Mechanisms underlying the pathogenesis of urinary bladder instability - new perspectives for the treatment of reflex incontinence

The urine storage ability of the urinary bladder is markedly impaired following inflammation of the urinary bladder and spinal cord injury because of a hyperexcitability of micturition reflexes. Using two rat models of inflammation-induced bladder overactivity and detrusor hyper-reflexia following spinal cord injury we investigated changes in the neuronal pathways to the urinary bladder which may underlie the development of this instability. Our results suggest that among the factors involved in inflammation-induced bladder instability are significant changes in the expression of the neuropeptides substance P, calcitonin gene-related peptide and galanin at the primary afferent level, as well as of the enzyme neuronal nitric oxide synthase (nNOS) at the afferent and postganglionic efferent level. In the lumbar and sacral spinal cord nNOS-immunoreactivity was depleted from dorsal horn neurones in both cystitis and spinal cord injured rats and from preganglionic parasympathetic neurones after spinal cord injury. Distension of the bladder in chronically spinalized rats elicited c-Fos expression in a significantly greater number of neurones throughout the lumbar and sacral segments than in rats with an intact neuraxis. Thus, under pathological conditions rather complicated changes in the synthesis of neuropeptides and nNOS occur at the primary afferent, spinal cord and postganglionic efferent level that together control the activity of the urinary bladder. Further mechanisms like unmasking of silent synapses and axonal sprouting in the spinal cord might further contribute to an increase in activity in micturition reflex pathways. Local cooling of the dorsal spinal cord at the level L6/S1 with temperatures between 14 and 20 °C proved a simple technique to control the unstable bladder and restore continence in both inflammation-induced detrusor overactivity and detrusor hyperreflexia following spinal cord injury. The effects of cooling are probably the result of a blockade of synaptic transmission within the dorsal cord which eliminates neuronal overactivity. Thus, local spinal cord cooling could offer a new method to treat bladder instability and reflex incontinence.     

生物反馈电刺激仪治疗腹腔镜前列腺癌根治术后尿失禁☆

目的：应用生物反馈电刺激仪可以指导患者进行正确自主的盆底肌肉训练，观察其对腹腔镜前列腺癌根治术后控尿功能恢复的作用。 方法：选择2005-07/2007-06中山大学附属第三医院泌尿外科收治腹腔镜前列腺癌根治术后尿失禁患者41例，轻度12例，中度23例，重度6例。采用加拿大Laborie 公司生产的UROSTIM型盆腔生物反馈电刺激治疗仪电刺激联合盆底肌肉训练，生物反馈电刺激每日1次，5次为1个疗程，根据患者尿失禁程度分别治疗一两个疗程。疗效判定标准：治愈，自觉尿失禁症状消失、小便能自控，排尿正常，尿垫试验阴性；有效，自觉尿失禁次数明显减少、尿垫试验连续3次以上阴性；无效，尿失禁症状无明显改善，尿垫试验阳性。治疗结束后4周评价其治疗效果，追踪观察随访3~12个月。 结果：41例术后不同程度尿失禁患者，治愈23例(56.1%) ，有效11例(26.9%) ，无效7例(17.0%) ，总有效率为83%。轻度尿失禁患者，治愈11例，有效1例；中度尿失禁患者，治愈11例，有效8例，无效3例；重度尿失禁患者，治愈1例，有效2例，无效3例。 结论：应用生物反馈电刺激仪可促进前列腺癌根治术后患者控尿功能的恢复。     

Cervical vagotomy increased the distal colon distention to urinary bladder inhibitory reflex in male rats

Purpose

Many studies have demonstrated the convergence of vagal inputs into brainstem centers with inputs from the urinary bladder and colon, as well as the convergence of vagal inputs into other centers controlling the urinary bladder and colon reflexes. However, the effect of the vagal inputs on the interaction between the urinary bladder and other pelvic organs has not been studied. In this study, the effect of bilateral cervical vagotomy on the distal colon to urinary bladder reflex was examined.

Methods

Changes to cystometry parameters in response to increased distal colon distensions (1, 2, and 3 ml) were tested in urethane-anesthetized male rats with or without bilateral cervical vagotomy.

Results

In animals with intact vagus nerves, 1 and 2 ml distal colon distentions had no significant effects on micturition frequency; however, 3 ml distal colon distention significantly decreased the frequency of micturition cycles. Also, 3 ml distal colon distention inhibited micturition cycles in 37.5 % of these animals. On the other hand, following cervical vagotomy, 1 ml distal colon distention was enough to significantly decrease the frequency of micturition cycles and to inhibit the cycles in 75 % of the animals.

Conclusion

These results demonstrate the presence of supraspinal inhibitory regulation, via the vagus nerve, over the distal colon to urinary bladder inhibitory reflex.

     

Opioid inhibition of reflex urinary bladder contractions: dissociation of supraspinal and spinal mechanisms

The supraspinal and spinal mechanisms of morphine induced inhibition of reflex urinary bladder contractions were studied in the urethane anesthetized rat. The inhibition of bladder contractions by intracerebroventricular (i.c.v.) morphine was abolished by intrathecal (i.t.) naloxone. In addition systemic reserpine (3.5–5.0 mg/kg, i.p.) abolished the inhibitory effect of both systemic morphine and i.c.v. morphine but not that of i.t. morphine. These data support the involvement of separate supraspinal and spinal mechanisms in the effects of morphine on bladder motility. The supraspinal effect appeared to be mediated indirectly via a monoaminergic system whereas the spinal action was mediated independently of monoamines. However, both the indirect supraspinal and the direct spinal mechanism involved a spinal naloxone-sensitive process possibly an endogenous enkephalinergic system.     

肌源干细胞注射治疗压力性尿失禁的研究进展**

背景：注射疗法治疗压力性尿失禁是一种微创的治疗手段,但是由于既往注射材料的限制,可出现各种并发症,远期疗效差,寻找新的注射材料具有重大意义。目的：对压力性尿失禁应用肌源性干细胞治疗的研究进行回顾分析。方法：由第一作者检索2003/2010 PubMed数据库、Springer数据库及中国知网数据库关于肌源性干细胞用于压力性尿失禁治疗研究方面的文献,英文检索词为“stress urinary incontinence, muscle-derived stem cell”,中文检索词为“压力性尿失禁,肌源干细胞”,排除重复性研究,计算机初检得到40篇文献,根据纳入标准保留24篇进一步归纳总结。结果与结论：压力性尿失禁的治疗方式主要包括非手术治疗和手术治疗,其中手术治疗存在多种并发症甚至出现矫枉过正的风险,而注射疗法作为一种非手术治疗方式,具有操作简便,患者可接受性更高。肌源性干细胞注射后可在体内长期存活,并具有不被分解、不易迁移、低免疫原性的优点,在注射治疗压力性尿失禁方面具有广阔的前景。     

Mechanisms underlying the beneficial effects of Kaiyu Granule for depression

The proprietary Chinese medicine preparation Kaiyu Granule is made of bupleurum, nutgrass ga- lingale rhizome, szechwan Iovage rhizome, turmeric root tuber, white peony alba, cape jasmine fruit fried semen ziziphi jujubae, and prepared liquorice root. It is a common recipe for the clinical treatment of depression in China. In this study, after 21 days of unpredictable stress exposure, Wistar rats exhibited similar behavioral changes to patients with depression. Moreover, G-protein-coupled inwardly rectifying K＋ channel 1 mRNA and protein expression were significantly reduced in rat hippocampal CA1 and CA3 regions. However, G-protein-coupled inwardly rectifying K＋ channel 1 mRNA, protein expression, and rat behavior were clearly better after administration of 12, 8, or 4 g/kg of Kaiyu Granule when depression model rats underwent stress. 12 g/kg of Kaiyu Granule had the most obvious effects on the increased expression of G-protein-coupled inwardly rectifying K＋ channel 1 mRNA and protein in rat hippocampal CA1 and CA3 regions. These results suggested that Kaiyu Granule improved depression by affecting G-protein-coupled inwardly recti- fying K＋ channel 1 expression in the rat hippocampus.     

等离子前列腺电切术后尿失禁神经损伤因素分析及治疗对策

目的：探讨等离子前列腺电切术后尿失禁原因及防治对策。方法选取2012‐01—2014‐01我院收治的140例前列腺增生患者,随机数字表法分为2组,即等离子前列腺电切术组（PKRP组,70例）和经尿道前列腺电切术组（TURP组, 70例）,统计分析2组患者的尿失禁发生情况。结果 PKRP组患者的尿失禁发生率10％,明显低于TURP组的28.6％（P＜0.05）;随着时间的推移2组尿失禁均得到有效恢复,PKRP组尿失禁恢复时间明显较TURP组短（P＜0.05）。结论等离子前列腺电切术后尿失禁发生率较经尿道前列腺电切术低,临床应积极分析其发生因素并采取有针对性的措施,从而降低尿失禁发生率。     

The pathogenesis of atherosclerosis and new opportunities for treatment and prevention

Atherosclerosis is the most common disease in the industrialised world and by 2020 is predicted to be the number 1 cause of death worldwide. It is a disease of the intima and media of small to medium sized arteries that develop slowly over many years. A number of risk factors for atherosclerosis have been identified, some of these are reversible and some are not. Most prominent amongst these is an elevated level of plasma cholesterol. The lowering of cholesterol reduces the risk of heart attacks, strokes and all forms of atherosclerotic vascular disease. Nonetheless, 70% of patients go on to get symptomatic disease. The disease process sets off an inflammatory response involving the vascular endothelium and both T and B cells of the immune system. Adhesion molecules are induced and proinflammatory cytokines and growth factors are produced by cells that orchestrate the atherosclerotic process. Narrowing the lumen of the artery leads to ischaemic symptoms. Within lesions under the influence of proteolytic enzymes released from activated macrophages (or foam cells--the hallmark of atherosclerosis) the centre of the plaque becomes liquefied to take on it's characteristic "gruel" like appearance. The shoulders of such plaque weaken and it becomes prone to rupture. Plaque rupture may lead to catastrophic thrombosis of coronary or cerebral arteries. The large amounts of tissue factor produced by macrophages make this a particularly likely event. On ulcerated plaques adherent platelets and thrombus create showers of emboli leading to ischaemic attacks. Like the effective treatment of LDL and it's role in the prevention of ischaemic attacks there has been a move to develop new drugs that raise HDL. The discovery of the role of a new class of ABC transporter, defective in Tangiers disease, responsible for cholesterol efflux from peripheral cells including the macrophage has created great excitement around ABC1 as a drug target. New areas, new possible targets and new genetic and genomic approaches will be discussed.     

人工反射弧建立后大鼠膀胱胆碱能神经的形态学变化

目的观察体神经一内脏神经人工反射弧建立后,大鼠膀胱肌间神经丛分布的改变以及神经肌肉接头处的变化。方法Sprague—Dawley大鼠随机分为三组：对照组、脊髓横断组和手术重建组。手术重建组大鼠术后饲养3个月,与脊髓横断组大鼠一起进行脊髓横断,再继续饲养3个月,对照组不做任何处理。DiI进行逆行神经追踪;免疫荧光的方法显示DiI阳性标记细胞中的胆碱乙酰转移酶（cholineacetyltransferase,CHAT）;改良的Kamovsky—Roots法检测膀胱铺片中神经纤维的分布。结果DiI阳性标记细胞主要分布于脊髓L3尾部至L5头侧前角,ChAT阳性细胞和DiI阳性标记细胞部分重叠。手术重建组和对照组相比,膀胱肌间神经纤维的数量较少,染色浓度也较浅护〈0．05）;而手术重建组神经纤维密度较脊髓横断组增大,染色浓度增强妒〈0．05）,且出现明显的神经再分布。结论人工体内脏神经反射弧建立后,新的传出支为体神经,可以长入副交感神经纤维,传出神经元的递质仍为乙酰胆碱,膀胱内胆碱能神经纤维再生和乙酰胆碱活性增强且出现神经再分布,这可能在膀胱的控制性排尿中起作用。     

人工反射弧建立后大鼠膀胱胆碱能神经的形态学变化(英文)

目的观察体神经—内脏神经人工反射弧建立后,大鼠膀胱肌间神经丛分布的改变以及神经肌肉接头处的变化。方法Sprague-Dawley大鼠随机分为三组:对照组、脊髓横断组和手术重建组。手术重建组大鼠术后饲养3个月,与脊髓横断组大鼠一起进行脊髓横断,再继续饲养3个月,对照组不做任何处理。DiI进行逆行神经追踪;免疫荧光的方法显示DiI阳性标记细胞中的胆碱乙酰转移酶(choline acetyltransferase,ChAT);改良的Karnovsky-Roots法检测膀胱铺片中神经纤维的分布。结果DiI阳性标记细胞主要分布于脊髓L3尾部至L5头侧前角,ChAT阳性细胞和DiI阳性标记细胞部分重叠。手术重建组和对照组相比,膀胱肌间神经纤维的数量较少,染色浓度也较浅(P<0.05);而手术重建组神经纤维密度较脊髓横断组增大,染色浓度增强(P<0.05),且出现明显的神经再分布。结论人工体内脏神经反射弧建立后,新的传出支为体神经,可以长入副交感神经纤维,传出神经元的递质仍为乙酰胆碱,膀胱内胆碱能神经纤维再生和乙酰胆碱活性增强且出现神经再分布,这可能在膀胱的控制性排尿中起作用。     

Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet

The clinical efficacy of the ketogenic diet (KD) has now been well-documented. However, the underlying bases of KD antiepileptic efficacy are still a matter of speculation. A number of suggestions regarding underlying mechanisms have been offered, but all require rigorous testing. Development of appropriate animal model systems, and clear statement of experimentally testable hypotheses, are needed. Among the general hypotheses of interest are the following: (1) the KD alters the nature, and/or degree, of energy metabolism in the brain -- therefore altering brain excitability; (2) the KD leads to changes in cell (neuronal and perhaps glial) properties, which decrease excitability and dampen epileptiform discharge; (3) the KD induces changes in neurotransmitter function and synaptic transmission -- thus altering inhibitory-excitatory balance and discouraging hyper-synchronization; (4) the KD is associated with changes in a variety of circulating factors which act as neuromodulators that can regulate CNS excitability; and (5) the KD gives rise to alterations in brain extracellular milieu, which serve to depress excitability and synchrony. An understanding of the mechanism underlying KD antiepileptic efficacy will help us not only to optimize the clinical use of the ketogenic diet, but also to develop novel antiepileptic treatments.     

Mechanisms underlying the emergence of object representations during infancy

The effects of individual versus category training, using behavioral indices of stimulus discrimination and neural ERPs indices of holistic processing, were examined in infants. Following pretraining assessments at 6 months, infants were sent home with training books of objects for 3 months. One group of infants was trained with six different strollers labeled individually, and another group was trained with the same six strollers labeled at the category level (i.e., "stroller"). Infants returned for posttraining assessments at 9 months. Discrimination of objects was facilitated for infants trained with the individually labeled strollers but was unchanged after training at the category level. Relative to pretraining and to category-level training, individual-level training resulted in increased holistic processing of strollers recorded over occipital brain regions. These results suggest that labeling nonface objects individually, in infancy, facilitates discrimination and leads to the emergence of holistic neural representations not present with category-level labeling.     

Mechanisms underlying the effects of amphetamine on particulate PKC activity

Amphetamine stimulates particulate protein kinase C (PKC) activity that is associated with the outward-transport of dopamine (DA) (Giambalvo [2003] Synapse 49:125-133). This stimulatory effect requires intracellular calcium ([Ca](i)) and endogenous DA and when DA release is diminished, the inward-transport of amphetamine inhibits PKC activity. This study examines the mechanisms involved. It was found that synaptoneurosomes incubated with amphetamine showed a dose-dependent increase in phospholipase C and A(2) activities. Furthermore, pretreatments with the phospholipase C inhibitor D609 or the phospholipase A(2) inhibitors quinacrine or p-bromophenacylbromide attenuated the amphetamine-induced increase in PKC activity. This suggests that both phospholipases were essential for the amphetamine-induced increase in PKC activity. The Na/Ca antiporter was also involved, since pretreatment with amiloride or benzamil attenuated the amphetamine-induced increase in PKC activity. Since these drugs by themselves increased PKC activity, the return to basal activity after addition of amphetamine suggests that, in the absence of Na/Ca exchange, amphetamine had an inhibitory effect on PKC activity. This inhibitory effect might be due to the activation of phospholipase A(2) through an increase in intracellular pH induced by amphetamine. This was supported by the finding that pretreatment with dimethylamiloride, an inhibitor of the Na/H antiporter that increases intracellular [H(+)], attenuated the effects of amphetamine on PKC activity. Other drugs that decrease intracellular [H(+)] (ammonia, monensin) also inhibited PKC activity without Ca. In contrast to amphetamine, monensin had no effect on PKC activity with Ca. This could be related to its large differential effects on phospholipase A(2) vs. phospholipase C activity. Thus, the monensin-mediated decrease in PKC activity seen without Ca was partially attenuated by pretreatment with quinacrine. Furthermore, when Na/Ca antiporter was inhibited with benzamil, monensin inhibited PKC activity. These results suggest that amphetamine, as well as monensin, may have dual effects on PKC activity, a Ca-dependent stimulatory effect via phospholipase C, and an inhibitory effect via phospholipase A(2).     

Innervation of the urinary bladder in higher primates

Stimulating electrodes were placed on the terminal branches of the pelvic nerves to the urinary bladder and the pudendal nerve to the sphincters in seven Rhesus monkeys and two chimpanzees. The proximity of the electrodes to these structures assured organ specificity. Evoked responses produced by stimulation of these terminal nerve branches were recorded in the fascicles and rootlets of the lower thoracic, lumbar, and sacral nerve roots. During identifical stimulating and recording conditions, the amplitude as well as presence or absence of the evoked responses recorded was variable within the various roots. The amplitude of the evoked responses or their absence depended on the number of fibers within a particular fascicle which conducted impulses to the urinary bladder or the urethral and anal sphincters. By this method, it was determined that there was segregation or compartmentalization of the nervous innervation to the urinary bladder and sphincters within the spinal roots. In addition, the segmental spinal cord origin of the innervation of the urinary bladder was determined for the Rhesus monkey and chimpanzee. In the Rhesus monkey, the pelvic nerves to the urinary bladder arose from the first and second sacral segments and to a much lesser extent from the seventh lumbar segment. In the chimpanzee the sacral segments one to four gave rise to innervation of the urinary bladder.