Hiding cosmic strings in supergravity D-term inflation

The influence of higher-order terms in the K\"{a}hler potential of the supergravity D-term inflation model on the density perturbation is studied. We show that these terms can make the inflaton potential flatter, which lowers the energy scale of inflation under the COBE/WMAP normalization. As a result, the mass per unit length of cosmic strings, which are produced at the end of inflation, can be reduced to a harmless but detectable level without introducing a tiny Yukawa coupling. Our scenario can naturally be implemented in models with a low cut-off as in Type I or Type IIB orientifold models.Comment: 15 pages, 4 figure

腹腔鏡下副腎摘除術202例の検討

Article信州医学雑誌 61(4):225-232(2013)journal articl

Pathways Involving Beta-3 Adrenergic Receptors Modulate Cold Stress-Induced Detrusor Overactivity in Conscious Rats

ObjectiveTo investigate pathways involving beta-3 adrenergic receptors (ARs) in detrusor overactivity induced by cold stress, we determined if the beta-3 AR agonist CL316243 could modulate the cold stress-induced detrusor overactivity in normal rats. MethodsTwodays prior to cystometric investigations, the bladders of 10-week-old female Sprague-Dawley rats were cannulated. Cystometric measurements of the unanesthetized, unrestricted rats were taken to estimate baseline values at room temperature (RT, 272 degrees C) for 20min. They were then intravenously administered vehicle, 0.1, or 1.0mg/kg CL316243 (n=6 in each group). Fiveminutes after the treatments, they were gently and quickly transferred to the low temperature (LT, 42 degrees C) room for 40min where the cystometric measurements were again made. Afterward, the rats were returned to RT for final cystometric measurements. The cystometric effects of CL316243 were also measured at RT (n=6 in each group). ResultsAt RT, both low and high dose of CL316243 decreased basal and micturition pressure while the high dose (1.0mg/kg) significantly increased voiding interval and bladder capacity. During LT exposure, the high dose of CL316243 partially reduced cold stress-induced detrusor overactivity characterized by increased basal pressure and urinary frequency. The high drug dose also significantly inhibited the decreases of both voiding interval and bladder capacity compared to the vehicle- and low dose (0.1mg/kg)-treated rats. ConclusionA high dose of the beta-3 agonist CL316243 could modulate cold stress-induced detrusor overactivity. Therefore, one of the mechanisms in cold stress-induced detrusor overactivity includes a pathway involving beta-3 ARs.ArticleLUTS-LOWER URINARY TRACT SYMPTOMS.7(1):50-55(2014)journal articl

脳卒中後遺症としての神経因性膀胱の成因および治療法に関する実験的研究

金沢大学医学部附属病院1)S-D種雄性ラットの左中大脳動脈をナイロン糸を用いて塞栓し、脳梗塞を作成した。その結果、ラット膀胱容量は有意に減少し(排尿反射の亢進)、梗塞作成2週後には偽手術ラットの2分の1以下になった。排尿反射の亢進は梗塞作成後4カ月の時点でも認められた。脳梗塞作成から4カ月経過後膀胱を摘出し、Magnus法に準じ利尿筋切片の薬理学的検討を行った。その結果、膀胱平滑筋細胞のチャンネル機構の障害あるいは収縮要素自体の障害が存在し、レセプターを増加させることで収縮力を補っている可能性が示唆された。2)グルタミン酸のNMDA受容体拮抗剤であるMK-801を脳梗塞ラットに静脈内投与すると、覚醒下では膀胱容量の減少を、ウレタン麻酔下では増大をみとめた。偽手術ラットではウレタン麻酔下高濃度のMK-801でないと膀胱容量の増大がみられなかった。脳梗塞ではNMDA受容体とAMPA/kainate受容体を共に遮断することで亢進した排尿反射の抑制が得られると推測された。3)脳梗塞後側脳室内にカルシウム拮抗剤を投与すると膀胱容量の増大が得られたが、最大膀胱収縮圧、残尿量は変化がみられなかった。偽手術ラットでは膀胱容量はほとんど変化が認められなかった。脳梗塞状態では、カルシウム拮抗剤は中枢に作用して排尿反射を抑制する効果があると思われた。以上より、脳梗塞ラットには排尿反射の亢進がみられるが、長期にわたり反射が亢進していても膀胱利尿筋に生ずる変化は比較的軽度であると思われる。また、排尿中枢における刺激伝達系にはグルタミン酸が関与しており、カルシウム拮抗剤は、NMDA受容体を介するカルシウムの流入を抑えることで、あるいは脳血流を改善することで亢進した排尿反射を抑制すると考えられる。研究課題/領域番号:08671802, 研究期間(年度):1996 – 1997出典：研究課題「脳卒中後遺症としての神経因性膀胱の成因および治療法に関する実験的研究」課題番号08671802（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-08671802/）を加工して作

脳卒中後遺症としての尿失禁における橋排尿中枢シグナル伝達機構と遺伝子治療について

これまでの研究により、脳血管障害に伴い生ずる頻尿・尿失禁は記憶/学習に関与すると推測されている海馬の長期増強(long-term potentiation, LTP)に類似していることが解明された。すなわち脳梗塞時橋排尿中枢では、興奮性神経伝達物質であるglutamateのN-methyl-D-aspartate(NMDA)受容体開口に始まる一連のシグナル伝達と最終的には新たなmRNAと蛋白質の合成が必要と推測された。本研究ではprotein kinase A inhibitorによるシグナル伝達や核内遺伝子の転写が、どのように排尿反射亢進に関与し、c-fosやzif268などの神経可塑性関連遺伝子の発現がNMDA受容体とどのようにリンクしているのかを検討した.また転写因子としてのc-fosやzif268で制御される下流遺伝子、COX-2/nNOSが尿失禁遺伝子である可能性についても検討した。1)protein kinase Aは転写因子の1つであるcAMP responsive element-binding protein(CREB)をリン酸化し、核内遺伝子の転写を促進する。この酵素の阻害剤(H-89)を橋背外側被蓋にmicroinjectionすると排尿反射を抑制することが可能であった.さらにこの抑制は脳梗塞後2時間の時点で1番効果的であった。従ってprotein kinase A依存性の反応が橋背外側被蓋において脳梗塞2時間以後に排尿反射の亢進をもたらし、脳梗塞4時間以後には作用していないことが明らかになった。2)actinomycin Dを背外側被蓋野にmicroinjetionしてDNAからRNAへの転写を阻害すると排尿反射の亢進は抑制されるという結果、さらに神経可塑性関連遺伝子の発現が抑制されるという結果は、排尿反射亢進に本質的な脳部位は吻側部橋の背外側被蓋野で、ここに頻尿/尿失禁遺伝子ともいうべき遺伝子が存在することを意味している。3)その候補の1つとしてCOX-2が挙げられると思われるが、COX-2 inhibitorが脳梗塞作成後でも排尿反射の抑制に有効か、あるいはCOX-2の下流に存在する遣伝子は何か、など今後検討すべき課題は多いと考えられる。Object: To investigate the signal transduction and molecular mechanisms in the pontine tegmental area (PTA) associated with bladder overactivity after cerebral infarction. Methods: Cerebral infarction was induced by left middle cerebral artery occlusion (MCAO) in SD rats. Bladder activity was monitored with continuous infusion cystometrography in awake rats. The influences of H-89 (protein kinase A inhibitor), actinomycin D (ACD; RNA synthesis inhibitor), or NS-398 (COX-2 inhibitor) on bladder activity and gene expression (c-fos and zif268) were examined. Expressions of c-fos and zif268 mRNA in the DPT were monitored with real-time PCR. Results: In cerebral infarcted (CI) rats pretreated with vehicle, bladder capacity (BC) was significantly reduced after MCAO and remained consistently below half of pre-occlusion capacity. H-89, when administered 2 hours after MCAO, inhibited the reduction in BC. ACD also blocked reduction in BC in CI rats. In ACD-treated CI rats, BC gradually recovered and returned to the control level prior to MCAO within 10 hours. Treatment with NS-398 before MCAO prevented the development of bladder overactivity dose-dependently, and did not influence infarction volume. One hour after MCAO, c-fos and COX-2 mRNA expression, three hours after MCAO, zif268 mRNA expression had significantly increased as compared to those in sham operated rats. Pretreatment with MK-801, glutamatergic NMDA receptor antagonist, inhibited the development bladder overactivity and significantly reduced these gene expressions in the PTA. ACD suppressed an increase in c-fos mRNA expression 1hour after MCA occlusion as well as in zif268 3hours after MCAO. Conclusion: These results indicate that the development of bladder overactivity following MCAO is mediated by the activation of an NMDA receptor and by an RNA synthesis. Transcription in the DPT was found to be necessary for maintenance of long-lasting bladder overactivity caused by cerebral infarction. Furthermore, COX-2 molecular mechanism in the brain seems to be related to bladder overactivity. Further research on the molecular mechanisms in the brain related to bladder overactivity may lead to pharmacological therapy which targets the micturition center.研究課題/領域番号:12470331, 研究期間(年度):2000-2001出典：「脳卒中後遺症としての尿失禁における橋排尿中枢シグナル伝達機構と遺伝子治療について」研究成果報告書　課題番号12470331 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

アルツハイマー型痴呆に伴う神経因性膀胱の成因解明及び遺伝子治療に関する実験的研究

Ibotenic acidを用いた前脳基底核破壊により、アルツハイマー型痴呆の類似した病態モデルを作成し、排尿反射の亢進が生じることを確認した。このモデルを用いてアルツハイマー型痴呆による過活動型神経因性膀胱の発生機序について薬理学的検討を行った。1)Ibotenic acid注入による前脳基底核破壊により、大脳皮質CAT活性は、約30%の低下がみられた。2)前脳基底核破壊ラット(basal forebrain lesion rats;BF群)は偽手術ラット(sham operated rats;SO群)に比べ有意な膀胱容量の減少が認められた。3)M1、M2受容体アゴニストであるoxotremorineMの右側脳室内累積投与によりSO群では膀胱容量の有意な減少がみられた。BF群では低用量で有意な膀胱容量の増大がみられ、高用量で膀胱容量は逆に減少し二相性の作用が認められた。5)M1受容体アンタゴニストであるpirenzepineの右側脳室内単回投与によりSO群、BF群とも膀胱容量の有意な増大がみられた。BF群はSO群に比べ10分の1の低用量より増大反応が認められた。6)膀胱容量を変化させない低用量のpirenzepineを前投与したラットにoxotremorineMを投与すると、BF群では、膀胱容量の増大が認められなかった。7)橋排尿中枢へのoxotremorineM局所投与により膀胱容量は減少した。pirenzepine投与により膀胱容量に変化は認められなかった。前脳基底核より大脳皮質に投射するACh系は排尿反射中枢に対し抑制性に投射していると考えられる。この投射系はpirenzepineにより遮断されることよりM1受容体を介するものであると思われる。脳幹部の橋排尿中枢におけるACh系は、おもにM2受容体を介すると考えられ、これは排尿反射に対し促進性に作用していると推測された。OBJECTS : To investigate the mechanisms of neurogenic bladder overactivity in Alzheimer type senile dementia in a conscious rat model.METHODS : Male Wistar rats were placed in a stereotaxic apparatus, and subjected to bilateral lesion of the basal forebrain by means of ibotenic acid (IA) injection (7.5 μg/rat on each side)(BF rats). Phosphate buffered saline (PBS) was injected to control rats (sham operated rats ; SO rats). Cystometrograms (CMG) were obtained 7 to 10 days after IA/PBS injection. After CMG recording, choline-acetyltransferase (CAT) activities in the frontal cortices were assayed to assess the damage to cholinergic neuronal projections from basal forebrain to frontal cortices. The influences of intracerebroventricular administration of Oxotremorine M, muscarinic receptor agonist, or pirenzepine, M1 muscarinic receptor antagonist were investigated in conscious BF or SO rats. Antagonized effects of pirenzepine were also examined in BF rats. The effects of oxotremorine M or pirensepine directly injected into the PMC (pontine micturition center) were examined under urethane anesthesia.RESULTS : Bladder capacity become significantly smaller than before IA injection. Seven to 10 days after IA injection, bladder capacity was approximately 43% of SO rats. CAT activity in the frontal cortices was reduced in BF rats. Oxotremorine M increased bladder capacity in BF rats, while decreased in SO rats. Pirensepine significantly increased bladder capacity both in BF and SO rats, and antagonised the effect of oxotremorine M. Direct injection of oxotremorine M into the PMC decreased bladder capacity in BF and SO rats, while injection of pirensepine had no effects on CMG.CONCLUSIONS : These results indicate that M1 muscarinic system in the cerebral cortex has inhibitory influence to micturition reflex pathway. Down-regulation of this inhibitory mechanism plays an important role on overactive bladder in Alzheimer type dementia. M2 muscarinic system in the brainstem is likely to have excitatory influence on micturition reflex pathway.研究課題/領域番号:10470334, 研究期間(年度):1998-1999出典：「アルツハイマー型痴呆に伴う神経因性膀胱の成因解明及び遺伝子治療に関する実験的研究」研究成果報告書　課題番号10470334 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作

Involvement of STAT3 in Bladder Smooth Muscle Hypertrophy Following Bladder Outlet Obstruction

We examined the involvement of the signal transducer and activator of transcription 3 (STAT3) in bladder outlet obstruction (BOO)-induced bladder smooth muscle hypertrophy using a rat in vivo and in vitro study. BOO induced increases in bladder weight and bladder smooth muscle thickness 1 week after the operation. By using antibody microarrays, 64 of 389 proteins blotted on the array met our selection criteria of an INR value between > or = 2.0 and < or = 0.5. This result revealed up-regulation of transcription factors, cell cycle regulatory proteins, apoptosis-associated proteins and so on. On the other hand, down-regulation (INR value < or = 0.5) of proteins was not found. In a profiling study, we found an increase in the expression of STAT3. A significant increase in nuclear phosphorylated STAT3 expression was confirmed in bladder smooth muscle tissue by immunohistochemistry and Western blot analysis. Cyclical stretch-relaxation (1 Hz) at 120% elongation significantly increased the expression of STAT3 and of alpha-smooth muscle actin in primary cultured bladder smooth muscle cells. Furthermore, the blockade of STAT3 expression by the transfection of STAT3 small interfering RNA (siRNA) significantly prevented the stretch-induced increase in alpha-smooth muscle actin expression. These results suggest that STAT3 has an important role in the induction of bladder smooth muscle hypertrophy

AJK2011-03076 EFFECTS OF WALL CONDITION OF A PLUNGING BODY ON SPLASH

ABSTRACT Splashes generated by hydrogel sphere were simulated numerically and experimentally for investigating the effects of slip like mucus of living things. Numerical simulation using MPS (Moving Particle Semi-implicit) method was carried out. We defined the slip ratio as the swelling degree of hydrogel and installed the slip ratio into the MPS method. The swelling degree is the ratio of the weight of water against that of hydrogel. We simulated the splashes generated by the hydrogel spheres which had the different swelling degree plunging into water. As the evaluation of swelling degree on the surface of actual hydrogel spheres we also tested by using the hydrogel spheres plunging into water experimentally. The height of splash as a result of reaction of the air cavity became higher according to the increase of the swelling degree. The speed of hydrogel sphere sinking in water tank was also quicker in the numerical simulation. The reason of these results was that the velocity of water around the hydrogel sphere became quicker due to the slip on the surface

Expression of 5-Hydroxytryptamine Receptors in Human Urinary Bladders with Benign Prostatic Hyperplasia

Introduction: This study investigated the mRNA expression pattern and distribution of 5-hydroxytryptamine (5-HT) receptors 5-HT2A, 5-HT2B, 5-HT3A, 5-HT4, and 5-HT7 within the urothelium and detrusor of normal bladder tissue and in the urothelium of bladders from patients with benign prostatic hyperplasia (BPH). Methods: Normal urinary bladder specimens were obtained from 13 patients undergoing radical cystectomy due to bladder cancer (normal group) and BPH specimens were obtained from 27 benign prostatic obstruction patients receiving transurethral prostatectomy or retropubic prostatectomy. Receptor subtype mRNA expression was determined by real-time reverse transcription polymerase chain reaction on urothelium, detrusor, and whole mucosal preparations. Receptor distribution was determined by immunohistochemistry. Results: In normal tissues, expressions of 5-HT2B and 5-HT7 receptor mRNAs in the urothelium, detrusor, and whole mucosa were greater than the average expression for all receptor subtype mRNAs. 5-HT2B receptor protein was distributed in the apical urothelium and among the detrusor smooth muscle layers. In contrast, the 5-HT7 receptors were within the urothelium middle cell layers and detrusor smooth muscle cells. The expression pattern of each 5-HT receptor subtype mRNA within the BPH urothelium was similar to that in the normal urothelium. The expression level of 5-HT2A receptor mRNA in the BPH group was significantly lower than the normal group; however, the expressions of both 5-HT3A and 5-HT7 mRNAs were significantly higher. The expressions of both 5-HT2B and 5-HT4 mRNAs were not significantly different between the normal and BPH groups. Conclusion: In normal urinary bladders, the expressions of both 5-HT2B and 5-HT7 mRNAs were higher compared to the 5-HT2A, 5-HT3A, and 5-HT4 mRNAs. The distributions of 5-HT2B and 5-HT7 receptors were different in the urothelium and detrusor layers. The 5-HT3A and 5-HT7 receptor mRNAs in the BPH group were significantly higher compared to the normal urothelium, while the 5-HT2A mRNA was significantly lower.ArticleADVANCES IN THERAPY.32:S29-S37(2015)journal articl