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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.

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.

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.

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl-3H]scopolamine specific binding in mouse cerebral cortex. At 10−5 M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl-3H]scopolamine binding by > 45%. Furthermore, the pKi values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors. Keywords: Antipsychotics, Anticholinergic effect, Mouse cerebral cortex

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.

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.

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...

Purpose: This study aims to clarify whether normobaric oxygen therapy improves the survival of auricular composite grafts in rats. Methods: For 10 male SD rats, 1.5 cm2 composite grafts were harvested from bilateral ear regions including whole auricles. The harvested grafts were transferred caudally and sutured there. The 10 rats were randomly divided into two groups and kept for 21 days in two different circumstances. The first group (Control group: five rats carrying 10 grafts) was kept in room air (20% oxygen) throughout the 21 days, and the second group―named NBO (normobaric oxygen) group (five rats carrying 10 grafts)―was kept in normobaric 60% oxygen for 3 days and then in room air for 18 days. All the 10 rats were sacrificed on the 21st day. Surviving areas of the grafts and the height of the surviving auricular cartilage were examined for statistical comparison of the two groups. Furthermore, the conditions of chondrogenesis occurring around the perichondrium were compared between the two groups. Results: Surviving areas did not present statistically significant differences between the two groups. The height of surviving cartilage was significantly greater for the NBO group (2610 ± 170 SD µm) than that for the Control group (1720 ± 190 SD µm). Chondrogenesis occurred at positions more distant from the recipient bed in the NBO group than that in the Control group. Conclusion: Normobaric oxygen therapy increases the thickness of surviving cartilage in auricular composite grafting in rats, thus suggesting that NBO therapy may also be effective in composite grafting for humans. Keywords: Composite graft, Oxygen, Blood, Cartilage, Ear, Auricle

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.

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.

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.

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.

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.

Background The purpose of this study was to investigate the efficacy of introducing microsurgical techniques to distal bypass surgery for critical limb ischemia. Methods Datasets of 83 consecutive microsurgical distal bypasses in a multicenter (SKY) study were compared with the results of the PREVENT III (PIII) study regarding the following: (1) patients' characteristics, (2) clinical severity according to the PIII risk score, (3) conduits and procedures for revascularization, (4) proximal and distal anastomosis sites, and (5) primary patency and amputation-free survival (AFS) rates at 1 year. Results The high-risk group in the SKY study was larger compared with that in the PIII study (37 vs. 9%, respectively; p Conclusions Our data demonstrated that microsurgical distal bypass is an effective and durable procedure, especially for high-risk patients. We believe that microsurgical techniques should be considered for distal bypass to optimize the treatment of ischemic limbs with severe peripheral artery disease.

We investigated the potential augmenting effects of 19 clinically available antidepressants on noradrenaline (NA)-induced contractions in guinea pig urethra smooth muscle (USM). Concentration-response curves for NA-induced contractions in guinea pig USM strips were obtained in the absence or presence of selected antidepressants. Desipramine, an active metabolite of imipramine, produced a contraction and potentiated NA-induced contraction at the distal urethra without affecting the proximal urethra. Further, nortriptyline and amoxapine, tricyclic antidepressants, produced a contraction and potentiated NA-induced contraction at the distal urethra. NA-induced contraction was unaffected or reduced by imipramine, clomipramine, trimipramine, and amitriptyline at the proximal and distal urethra. Maprotiline, a tetracyclic antidepressant, potentiated NA-induced contraction at the distal urethra. NA-induced contraction was unaffected by mianserin at the proximal and distal urethra. Paroxetine, a selective serotonin reuptake inhibitor (SSRI), potentiated NA-induced contraction at the distal urethra, while NA-induced contraction was unaffected by fluvoxamine, sertraline, and escitalopram at the proximal and distal urethra. Milnacipran, a serotonin-noradrenaline reuptake inhibitor (SNRI), potentiated NA-induced contraction at the proximal and distal urethra, whereas duloxetine potentiated it at the distal urethra. Mirtazapine slightly inhibited NA-induced contraction at the distal urethra. Aripiprazole and sulpiride did not affect NA-induced contractions at the proximal nor distal urethra. Trazodone inhibited NA-induced contraction at both urethras. Desipramine, nortriptyline, amoxapine, maprotiline, paroxetine, milnacipran, and duloxetine likely induce urinary disturbance by increasing urethral resistance and augmenting NA-induced contraction, which should be carefully considered when delivering guidance for drug administration to patients.

Highlights • Different strategies are available for the re-correction after pectus excavatum surgery. • We cultured and propagated chondrocytes taken from a patient’s auricular cartilage. • The cultured chondrocytes are transplanted to the concave part of the chest. • The chest shape improved and the transplanted cells consolidated, forming part of the chest wall. • Transplantation of cultured chondrocytes is a useful treatment for pectus excavatum., Introduction For some cases of pectus excavatum, ideal chest shape cannot be achieved solely by performing the Nuss procedure. This manuscript presents a case where the residual deformity following Nuss was corrected using injection-transplantation of cultured autologous chondrocytes. Presentation of case The treatment was performed for an 18-year-old male, who sought improvement of his chest shape after previously undergoing the Nuss procedure. A 1 cm2 auricular cartilage piece was harvested from his ear. Chondrocytes were isolated from the cartilage piece and were cultured. The cultured chondrocytes were processed into gel form and were injection-transplanted to the deformed region of the patient's chest. The grafted chondrocytes consolidated in one month, presenting elasticity equivalent to ordinary costal cartilage. The patient's chest remains in an optimal shape after a one-year postoperative follow up. Discussion Secondary correction of the chest deformity after previous operation for pectus excavatum is often tricky, because of the possible adhesion of the lungs or pericardium with the thoracic wall. Transplantation of cultured autologous chondrocytes does not require intra-thoracic maneuvers, and so is less invasive than other surgical interventions. Hence, priority can be placed, in some cases, on the chondrocyte transplantation rather than the re-correction of the thorax with the Nuss procedure or Ravitch procedure. Conclusion Transplantation of cultured autologous chondrocytes is recommended as a useful option for secondary correction of chest deformity after the Nuss procedure.

Aim To determine the effectiveness of ventilations in bystander cardiopulmonary resuscitation (BCPR) and to identify the factors associated with ventilation-only BCPR. Methods From out-of-hospital cardiac arrest (OHCA) data prospectively collected from 2005 to 2011 in Japan, we extracted data for 210,134 bystander-witnessed OHCAs with complete datasets but no prehospital involvement of physician [no BCPR, 115,733; ventilation-only, 2093; compression-only, 61,075; and conventional (compressions+ventilations) BCPR, 31,233] and determined the factors associated with 1-month neurologically favourable survival using simple and multivariable logistic regression analyses. In 91,885 patients with known BCPR durations, we determined the factors associated with ventilation-only BCPR. Results The rate of survival in the no BCPR, ventilation-only, compression-only and conventional group was 2.8%, 3.9%, 4.5% and 5.0%, respectively. After adjustment for other factors associated with outcomes, the survival rate in the ventilation-only group was higher than that in the no BCPR group (adjusted OR; 95% CI, 1.29; 1.01–1.63), but lower than that in the compression-only (0.76; 0.59–0.96) or conventional groups (0.70; 0.55–0.89). Conventional CPR had the highest OR for survival in almost all OHCA subgroups. The adjusted OR (95% CI) for survival after dividing BCPR into ventilation and compression components was 1.19 (1.11–1.27) and 1.60 (1.51–1.69), respectively. Older guidelines, female sex, younger patient age, bystander-initiated CPR without instruction, early BCPR and short BCPR duration were associated with ventilation-only BCPR. Conclusions Ventilation is a significant component of BCPR, but alone is less effective than compression in improving neurologically favourable survival after OHCAs.

Background Neutropenia has been reported with interleukin-6 (IL-6) pathway inhibitors and could potentially be associated with increased rates of infection. The reduced neutrophil counts seen with IL-6 inhibitors may be due to effects on margination of circulating neutrophils as opposed to a decrease in bone marrow production or reduced survival. Efficacy of sirukumab (SIR), a human anti-IL-6 cytokine monoclonal antibody, has recently been shown in several phase 3 trials. Objectives To assess incidence of neutropenia from completed and ongoing SIRROUND clinical studies. Methods Neutrophil counts were compared for SIR 50mg q4w and 100mg q2w doses vs placebo (pbo) in the pbo-controlled period (Wks 0–18) of 2 phase 3 trials and in long-term analysis for the 5-trial, phase 3 program. Results 2926 pts received SIR for up to 3.4y with a median duration of 1.46y. For the 18-wk pbo-controlled period, neutropenia was more frequent in both SIR groups compared with pbo. Across all groups, the majority of the decreases in neutrophil counts were National Cancer Institute Common Terminology Criteria for Adverse Events grade 0/1, within the normal range, and the incidence of grade 3/4 decreases was low across groups (Table). Neutropenia began at Wk 2 and persisted through the study period. In long-term analysis, the proportions of pts with grade 1, 2, or 3 neutropenia were slightly higher than in the 18-wk pbo-controlled period, suggesting the majority of events occurred early. No dose relationship was observed in the grade or frequency of neutropenia. Grade 3/4 neutropenia was mostly transient and resolved after interrupting the dose or resolved within the dosing interval such that no change in dose schedule was required. The majority of grade 4 decreases in neutrophils were not correlated with infections; 2 cases of serious infections occurred with grade 4 neutropenia. The distribution of neutropenia by grade was similar in pts who did or did not use disease-modifying antirheumatic drugs (DMARDs) at baseline. Conclusions Across phase 3 studies, there was no dose effect of SIR on neutropenia, and the use of DMARDs did not have an apparent effect on neutropenia. The majority of grade 4 neutropenia with SIR was not associated with infections. Disclosure of Interest T. Takeuchi Grant/research support from: Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., and SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol-Myers K.K., and Nipponkayaku Co. Ltd., Speakers bureau: AbbVie GK., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Astellas Pharma, Daiichi Sankyo Co., Ltd., Celtrion, and Nipponkayaku Co. Ltd., Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, and Eisai, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, and GlaxoSmithKline, M. Schiff Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, UCB, Speakers bureau: AbbVie, M. Harigai Grant/research support from: AbbVie Japan, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Ono Pharmaceuticals, Santen Pharmaceutical, Takeda Pharmaceutical, UCB Japan, Teijin Pharma, Consultant for: AbbVie Japan, Janssen Pharma, Chugai Pharmaceutical, Teijin Pharma, Eli Lilly Japan, and Zenyaku Kogyo, K. Brown Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, R. Rao Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, S. Popik Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, K. Yoshizawa Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, Q. Wang Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Objective The present study elucidates whether or not preserving fat tissues deeper than the Scarpa's fascia in zone 3 and zone 4 reduces postoperative fluid collection after harvesting the transverse rectus-abdominis muscle (TRAM) flap. Methods Thirty-one patients for whom breast reconstruction with free TRAM flaps had been performed were included in the study. Fat tissues deeper than the Scarpa's fascia in zone 3 and zone 4 were addressed in two ways. With 17 patients, these tissues were preserved on the abdominal wall; with 14 patients, these fat tissues were harvested as part of the TRAM flap. The former and latter groups were named the Preservation Group and Non-Preservation Group, respectively. Drainage tubes were placed at the donor site until daily drainage became less than 20 ml, at which time the tubes were removed. The total amount of postoperative fluid drained from the donor site and the days required before tube removal were compared between the two groups. Results The total volume of drained fluid was significantly greater for the Non-Preservation Group (444 ± 48.2 ml) than for the Preservation Group (230 ± 21.9 ml); the period before removal of drainage tubes was significantly longer for the Non-Preservation Group (12.4 ± 0.84 days) than for the Preservation Group (7.6 ± 0.55 days). Conclusion Preservation of deep-fat tissues in zone 3 and zone 4 reduces postoperative fluid exuded from the donor site, and enables earlier removal of drainage tubes. For cases where optimal breast shape can be achieved without these fat tissues, the fat tissues should be preserved.

This journal suppl. entitled: Special Issue: The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2013

Recently, one of the rare sugars, D-allose, has received attention from many researchers because of its availability for mass production and its various physiological functions. Among these, an antioxidative effect has been strongly suggested. In this study, we investigated whether this effect is also applicable to the field of skin surgery.In ischemia-reperfusion injury model using the rat abdominal skin island flap (male Wistar rats, n = 110), D-allose was injected intravenously 15 min before 8-h ischemia. The survival area (%) was measured by digital photographic assessment 1 wk after surgery, and multiple comparisons (Fisher's protected least significant difference) were carried out. Histopathological examination (neutrophilic infiltration into dermis in hematoxylin and eosin stain) and immunostaining (of ectodermal dysplasia-1 (ED1)-positive cells/flap) were assessed. Myeloperoxidase (MPO) activity in the skin flap (sampling at the time of 8 h after reperfusion) was measured spectrophotometrically, and Student t-test was performed.D-allose extended the survival of the remaining flaps, and a dose greater than 30 mg (0.1 mg/g) was necessary to be effective. The flap survival rates in the 30, 60, and 150 mg groups were significantly higher than that in the control (saline) group: 75.87 ± 5.90, 79.27 ± 7.81, and 77.87 ± 6.20 versus 50.53 ± 9.66, respectively (P0.05). ED1-positive cells/flap in 60 mg of D-allose and control (saline) were 78 ± 25.7 versus 124 ± 15.8, respectively (P = 0.08). The MPO activity in the D-allose 60 mg group was 0.40 ± 0.04, and that in the control (saline) was 0.72 ± 0.12. D-allose significantly reduced the skin tissue MPO activity (P0.05) compared with that in the control (saline) group.We proved that D-allose has a reducing effect against ischemia-reperfusion injury on the skin island flap model, and the mechanism is related to inhibiting the activity of neutrophils in the skin tissues. Compared with chemo-synthetic materials, rare sugars are safer for our bodies as well as the environment; therefore, this rare sugar project is expected to lead to the development of a safer antioxidant for skin flap surgery.

The purpose of this study was to investigate whether there is a risk of thrombosis in the temporary arteriovenous shunt loop (TAVSL). The authors established a TAVSL model in the rabbit. Experimental groups were divided into non-heparin treated and heparin treated. The maximum blood flow volume, blood viscosity, and radius of curvature were measured, and the Reynolds number and the sheer stress were calculated. Computational fluid dynamics (CFD) was used to predict the flow pattern in the TAVSL, and these predicted data were compared with histological results. Early occlusion was noted in 70% (7/10) of the non-heparin-treated group and 22% (2/9) of the heparin-treated group. CFD analysis predicted a high shear stress at the arterial anastomosis region and the outer luminal surface of the curved section. The intimal structure at the luminal surface of the curved section was extensively lost histologically. In the patent group, severe stenosis of the lumen was noted at the apex of the loop due to an organized thrombus. Thus, thrombosis is likely to occur in the TAVSL due to endothelium injury caused by high shear stress, and this results in the formation of white thrombi at an early stage and an organized thrombus at a late stage.

Review: An increased number of rescuers may improve the survival rate from out-of-hospital cardiac arrests (OHCAs). The majority of OHCAs occur at home and are handled by family members. Materials and methods: Data from 5078 OHCAs that were witnessed by citizens and unwitnessed by citizens or emergency medical technicians from January 2004 to March 2010 were prospectively collected. The number of rescuers was identified in 4338 OHCAs and was classified into two (single rescuer (N = 2468) and multiple rescuers (N = 1870)) or three (single rescuer, two rescuers (N = 887) and three or more rescuers (N = 983)) groups. The backgrounds, characteristics and outcomes of OHCAs were compared between the two groups and among the three groups. Results: When all OHCAs were collectively analysed, an increased number of rescuers was associated with better outcomes (one-year survival and one-year survival with favourable neurological outcomes were 3.1% and 1.9% for single rescuers, 4.1% and 2.0% for two rescuers, and 6.0% and 4.6% for three or more rescuers, respectively (p = 0.0006 and p < 0.0001)). A multiple logistic regression analysis showed that the presence of multiple rescuers is an independent factor that is associated with one-year survival (odds ratio (95% confidence interval): 1.539 (1.088-2.183)). When only OHCAs that occurred at home were analysed (N = 2902), the OHCAs that were handled by multiple rescuers were associated with higher incidences of bystander CPR but were not associated with better outcomes. Conclusions: In summary, an increased number of rescuers improves the outcomes of OHCAs. However, this beneficial effect is absent in OHCAs that occur at home. © 2012 Elsevier Ireland Ltd. All rights reserved.

SUMMARY A virtual machine (VM) migration is useful for improving flexibility and maintainability in cloud computing environments. However, VM monitor (VMM)-bypass I/O technologies, including PCI passthrough and SR-IOV, in which the overhead of I/O virtualization can be significantly reduced, make VM migration impossible. This paper proposes a novel and practical mechanism, called Symbiotic Virtualization (SymVirt), for enabling migration and checkpoint/restart on a virtualized cluster with VMM-bypass I/O devices, without the virtualization overhead during normal operations. SymVirt allows a VMM to cooperate with a message passing layer on the guest OS, then it realizes VM-level migration and checkpoint/restart by using a combination of a user-level dynamic device configuration and coordination of distributed VMMs. We have implemented the proposed mechanism on top of QEMU/KVM and the Open MPI system. All PCI devices, including Infiniband, Ethernet, and Myrinet, are supported without implementing specific para-virtualized drivers; and it is not necessary to modify either of the MPI runtime and applications. Using the proposed mechanism, we demonstrate reactive and proactive FT mechanisms on a virtualized Infiniband cluster. We have confirmed the effectiveness using both a memory intensive micro benchmark and the NAS

Background/Aims: To investigate the potential inhibitory effects of 18 clinically available antidepressants on acetylcholine (ACh)-induced contractions in guinea pig urinary bladder smooth muscle (UBSM) in order to predict whether they may induce voiding impairment. Methods: Concentration-response curves for ACh-induced contractions in guinea pig UBSM strips were obtained in the absence or presence of selected antidepressants. When inhibitory effects indicated competitive antagonism, pA2 values against ACh were calculated and compared to plausible antidepressant blood concentrations. Results: ACh-induced contraction was antagonized competitively within clinical dose ranges by tricyclic antidepressants (imipramine, amitriptyline, trimipramine, clomipramine, nortriptyline, and amoxapine), maprotiline (a tetracyclic antidepressant), and mirtazapine (a noradrenergic and specific serotonergic antidepressant). ACh-induced contraction was also significantly inhibited by mianserin (a tetracyclic antidepressant), paroxetine and sertraline (serotonin-selective reuptake inhibitors, SSRIs), and duloxetine (a serotonin noradrenaline (norepinephrine) reuptake inhibitor, SNRI), albeit at concentrations that substantially exceeded clinically achievable blood levels. However, ACh-induced contractions were not significantly affected by fluvoxamine and escitalopram (SSRIs), milnacipran (an SNRI), trazodone (a serotonin 5-HT2A receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), or aripiprazole (a dopamine partial agonist). Conclusion: These findings suggest that in addition to tricyclics, some relatively novel antidepressants such as mirtazapine can induce voiding impairment, attributed to diminished UBSM contractility from the inhibition of muscarinic receptors in the UBSM.

Review: In 2007, the Ishikawa Medical Control Council initiated the continuous quality improvement (CQI) project for telephone-assisted cardiopulmonary resuscitation (telephone-CPR), which included instruction on chest-compression-only CPR, education on how to recognise out-of-hospital cardiac arrests (OHCAs) with agonal breathing, emesis and convulsion, recommendations for on-line or redialling instructions and feedback from emergency physicians. This study aimed to investigate the effect of this project on the incidence of bystander CPR and the outcomes of OHCAs. Materials and methods: The baseline data were prospectively collected on 4995 resuscitation-attempted OHCAs, which were recognised or witnessed by citizens rather than emergency medical technicians during the period of February 2004 to March 2010. The incidence of telephone-CPR and bystander CPR, as well as the outcomes of the OHCAs, was compared before and after the project. Results: The incidence of telephone-CPR and bystander CPR significantly increased after the project (from 42% to 62% and from 41% to 56%, respectively). The incidence of failed telephone-CPR due to human factors significantly decreased from 30% to 16%. The outcomes of OHCAs significantly improved after the projects. A multiple logistic regression analysis revealed that the CQI project is one of the independent factors associated with one-year (1-Y) survival with favourable neurological outcomes (odds ratio = 1.81, 95% confidence interval = 1.20-2.76). Conclusions: The CQI project for telephone-CPR increased the incidence of bystander CPR and improved the outcome of OHCAs. A CQI project appeared to be essential to augment the effects of telephone-CPR. © 2012 Elsevier Ireland Ltd. All rights reserved.

Plan the use of factors related to the implementation of continuous improvement projects increases the potential for success and effectiveness of them. The objective of this paper is to analyze factors for the implementation of projects in the shop floor environment. This research involves perspectives of consultants and project leaders in different organizations. It is qualitative research and has two steps of data collection: (a) interviews (semi-structured questionnaires) with consultants and improvements project leaders in industries from various sectors (agricultural chemicals, automotive, machining, stamping and aerospace) and (b) questionnaire in three plants of a large chemical group with a tradition of research and development. This study is delimited to industrial and consulting firm specializing in continuous improvement projects. Critical factors as top management commitment, leadership, projects aligned with business goals, culture of continuous improvement, goals, leader’s behaviour highlighted.

The high-performance Geospatial Information System (GIS) is expected to provide an innovative infrastructure for Earth sciences, enabling near-real-time data and processing services. Stereo-matching software has often been used in generating a Digital Elevation Model (DEM) from a pair of satellite imagery data sets to compute height from a parallax views using two photographic images. There is a need to reduce the computation time required for processing large images. We optimize stereo-matching software on multi-core/many-core processors, including Xeon, Cell and GPGPU. We describe optimization approaches of the correlation calculation part which occupied about 55% of the ovarall computation time. After porting and optimizing software for multi-core/many-core processors, we achieved processing time of 4.79 second (Xeon), 2.28 second (Cell) and 0.97 second (GPGPU) on each platform.

Atualmente, a competitividade do mercado exige que as organizações busquem melhorias em seus processos e o OEE (Overall Equipment Effectiveness) tornou-se uma ferramenta importante na busca da eficiência do processo quando combinado com outras tecnologias. Este estudo teve como objetivo investigar o efeito do monitoramento do OEE em tempo real no processo de tomada de decisão em uma empresa. Utilizou-se de uma pesquisa exploratória e o um estudo de caso de uma empresa de fabricação de brinquedos, onde se verificou que a adoção do sistema de monitoramento em tempo real foi importante para a melhoria na tomada de decisões, pois permitiu o monitoramento rápido e dinâmico, bem como a possibilidade de priorizar melhorias nos processos de produção.

In this paper, we report on the design and implementation of the GEO (Global Earth Observation) Grid IT infrastructure as an example of E-Science. Using Grid technologies, the GEO Grid provides an IT infrastructure that integrates wide varieties of data sets and computing services for the Earth science community. This paper presents an example of Grid-based E-Science and its application to a wide range of scientific communities. A methodology for system development based on many different software components is also discussed.

As the Earth's ecosystem is a spatially and temporally complex system by nature, it is not sufficient to observe such events and phenomena locally; problems must be solved on a global scale. Therefore, the accumulation of knowledge about the Earth in various forms and a scientifically correct understanding of the Earth are necessary. The authors have been leading the ldquoGlobal Earth Observation (GEO) Gridrdquo project since 2005, which is primarily aimed at providing an e-Science infrastructure for the worldwide Earth sciences community. In the community, there are wide varieties of existing datasets including satellite imagery, geological data, and ground sensed data that each data owner insists own licensing policy. Also, there are so many related projects that will be configured as a virtual organization (VO) enabled by Grid technology. The GEO Grid is designed to integrate all of the relevant data virtually, again enabled by Grid technology, and is accessible as a set of services. In this paper, first we describe design principles of the GEO Grid that are determined based on accommodating users requirements for publishing, managing, and using data. Second, software architecture and its preliminary implementations are specified where we take the Grid computing and Web service technologies as the core components that comply with a standard set of technologies and protocols. In addition, GEO Grid has been recognized to contribute to GEO or Global Earth Observation System of Systems (GEOSS) as a part of the Japanese government's commitment.

We developed a toolbox called BAX (brain activation explorer) for the dynamic analysis of functional magnetic resonance imaging (fMRI) datasets using the general linear model. The toolbox provides a graphical user interface where several routines can be accessed to extract different sets of information from a given series of functional images. The dynamic analysis can be implemented using either an incremental approach or a sliding window approach. In particular, BAX can be used to construct dynamic activation maps that can be used to assess the contribution of newly added volumes in the final activation map, detect problematic segments in the dataset, or localize in time dynamic changes in brain activity. Consistency maps, which graphically represent the number of times voxels are consecutively detected as active in a given analysis, can also be constructed using either incremental or sliding window analysis. BAX runs under Matlab (MathWorks, Inc.) and requires some routines from SPM2 (Wellcome Department of Cognitive Neurology, London, UK) for its operation. It can be freely downloaded at http://www.medgrid.org/ website.

Ontological engineering is one of the most challenging topics in biomedical informatics because of its key role in integrating the heterogeneous database used by biomedical information services. Ontology can translate concepts and their real-world relationships into expressions that can be processed by computer programs or web services, providing a unique taxonomic frame to describe a pathway for extracting, processing, storing, and retrieving information. In developing clinical functional neuroimaging, which requires the integration of heterogeneous information derived from multimodal measurement of the brain, these features will be indispensable. Neuroimaging ontology is remarkable in that it requires detailed description of the hypothesis, the paradigm employed, and a scheme for data generation. Neuroimaging modalities, such as functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), electroencephalography (EEG), and near infrared spectroscopy (NIRS), share similar application purposes, imaging protocol, analyzing methods, and data structure; semantic gaps that remain among the modalities will be bridged as ontology develops. High-performance, global resource information database (GRID) computing and the applications organized as service-oriented computing (SOC) will support the heavy processing to integrate the heterogeneous neuroimaging system. We have been developing such a distributed intelligent neuroimaging system for real-time fMRI analysis, called BAXGRID, and a neuroimaging database. The fMRI ontology of this system will be integrated with established medical ontologies, such as the Unified Medical Language System (UMLS).

Objective The present study aims to elucidate whether or not scoring deformed cartilages reduces postoperative pain after the Nuss procedure for pectus excavatum patients. Methods A total of 46 pectus excavatum patients for whom the Nuss procedure was conducted were included in the study. The patients were categorized into two groups, depending on whether or not the supplementary maneuver of scoring deformed cartilages was performed in addition to the Nuss procedure. Patients for whom deformed costal cartilages were scored were categorized as the Scoring Group (n = 24); those who received no such scoring were categorized as the Non-Scoring Group (n = 22). After evaluating the maximum stresses occurring on the thoraces by means of dynamic simulation using finite element analyses, intergroup comparison of the maximum von-Mises stress values was performed. Furthermore, after quantifying postoperative pain as the frequency with which patients injected anesthetics through an epidural pain-control system within 2 postoperative days, the degree of pain was compared between the two groups. Results The maximum stresses occurring on the thorax were significantly greater for the Non-Scoring Group than for the Scoring Group; injection frequency was also greater for the Non-Scoring Group (average 4.9 times for 2 days) than for the Scoring Group (average 2.5 times for 2 days). Conclusion High stresses occur due to the performance of the Nuss procedure, causing postoperative pain. The stresses can be reduced by performing supplementary scoring on deformed cartilages. Accordingly, postoperative pain is reduced.

Purposes. The present paper reports clinical cases where nummular eczema developed during the course of breast reconstruction by means of implantation and evaluates the occurrence patterns and ratios of this complication. Methods. 1662 patients undergoing breast reconstruction were reviewed. Patients who developed nummular eczema during the treatment were selected, and a survey was conducted on these patients regarding three items: (1) the stage of the treatment at which nummular eczema developed; (2) time required for the lesion to heal; (3) location of the lesion on the reconstructed breast(s). Furthermore, histopathological examination was conducted to elucidate the etiology of the lesion. Results. 48 patients (2.89%) developed nummular eczema. The timing of onset varied among these patients, with lesions developing after the placement of tissue expanders for 22 patients (45.8%); after the tissue expanders were replaced with silicone implants for 12 patients (25%); and after nipple-areola complex reconstruction for 14 patients (29.2%). Nummular eczema developed both in periwound regions (20 cases: 41.7%) and in nonperiwound regions (32 cases: 66.7%). Histopathological examination showed epidermal acanthosis, psoriasiform patterns, and reduction of sebaceous glands. Conclusions. Surgeons should recognize that nummular eczema is a potential complication of breast reconstruction with tissue expanders and silicone implants.