Acid-induced modulation of airway basal tone and contractility: role of acid-sensing ion channels (ASICs) and TRPV1 receptor

The role of extracellular acidosis in inflammatory airway diseases is not well known. One consequence of tissue acidification is the stimulation of sensory nerves via the polymodal H(+)-gated transmembrane channels ASICs and TRPV1 receptor. The present study investigated the effect of acidosis on airway basal tone and responsiveness in the guinea pig. Acidosis (pH 6.8, 10 min, 37 degrees C) significantly decreased the basal tone of tracheal rings (p<0.01 vs. paired control). Moreover, pH fall raised the maximal contraction of tracheal rings to acetylcholine (p<0.05 vs. paired control). The pH-induced relaxation of airway basal tone was inhibited by pretreatments with ASIC1a or ASIC3/ASIC2a inhibitors (0.5 mM ibuprofen, 0.1 mM gadolinium), nitric oxide synthase inhibitor (1 mM L-NAME), and guanylate cyclase inhibitor (1 microM ODQ). In contrast, the pH-induced relaxation of airway basal tone was not modified by epithelium removal or pretreatments with a TRPV1 antagonist (1 microM capsazepine), a combination of NK(1,2,3) receptor antagonists (0.1 microM each), a blocker of voltage-sensitive Na(+) channels (1 microM tetrodotoxin), a cyclooxygenase inhibitor with no activity on ASICs (1 microM indomethacin) or ASIC3 and ASIC3/ASIC2b inhibitors (10 nM diclofenac, 1 microM aspirin). Furthermore, acid-induced hyperresponsiveness to acetylcholine was inhibited by epithelium removal, capsazepine, NK(1,2,3) receptor antagonists, tetrodotoxin, amiloride, ibuprofen and diclofenac. In summary, the initial pH-induced airway relaxation seems to be independent of sensory nerves, suggesting a regulation of airway basal tone mediated by smooth muscle ASICs. Conversely, the pH-induced hyperresponsiveness involves sensory nerves-dependent ASICs and TRPV1, and an unknown epithelial component in response to acidosis.     

2型糖尿病合并高血压患者血清同型半胱氨酸水平与肾功能和颈动脉粥样硬化的相关性分析

摘要 目的：探讨2型糖尿病（T2DM）合并高血压患者血清同型半胱氨酸（Hcy）水平与肾功能和颈动脉粥样硬化的关系。方法：回顾性分析2018年7月~2021年5月安徽省第二人民医院收治的168例T2DM患者的临床资料,按照是否合并高血压分为T2DM合并高血压组（合并组）87例和单纯T2DM组（T2DM组）81例,另选取同期健康体检者87例为对照组,比较各组血清Hcy水平、肾功能指标[血清肌酐（Scr）、尿液肌酐（CR）、尿微量白蛋白/肌酐(ACR)、尿免疫球蛋白G/肌酐(IGU/CR)、尿转铁蛋白/肌酐(TRU/CR)、尿α1-微量球蛋白/肌酐(α1/CR)、肾小球滤过率（eGFR）]及左侧、右侧颈动脉内膜中层厚度（IMT）、Crouse积分,Pearson相关性分析Hcy水平与肾功能指标、IMT、Crouse积分的相关性。结果：合并组、T2DM组血清Hcy、Scr、CR、ACR、IGU/CR、TRU/CR、α1/CR水平及左侧IMT、右侧IMT、Crouse积分高于对照组,且合并组以上指标高于T2DM组（P＜0.05）;合并组、T2DM组eGFR水平低于对照组,且合并组低于T2DM组（P＜0.05）;Pearson相关性分析结果显示：T2DM合并高血压患者血清Hcy水平与Scr、CR、ACR、IGU/CR、TRU/CR、α1/CR水平及左侧IMT、右侧IMT、Crouse积分呈正相关（P＜0.05）,与eGFR水平呈负相关（P＜0.05）。结论：T2DM合并高血压患者血清Hcy水平异常升高,其与患者肾功能损伤及颈动脉粥样硬化有关。     

昆仙胶囊联合来氟米特治疗狼疮性肾炎临床疗效的回顾性研究

摘要 目的：探讨昆仙胶囊联合来氟米特对狼疮性肾炎患者的治疗效果。方法：回顾性分析2017年1月至2019年7月于本院接受治疗的120例狼疮性肾炎患者的临床资料,按照治疗方案的不同将其分为对照组（n=60）和观察组（n=60）。对照组给予来氟米特治疗,观察组在此基础上联合昆仙胶囊治疗。比较两组患者治疗后的疗效、狼疮疾病活动指数（SLEDAI）评分、肾功能和实验室指标、不良反应和复发情况。结果：治疗后,观察组总有效率为93.33%（56/60）,高于对照组73.33%（44/60）（P<0.05）。治疗后,观察组患者24 h尿蛋白定量（24 h UP）、血肌酐（Scr）、SLEDAI评分、红细胞沉降率（ESR）、C反应蛋白（CRP）显著低于对照组,血浆白蛋白（Alb）、补体C3与C4水平显著高于对照组（P<0.05）;观察组的复发率（8.33%）以及不良反应发生率（13.33%）均显著低于对照组的23.33%、30.00%,差异具有统计学意义（P<0.05）。结论：昆仙胶囊联合来氟米特可以有效治疗狼疮性肾炎,明显改善患者病情活动度和肾功能,同时降低复发率和不良反应发生率,在临床上具有一定的应用价值。     

AVF与TCC血管通路在慢性肾衰竭患者中的血液透析效果比较及对炎性因子、营养水平和肾功能的影响

摘要 目的：探析自体动静脉内瘘（AVF）、带隧道带涤纶套透析导管（TCC）在慢性肾衰竭（CRF）患者中的血液透析效果比较及对炎性因子、营养水平和肾功能的影响。方法：将2019年1月-2021年1月在安徽医科大学附属巢湖医院接受诊治的150例CRF患者纳入研讨,所有患者根据随机数字表法分为AVF组、TCC组两组,例数各为75例。观察两组血液透析效果并进行比较,对比两组炎性因子、营养水平和肾功能的变化情况,记录两组并发症发生情况。结果：AVF组透析6个月后尿素清除指数（KT/V）、尿素清除率（URR）高于TCC组（P<0.05）。AVF组透析6个月后白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、超敏C反应蛋白（hs-CRP）低于TCC组（P<0.05）。AVF组透析6个月后白蛋白（ALB）、前白蛋白（PAB）高于TCC组（P<0.05）。两组透析6个月后尿素氮（BUN）、肌酐（Scr）较治疗前下降,且AVF组低于TCC组（P<0.05）。AVF组的并发症发生率低于TCC组（P<0.05）。结论：CRF患者采取AVF通路行血液透析治疗,临床效果较采取TCC通路更为显著,可有效改善患者肾功能,降低血液炎性因子水平,同时还可以降低并发症发生率,对机体营养状况的影响相对轻微,具有较好的临床应用价值。     

Psychomotor functions at various weeks of chronic renal failure in rats

In chronic renal failure there is a gradual retention of substances in the tissues and body fluids, called as uremic retention toxins, which can bring about a number of biochemical activities in the body. Chronic renal insufficiency also leads to progressive behavioural conflict. Uremic toxins can affect both the central and the peripheral nervous system. Uremic encephalopathy is also associated with problems in cognition and memory. To study the psychomotor functional disorders in rats with progressive chronic renal failure surgical nephrectomy was done by resection method. The animals were grouped into two control groups, Sham control (SC) and normal control (NC) and two uremic groups, moderate uremia (G_M) and severe uremia (G_S). Psychomotor analysis was done by passive avoidance and open field in these animals at 4, 8, 12, and 16 weeks. After the incubation period, the nephrectomised groups (G_M and G_S) showed significant changes in exploratory, locomotor and emotional behaviour when compared to the controls (NC and SC). Psychomotor changes involve poor cognition, reduced memory, reduced locomotor activity and decreased exploratory drive and emotional disturbance like increased fear during the initial stages. During the later stages a restless behaviour was noticed, associated with diminished fear.     

Mesenteric Organ Production, Hepatic Metabolism, and Renal Elimination of Norepinephrine and Its Metabolites in Humans

Abstract: This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys. Higher concentrations of norepinephrine, its glycol metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol and their sulfate conjugates in portal venous than arterial plasma indicate substantial production of norepinephrine by mesenteric organs (15.5 nmol/min). Much lower concentrations of norepinephrine and its glycol metabolites in plasma leaving than entering the liver indicate their efficient hepatic removal (20 nmol/min). Higher concentrations of vanillylmandelic acid in the hepatic outflow than inflow indicate that this metabolic end product is produced largely from the norepinephrine and glycol metabolites removed by the liver. Renal elimination of vanillylmandelic acid (18–20 nmol/min), produced mainly by the liver (17 nmol/min), and of 3-methoxy-4-hydroxyphenylglycol sulfate (7–9 nmol/min), produced largely by mesenteric organs (7 nmol/min), comprised 86–91% of the total renal elimination of norepinephrine metabolites. The results show that mesenteric organs produce about one-half of the norepinephrine formed in the body. The liver removes substantial amounts of circulating norepinephrine and its glycol metabolites and converts these compounds to vanillylmandelic acid, which is then eliminated from the body by the kidneys. The sulfate conjugates are also metabolic end products eliminated by the kidneys. However, these metabolites are produced by extrahepatic tissues, in particular, mesenteric organs, which represent a significant source of sulfate-conjugated norepinephrine and 3,4-dihydroxyphenylglycol, and the main source of sulfate-conjugated 3-methoxy-4-hydroxyphenylglycol.     

Adrenal medulla and exercise training

The adrenaline release from the adrenal medulla increases during exercise, but at a given absolute work intensity the magnitude of this response is less pronounced in endurance trained vs sedentary individuals most likely due to a lower sympathetic stimulation of the adrenal medulla. However, when trained and untrained subjects are compared at identical relative work loads as well as in response to numerous non-exercise stimuli, endurance trained athletes have a higher epinephrine secretion capacity compared to sedentary individuals. This indicates a development of a so-called “sports adrenal medulla” as a result of a long term adaption of an endocrine gland to physical training. Such an adaptation is parallel to adaptations taking place in other tissues like skeletal muscle and the heart, and can be advantageous in relation to both exercise performance in the competing athlete and cause a biological rejuvenation in relation to aging. Accepted: 4 September 1997     

Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy

A decrease in lymphocyte signal-transduction molecules, described in cancer patients and patients with chronic infectious diseases, has been proposed as a possible mechanism leading to an impaired immune response in cancer patients. Here we report the effects of combination immunotherapy on the levels of T cell receptor zeta chain and p56lck tyrosine kinase in a retrospective study of cryopreserved lymphocytes from 26 metastatic renal cell carcinoma patients treated with high-dose interleukin-2 (IL-2), interferon alpha (IFNalpha) and ex vivo IL-2-activated lymphocytes. Of the 26 patients, 12 were responders (5 complete and 7 partial) and 14 were non-responders (6 stable and 8 with progressive disease). Prior to treatment, 21 of 26 patients (81%) and 13 of 21 patients (62%) respectively expressed zeta chain and p56lck at less than 50% of the levels observed in healthy controls. During therapy, this low zeta chain and p56lck expression increased to at least 50% of normal in 13 of the 21 patients (62%) and in 6 of the 13 patients (46%) respectively; in the remaining patients expression levels remained at 50% of normal or more, or declined. Although, in this limited study, pretreatment levels of and p56lck did not show significant correlation with antitumor response, 4 of 5 patients that achieved a complete response (80%) corrected both zeta chain and p56lck levels to at least 50% of normal, while restoration of both signal-transduction molecules to such levels was only observed in 3 of 7 partial responders (43%), 1 of 5 patients with stable disease (20%) and 2 of 7 patients with progressive disease (29%). Thus, these results suggest that analysis of changes in signal-transduction molecules may a be useful tool for immunological monitoring of patients throughout immunotherapy, and could provide important information for designing new clinical trials that restore impaired signal transduction while activating T cell responses.     

Semiquantitative analysis of Th1 and Th2 cytokine expression in CD3+, CD4+, and CD8+renal-cell-carcinoma-infiltrating lymphocytes

The mRNA expression of Th1 and Th2 cytokines was compared in freshly isolated CD3⁺ tumor-infiltrating lymphocytes (CD3⁺ TIL) and in autologous CD3⁺ peripheral blood lymphocytes (CD3⁺ PBL) obtained simultaneously from 20 patients with renal cell carcinomas (RCC). In addition cytokine expression was compared in CD4⁺ TIL and CD8⁺ TIL from another group of 20 patients with RCC. TIL were isolated from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation and subsequent selection with anti-CD3, anti-CD4 or anti-CD8 magnetic beads. In these pure lymphocyte preparations the constitutive expression of interleukin-1 (IL-1), IL-2, IL-10, interferon γ (IFN), and tumor necrosis factor α (TNF) was determined by using a polymerase-chain-reaction-assisted mRNA amplification assay. In the CD3⁺ TIL, levels of mRNA for IFN, IL-10, IL-1 and TNF were significantly higher than in the autologous CD3⁺ PBL whereas IL-2 expression was rather low and did not differ in the two populations. Comparison of cytokine mRNA expression in CD4⁺ TIL and simultaneously obtained CD8⁺ TIL revealed a significantly higher expression of IFN in the CD8⁺ cells. These data reflect an in vivo activation of RCC-infiltrating lymphocytes at the mRNA level with respect to the Th1 as well as the Th2 immune response. Th1 activation seems to be most evident in the CD8⁺ TIL. Received: 14 January 1999 / Accepted: 30 April 1999     

急性肾功能衰竭对肝损害的实验研究

探讨急性肾功能衰竭 (以下简称为 ARF)时尿毒症毒素对肝的损害情况 ,为临床防治提供形态学依据。Wistar大白鼠 32只 ,随机分成正常对照组 ,14只 ;双输尿管结扎结扎组 ,18只。模型建成后 2 3- 37小时内将动物处死 ,取肝组织作NOS、 MAO、 SDH、 L DH、 Ch E、 ATPase、 ACP等项酶组织化学显色及超微结构观察。结果显示 :实验组 SDH、 Mg2 + -ATPase 的活性均由正常的强阳性 ( )下降为阳性 (+) ;MAO、 Ch E的活性均由正常的中等阳性 ( )下降为阳性(+) ;ACP、 L DH的活性均由阳性 (+)增强到中等阳性 ( ) ;NOS活性由正常的弱阳性 (± )增强为阳性 (+) ;肝细胞器结构受损。结果表明 :ARF的尿毒素的大量淤积通过影响肝脏酶的活性来干扰和抑制糖代谢、三羧酸循环、蛋白质合成及解毒等功能 ,并导致肝损害发生。 2用改良的 NADPH-黄递酶法可显示肝组织 NOS的存在 ,该法操作简便 ,经济 ,特别适用于同时需要留取活组织做其它检查者。当输尿管结扎时 ,NOS的确切作用有待于进一步探讨