Elevated fasting cholecystokinin levels in pancreatic exocrine impairment: evidence to support feedback regulation

Previous studies have suggested that intraduodenal protease suppression of pancreatic exocrine secretion may be mediated through cholecystokinin (CCK) release. Our study compares basal plasma immunoreactive CCK concentrations in normal human subjects with those obtained in patients with chronic pancreatitis. Fasting plasma samples were collected from 18 normal subjects and from 18 patients with chronic pancreatitis. Eight patients had mild to moderate pancreatic exocrine impairment, and 10 had severe exocrine insufficiency. Venous plasma immunoreactive CCK concentrations were measured with two distinct peptide region-specific antibodies. Basal plasma CCK concentration in controls was 14.3 +/- 1.3 fmol/ml (mean +/- SEM), a value significantly less than that obtained in all patients with chronic pancreatitis, 30.1 +/- 4.0 fmol/ml (p less than 0.001). Patients with mild to moderate impairment had a fasting plasma CCK concentration of 32.8 +/- 7.9 fmol/ml (vs. control p less than 0.01), and those with severe disease 27.9 +/- 3.6 fmol/ml (vs. control p less than 0.001). In five patients with mild to moderate impairment of exocrine function and pancreatic extract-responsive abdominal pain, there was a 39 +/- 11% decrease in basal CCK levels during extract therapy (p less than 0.05). Results of this study indicate that pancreatic exocrine impairment is associated with elevated basal CCK levels, which may reflect a failure to provide feedback downmodulation of CCK release.     

伊马替尼治疗慢性粒细胞白血病疗效分析

目的分析伊马替尼治疗慢性粒细胞白血病（CML）的疗效,进一步探讨影响伊马替尼疗效的因素。方法63例慢性粒细胞白血病患者,给予口服伊马替尼治疗;其中慢性期（CP）51例,加速期（AP）5例,急变期（BP）7例。结果完全血液学缓解率（CHR）：CP94．1％（48／51）,AP40．0％（2／5）,BP28．6％（2／7）,累计82．5％（52／63）;完全遗传学缓解率（CCR）：CP60．8％（31／5]）,AP20．0％（1／5）,BP14．3％（1／7）,累计52．4％（33／63）;部分遗传学缓解率（MCR）：CP82．4％（42／51）,AP40．0％（2／5）,BP28．6％（2／7）,累计73．0％（46／63）。可评估分子效应的21例患者中,8例达完全分子效应（38．1％）,4例发生主要分子效应（19．0％）,累计57．1％（12／21）。血液学不良反应主要为不同程度的血细胞减少和骨髓抑制,可通过调整剂量或药物治疗控制。非血液学不良反应（如恶心、水肿等）发生率较高,但大多程度轻微且可耐受或自行消失。结论伊马替尼治疗慢性粒细胞白血病有较高的完全血液学缓解率和遗传学缓解率及分子效应,不良反应轻微。常见血液学不良反应为中性粒细胞减少、血小板减少,非血液学不良反应为消化道反应及轻度水肿,大多程度轻微,患者能够耐受。个体化正规治疗有望进一步提高疗效。     

Managing acute and chronic pancreatitis

Pancreatitis may be acute or chronic. Although both can be caused by similar aetiologies, they tend to follow distinct natural histories. Around 80% of acute pancreatitis (AP) diagnoses occur secondary to gallstone disease and alcohol misuse. AP is commonly associated with sudden onset of upper abdominal pain radiating to the back that is usually severe enough to warrant the patient seeking urgent medical attention. Onset of pain may be related to a recent alcohol binge or rich, fatty meal. The patient may appear unwell, be tachycardic and have exquisite tenderness in the upper abdomen. Overall, 10-25% of AP episodes are classified as severe, leading to an associated mortality rate of 7.5%. Disease severity is best predicted from a number of clinical scoring systems which can be applied at diagnosis in association with repeated clinical assessment, measurement of acute inflammatory markers, and CT. All patients with suspected AP should be referred urgently. Chronic pancreatitis (CP) follows continued, repetitive or sustained injury to the pancreas and 70% of diagnoses occur secondary to alcohol abuse. The characteristic presenting feature of CP is insidious progression of chronic, severe, upper abdominal pain, radiating to the back, caused by a combination of progressive pancreatic destruction, inflammation and duct obstruction. Signs and symptoms include weight loss and steatorrhoea and later on diabetes. CP patients may also present with recurrent episodes mimicking AP, both symptomatically and metabolically. Diagnosis of CP should be based on symptom profile, imaging and assessment of exocrine and endocrine pancreatic function. CT should be the first-line imaging investigation.     

慢性髓系白血病不同bcr/abl融合基因转录子与临床关系的研究

目的研究慢性髓系白血病(CML)bcr/abl融合基因转录子类型与临床的关系.方法采用RT-PCR技术检测537例临床怀疑CML的患者新鲜骨髓标本三种bcr/abl(M、m及μ型)融合基因的表达.结果 479例CML患者 M-bcr/abl阳性,其中慢性期(CP)370例,加速/急变期(AP/BC)109例,CP期和AP/BC期患者表达b2a2型融合基因转录子的百分率分别为32.4%(370例中120例)及36.7%(109例中40例)(P>0.05),急淋变及急髓变患者b2a2型百分率分别为52.6%(19例中10例)及33.3%(90例中30例) (P>0.05);b3a2型患者初诊时外周血血小板数明显高于b2a2型患者[(485.9±333.8)×109/L] vs [(380.5±321.9)ⅹ109/L](P<0.05);66.0%CP及64.4%AP/BC患者同时表达M-bcr/abl及m-bcr/abl;1例单纯m-bcr/abl(+)患者表现为急性髓系白血病(AML);2例μ-bcr/abl(+)患者均具有典型CML表现.结论典型CML患者几乎均为M-bcr/abl融合基因阳性,大部分患者同时伴有m-bcr/abl表达,个别CML患者可以为μ型;除了急性淋巴细胞白血病(ALL)外,单纯m-bcr/abl(+)也可见于AML或CML急粒变的患者; b3a2型患者初诊时更易有血小板数增高表现.     

Protein status in pancreatitis--transthyretin is a sensitive biomarker of malnutrition in acute and chronic pancreatitis.

Malnutrition may develop in acute pancreatitis (AP), accompanied by hypermetabolism and high nutritional requirements, and in chronic pancreatitis (CP). We measured the incidence of protein malnutrition in AP and CP by comparing different serum biomarkers of protein metabolism and inflammation. Thirty-five patients with acute (27 moderate, 8 severe), and 35 with chronic, pancreatitis were enrolled in the study. Serum transthyretin, albumin, transferrin and C-reactive protein (CRP) concentrations were measured in AP at admission, after 1 and 2 weeks of jejunal feeding, and in patients with CP at follow-up. In AP, at admission the transthyretin level was low in 74%, transferrin in 48%, and albumin in 29% of patients. In severe pancreatitis, transthyretin levels were significantly lower than in moderate forms (7.5 +/- 2.43 vs. 14.39 +/- 6.8 mg/dl, p < 0.005). Transthyretin levels increased significantly after 2 weeks of jejunal feeding (p < 0.05). In CP, transthyretin levels were decreased in 37%, transferrin in 27%, and albumin in 12% of patients. We found significantly lower transthyretin levels in alcohol-related CPthan in other forms (18.5 +/- 8.3 vs. 30.2 +/- 5.7, p < 0.01). Transthyretin correlated positively with albumin and transferrin and negatively with CRP Transthyretin seems to be a sensitive biomarker of protein status and metabolic stress. Monitoring nutritional status through measurement of serum proteins is important for optimal treatment of AP and CP.     

Efficacy and safety of imatinib in treatment of 151 chronic myeloid leukemia patients]

OBJECTIVE: To evaluate the safety and efficacy of imatinib in treatment of chronic myeloid leukemia (CML) patients. METHODS: From December 2003 to March 2007, 151 patients entered Glivec International Patient Assistance Program (GIPAP) in our center and received imatinib therapy. The overall and progression free survival, hematologic, cytogenetic and molecular response, and adverse events were evaluated. The factors associated with outcome of imatinib therapy were also analysed. RESULTS: One hundred and forty-two patients were evaluable with a median follow-up duration of 21.5 (6 -78) months. (1) The rate of cumulative complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and complete molecular response (CMoR) in chronic phase (CP) CML patients were 96.9%, 82.6%, 76.1% and 29.4%, respectively. These rates were significantly higher in patients with CP than in those with accelerated phase (AP) and blast crisis (BC) (P < 0.0001). (2) The overall survival (OS) rates at 1, 2 and 3 year were 100%, (97.3 +/- 1.9)% and (95.8 +/- 2.4)% for CP patients, they were (84.7 +/- 8.2)%, (77.0 +/- 10.4)% and (69.3 +/- 11.9)% for AP patients, and (62.9 +/- 8.9)%, (41.9 +/- 9.2)% and (28.5 +/- 9.1)% for BC patients, respectively (P < 0.0001). The progression-free survival (PFS) rates at 1, 2 and 3 year were (98.9 +/- 1.1)%, (93.9 +/- 2.7)%, (93.9 +/- 2.7)% for CP patients, (68.9 +/- 10.6)%, (61.3 +/- 11.9)%, (61.3 +/- 11.9)% for AP patients, (36.4 +/- 8.8)%, (25.4 +/- 8.1)%, (10.1 +/- 8.2)% (P < 0.0001) for BC patients respectively. (3) Among 92 CP patients, the rates of MCyR and CCyR in newly diagnosed patients were significantly higher than those in interferon therapy failure patients (P = 0.015, P = 0.010). Patients obtained CCyR at 12 months after the initiation of imatinib treatment were associated with longer PFS (P = 0.0099). According to the Sokal scoring system, the rates of MCyR and CCyR in low-risk patients were significantly higher than those in intermediate-risk and high-risk patients (P = 0.0013, P = 0.0024). Sokal score was also significantly associated with disease progression (P = 0.0467). (4) The adverse events of imatinib were moderate and tolerable. CONCLUSIONS: Treatment of CML patients in CP with imatinib can induce high hematologic, cytogenetic and molecular response and overall survival, but can not do satisfactorily for patients in AP and BC.     

Evaluation of a radioimmunoassay for cholecystokinin in human plasma

A sensitive and specific radioimmunoassay for cholecystokinin (CCK) in human plasma was developed using an antiserum specific for sequence 26-29 of CCK-33 and 125I-Bolton-Hunter labelled sulphated CCK-8 as tracer. Plasma was extracted in 96% ethanol before assay. The detection limit of the assay was 0.3 pmol/l. CCK-33 and CCK-8 were stable in plasma at 0 degree C for at least 3 h, but CCK-8 was degraded at 21 degrees C. The trypsin inhibitor, aprotinin, did not affect the degradation of CCK-8, while the aminopeptidase inhibitor, bestatin, had a significant inhibitory effect. The basal plasma concentration of CCK in 44 normal subjects was 1.6 +/- 0.2 pmol/l, ranging from undetectable (less than 0.3 pmol/l) to 4.4 pmol/l. After the ingestion of a mixed meal in seven normal subjects, concentrations of plasma CCK rose from 2.0 +/- 0.2 to 7.4 +/- 0.7 pmol/l. Diurnal registration in nine people showed similar increments after each meal. The validity of the assay was further substantiated by a strong correlation between CCK measurements of identical samples with other CCK specific antisera.     

Meal-stimulated cholecystokinin release and exocrine pancreatic secretion in dogs

To confirm the role of cholecystokinin (CCK) and secretin in digestion, exocrine pancreatic secretion, plasma CCK, and secretin were measured simultaneously in six dogs prepared with gastric and pancreatic fistulas after feeding a solid meal. Plasma CCK concentration determined by radioimmunoassay increased significantly from the basal level, reached a peak 35 min after meal ingestion, and after a dip it further increased toward the end of the 3-h observation. Pancreatic protein output increased significantly, peaked at the fifth 10-min period, and then declined progressively. Plasma CCK concentration and pancreatic protein output correlated significantly during the first postprandial hour. Plasma secretion demonstrated significant elevation at 15 min and a peak at 25 min after a meal. Plasma secretin correlated significantly with both bicarbonate output and flow rate during the 3 h. Simultaneous measurements of plasma CCK and secretin and of pancreatic secretion suggested that postprandial pancreatic secretion is primarily mediated by releases of CCK and secretin, but these hormones do not seem to be the only factors responsible for the secretion.     

伊马替尼治疗95例慢性粒细胞白血病的远期疗效及其影响因素分析

目的 分析伊马替尼治疗慢性粒细胞白血病(CML)的疗效和患者生存情况,并初步探讨影响伊马替尼疗效的因素.方法 对2002年5月至2006年5月接受伊马替尼治疗的95例CML患者随访至2006年10月31日,分析患者的治疗转归及相关影响因素.结果 ①慢性期组伊马替尼治疗后12个月95.5%患者获得完全血液学缓解(CHR);其中遗传学资料完整的52例患者中初治19例,复治33例,初治组治疗后6、12、18、24、30个月的主要细胞遗传学缓解(MCyR)率分别为84.2%、84.2%、89.5%、89.5%和94.7%,复治组分别为36.4%、39.4%、39.4%、39.4%和39.4%,两组比较差异有统计学意义(P＜0.01);全组患者治疗后12、24、36、50个月预期生存率分别为(98.1±1.9)%、(87.8±7.1)%、(81.9±8.7)%和(81.9±8.7)%.②加速期组伊马替尼治疗后12个月70%患者获得CHR,10%获得MCyR;治疗后12、24和36个月预期生存率分别为(63.0±17.7)%、(15.8±14.3)%和(15.8±14.3)%.③急变期组伊马替尼治疗后6个月57.9%患者获得CHR;治疗后12、24个月预期生存率分别为(40.6±12.3)%和0.④对慢性期组进行COX多因素预后分析显示,伊马替尼治疗前有无其他治疗是影响无进展生存和获得MCyR的独立预后不良因素.结论 ①伊马替尼作为一线治疗药物用于CML慢性期,对患者生存质量的改善明显优于作为替换治疗药物或用于加速、急变期治疗,因此伊马替尼应明确作为首选的一线治疗药物.②伊马替尼治疗加速期和急变期CML也能获得一定血液学、遗传学疗效,延长患者生存期.     

External respiration function and quality of life in patients with bronchial asthma in correction of selenium deficiency

AIM: To examine the effect of selenium (Se) adjuvant therapy on external respiration function (ERF) and quality of life (QOL) in bronchial asthma (BA) patients. MATERIAL AND METHODS: 26 patients with BA received standard therapy and adjuvant 200 mcg/day selenium (SelenoPRECISE, PharmaNord, Denmark) for 16 weeks. ERF was estimated by FEV1 and FVC, QOF--by the response to Juniper Adult Asthma Quality of life Short Questionnaire (AQLQ-S) at initiation and end of the study. Difference with the baseline was assessed using Paired Samples T-Test, SPSS 14.0. RESULTS: Paired-samples T-test showed that FVC increased significantly from 76.5 +/- 23.8% to 81.8 +/- 23.2% (p = 0.015). FEV1 showed a significant increase from 62.3 +/- 29.6% to 67.7 +/- 28.1% (p = 0.018). Total AQLQ score elevated from 3.25 to 4.71 (p = 0.01). CONCLUSION: Correction of Se deficiency in BA patients on standard therapy improves ERF and BA-related QOL. Mechanisms of a protective Se action are involved in antioxidant defense by means of Se participation in enzymatic detoxication of peroxides and a stabilizing effect on biomembranes.     

Isometric handgrip training does not improve flow-mediated dilation in subjects with normal blood pressure

Isometric HG (handgrip) training lowers resting arterial BP (blood pressure), yet the mechanisms are elusive. In the present study, we investigated improved systemic endothelial function as a mechanism of arterial BP modification following isometric HG training in normotensive individuals. This study employed a within-subject repeated measures design primarily to assess improvements in BA FMD (brachial artery flow-mediated dilation; an index of endothelium-dependent vasodilation), with the non-exercising limb acting as an internal control. Eleven subjects performed four 2-min unilateral isometric HG contractions at 30% of maximal effort, three times per week for 8 weeks. Pre-, mid- and post-training resting ABP and BA FMD (exercised arm and non-exercised arm) were measured via automated brachial oscillometry and ultrasound respectively. BA FMD (normalized to the peak shear rate experienced in response to the reactive hyperaemic stimulus) remained unchanged [exercised arm, 0.029+/-0.003 to 0.026+/-0.003 to 0.029+/-0.004%/s(-1) (pre- to mid- to post-training respectively); non-exercised arm, 0.023+/-0.003 to 0.023+/-0.003 to 0.024+/-0.003%/s(-1) (pre- to mid- to post-training respectively); P=0.22]. In conclusion, improved systemic endothelial function is unlikely to be responsible for lowering arterial BP in this population.     

Regulation of gastric emptying in humans by cholecystokinin.

In the present study we used a bioassay system for measuring plasma cholecystokinin (CCK) to evaluate whether CCK has a physiologic role in regulating gastric emptying in humans. Plasma CCK levels and gastric emptying after ingestion of a mixed liquid meal were determined in five normal male volunteers. Fasting CCK levels averaged 0.8 +/- 0.1 pM and increased to 6.5 +/- 1.0 pM within 10 min of drinking the mixed meal. CCK levels remained elevated for up to 90 min. Gastric emptying after a meal was slow; at the end of the 90 min 68% of the original volume remained in the stomach. The rate of gastric emptying of water was then measured in the same individuals with a simultaneous infusion of either saline, or one of two doses of CCK (12 pmol/kg per h and 24 pmol/kg per h). With the saline infusion, plasma CCK levels did not increase above basal and gastric contents emptied rapidly. At the end of 90 min only 7% of the original volume remained in the stomach. The lower dose of CCK resulted in a plasma level of 3.4 pM which both reproduced the average postprandial plasma level and caused a significant delay in gastric emptying. The higher dose of CCK achieved plasma levels of 8 pM and resulted in a delay in gastric emptying that was similar to that seen with the mixed meal. Since exogenous CCK at concentrations which occur postprandially delays gastric emptying, we conclude that CCK is a physiologic regulator of gastric emptying.     

Serotonin and superior mesenteric artery resistance index

OBJECTIVE: Serotonin is a vasoactive neuroendocrine substance and serotonergic drugs are promising agents for the treatment of functional gastrointestinal disorders. The effect of serotonin on superior mesenteric blood flow in humans is unknown. The aim of this study was to examine the effect of exogenous serotonin on superior mesenteric artery blood flow, as estimated by the resistance index with Doppler ultrasound, in healthy human volunteers. MATERIAL AND METHODS: Six fasting healthy adult volunteers of both genders were studied. Transabdominal Doppler ultrasound was used to evaluate the effects of either a standard meal or intravenous infusion of serotonin (2.5-20 nmol kg-1 min-1) on the superior mesenteric artery resistance index, platelet-depleted plasma levels of serotonin, blood pressure, heart rate and electrocardiogram. RESULTS: All subjects had the same patterns of response to meal and serotonin stimulation. Meal stimulation decreased the mean resistance index from 0.84+/-0.04 to 0.72+/-0.02 (p = 0.0004) and increased platelet-depleted-plasma levels of serotonin from 50+/-36 to 61+/-46 nmol L-1 (p = 0.04). Serotonin stimulation increased the mean resistance index from 0.82+/-0.04 to 0.88+/-0.03 (p = 0.006) and mean platelet-depleted-plasma levels of serotonin from 44+/-24 to 83+/-37 nmol L-1 (p = 0.03). Most subjects reported minor short-lived adverse effects. Electrocardiogram results were unchanged during all examinations. CONCLUSIONS: We conclude that intravenous infusion of serotonin increases the resistance index of the superior mesenteric artery (increases downstream resistance) in healthy adult volunteers.     

Postprandial exocrine pancreatic function during long-term treatment with the somatostatin analogue SMS 201–995 in acromegalic patients

Long-term treatment with the somatostatin analogue SMS 201-995 (SMS) might impair exocrine pancreatic function, secretion of cholecystokinin (CCK) and pancreatic polypeptide (PP), and pancreatic size. In five acromegalics on chronic treatment with SMS, we investigated postprandial 6-h urinary excretion of p-aminobenzoic acid (PABA) and p-aminosalicylic acid (PAS) after s.c. injection of 100 micrograms SMS or placebo and after ingestion of 2 mmol nBT-PABA and 2 mmol PAS. In the acromegalics, urinary PABA/PAS ratio (reflecting exocrine pancreatic function) after SMS was similar to that after placebo (P greater than 0.10) and higher than in healthy volunteers (n = 8, P = 0.05). The initial inhibition of plasma CCK secretion by SMS was cancelled during the 3rd h after the meal, whereas PP release remained completely abolished. Pancreatic size as measured by ultrasonography, was not reduced in seven acromegalics compared with 14 healthy volunteers. It is concluded that despite a blunted release of the trophic hormone CCK, long-term treatment with SMS 201-995 neither induces an abnormally small pancreas nor deterioration of postprandial exocrine pancreatic function in patients with acromegaly.     

Effect of apolipoprotein E polymorphism on serum uric acid levels in healthy subjects.

BACKGROUND: We have previously shown that apolipoprotein E (apo E-) polymorphism may affect serum creatinine concentration and predicted glomerular filtration rate in healthy individuals. On the other hand, there are limited data regarding the possible influence of apo E- polymorphism on serum uric acid (SUA) levels. METHODS: Two hundred ninety (148 male, 142 female) apparently healthy white individuals were studied. apo E- genotypes, serum lipid parameters including apolipoproteins, insulin resistance using the homeostasis model assessment (HOMA) as a marker, serum and urine creatinine levels, and serum and urine uric acid concentration were determined in all participants. RESULTS: The apo E-2 allele was associated with lower serum levels of total cholesterol, higher levels of triglycerides and apo E-, and increased serum creatinine concentration compared with the apo E-3 and apo E-4 alleles in our population. Furthermore, the apo E-2 allele was associated with higher SUA levels (321.3+/-101.1 micrmol/L [5.4+/-1.7 mg/dL]) compared with the apo E-3 allele (261.8+/-89.2 micromol/L [4.4+/-1.5 mg/dL]; p= .012) and the apo E-4 allele (243.9+/-65.4 micromol/L [4.1+/-1.1 mg/dL]; p= .010), whereas the apo E-2 allele was associated with a nonsignificantdecrease in the fractional renal excretion of uric acid (FEUA) compared with the apo E-3 and apo E-4 alleles (7.9+/-2.2% vs 8.7+/-4.2% vs 8.9+/-5.1%, respectively; p = .53). These observations remained statistically significant when the effect of apo E- polymorphism on SUA levels was adjusted for gender, age, systolic and diastolic blood pressure, body mass index, serum creatinine, and triglyceride and apo E- levels, as well as for HOMA index and FEUA. CONCLUSIONS: Our data provide evidence, for the first time, that the apo E-2 allele is independently associated with increased SUA levels in healthy individuals.     

Prognostic value of the degree of night decrease of systolic pressure in patients with mild and moderate forms of hypertension (7-9-year prospective study)

AIM: To study a relationship between a carcadian blood pressure (BP) rhythm and cardiovascular events (CE) during 7-9 year follow-up in males with mild to moderate essential hypertension (EH). MATERIAL AND METHODS: 50 males (mean age 48.6 +/- 0.7 years) with mild to moderate EH were prospectively followed up for 7-9 years (8.4 +/- 0.1 years). We analysed 24-h BP recordings and protocol of echocardiography performed during the first hospitalization. The patients were divided into three groups: group 1 (n = 18) with normal (10-20%) nocturnal fall of systolic BP (NF SBP) and normal left ventricular mass index (LVMI < 125 g/m2); group 2 (n = 16) with insufficient (< 10%) NF SBP and normal LVMI; group 3 (n = 16) with LVMI > 125 g/m2. In these groups we assessed the prevalence of CE: myocardial infarction (MI), stroke (S), sudden death (SD), new cases of angina pectoris (AP), transient cerebral ischemic attack (TIA). RESULTS: No significant differences were found between the groups by mean age, body mass index, duration of arterial hypertension, mean 24-h and awake systolic and diastolic BP while significant differences were by nighttime BP profile parameters. During the follow-up 16 CE in 12 patients were documented (3 fatal and 13 nonfatal). In group 1 CE were observed in 1 patient (twice MI), in group 2-7 cases of CE (1 S, 1 TCIA, 2 MI, 2 AP) in 6 patients, in group 3-7 cases (2 MI, 3 TIA, 2 AP) in 5 patients, 3 of them were fatal. CONCLUSION: Insufficient nocturnal fall of SBP (< 10%) is an adverse prognostic factor for cardiovascular morbidity in mild to moderate essential male hypertensives.     

Radioimmunoassay of cholecystokinin in plasma

A sensitive and specific radioimmunoassay for cholecystokinin (CCK) has been developed. Synthetic unsulfated carboxy-terminal fragment, CCK-8, was radioiodinated by the conventional Chloramine-T method. Antibodies were raised against sulfated CCK-8 covalently coupled to bovine thyroglobulin via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. By purification, highly immunoreactive 125I-labeled CCK-8 was obtained. The antiserum was highly avid, and plasma could be assayed directly. The detection limit of the assay was 5 pmol of sulfated CCK-8 per liter. The assay measured fragments CCK-8, CCK-33, and CCK-39 with equimolar potency. CCK-4, gastrin, and vasoactive intestinal polypeptide were not detected, even at higher concentrations. The concentration of CCK, as the sum of these CCK peptides, in plasma during fasting was low (10.5 +/- 2.1 pmol/L, mean +/- SEM) but still detectable in all normal subjects examined (range, 6.4-20.1 pmol/L). After ingestion of a test meal, CCK in plasma increased rapidly, peaking at 41.3 (SEM 5.7) pmol/L at 40 min and remaining high for 3 h after the meal. This supports the concept that CCK has important roles in digestion and absorption.     

The effect of equicaloric medium-chain and long-chain triglycerides on pancreas enzyme secretion

It has been shown previously that medium chain triglycerides (MCT) do not affect gallbladder emptying and cholecystokinin (CCK) release. The effect of MCT on exocrine pancreas secretion in humans is unknown. We have compared the effect of enteral administration of MCT versus long chain triglycerides (LCT) on exocrine pancreatic secretion. Eight healthy subjects (three female, five male; mean age 22 +/- 1.9 years) participated in two experiments, performed in random order. Duodenal contents, obtained by aspiration, were used to calculated the output of pancreatic enzymes and bilirubin. An equicaloric amount of either MCT or LCT (2 kcal min-1) oil was continuously administered in the proximal jejunum for 2 h. Gallbladder volume was measured by ultrasonography and blood samples were drawn for determination of CCK. The experiments consisted of 1 h basal secretion, 2 h of continuous oil administration and 1 h poststimulation. During the LCT feeding the pancreatic enzyme secretion, bilirubin output, gallbladder emptying and CCK release increased significantly (P < 0.05) over basal levels. MCT had no effect on pancreatic enzyme secretion nor gallbladder emptying or CCK release. We conclude that enteral administration of MCT in the proximal jejunum does not stimulate exocrine pancreatic secretion nor gallbladder contraction or CCK release, in contrast to an equicaloric amount of LCT.     

Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction.

A sensitive and specific bioassay for the measurement of cholecystokinin (CCK) in human plasma was developed to determine the molecular forms of CCK in circulation, CCK responses to feeding, and the physiologic role of CCK in gallbladder contraction. First, plasma was quantitatively extracted and concentrated with octadecylsilylsilica, and the extracts were then assayed for their ability to stimulate amylase release from isolated rat pancreatic acini. Acini were highly sensitive to CCK whereas gastrin reacted only weakly in this system. With the assay, plasma levels of cholecystokinin octapeptide (CCK-8) bioactivity as low as 0.2 pM were detectable. CCK bioactivity in plasma was inhibited by the CCK antagonist, bibutyryl cyclic guanosine monophosphate, and was eliminated by immunoadsorption with an antibody directed against the carboxyl terminus of CCK. Detection of fasting levels of CCK was possible in all individuals tested and averaged 1.0 +/- 0.2 pM (mean +/- SE, n = 22) CCK-8 equivalents. Plasma CCK biological activity was normal in patients with gastrin-secreting tumors. After being fed a mixed liquid meal, CCK levels rose within 15 min to 6.0 +/- 1.6 pM. The individual food components fat, protein, and amino acids were all potent stimulants of CCK secretion; in contrast, glucose caused a significant but smaller elevation in plasma CCK levels. Gel filtration studies identified three major forms of CCK bioactivity in human plasma: an abundant form that eluted with CCK-33, a smaller form that eluted with CCK-8, and an intermediate form that eluted between CCK-33 and CCK-8. Ultrasonic measurements of gallbladder volume indicated that this organ decreased 51% in size 30 min after feeding a mixed liquid meal. This contraction occurred coincidentally with the increase in plasma CCK levels. Next CCK-8 was infused to obtain CCK levels similar to postprandial levels. This infusion caused a decrease in gallbladder volume, similar to that seen with a meal. The present studies indicate, therefore, that CCK can be bioassayed in fasting and postprandial human plasma. These studies also suggest that CCK may be an important regulator of gallbladder contraction.     

Lundh meal: a single non-invasive challenge test for evaluation of exocrine and endocrine pancreatic function in cystic fibrosis patients

The determination of endocrine and exocrine pancreatic function in cystic fibrosis patients is clinically important. Recently, a new non-invasive test, in which pancreatic stimulation by a Lundh meal is followed by sequential serum lipase measurements, was found to be a good indicator of exocrine pancreatic status. Since the Lundh meal also contains glucose, the present study assessed whether it also might be suitable for evaluation of the pancreatic endocrine axis. After an overnight fast, 10 healthy non-diabetic subjects and 14 cystic fibrosis patients ingested a Lundh meal. Glucose, insulin, and C peptide levels were measured at various time intervals following the meal. For purposes of comparison, the oral glucose tolerance test was also performed on the cystic fibrosis patients. All healthy subjects demonstrated an increase in glucose levels post Lundh meal, peaking at 45 min (mean 140+/-21 mg/dl) and then gradually declining and reaching the normal range at 120 min. Concordant peaks of insulin (46.3+/-20 IU/ml) and C peptide (5.8+/-1. 5 ng/ml) levels were noted at 60 min. All 14 cystic fibrosis patients had normal basal glucose levels: in 8, the pattern of glucose, insulin, and C peptide post Lundh meal was similar to that of the healthy controls. These 8 patients also had a normal oral glucose tolerance test, and their hemoglobin A(1C) levels were within the normal range. The other 6 cystic fibrosis patients demonstrated glucose levels above 200 mg/dl 30-60 min post Lundh meal, and all also had an impaired oral glucose tolerance test. Of these 6, 4 had high levels of hemoglobin A(1C). This study demonstrates that the Lundh meal challenges the endocrine pancreas as well as the oral glucose tolerance test. Thus, determination of both exocrine and endocrine pancreatic status can be achieved by a single non-invasive test.