Delayed puberty and response to testosterone in a rat model of colitis.

Delayed puberty is a frequent complication of inflammatory bowel disease. The precise etiological mechanisms are not known. In this study, we wanted to determine the relative contribution of undernutrition and inflammation to delayed puberty and the effect of inflammation on the reproductive axis. Puberty was assessed in rats with 2,4,6-trinitrobenzenesulfonic acid induced-colitis, healthy controls, and animals pair fed to match the food intake of the colitic group. The response to testosterone administration was assessed in colitic rats. We found that induction of colitis was associated with hypophagia and reduced weight gain, and undernutrition in healthy females (i.e., pair fed) resulted in a delay in the onset (by 4.8 days, P < 0.001) and progression of puberty (normal estrous cycles in 42%, P = 0.04) compared with controls. However, puberty was further delayed in the colitic group (1.4 days after pair fed) with the absence of normal estrous cycling in all rats. In males, the onset of puberty was also delayed, and weights of accessory sex organs were reduced compared with pair-fed controls. Plasma testosterone concentrations were low, and gonadotropin concentrations were normal in colitic rats. Testosterone treatment normalized puberty in male rats with colitis. In conclusion, in rats with experimental colitis, inflammation appears to potentiate the effect of undernutrition on puberty. The weights of secondary sex organs and the onset of puberty were normalized by testosterone treatment.

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat.

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.

Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis.

BACKGROUND: Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known. AIMS: To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis. METHODS: Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation). RESULTS: Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44-60%. CONCLUSIONS: It seems likely that approximately 30-40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.

Octreotide in the treatment of intestinal lymphangiectasia.

Primary intestinal lymphangiectasia is characterized by dilated small bowel lymphatics and loss of lymph into the bowel lumen resulting in hypoproteinaemia and oedema. Some patients have a more generalized lymphatic abnormality associated with lymphoedema of the limbs and chylous pleural effusions. There is no specific treatment although enteric protein loss may decrease with a low-fat diet. This report describes a patient with severe primary intestinal lymphangiectasia, associated with limb oedema and recurrent pleural effusions, who responded to treatment with octreotide. Before starting octreotide she required weekly intravenous albumin infusions to maintain the serum albumin above 20 g/l. Bilateral pleural effusions repeatedly reaccumulated despite pleurectomy and subsequently tetracycline pleurodesis. Treatment with octreotide, 200 microg twice daily, resulted in a reduction in enteric protein loss from 16 to 4.1% in 5 days (normal less than 1%) and the serum albumin was maintained between 22 and 26 g/l without the need for albumin infusion. Oedema in the arms resolved completely and the pleural effusions did not reaccumulate. The mechanism of action of octreotide in this condition appears to be due to a reduction in gut protein loss and another, as yet unidentified, action.

Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction.

BACKGROUND: Surgery in patients with malignant bile duct obstruction is associated with high postoperative morbidity and mortality. Tumour necrosis factor alpha (TNF-alpha) plays a key role in the pathogenesis of these complications. AIMS: To determine the effect of biliary drainage on plasma concentrations of TNF-alpha, its soluble circulating receptors (sTNFr), and other proinflammatory cytokines. METHODS: Plasma concentrations of TNF-alpha, sTNFr-P75, interleukin 6 (IL-6), and IL-1 alpha were measured in 25 patients with malignant bile duct obstruction before and after endoscopic stent insertion. RESULTS: Mean serum bilirubin was 157 mumol/l before stent insertion and 35.2 mumol/l one week post stent insertion. There was complete relief of jaundice in 77% of patients by four weeks. Plasma concentrations of TNF-alpha and IL-1 alpha were below the detection limit of the assays in all samples. Median plasma sTNFr-P75 in the cancer patients was 960 ng/l (range 400-6600), before stent insertion and remained unchanged at one and four weeks after stenting. Plasma sTNFr-P75 in cancer patients was significantly higher (p < 0.01) than in healthy controls (250 (200-650) ng/l). Before stent insertion, plasma IL-6 concentrations were detectable (above 5 ng/l) in 17 (68%) patients. After relief of biliary obstruction IL-6 levels fell from a prestent median of 13.2 to less than 5 ng/l at one week after stent insertion. Plasma concentrations of IL-6 were undetectable in 76% of patients at this time. CONCLUSION: Activation of the TNF/sTNFr complex is unchanged after biliary drainage in patients with malignant bile duct obstruction. This may explain why preoperative drainage does not influence the high morbidity and mortality associated with surgery in these patients.

An evaluation of the safety of mixed micelles in healthy subjects.

BACKGROUND: Fat and water soluble vitamins are an essential part of i.v. nutrition (IVN). However, they are unstable in solution and may adhere to the bags and tubing containing the IVN. This study has examined the safety and side-effect profile of mixed micelles (mixed bile-salt lecithin micelles) used to solubilize water and fat soluble vitamins for i.v. administration. METHODS: Two groups of six healthy male subjects received either placebo or mixed micelles daily for 5 days by i.v. infusion in a randomized crossover design with a 9-day washout period separating the two treatment periods. RESULTS: Infusion of mixed micelles resulted in a significant increase in serum glycocholic acid from a median of 26.5 micrograms/dL (interquartile range 18 to 38) to 115 micrograms/dL (70 to 155) postinfusion. Glycocholic acid may have a lytic effect on cell membranes; however, in this study there was no evidence of hemolysis or increase in serum transaminases during mixed micelle infusion. There was no increase in reported side effects during mixed micelle infusion compared with placebo. CONCLUSION: Mixed micelles can be used safely for the solubilization of fat- and water-soluble vitamins and drugs that are to administered by i.v. injection.

Is intervention necessary after a first episode of acute idiopathic pancreatitis?

Acute idiopathic pancreatitis is a term used when no underlying cause has been identified on routine investigation. However, more specialised investigations may identify aetiological factors, biliary sludge and sphincter of Oddi dysfunction for example, in 38-72% of patients with recurrent episodes. Treatment of these abnormalities may prevent further episodes of pancreatitis. The aim of this study was to follow up and determine the outcome in patients with a first episode of idiopathic pancreatitis, and thus determine the need for further investigation and treatment in this group of patients. Thirty one patients with a single episode of idiopathic pancreatitis were studied who had no specialised investigations or specific treatment. During a median follow up of 36 months only one patient has had recurrent pancreatitis. Two patients experienced a single episode of unexplained abdominal pain; serum amylase, liver biochemistry, and abdominal ultrasound were all normal and the pain resolved within 48 hours. In conclusion, in the medium term, the prognosis is good after a first episode of idiopathic pancreatitis and specialised investigation is unnecessary.

L-phenylalanine releases cholecystokinin (CCK) and is associated with reduced food intake in humans: evidence for a physiological role of CCK in control of eating.

Exogenous administration of cholecystokinin (CCK) reduces food intake in humans; however, it is not clear if endogenous CCK is a true satiety hormone. The aim of this experiment was to manipulate endogenous release of CCK using L-phenylalanine (L-PA), a potent releaser of CCK, and to measure subsequent food intake. On separate occasions, six normal-weight fasted subjects (four men, two women) were administered 10 g of L-PA, D-PA, or placebo 20 minutes before being presented with a standard meal of known calorie content. Preliminary experiments had shown that peak plasma concentrations of CCK were obtained 20 minutes after administering L-PA. The test meal was given to coincide with this peak. One hundred-millimeter visual analog scales (VAS) to assess hunger, desire to eat, and fullness were completed premeal, postmeal, and at intervals thereafter. Blood was taken before administering PA/placebo immediately premeal and postmeal and stored for measurement of CCK levels by bioassay. Subjects consumed 1,089 +/- 86 kcal after L-PA (P = .03) compared with 1,587 +/- 174 kcal after placebo and 1,492 +/- 126 kcal after D-PA. The reduction in calorie intake after L-PA was associated with a significantly greater sensation of fullness. Basal levels of CCK were 1.10 +/- 0.12 pmol/L; 20 minutes after L-PA, CCK levels increased to 5.49 +/- 0.83 pmol/L. There was no increase in CCK following D-PA or placebo. Release of CCK by L-PA is associated with a reduction in subsequent food intake, and this suggests that CCK is an important satiety hormone in humans.

Symptom relief and quality of life after stenting for malignant bile duct obstruction.

Palliative treatment is appropriate for most patients with cancer of the head of pancreas. Insertion of a biliary stent relieves jaundice and pruritus but it is not known if stenting affects other symptoms or changes the quality of life. Nineteen patients have completed a standard questionnaire to assess symptom relief and quality of life after stent insertion. After stenting there was complete relief of jaundice and pruritus. Furthermore, there was also considerable improvement in anorexia and indigestion. All patients had anorexia before stent insertion, this was moderate/severe in 13 (68.4%). Anorexia was significantly better (p < 0.01) a week after stenting and this benefit was maintained at 12 weeks (p < 0.01). Sixteen (84.2%) patients complained of indigestion before stenting, moderate/severe in 11 (57.9%). This was significantly better (p < 0.01) a week after stenting with complete relief in six at eight weeks (p < 0.01). Fifteen (78.9%) felt that their mood was good/very good before stent insertion and this was unchanged even at the 12 week assessment. A similar result was obtained for physical health and level of activity. In conclusion stent insertion not only relieves jaundice and pruritus in these patients but also improves other symptoms and quality of life. The considerable improvement in appetite after stenting was of particular benefit.

Erythromycin induces supranormal gall bladder contraction in diabetic autonomic neuropathy.

Gall bladder motor function is impaired in some patients with diabetes. It has been suggested that the abnormalities of gall bladder motility are confined to those patients with autonomic neuropathy. Erythromycin, a motilin receptor agonist, causes gall bladder contraction in both normal subjects and patients with gall stones with impaired gall bladder emptying. The effect of erythromycin on gall bladder motility in seven patients with diabetes with an autonomic neuropathy, six patients with diabetes without autonomic neuropathy, and 17 normal subjects was studied using ultrasound. There was no significant difference in gall bladder fasting volume between the three groups, but the patients with diabetes with autonomic neuropathy had impaired postprandial gall bladder emptying compared with normal subjects (percentage emptied (SEM) 40 (10.3)% v 64 (2.8)%, p < 0.01) and those with autonomic neuropathy (48 (7.7)%, NS). Erythromycin produced a dramatic reduction in gall bladder fasting volume in patients with diabetes with an autonomic neuropathy, compared with either normal subjects or patients with diabetes without autonomic neuropathy (percentage reduction 62 (4.6)% in patients with autonomic neuropathy, v 37 (17.6)% in those without autonomic neuropathy, and 26 (7.3)% in the normal subjects, (p < 0.02) and returned gall bladder emptying to normal in all patients with impaired emptying. The pronounced effect of erythromycin in diabetic autonomic neuropathy suggests denervation supersensitivity and that the action of erythromycin on the gall bladder is neurally modulated.

Dose-dependent stimulation of gallbladder contraction by intravenous erythromycin in man.

We have previously shown that a single oral dose of 500 mg erythromycin causes gallbladder contraction. The effect of intravenous erythromycin on antroduodenal motility is dose-dependent; < 3 mg/kg body weight stimulates propagated contractions in a fashion similar to motilin while doses > 7 mg/kg cause giant non-propagated antral contractions not seen with motilin. Using ultrasound, we have examined the effect of differing doses of intravenous erythromycin on gallbladder motility in man. Erythromycin (1 mg/kg) caused fasting gallbladder contraction to 52% of basal gallbladder volume (P < 0.001), and increased gallbladder emptying following a liquid meal (maximal percentage emptied 75 +/- 6.8% vs. 58 +/- 9.0% following saline, P < 0.05). Erythromycin (7 mg/kg) however, had no effect on gallbladder fasting or post-prandial motor activity. We conclude that the effect of erythromycin on gallbladder motility is dose-dependent, with higher doses having no effect. It is possible that at higher doses erythromycin stimulates other receptors in addition to the motilin receptor, and that the combined effect is different to the stimulation of the motilin receptor alone.