CNTF restores gallbladder contractility in leptin-resistant obese diabetic mice

Background. Obesity and diabetes are major risk factors for the development of cholesterol gallstones, and the majority of obese people have leptin-resistant obesity. Previous studies from our laboratory have demonstrated that both leptin-deficient (Lep^ob) and leptin-resistant (Lep^db) obese diabetic mice have decreased in vitro gallbladder motility. We have also shown that leptin administration to leptin-deficient (Lep^ob) animals restores gallbladder motility and reverses obesity and hyperinsulinemia. However, the administration of additional leptin to leptin-resistant (Lep^db) mice would not be expected to ameliorate their physiologic parameters. In contrast, recent studies have demonstrated that ciliary neurotrophic factor (CNTF) can reduce weight and hyperinsulinemia in leptin-resistant obesity. Hypothesis. CNTF would cause weight loss, lower blood sugars, and restore gallbladder contractility in leptin-resistant (Lep^db) mice. Methods. To test this hypothesis, 20 C57b/6J and 20 Lep^db 8-week-old mice were injected intraperitoneally daily with either saline or 0.3 μg/g CNTF_Ax15 for 17 days. At 11 weeks, mice were weighed and underwent cholecystectomy. Intact gallbladders were mounted in 3 mL muscle baths and stimulated with acetylcholine (ACh) and cholecystokinin (CCK). Serum glucose levels were measured. Data were analyzed by two-way ANOVA. Results are shown in the table. Conclusions. These data suggest that daily administration of ciliary neurotrophic factor (CNTF) causes (1) significant weight loss, (2) improvement of diabetes, and (3) significant alterations in gallbladder motility which is decreased in lean nondiabetic mice and improved in obese diabetic mice. We conclude that ciliary neurotrophic factor may improve gallbladder contractility in leptin-resistant obese diabetes.

TABLE—ABSTRACT 48.

Strain	Wt (g)	Glucose (mg/dL)	ACh 10−5 M (N/cm2)	CCK 10−8 M (N/cm2)
Saline C57	17 ± 0	110 ± 12	.39 ± .04	1.14 ± .13
CNTF C57	13 ± 0∗	101 ± 7	.20 ± .04∗	0.59 ± .08∗
Saline Lepdb	41 ± 2†	440 ± 26†	.13 ± .03∗	0.46 ± .08∗
CNTF Lepdb	22 ± 1‡	200 ± 33†	.54 ± .10‡	1.02 ± .09‡

∗

P < 0.05 versus Saline C57;

†

P < 0.01 versus other groups;

Ddagger;

P < 0.001 versus Saline lep^db.

Full-size table

     

Nonobese diabetic mice have diminished gallbladder motility and shortened crystal observation time

Diabetes and obesity are strongly associated and are risk factors for cholesterol gallstone disease. Leptinde ficient and leptin-resistant diabetic obese mice have enlarged, hypomotile gallbladders. In addition, bile from gallbladders of leptin-deficient mice has enhanced cholesterol crystal formation, whereas bile from gallbladders of leptin-resistant mice has delayed crystal observation time. To determine the effect of diabetes alone, we hypothesized that leptin-normal, nonobese diabetic (NOD) mice would have reduced biliary motility and rapid crystal formation. Twenty control and 9 prediabetic and 11 diabetic NOD, 12- to 26-week-old mice underwent glucose measurement and cholecystectomy for muscle bath stimulation with neurotransmitters. An additional group of 200 control and 78 NOD 12-week-old mice underwent microscopic bile examination for cholesterol crystal formation. Compared with control mice, prediabetic NOD mice had similar glucose levels and gallbladder volumes. Diabetic NOD mice had higher sugar levels and larger gallbladder volumes (P < 0.001) than control mice. Prediabetic NOD gallbladders had less contractility (P < 0.01) than control gallbladders, and contractility worsened (P < 0.01) in diabeticNODmice.NODmice formed cholesterol crystals earlier than did control mice (P<0.05). Nonobese diabetic NOD mice have (1) decreased gallbladder contraction to neurotransmitters, which worsens with development of diabetes, and (2) rapid crystal formation. We conclude that diabetes alone alters gallbladder motility and cholesterol crystal formation. Presented at Digestive Disease Week, 2004 SSAT Plenary Session, and Residents’ Conference, New Orleans, Louisiana, May 15–21, 2004 (oral presentation). This work was supported by National Institutes of Health grant R01-DK44279.     

Gallbladder motility in agouti-yellow and leptin-resistant obese mice

BACKGROUND: Obesity is a polygenic disorder that is associated with gallstone disease. We have previously shown that leptin deficiency in obese mice correlates with decreased gallbladder motility, suggesting that leptin plays a role in the link between gallstone disease and obesity. However, most obese humans are leptin-resistant, and relatively few are leptin-deficient. To confirm that leptin dysfunction is responsible for impaired gallbladder motility in obese mice, we hypothesized that leptin-resistant obese mice (Lep(db)) would have abnormal gallbladder motility while obese mice with intact leptin function (Agouti Yellow, A(y)) would have normal gallbladder motility. MATERIALS AND METHODS: Eighteen lean control (C57BL/6J), 10 A(y) and 12 Lep(db) female mice were fasted overnight, weighed, and livers and gallbladders were harvested. Liver weights and gallbladder volumes were measured. Gallbladder contractile responses (N/cm(2)) to acetylcholine (10(-5)M), neuropeptide Y (10(-8,-7,-6) M) and cholecystokinin (10(-10,-9,-8,-7)M) were determined in muscle bath chambers. Results were analyzed by analysis of various (ANOVA) and with the Mann-Whitney Rank Sum Test. RESULTS: Both Agouti yellow (A(y)) and leptin-resistant (Lep(db)) obese mice had body weights, liver weights and gallbladder volumes that were significantly greater (P < 0.01) than lean control mice. Leptin-resistant obese mice had gallbladder responses to acetylcholine, neuropeptide Y and cholecystokinin that were significantly less (P < 0.01) than both lean control and Agouti yellow obese mice. CONCLUSIONS: These data suggest that (1). leptin-resistant obese mice (Lep(db)) have abnormal gallbladder motility and (2). obese mice with normal leptin metabolism (A(y)) have normal gallbladder response to neurotransmitters. We conclude that leptin represents a link between obesity, gallbladder motility and gallstone formation.     

Decreased gallbladder response in leptin-deficient obese mice

Obesity is a major risk factor for gallstone formation, but the pathogenesis of this phenomenon remains unclear. Human data on gallbladder emptying are conflicting, and no animal data exist on the effect of obesity on gallbladder motility. Leptin, a hormone produced by adipocytes, is known to have central effects on neuropeptide Y and cholecystokinin, but the influence of leptin on the biliary effects of these hormones is unknown. Therefore we tested the hypothesis that leptin-deficient C57BL/6J-lep^ob obese mice would have decreased gallbladder responses to excitatory stimuli. Twelve-week-old lean control (C57BL/6J) (n = 22) and C57BL/6J-lep^ob obese (n = 20) female mice were fed a nonlithogenic diet. The mice were fasted overnight and underwent cholecystectomy. Whole gallbladders were placed in 3 ml muscle baths. After optimal length was determined with acetylcholine (10^-5 mol/L, responses to increasing doses of neuropeptide Y (10^-8 to 10^-6 mol/L) and cholecystokinin-8 (10^-10 to 10^-7 mol/L) were measured. Student’s t test and two-way analysis of variance were used where appropriate. Results were expressed as Newtons per cross-sectional area. The lean control mice had significantly greater excitatory responses to acetylcholine than the obese mice (0.37 ± 0.05 vs. 0.16 ± 0.02, P < 0.01). The gallbladder responses were also greater when mice were treated with neuropeptide Y (10^-8 mol/L: 0.00 ± 0.00 vs. 0.00 ± 0.00, NS; 10^-7 mol/L: 0.12 ± 0.02 vs. 0.05 ± 0.01, P < 0.01; 10^-6 mol/L: 0.26 ± 0.08 vs. 0.06 ± 0.01, P < 0.01) and cholecystokinin (10^-10 mol/L: 0.27 ± 0.04 vs. 0.13 ± 0.02, P < 0.01; 10^-9 mol/L: 0.59 ± 0.08 vs. 0.27 ± 0.04, P < 0.01; 10^-8 mol/L: 0.80 ± 0.11 vs. 0.37 ± 0.05, P < 0.01; 10^-7 mol/L: 0.86 ± 0.11 vs. 0.44 ± 0.06, P < 0.01). These data suggest that genetically obese, leptin-deficient mice have decreased responses to acetylcholine, neuropeptide Y, and cholecystokinin. We conclude that decreased gallbladder motility contributes to the increased incidence of gallstones associated with obesity. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (oral presentation). Supported by grant RO1-DK442 79–07 from the National Institutes of Health.     

Pioglitazone increases gallbladder volume in insulin-resistant obese mice

BACKGROUND: Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione that has been shown to improve insulin resistance. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice fed a 25% carbohydrate diet. MATERIALS AND METHODS: Twenty eight-week-old insulin-resistant obese (Lep(ob)) mice fed a 25% carbohydrate diet for 4 weeks. Half of the animals had 0.3 g/kg pioglitazone added to their diet. At 12 weeks all animals were fasted and underwent cholecystectomy. Gallbladder volume and weight were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine (ACh 10(-5)M), neuropeptide Y (NPY 10(-8,-7,-6)M) and cholecystokinin (CCK 10(-10,-9,-8,-7)M). Serum glucose and insulin were measured, and HOMA Index, a measure of insulin resistance, was calculated. RESULTS: Fasting serum insulin and HOMA Index were significantly decreased (P < 0.03), but gallbladder volume was significantly increased (P < 0.03) in the pioglitazone treated group. Pioglitazone did not alter gallbladder weight or response to ACh, NPY, or CCK. CONCLUSION: These data suggest that in insulin-resistant obese mice pioglitazone 1) lowers insulin-resistance, 2) increases resting gallbladder volume, and 3) does not alter gallbladder response to neurotransmitters. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.     

Leptin-resistant obese mice do not form biliary crystals on a high cholesterol diet

INTRODUCTION: Human obesity is associated with leptin resistance and cholesterol gallstone formation. Previously, we demonstrated that leptin-resistant (Lep(db)) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite elevated serum cholesterol. Obese humans, however, consume a high cholesterol diet. Therefore, we hypothesized that on a high cholesterol diet, leptin-resistant mice would have cholesterol saturated bile and would form biliary crystals. METHODS: Eight-week old female lean control (n = 70) and leptin-resistant (n = 72) mice were fed a 1% cholesterol diet for 4 weeks. All animals then had cholecystectomies. Bile was collected, grouped into pools to determine cholesterol saturation index (CSI), and examined for cholesterol crystals. Serum cholesterol and leptin were also measured. RESULTS: Gallbladder volumes for Lep(db) mice were enlarged compared with the lean mice (35.8 microl versus 19.1 microl, P < 0.001), but the CSI for the Lep(db) mice was lower than for the lean animals (0.91 versus 1.15, P < 0.03). The obese animals did not form cholesterol crystals, whereas the lean animals averaged 2.2 crystals per high-powered field (hpf) (P < 0.001). Serum cholesterol and leptin were also elevated (P < 0.001) in the obese animals. CONCLUSIONS: These data suggest that Lep(db) obese mice fed a high cholesterol diet have increased gallbladder volume and decreased biliary cholesterol saturation and crystal formation despite elevated serum cholesterol compared with lean control mice. We conclude that the link among obesity, diet, and gallstone formation may not require hypersecretion of biliary cholesterol and may be related to the effects of diabetes, hyperlipidemia, or both on gallbladder motility.     

Diabetes and hyperlipidemia correlate with gallbladder contractility in leptin-related murine obesity

Obesity is associated with many comorbid conditions including diabetes, hyperlipidemia, and gallstones. However, the interaction among these modalities remains unclear. We recently demonstrated that both leptin-deficient and leptin-resistant obese mice have impaired biliary motility. These obese mice also are diabetic and hyperlipidemic. Therefore, we tested the hypothesis that serum glucose, insulin, cholesterol, and triglyceride levels would correlate with gallbladder contractility. Thirty-four lean control, 10 lean heterozygous leptin-deficient, 18 obese homozygous leptin-deficient, and 12 obese homozygous leptin-resistant mice were fed a nonlithogenic chow diet while nine lean control and nine obese homozygous leptin-deficient mice were fed a high-cholesterol diet for 4 weeks. In vitro gallbladder responses to cholecystokinin (CCK; 10^-8 mol/L), acetylcholine (ACh; 10^-5 mol/L), and neuropeptide Y (NPY; 10^-6 mol/L) were measured. Serum glucose, insulin, cholesterol, and triglyceride levels were measured from pooled serum from an additional 704 animals. Gallbladder responses were greatest for CCK, intermediate for ACh, and least for NPY. Serum glucose, insulin, cholesterol, and triglyceride levels and body weight all correlated similarly, negatively, and significantly (P < 0.001) with gallbladder contractility. Hyperglycemia, insulin-resistance, hyperlipidemia, and body weight in obese mice with leptin dysfunction are associated with poor gallbladder contractility, which in turn may contribute to the association between obesity and gallstone formation. Presented in part at Digestive Disease Week 2003, SSAT Plenary Session and Residents’ Conference, Orlando, Florida, May 17–22, 2003 (oral presentation); and at the Association for Academic Surgery, Poster Session, Boston, Massachusetts, November 7–9, 2002. Supported by grant NIH R-01 DK44279 from the National Institutes of Health.     

Cyclic motor activity of the gallbladder maintained in a pylorus-preserving gastrectomy in dogs

The gallbladder has cyclic motor activity (CMA), which is impaired after a conventional gastrectomy. We conducted experiments to determine whether or not a pylorus-preserving gastrectomy (PPG) could maintain gallbladder CMA. Six strain gauge force transducers were implanted into the gastrointestinal tract and gallbladder of six dogs, respectively. The motor activity of the gastrointestinal tract and gallbladder was recorded as a control. PPG was then carried out. The phasic contractions of the gallbladder, which were correlated with the antral contractions in the control state, were synchronized with contractions of the pylorus after PPG. Intravenous administration of CCK-OP (40 ng/kg) induced phasic contractions of the gallbladder at 4.6±0.2c/min in 3 of the 6 dogs with gastric contractions. After PPG, the gallbladder had phasic contractions (4.5±0.2c/m), which were synchronized with the contractions of the pylorus in all dogs regardless of the contractions in the remnant stomach. These findings suggest that gallbladder CMA has a closer relationship with the CMA of the pylorus than with the remnant stomach after PPG. Thus, a preservation of the pylorus at the time of gastric surgery will help in maintaining gallbladder function and coordination with the remnant stomach.Supported in part by grant no. 04670789 from the Ministry of Education, Japan.     

Ciliary neurotrophic factor improves nerve conduction and ameliorates regeneration deficits in diabetic rats

Ciliary neurotrophic factor (CNTF) protein and bioactivity are reduced in the peripheral nerve of hyperglycemic rats with a cause related to metabolism of hexose sugars by aldose reductase. Here the efficacy of CNTF treatment against disorders of nerve function in hyperglycemic rats was investigated. CNTF treatment from the onset of 8 weeks of galactose feeding prevented nerve conduction slowing in a dose-dependent manner. Streptozotocin-induced diabetic rats were maintained for 4 weeks before CNTF treatment was initiated. Four weeks of CNTF treatment significantly improved nerve conduction compared with untreated diabetic rats and also normalized the recovery of toe spread after sciatic nerve crush. One week of CNTF treatment significantly improved the distance of sensory nerve regeneration achieved after nerve crush injury compared with untreated diabetic rats. CNTF was without effects on any parameter in nondiabetic rats. Eight weeks of diabetes did not impair macrophage recruitment 1 and 7 days after nerve crush; neither did intraneural injections of CNTF and CNTFRalpha enhance recruitment in diabetic or control rats. These observations point to the potential utility of CNTF in treating nerve dysfunction in experimental diabetes.     

Mechanisms of impaired gallbladder contractile response in chronic acalculous cholecystitis

The mechanisms involved in the impaired gallbladder contractile response in chronic acalculous cholecystitis are unknown. To determine the mechanisms that may lead to impaired gallbladder emptying in chronic acalculous cholecystitis, gallbladder specimens removed during hepatic resection (controls) and after cholecystectomy for chronic acalculous cholecystitis were attached to force transducers and placed in tissue baths with oxygenated Krebs solution. Electrical field stimulation (EFS) (1 to 10 Hz, 0.1 msec, 70 V) or the contractile agonists, CCK-8 (10^-9 to 10^-5) or K⁺ (80 mmol/L), were placed separately in the tissue baths and changes in tension were determined. Patients with chronic acalculous cholecystitis had a mean gallbladder ejection fraction of 12% ± 4%. Pathologic examination of all gallbladders removed for chronic acalculous cholecystitis revealed chronic cholecystitis. Spontaneous contractile activity was present in gallbladder strips in 83% of control specimens but only 29% of gallbladder strips from patients with chronic acalculous cholecystitis (P < 0.05 vs. controls). CCK-8 contractions were decreased by 54% and EFS-stimulated contractions were decreased by 50% in the presence of chronic acalculous cholecystitis (P < 0.05 vs. controls). K⁺-induced contractions were similar between control and chronic acalculous cholecystitis gallbladder strips. The impaired gallbladder emptying in chronic acalculous cholecystitis appears to be due to diminished spontaneous contractile activity and decreased contractile responsiveness to both CCK and EFS. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (poster presentation). Supported by the Veterans Administration Research Service and National Institutes of Health training grant HLO 7485-19.     

Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma: A prospective study of 592 cases

The development of gallbladder carcinoma has been correlated with the presence of a single large gallstone in two retrospective studies. The objective of the present study was to determine the number and size of gallstones in patients with gallbladder carcinoma compared to asymptomatic and symptomatic female patients with gallstones. The following three groups of patients were included in this prospective trial: (A) 78 asymptomatic patients with gallstones; (B) 365 symptomatic patients with gallstones; and (C) 149 patients with gallbladder carcinoma. At the end of the operation, the resected gallbladder was opened and the number of stones counted. The maximum size of the stones was determined using calipers. Patients with gallbladder carcinoma were significantly older than patients in the other two groups (P <0.001). In the group with asymptomatic gallstones, there were significantly more patients with one single stone, whereas in the group with gallbladder carcinoma there were significantly more patients with multiple stones (more than 11; P <0.01). Patients with gallbladder carcinoma had significantly larger stones, regardless of the number of stones present (P <0.001). We postulate that the increase in the number and size of the stones among patients with gallbladder carcinoma could simply be an effect of aging or it could be a reflection of the long-term presence of stones in the gallbladder rather than some particular chemical or physical influence.     

Nonalcoholic fatty gallbladder disease: The influence of diet in lean and obese mice

The obesity epidemic has contributed to an increased prevalence of gallstones and a higher percentage of chronic acalculous cholecystitis. Obesity is associated with Type II diabetes and hyperlipidemia in murine models. In addition, we have previously demonstrated that serum glucose, insulin, cholesterol, and triglycerides correlated with gallbladder contractility in murine models. However, the relative role of in sulin resistance and gallbladder fat infiltration in this phenomenon remain unclear. Therefore, we tested the hypothesis that gallbladder wall lipids are related to obesity and diet and are inversely correlated with gallbladder contractility. One hundred lean control (C7BL/6J) and 36 obese leptin-deficient (Lep^ob) 8-week-old female mice were fed either a chow diet or a 1.0% cholesterol, 15% butterfat (high-lipid) diet for four weeks. Pooled gallbladders were then analyzed for free fatty acids (FFA), phospholipids (PL), total cholesterol (TC), and triglycerides (TG). Cholesterol/phospholipid ratios were then calculated. The Lepob mice fed a chow diet had significantly higher (P<0.01) gallbladder lipids than the three other groups. The lean mice that were fed a high-lipid diet had increased (P<0.05) gallbladder TC compared to the lean mice on a chow diet. In addition, the cholesterol/phospholipid ratio was significantly in creased (P<0.01) in the lean mice fed a high-lipid diet compared to the other three groups. Finally, the high-lipid diet decreased gallbladder FFA (P<0.01), PL (P=0.08), and TC (P<0.05) in Lep^ob mice. These data suggest that (1) obese mice have increased gallbladder lipids; (2) a high-cholesterol, high-fat diet increases gallbladder lipids and the cholesterol/phospholipid ratio in lean mice; but (3) de creases gallbladder fatty acids, phospholipids, and cholesterol in obese mice. Prior studies have docu mented similarly decreased gallbladder response to neurotransmitters in obese mice on a chow diet, as well as lean and obese mice on a high-lipid diet. Therefore, we conclude that leptin-deficient obesity and/or a high-fat diet causes nonalcoholic fatty gallbladder disease, which is manifested by diminished gallbladder contractility. Presented at the 2005 American Hepato-Pancreato-Biliary Association Congress, Hollywood, Florida, April 14–17, 2005. Supported by NIH grant R-01 DK44279.     

红霉素收缩金黄地鼠胆囊的研究

通过离体试验观察红霉素对金黄地鼠胆囊运动的影响，结果发现红霉素可以使正常组和致石组胆囊产生剂量依赖性收缩，而且发现在胆囊结石形成前后红霉素的作用同样存在，红霉素收缩金黄地鼠胆囊的作用可能是通过激活胃动素受体介导的，这一发现有助于胆囊运动能障碍的治疗。     

The effect of phosphodiesterase inhibition on gallbladder motility in vitro

BACKGROUND: Coffee consumption decreases the risk of gallstone disease. The proposed motility effects of caffeine, a phosphodiesterase (PDE) inhibitor, are unknown. The aim of our study was to determine the effect of caffeine and specific PDE inhibitors on gallbladder motility in vitro. METHODS: Gallbladder muscle strips from opossums were attached to force transducers. Baseline tone, electrical field stimulation (EFS)-induced nitric oxide-mediated off responses, and changes in the cholecystokinin (CCK)-8 dose-response relationship were measured. Caffeine; vinpocetine (VIN), type I PDE inhibitor; erythro-9-[2-hydroxy-3-nonyl]adenine HCl (EHNA), type II PDE inhibitor; zarderverine (ZARD), type III/IV PDE inhibitor; Ro 20-1724, type IV PDE inhibitor; and zaprinast (ZAP), type V PDE inhibitor were added to the tissue baths. RESULTS: Caffeine and all specific PDE inhibitors decreased baseline tone. Caffeine, VIN, EHNA, ZARD, Ro 20-1724, and ZAP decreased the EFS-induced off response. Caffeine (10(-5) M) and EHNA increased the CCK-8 dose-response contractions. This effect was not inhibited by atropine. Caffeine increased the tissue levels of cyclic 3',5'-guanosine monophosphate but not cyclic 3',5'-adenosine monophosphate. Caffeine decreases baseline tone and the off response via type I-V PDE pathways. Caffeine also increases CCK-induced gallbladder contractions via type II PDE pathways. CONCLUSION: These effects may be a mechanism that contributes to the decreased gallstone formation with caffeine consumption.     

Effects of ceftriaxone sodium on in vitro gallbladder contractility in guinea pigs

BACKGROUND/PURPOSE: It has been reported that ceftriaxone may induce the formation of gallstones. Changes of gallbladder motility may play a role in this phenomenon. The present study was designed to analyze the gallbladder contractility of ceftriaxone sodium-treated guinea pigs in response to different agonists. MATERIALS AND METHODS: Twenty adult guinea pigs were randomly divided into two groups. Ten guinea pigs were treated with ceftriaxone sodium (100 mg/kg/day) for 10 days, whereas the remaining 10 served as the control group, receiving 1 ml of distilled water during 10 days as placebo. By the end of the experimental period the animals were sacrificed and the gallbladders were removed. The responses to KCl, papaverine, sodium nitroprusside, carbachol, and histamine on gallbladder strips from control and experimental groups were recorded and analyzed. RESULTS: There was no significant difference between the responsiveness to KCl, papaverine, and sodium nitroprusside on tissues isolated from experimental and control groups. Comparison of the two groups revealed that the maximum responses (E(max)) to carbachol and histamine were significantly reduced in the experimental group, without any change in the pD(2) values. CONCLUSION: These data indicate that, after ceftriaxone sodium therapy, the decreased maximum contractile response to carbachol and histamine may contribute to the formation of gallstones.     

Decreased urinary epidermal growth factor levels in diabetic patients

Urinary human epidermal growth factor levels were assayed in diabetic patients and controls before and after surgery. The preoperative levels in the diabetic patients were decreased and postoperatively, did not show the trough and peak pattern which was seen in the controls.     

胆囊结石患者CCK受体mRNA测定的临床意义

目的:探讨胆囊结石患者缩胆囊素(CCK)受体基因表达及其与胆囊排空功能的关系.方法:术前用B超测定100例胆囊结石患者和50例胃癌无胆囊结石患者的胆囊排空功能.胆囊壁CCK受体mRNA表达的测定用RT-PCR法.结果:胆囊结石组CCK受体mRNA表达(0.59±0.11)明显低于对照组(0.91±0.06)(P<0.01),该基因表达的降低与胆囊结石胆囊排空功能损害有关.胆囊结石患者的胆囊平滑肌细胞膜CCK受体mRNA表达与胆囊残余指数(RV/FV×100%)呈负相关(Y=0.61-0.45X,r=-0.65,P<0.01).结论:胆囊结石患者CCK受体基因表达下调与胆囊排空功能的损害有关.     

犬胆囊、Oddi括约肌电活动和胆囊胆总管压力的同步检测

目的探讨同步检测犬胆囊、Oddi括约肌肌电和胆囊、胆总管压力的实验方法。方法采用多通道生理仪同步记录麻醉后犬的胆囊和Oddi括约肌的肌电图以及胆囊、胆总管压力。剖腹显示肝、胆、胃及十二指肠,用7F静脉深穿管经肝穿刺进入胆囊腔内作为测压通道,再将一对铂金电极缝在胆囊底部浆膜上。把另一条7F静脉深穿管制作成带一对铂金电极的胆总管测压和Oddi括约肌肌电检测通道。结果Oddi括约肌峰电位为0．18～0．20mV,频率为2～5次／min;其慢波电位0．06～0．08mV,频率为8～10次／min,峰电位往往在某次慢波电位的基础上突然出现。胆囊肌电不明显。胆囊的压力为7～9cmH2O,胆总管压力为11～15cmH2O。结论同步检测Oddi括约肌肌电活动与胆囊、胆总管压力的实验方法是可行的,有利于研究Oddi括约肌肌电活动与胆囊及胆总管压力的关系,但是对于记录在体胆囊的肌电活动方法需要进一步改进。     

Effect of peritonitis on gallbladder smooth muscle contractility in guinea pigs

BACKGROUND: The mechanisms involved in the impaired gallbladder contractile response in peritonitis are unknown. The aim of this study was to determine the effect of peritonitis on the contraction and relaxation responses to different agonists in gallbladder smooth muscle in guinea pig. MATERIALS AND METHODS: Peritonitis was induced by cecal ligation and puncture (CLP) in 10 guinea pigs. Another group of 10 guinea pigs underwent a sham operation and acted as controls. Twenty-four hours after the operation, the guinea pigs were killed, and gallbladder strips were placed in organ bath. The contraction responses to KCl, carbachol, and histamine, and relaxation responses to cyclooxygenase inhibitors (indomethacin, nimesulide, and DFU) on KCl-induced contractions were recorded. RESULTS: There was no significant difference between the contractile responsiveness to KCl, but maximum contractile responses (E(max)) to carbachol and histamine were significantly reduced. Indomethacin, nimesulide, and DFU concentration dependently inhibited on KCl-induced contractions of gallbladder smooth muscle. E(max) values of indomethacin, nimesulide, and DFU were significantly reduced in the peritonitis group compared with controls (P < 0.05). The inhibitor effects of nimesulide and DFU were considerably similar, but inhibitor effect of indomethacin was significantly less than that measured for nimesulide and DFU in both control and peritonitis groups (P < 0.05). CONCLUSIONS: The contraction responses to carbachol and histamine and relaxation responses to COX inhibitors on gallbladder smooth muscle are significantly decreased by peritonitis. Although the mechanism of the decrease in contraction and relaxation responses in CLP-induced peritonitis is completely unknown, we speculate that impaired smooth muscle responses may be related to an alteration in the regulation of receptor/postreceptor excitation-response coupling and/or through changes on Ca(2+) influx.     

PTGBD联合LC对高龄急性胆囊炎合并糖尿病的疗效分析

目的 探讨经皮经肝胆囊穿刺引流(PTGBD)联合腹腔镜胆囊切除术(LC)对高龄急性胆囊炎合并糖尿病患者的疗效。方法 本回顾性研究以44例高龄急性胆囊炎合并糖尿病患者为研究对象,根据LC术前接受的治疗情况不同分为研究组(PTGBD组,n=20)和对照组(保守治疗组,n=24)。比较两组患者术中、术后各项指标的变化情况和并发症发生率。结果 研究组平均手术时间[(52.78±6.65)min vs(72.56±10.63)min]、术中出血量[(12.10±2.77)mL vs (18.52±2.47)mL]和术后住院时间[(5.85±0.75)d vs (8.91±1.09)d]均少于对照组(P<0.05),研究组首次排气时间[(20.33±2.99)h vs (28.27±4.38)h]及早期下床活动时间[(28.66±3.29)h vs (39.31±4.33)h]均早于对照组(P<0.05)。两组患者术后1 d的WBC、CRP、VAS评分差异没有统计学意义,但术后3 d两组WBC[(5.84±1.01)×10⁹/L vs (6.72±0.67)×10...