAF may serve as both an endogenous UBSM constrictor and an endogenous mediator leading to detrusor overactivity.

We investigated the potential inhibitory effects of docosahexaenoic acid (DHA) on the contractions of guinea pig tracheal smooth muscles in response to U46619 (a thromboxane A

This study was performed to elucidate whether eicosapentaenoic acid (EPA) suppresses spasm-prone blood vessel contractions induced by a thromboxane mimetic (U46619) and prostaglandin F2α (PGF2α) and determine whether the primary target of EPA is the prostanoid TP receptor. Accordingly, we assessed: (1) the tension changes in porcine basilar and coronary arteries, and (2) changes in the Fura-2 (an intracellular Ca2+ indicator) fluorescence intensity ratio at 510 nm elicited by 340/380 nm excitation (F340/380) in 293T cells expressing the human TP receptor (TP-293T cells) and those expressing the human prostanoid FP receptor (FP-293T cells). EPA inhibited both porcine basilar and coronary artery contractions induced by U46619 and PGF2α in a concentration-dependent manner, but it did not affect the contractions induced by 80 mM KCl. EPA also inhibited the increase in F340/380 induced by U46619 and PGF2α in TP-293T cells. In contrast, EPA showed only a marginal effect on the increase in F340/380 induced by PGF2α in FP-293T cells. These findings indicate that EPA strongly suppresses the porcine basilar and coronary artery contractions mediated by TP receptor and that inhibition of TP receptors partly underlies the EPA-induced inhibitory effects on these arterial contractions.

Cooperative manipulation through dual-arm robots is widely implemented to perform precise and dexterous tasks to ensure automation; however, the implementation of cooperative micromanipulation through dual-arm optical tweezers is relatively rare in biomedical laboratories. To enable the bimanual and dexterous cooperative handling of a nonspherical object in microscopic workspaces, we present a dual-arm visuo-haptic optical tweezer system with two trapped microspheres, which are commercially available end-effectors, to realize indirect micromanipulation. By combining the precise correction technique of distortions in scanning optical tweezers and computer vision techniques, our dual-arm system allows a user to perceive the real contact forces during the cooperative manipulation of an object. The system enhances the dexterity of bimanual micromanipulation by employing the real-time representation of the forces and their directions. As a proof of concept, we demonstrate the cooperative indirect micromanipulation of single nonspherical objects, specifically, a glass fragment and a large diatom. Moreover, the precise correction method of the scanning optical tweezers is described. The unique capabilities offered by the proposed dual-arm visuo-haptic system can facilitate research on biomedical materials and single-cells under an optical microscope.

We examined the potential stimulatory effects of U46619 (a prostanoid TP receptor agonist) and five prostanoids on the contractile activities of urinary bladder smooth muscle (UBSM), focusing on the role of the TP receptor and its associated CaChanges in the basal tone and spontaneous contractile activity (amplitude and frequency) of isolated guinea pig UBSM were measured isotonically. The presence of TP receptors in UBSM was examined by RT-qPCR and immunofluorescence.U46619, prostaglandin (PG) EProstanoids can enhance UBSM contractile activities and thus may be endogenous candidates for induction of detrusor overactivity. The TP receptor and TP-receptor-activated VDCCs/SOCCs are key molecules responsible for these effects.

Distigmine bromide (distigmine) is a reversible carbamate cholinesterase (ChE) inhibitor that is used to treat myasthenia gravis. In Japan, it is also used as a remedy for urination disorder (underactive bladder). The most distinctive pharmacological feature of distigmine is its long-lasting action compared to that of other ChE inhibitors. In animals and humans, distigmine was reported to inhibit acetylcholinesterase (AChE) and improve myasthenia gravis for an extended period. Few studies have examined the sustainability of this enhancing effect on the contractile function of urinary bladder smooth muscle. In addition, the cause of this long-lasting feature remains unclear. In this review, we present our findings for the long-lasting feature of distigmine on isolated urinary bladder contraction and in vivo urinary function of guinea pig. We also present our results on the mechanism of its long-lasting sustainability using recombinant human AChE.

β-Adrenoceptors are subclassified into 3 subtypes (β1-β3). Among these, β3-adrenoceptors are present in various types of smooth muscle and are believed to play a role in relaxation responses of these muscles. β3-Adrenoceptors are also present in urinary bladder smooth muscle (UBSM), although their expression varies depending on the animal species. To date, there has been little information available about the endogenous ligand that stimulates β3-adrenoceptors to produce relaxation responses in UBSM. In this study, to determine whether noradrenaline is a ligand of UBSM β3-adrenoceptors, noradrenaline-induced relaxation was analyzed pharmacologically using rat UBSM. We also assessed whether noradrenaline metabolites were ligands in UBSM. In isolated rat urinary bladder tissues, mRNAs for β1-, β2-, and β3-adrenoceptors were detected using RT-PCR. In UBSM preparations contracted with methacholine (3 × 10-5 M), noradrenaline-induced relaxation was not inhibited by the following antagonists: atenolol (10-6 M; selective β1-adrenoceptor antagonist), ICI-118,551 (3 × 10-8 M; selective β2-adrenoceptor antagonist), propranolol (10-7 M; non-selective β-adrenoceptor antagonist), and bupranolol (10-7 M; non-selective β-adrenoceptor antagonist). In the presence of propranolol (10-6 M), noradrenaline-induced relaxation was competitively inhibited by bupranolol (3 × 10-7-3 × 10-6 M) or SR59230A (10-7-10-6 M; selective β3-adrenoceptor antagonist), with their pA2 values calculated to be 6.64 and 7.27, respectively. None of the six noradrenaline metabolites produced significant relaxation of methacholine-contracted UBSM. These findings suggest that noradrenaline, but not its metabolites, is a ligand for β3-adrenoceptors to produce relaxation responses of UBSM in rats.

The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.

Background: A report examining whether clinically available antidepressants increase urethral smooth muscle contraction via antagonistic effects on the α2-adrenoceptor (α2-AR) is lacking. Objectives: The present study was performed to evaluate the potential of clinically available antidepressants to reverse α2-AR-mediated contractile inhibition in rat vas deferens, in order to predict whether they can induce voiding impairment. Method: The effects of 18 antidepressants of different classes on electrical field stimulation (EFS)-induced contractions suppressed by 10–8 mol/L clonidine (a selective α2-AR agonist) in isolated rat vas deferens were investigated and related to their respective clinical blood concentrations. Results: The EFS-induced contractions suppressed by clonidine were recovered by amitriptyline (a tricyclic antidepressant), mirtazapine (a noradrenergic and specific serotonergic antidepressant), and trazodone (a serotonin 5-HT2A receptor antagonist) at concentrations close to the clinical blood levels. EFS-induced contractions were also recovered by trimipramine, clomipramine (tricyclic antidepressants), mianserin (a tetracyclic antidepressant), sertraline (a selective serotonin reuptake inhibitor [SSRI]), and sulpiride (a dopamine D2-receptor antagonist), albeit at concentrations that substantially exceeded their clinically-achievable blood levels. EFS-induced contractions were not significantly affected by imipramine, nortriptyline, amoxapine (tricyclic antidepressants), maprotiline (a tetracyclic antidepressant), fluvoxamine, paroxetine, escitalopram (SSRIs), milnacipran, duloxetine (serotonin and noradrenaline reuptake inhibitors), and aripiprazole (a dopamine partial agonist). Conclusions: These findings suggest that amitriptyline, mirtazapine, and trazodone induce voiding impairment caused by increased urethral resistance by enhancing sympathetic nerve activities attributed to α2-AR antagonism.

Double-arm manipulators are unfamiliar as equipment used in microscopic work in biomedical laboratories, whereas they are prevalent in factory automation and humanoids. For non-contact micromanipulation in three-dimensional (3D) workspaces, we propose and design a double-arm optical tweezer system that can easily exchange two types of end-effectors (i.e., optical landscapes for laser trapping) with a focus tunable lens and a microlens array. With a time-shared scanning approach under interactive personal computer (PC) mouse controls, the system can perform the precise and dexterous handling of micro-objects in a 3D workspace. As a proof of concept, we demonstrate the two-dimensional (2D) and 3D dexterous handling of microbeads in the motions of solving puzzle rings. We also demonstrate the precise and periodic patterning of microbeads for massive dynamic arrays. This double-arm system can be applied with versatile tools used for various non-contact micromanipulations in the biomedical field and for dynamic arrays in single cell and 3D biology.

Docosahexaenoic acid (DHA, an n-3 polyunsaturated fatty acid) inhibits U46619 (a TP receptor agonist)- and prostaglandin F

Distigmine bromide (distigmine) is a carbamate cholinesterase (ChE) inhibitor, which is mainly used for the treatment of myasthenia gravis. Distigmine is also used in Japan for the treatment for underactive bladder and glaucoma. The effectiveness of distigmine for underactive bladder treatment has been confirmed by many clinical reports, and this effect is thought to be caused by potentiating urinary bladder smooth muscle contraction due to inhibition of acetylcholine degradation during micturition. However, the pharmacological effects of distigmine on urinary bladder smooth muscle have not been well studied. The most distinctive pharmacological feature of distigmine is that it shows long-lasting effects than other ChE inhibitors; however, few studies have investigated the persistence of the enhancing effect of distigmine on the contractile function of urinary bladder smooth muscle. Moreover, this mechanism remains unclear. In this review, we present our findings on the mechanism of the potentiating effect of distigmine on isolated guinea pig urinary bladder smooth muscle contraction. We also discuss the long-lasting potentiating effect of distigmine on urinary bladder motility and the mechanism of these effects using guinea pig urinary bladder smooth muscle in vivo and in vitro. In addition, we present our investigations on the long-lasting mechanism of distigmine using recombinant human acetylcholinesterase.

The popularization of mobile internet and transport applications making passenger transport real-time information available to the general public. In the Metropolitan Area of Sao Paulo (MASP), the largest urban agglomeration in South America with 21 million inhabitants carrying out their activities every day, these systems have been changing the user’s behaviour. The purpose of this study is to evaluate the perception and use of these applications called Mobility as a Service (MaaS) for the passenger in MASP. To do so, we conducted a survey with 138 respondents that live in MASP in May 2020 regarding the services: Google Maps, Moovit and Citymapper. They evaluated what the application they prefer to, how the applications functions are used by theirs and the public transportation frequence of use and after the anwers were used in a descripitive statistics analysis. The results indicated a predominance of youth users that plan their trips using public transportation and seek real-time information through by these applications.

The β-adrenoceptor (β-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (β2-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (β1-AR dominant), normetadrenaline (NMA) and MA (10-4 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10-4 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10-4 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10-4 M) significantly suppressed ISO-induced relaxation. DHPG (10-4 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10-4 M) significantly suppressed relaxation induced by CGP-12177 A (a β3-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess β2-AR agonistic action; 2) NMA and MA augment β2-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing β1-, β2-AR antagonistic action (β2 > β1); 3) DHPG exhibits β1-, β2-, β3-AR antagonistic action, and this is particularly marked for β3-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.

Objective: To investigate the impact of epinephrine on prehospital rearrest and re-attainment of prehospital return of spontaneous circulation (ROSC). Methods: Data for 9,292 (≥ 8 years) out-of-hos...

A classificação de qualidade de frutas e vegetais é utilizada para selecionar produtos seguros para o consumo humano. Assim, este trabalho tem como objetivo investigar o sistema de classificação da qualidade da cadeia produtiva da banana no varejo e no atacado da região do Alto Tietê, Brasil. Foi coletado 239 bananas dos 12 principais varejo-atacadistas e aplicado os Critérios de Classificação da Banana, do Programa Brasileiro de Modernização da Horticultura e Produção Integrada de Frutas. Portanto, foram considerados os critérios de qualidade: peso bruto e líquido, comprimento, calibre, grau de maturação e número de defeitos. Observou-se que a banana apresentou uma boa classificação com média de peso bruto e líquido respectivamente 156,49 ± 39,62 e 98,93 ± 30,11, comprimento 21,11 ± 2,35, calibre 37,06 ± 3,08. Ainda, notou-se associação entre os critérios de qualidade e a classificação das bananas (teste de Dunn, p < 0,05), bem como, entre os tipos de defeitos e lotes analisados (χ² = 98,11; p < 0,05). Do total de bananas analisadas, 38% estavam isentas de defeitos, mas 62% apresentaram algum tipo de defeito. Além disso, foi proposto uma estrutura estratégica para a destinação correta de bananas, como: 44% das bananas devem ser enviadas para a produção de compostagem, 17% para a indústria de ração animal, 1% para a produção de alimentos processados e 38% para a comercialização no mercado para consumo humano. Concluiu-se que o processo de classificação auxilia na transparência da cadeia produtiva de alimento, e que o monitoramento e controle da qualidade devem ser contínuos durante a exposição dos frutos para venda ao consumidor, garantindo a segurança alimentar, redução do desperdício e destinação correta das bananas não aptas para comercialização.

We investigated the reproducibility of creating a vascularized tissue flap in an in vivo tissue engineering chamber by incubating a vascular pedicle imbedded in a collagen sponge with activated platelet-rich plasma (aPRP) and basic fibroblast growth factor (bFGF).Collagen sponge soaked with saline (control group), bFGF (Group 1), aPRP (Group 2), and aPRP/controlled release bFGF (Group 3) was implanted with a saphenous arteriovenous pedicle into a tissue engineering chamber, located subcutaneously in the groin of rabbits. After 4 weeks of implantation, the contents in the chamber were harvested for volumetric and histological analyses.The total volume of generated tissue in Group 3 was the largest among the Groups (control group vs. Group 3, p 0.01). The volume of the pedicle vascular bundle/adipose tissue component was larger in Groups 1 and 3 than that in the control group (p 0.05 and p 0.01, respectively). The inflammatory tissue volume was larger in Groups 2 and 3 (control group vs. Group 3, p 0.05). In a smaller long-term study, inflammatory tissue at 4 weeks was gradually replaced by the adipose tissue within 8 weeks.PRP-induced inflammatory reactions were considered to be necessary to stimulate cell migration into the chamber, leading to more tissue regeneration with abundant cell components. We conclude that PRP contributes to the reproducibility of preparing vascularized flaps in an in vivo chamber.

The effects of bovine serum albumin and human serum albumin on the unbound hepatic uptake clearance (PSu,inf) of the organic anion-transporting polypeptide substrates 1-anilino-8-naphthalene sulfonate (ANS) and pitavastatin (PTV) were determined using primary cultured rat hepatocytes and isolated human hepatocytes, respectively. The PSu,inf value of hepatocytes was estimated by dividing the initial uptake rate of these anions by their unbound concentrations. The PSu,inf values for ANS and PTV were enhanced in the presence of albumin, thereby demonstrating the phenomenon of "albumin-mediated" hepatic uptake. We previously constructed a "facilitated-dissociation" model, in which the interaction of the ligand-albumin complex with the cell surface enhanced the dissociation of that complex to provide unbound ligand for uptake to the hepatocytes [J Pharmacokinet Biopharm 16:165-181 (1988)]. That model was able to describe accurately the relationship between the enhancement of the PSu,inf values and the albumin concentration. By considering the enhancement of hepatic uptake clearance by albumin using this facilitated-dissociation model, we could predict accurately the PSu,inf in vivo from that obtained in isolated hepatocytes. In the light of these findings, we suggest that the facilitated-dissociation model is applicable to describing the phenomenon of albumin-mediated hepatic uptake via organic anion transporters and to evaluating hepatic uptake clearance in vivo.

Object We identified the β-adrenoceptor (β-AR) subtypes responsible for the relaxant responses to adrenaline (AD) and noradrenaline (NA) in the rat thoracic aorta and examined the role of cAMP which is involved in these relaxant responses. Methods The effects of β-AR antagonists or the adenylyl cyclase inhibitor SQ 22,536 on AD- and NA-induced relaxant responses in phenylephrine-induced contraction and increases in cAMP levels were examined in isolated, endothelium-denuded rat thoracic aorta segments. Results AD-induced relaxation was completely suppressed by propranolol (10−7 M) or by ICI-118,551 (10−8 M) plus atenolol (10−6 M), and was also very strongly inhibited by ICI-118,551 (10−8 M) alone. AD (10−5 M) increased tissue cAMP levels by approximately 1.9-fold compared with that in non-stimulated aortic tissue, but did not significantly increase cAMP levels in the presence of ICI-118,551 (10−8 M) or SQ 22,536 (10−4 M). AD-induced relaxation was strongly suppressed by SQ 22,536 (10−4 M). NA-induced relaxation was almost completely suppressed by atenolol (10−6 M) plus ICI-118,551 (10−8 M) although it was hardly affected by ICI-118,551 (10−8 M) alone. NA (10−5 M) increased tissue cAMP levels by approximately 2.2-fold compared with that in non-stimulated aortic tissue, but did not significantly increase cAMP levels in the presence of atenolol (10−6 M) or SQ 22,536 (10−4 M). NA-induced relaxation was strongly suppressed by SQ 22,536 (10−4 M). Conclusion In rat thoracic aorta, AD- and NA-induced relaxations, which are both strongly dependent on increased tissue cAMP levels, are mainly mediated through β2- and β1-adrenoceptors respectively.

Aims We examined the potential stimulatory effects of U46619 (a prostanoid TP receptor agonist) and five prostanoids on the contractile activities of urinary bladder smooth muscle (UBSM), focusing on the role of the TP receptor and its associated Ca2+ influx routes to understand the roles of prostanoids in the regulation of UB contractile activity. Main methods Changes in the basal tone and spontaneous contractile activity (amplitude and frequency) of isolated guinea pig UBSM were measured isotonically. The presence of TP receptors in UBSM was examined by RT-qPCR and immunofluorescence. Key findings U46619, prostaglandin (PG) E2, PGF2α, and PGA2 enhanced UBSM basal tone and spontaneous contractile activities, which were measured as amplitudes and frequencies. The enhancing effects of U46619 were completely suppressed by SQ 29,548 (a TP receptor antagonist), which also partially suppressed the stimulating effects of other prostanoids. The expression of TP receptors in UBSMs was verified at the mRNA and protein level. The enhancing effects of U46619 completely disappeared in Ca2+-free solution. U46619-enhanced basal tone was completely suppressed by verapamil, an inhibitor of voltage-dependent Ca2+ channels (VDCCs), and verapamil strongly decreased the spontaneous contraction frequency. The spontaneous contractions remaining in the presence of verapamil were strongly suppressed by SKF-96365 (an inhibitor of receptor-operated Ca2+ channels (ROCCs)/store-operated Ca2+ channels (SOCCs)), but not by LOE-908 (an inhibitor of ROCCs). Significance Prostanoids can enhance UBSM contractile activities and thus may be endogenous candidates for induction of detrusor overactivity. The TP receptor and TP-receptor-activated VDCCs/SOCCs are key molecules responsible for these effects.

Docosahexaenoic acid (DHA, an n-3 polyunsaturated fatty acid) inhibits U46619 (a TP receptor agonist)- and prostaglandin F2α-induced contractions in rat aorta and mesenteric arteries. However, whether these effects could be replicated in vasospasm-prone vessels, such as coronary and cerebral arteries, remains unknown. Here, we evaluated the changes in pig coronary and basilar artery tensions and intracellular Ca2+ concentrations in human prostanoid TP or FP receptor-expressing cells. We aimed to clarify whether DHA inhibits U46619- and prostaglandin F2α-induced contractions in spasm-prone blood vessels and determine if the TP receptor is the primary target for DHA. In both pig coronary and basilar arteries, DHA suppressed U46619- and prostaglandin F2α-induced sustained contractions in a concentration-dependent manner, but did not affect contractions induced by 80 mM KCl. SQ 29,548 (a TP receptor antagonist) suppressed U46619- and prostaglandin F2α-induced contractions by approximately 100% and 60%, respectively. DHA suppressed both U46619- and prostaglandin F2α-induced increases in intracellular Ca2+ concentrations in human TP receptor-expressing cells. However, DHA did not affect prostaglandin F2α-induced increases in intracellular Ca2+ concentrations in human FP receptor-expressing cells. These findings suggest that DHA potently inhibits TP receptor-mediated contractions in pig coronary and basilar arteries, and the primary mechanism underlying its inhibitory effects on arterial contractions involves inhibiting TP receptors.

Dynamical and precise arrangement of micro-objects into the specified various pattern offers great flexibility and potential as platforms for many scientific applications, especially in bio-sensing and biomedical fields such as bio-MEMS and Lab-on-a-Chip. Multi-beam optical tweezers are one of the most suitable tools for assembling precise dynamic arrays of micro-objects. Herein, a dynamic patterning method based on software-oriented approach is proposed (i.e. time-shared scanning technique) using the dual optical tweezers with a microlens array. The proposed method can expand the patterning capability of this dual optical tweezers system to simply fabricate various quasi-periodic structures. The work also demonstrates kaleidoscopic patterning (periodic or symmetric arrangements such as Escher's paintings) of numerous microbeads and subsequent morphing. In the demonstrations, microbeads with different properties (size and colour) as well as homogeneous microbeads are arranged dynamically into the specified patterns, including their clusters.

Experimental studies and epidemiological surveys have indicated that chronic oral administration of the n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic (DHA) or eicosapentaenoic (EPA) acids reduces blood pressure in hypertensive patients. However, few reports have described the acute blood pressure lowering effects of these PUFAs. In this study, we determined the acute effects of DHA and EPA on blood pressure of rats with increased blood pressure resulting from continuous injection of pressor substances. U46619 (a TXA2 receptor agonist) and noradrenaline (NA) were continuously infused (500 μg/kg/h each) into urethane-anesthetized male Wistar rats and produced sustained elevated mean blood pressure (MBP). In both U46619- and NA-infused rats, bolus administration of DHA (3–30 mg/kg, i.v.) reduced blood pressure in a dose-dependent manner, although the MBP reduction was greater in U46619-infused rats. Similarly, administration of EPA (3–30 mg/kg, i.v.) also induced a greater reduction in MBP of U46619-infused rats. In contrast, bolus administration of linoleic acid (3–30 mg/kg, i.v.), an n-3 type unsaturated fatty acid, failed to reduce blood pressure in all drug-infused rats. Finally, administration of the nitric oxide donor sodium nitroprusside (0.3–100 μg/kg, i.v.) showed a similar blood pressure drop in all drug-infused rats. These findings clearly indicate that both DHA and EPA induce acute blood pressure reduction in anesthetized rats, and suggest that the blood pressure drop is mediated via the TXA2 receptor. These characteristic blood pressure lowering effects of these PUFAs are likely to be useful for prevention and treatment of hypertension.

This paper introduces our original technique of free jejunum transfer, in which a sero-muscular patch is used to cover the jejunum. Our results demonstrate its effectiveness for touch-up surgery after esophageal leakage.

Aims β-Adrenoceptors (β-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on β-ADR-mediated relaxation were examined. Main methods The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA β-ADR was detected using RT-PCR. Key findings In endothelium-denuded SMAs contracted with ≥10−7 M phenylephrine (an α1-ADR agonist), isoprenaline (a β-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10−9–10−8 M propranolol (a β1,2-ADR antagonist), but not further affected by ≥10−8 M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10−9–10−8 M; a β2-ADR antagonist), it was competitively inhibited by atenolol (10−7–3 × 10−7 M; a β1-ADR antagonist) in the presence of ICI-118,551. In the presence of 10−7 M propranolol, isoprenaline- and CGP-12177A (a β3-ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a β1,2,3-ADR antagonist), with pA2 values of 6.49 and 5.76, respectively. We detected the mRNA of β1- and β3-ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10−7 M propranolol, but not CGP-12177A-induced relaxation. Significance Isoprenaline-induced relaxation of rat SMAs is mediated by β1- and β3-ADRs. β-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple β3-ADRs with different pharmacological properties.

Certain catecholamine metabolites exert significant pharmacological effects. Herein, we evaluated the pharmacological activities of catecholamine metabolites in the rat thoracic aorta, prostate, and spleen to determine whether these metabolites affect the contractile functions of smooth muscle tissue via direct action on α-adrenoceptors and α-adrenoceptor subtypes. Among the catecholamine metabolites examined, normetadrenaline and metadrenaline (10

ObjectiveTo investigate the association of school hours with outcomes of schoolchildren with out-of-hospital cardiac arrest (OHCA).MethodsFrom the 2005–2014 nationwide databases, we extracted the data for 1660 schoolchildren (6–17 years) with bystander-witnessed OHCA. Univariate analyses followed by propensity-matching procedures and stepwise logistic regression analyses were applied. School hours were defined as 08:00 to 18:00.ResultsThe neurologically favourable 1-month survival rate during school hours was better than that during non-school hours only on school days: 18.4% and 10.5%, respectively. During school hours on school days, patients with OHCA more frequently received bystander cardiopulmonary resuscitation (CPR) and public access defibrillation (PAD), and had a shockable initial rhythm and presumed cardiac aetiology. The neurologically favourable 1-month survival rate did not significantly differ between school hours on school days and all other times of day after propensity score matching: 16.4% vs 16.1% (unadjusted OR 1.02; 95% CI 0.69 to 1.51). Stepwise logistic regression analysis during school hours on school days revealed that shockable initial rhythm (adjusted OR 2.44; 95% CI 1.12 to 5.42), PAD (adjusted OR 3.32; 95% CI 1.23 to 9.10), non-exogenous causes (adjusted OR 5.88; 95% CI 1.85 to 20.0) and a shorter emergency medical service (EMS) response time (adjusted OR 1.15; 95% CI 1.02 to 1.32) and witness-to-first CPR interval (adjusted OR 1.08; 95% CI 1.01 to 1.15) were major factors associated with an improved neurologically favourable 1-month survival rate.ConclusionsSchool hours are not an independent factor associated with improved outcomes of OHCA in schoolchildren. The time delays in CPR and EMS arrival were independently associated with poor outcomes during school hours on school days.

Distigmine bromide (distigmine) is a reversible carbamate cholinesterase (ChE) inhibitor. Its principle clinical application is in the treatment of myasthenia gravis. Distigmine is also used as a remedy for dysuria and glaucoma. Its effectiveness in the management of dysuria has been demonstrated in several clinical reports. Distigmine may improve (enhance) urinary bladder smooth muscle (UBSM) contraction during micturition by inhibiting acetylcholine (ACh) decomposition. However, the pharmacological effects of distigmine on UBSM have not been adequately studied so far. In this review article, we summarize the reported effects of distigmine on the contractile responses elicited by exogenous and endogenous ACh in isolated UBSM preparations. We also discuss the effects of distigmine on the UBSM basal tone and the contractile response of UBSM to ATP, which is co-released with ACh from parasympathetic nerve terminals.

O trânsito congestionado nas grandes cidades impacta significativamente a vida das pessoas em termos de saúde, tempo e produtividade. Há a necessidade do aumento da utilização do transporte coletivo com o intuito de diminuir o nível de trânsito, mas alguns elementos têm desestimulado o seu uso. Foi realizado um estudo de caso, com pesquisa documental e quantitativa, com o objetivo de analisar o desempenho de uma linha de ônibus da cidade de São Paulo à luz da teoria das restrições, de modo a identificar e propor soluções aos possíveis gargalos que impedem o aumento do fluxo de passageiros. As soluções propostas tiveram o intuito de diminuir as reclamações de atendimento ao cliente. Os resultados indicaram potencial significativo de aumento no fluxo de passageiros com a proposta de melhoria baseada na teoria das restrições.

Angiotensin II (Ang II) is an intrinsic peptide having strong vasopressor effects, and thus, it plays an important role in the physiological regulation of blood pressure. The vasopressor effects of Ang II include direct contraction of myocardium and vascular smooth muscles (SMs) along with aldosterone-mediated sodium retention. In addition, indirect vascular contractions induced by noradrenaline (NA), the release of which is mediated through Ang II receptor type 1 (AT1) existing at the sympathetic nerve terminals (SNTs), also contribute to the vasopressor effects of Ang II. Stimulation of NA release from SNTs by Ang II also occurs in the myocardium leading to an increase in heart rate and cardiac contraction. Furthermore, Ang II enhances the contractions of non-vascular SMs, such as vas deferens, through induction of NA release from the SNTs. We have found that Ang II attenuated vagus nerve stimulation-induced bradycardia in a losartan-sensitive manner. This suggests that Ang II attenuates vagus nerve stimulation-induced bradycardia by inhibiting acetylcholine (ACh) release from the parasympathetic nerve terminals (PNTs) through activation of the AT1 receptor. Ang II was also reported to attenuate the release of ACh from the PNTs in SMs, such as stomach and airway, thus suppressing their contractile functions. There are, however, conflicting reports of the effects of Ang II on parasympathetic nerve-mediated contractile regulation of SMs. In this review, we have highlighted the relevant research articles including our experimental reports on the regulation of sympathetic and parasympathetic nerve-mediated excitation and contraction by Ang II along with the future prospects.

β-Adrenoceptors are subclassified into 3 subtypes (β

Background: Vildagliptin is indicated for type 2 diabetes mellitus (T2DM); however, the onset and exacerbation of diabetic complications in Japanese T2DM patients treated with vildagliptin is unknown. Research design and methods: This 2-year post-marketing surveillance (PMS) assessed the real-world safety and efficacy of vildagliptin therapy in 19,218 Japanese T2DM patients. The relationship between the incidence of macro- and microvascular complications with patient characteristics and changes in glycemic control (HbA1c) were evaluated. Results: The incidences of macro- and microvascular diseases were 1.14% and 3.09%, respectively. Patients with HbA1c ≥8.4% had a higher odds ratio (OR) for micro- and macrovascular disease (OR: 2.02 and 1.90) compared with patients with HbA1c Conclusions: Vildagliptin elicited no increases/exacerbations of diabetic complications; this PMS suggested that the incidence of diabetic complications tends to be low in subjects with good HbA1c control.