Sympathetic nervous system and chronic bladder pain: a new tune for an old song

Chronic bladder pain (CBP) patients present with pelvic pain or discomfort during bladder filling, for at least a period of 6 months, which may be accompanied by lower urinary tract symptoms such as frequency, nocturia, and urgency. However, both the etiology of CBP and pathophysiological mechanisms are not well described. A number of clinical and basic animal model findings support involvement of sympathetic nervous system in chronic pain syndromes such as CBP. Examples include sympathetic overactivity and high plasma or urinary catecholamine levels that have a high correlation with nociceptive symptoms. In this review, we explored the current evidence in support of the involvement of sympathetic overactivity in CBP. As bladder inflammation often occurs among subgroups of CBP patients, we discuss the possible role of sympathetic nervous system in mastocytosis as well examples examples of animal models that further support the involvement of sympathetic dysfunction in CBP. As there is substantive evidence for cross-organ sensitization in the pelvis can lead to co-morbidity of genitourinary and gastrointestinal dysfunctions, we also include how sympathetic dysfunction may play a role in a number of co-morbid chronic pain syndromes.     

Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein–Taybi syndrome

In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein–Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.

     

连续性血液净化治疗对危重患者药物清除率影响的研究进展

本文通过查阅文献,了解药物本身药理学及连续性血液净化治疗（ CBP）的滤过膜材料、面积、孔径大小,透析液／超滤液流速,过滤器使用时间,血液滤过模式及滤过原理等对药物清除率的影响,总结连续性血液滤过治疗对各类药物清除率的研究进展。为临床医师调整治疗方案,更好地进行个体化治疗提供参考,同时为药物清除率的进一步研究开拓思路。     

Testis‐specific calcium‐binding protein CBP86‐IV (CABYR) binds with phosphoglycerate kinase 2 in vitro and in vivo experiment

The investigation of the interacting proteins with testis‐specific calcium‐binding protein CBP86‐IV (CABYR) was carried out in human spermatozoa. The total RNA from human spermatozoa was extracted, and the ORF sequence of TSCBP86‐IV gene was amplified and cloned into expression vector pET‐28a. The positive recombinant clones were transformed into Escherichia coli strain BL21 (DE3) to express fusion protein. Then, co‐immunoprecipitation (Co‐IP) of TSCBP86‐IV was performed in BL21 cell lysate expressing CBP86‐IV recombinant protein. The immune complex was captured and identified by mass spectrometry. Reverse Co‐IP of potential interacting proteins was performed in human sperm cell lysate. The potential protein interactions were confirmed by yeast two‐hybrid system. Thirteen proteins were successfully identified in immune complex from E. coli cell lysate. Phosphoglycerate kinase 2 (PGK2) further showed positive results both in reverse Co‐IP and yeast two‐hybrid experiments and was confirmed to be interacted with TSCBP86‐IV in human sperm cells.     

Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes

Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines such as interleukin-8 (IL-8) and interleukin-6 by human fibroblast-like synoviocytes from patients with rheumatoid arthritis (RAFLS). In those cells LPA was reported to induce IL-8 secretion through activation of various signaling pathways including p38 mitogen-activated protein kinase (p38 MAPK), p42/44 MAPK, and Rho kinase. In addition to those pathways we report that mitogen- and stress-activated protein kinases (MSKs) known to be activated downstream of the ERK1/2 and p38 MAPK cascades and CREB are phosphorylated in response to LPA. The silencing of MSKs with small-interfering RNAs and the pharmacological inhibitor of MSKs SB747651A shows a role for both MSK1 and MSK2 in LPA-mediated phosphorylation of CREB at Ser-133 and secretion of IL-8 and MCP-1. Whereas CREB inhibitors have off target effects and increased LPA-mediated IL-8 secretion, the silencing of CREB1 with short hairpin RNA significantly reduced LPA-induced chemokine production in RAFLS. Taken together the data clearly suggest that MSK1 and MSK2 are the major CREB kinases in RAFLS stimulated with LPA and that phosphorylation of CREB1 at Ser-133 downstream of MSKs plays a significant role in chemokine production.     

连续性血液净化辅助治疗重症急性胰腺炎的临床效果及安全性

目的观察连续性血液净化治疗重症急性胰腺炎（SAP）的临床效果,分析此治疗方法的可行性与安全性,为临床应用提供理论依据。方法从2013年1月-2014年1月来本院消化科就诊的SAP患者中选取82例,随机分为观察组和对照组,每组各41例。两组患者在常规治疗的基础上,对照组加用乌司他丁,观察组加用乌司他丁与持续性血液净化。比较两组患者的腹痛等症状、体征减轻时间,C反应蛋白、血淀粉酶、脂肪酶等辅助检查结果恢复的正常时间,患者治愈时间、局部并发症发生率、改行手术治疗率和死亡率。结果经治疗,治疗组和对照组患者的腹痛等症状体征缓解时间及C反应蛋白、血淀粉酶及脂肪酶等辅助检查结果恢复正常时间,患者治愈时间、胰腺假性囊肿以及胰瘘等局部并发症发生率、改行手术治疗率差异均有统计学意义（P〈0.05）;两组患者的死亡率差异无统计学意义（P〉0.05）。结论连续性血液净化联合乌司他丁辅助治疗重症急性胰腺炎较常规治疗组症状、体征各项辅助检查结果恢复时间短,可降低局部并发症的发生率和改行手术治疗率,可行性、安全性高,值得临床推广应用。