Histiocytic infiltration in ulcerative colitis, simulating malignancy.
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Aged↗
Biomedical subjects
C M Edwards
Publications and source records attributed to C M Edwards.
'Microscopic colitis': classification and terminology.
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Algorithms↗
Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem.
The orexins are neuropeptides originally reported to be involved in the stimulation of food intake. However, analysis of orexin immunoreactive fibres have revealed the densest innervation in brain sites involved in arousal and sleep-wake control, notably the noradrenergic locus coeruleus, an area that also expresses orexin receptor 1 (OX1R) messenger RNA (mRNA). We report here that, in the rat, a single intracerebroventricular injection of orexin A (1 and 3 nmol) or orexin B (3 nmol), during the early light phase, did not increase food intake over the first 4 h postinjection. However, the frequency of active behaviors such as grooming, rearing, burrowing and locomotion increased. Feeding behavior and food intake subsequently decreased over the following 20 h (4-24 h postinjection period) in the orexin A 3 nmol injected group whilst the frequency of inactive behavior (still or asleep) in this group increased. Using riboprobes, we performed in situ hybridization histochemistry to map the distribution of orexin receptor 2 (OX2R) mRNA within the rat brainstem. We report here, for the first time, the presence of OX2R mRNA in the nucleus of the solitary tract and the lateral reticular field (LRt). The LRt is a brainstem site that, amongst other functions, is implicated in attention and wakefulness. This distribution of OX2R and the effects on behavior support recent reports that the orexins might modulate central nervous system arousal and sleep-wake mechanisms rather than exclusively being involved in the control of food intake.
Animals↗
Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers.
Exendin-4 is a long-acting potent agonist of the glucagon-like peptide 1 (GLP-1) receptor and may be useful in the treatment of type 2 diabetes and obesity. We examined the effects of an intravenous infusion of exendin-4 (0.05 pmol. kg(-1). min(-1)) compared with a control saline infusion in healthy volunteers. Exendin-4 reduced fasting plasma glucose levels and reduced the peak change of postprandial glucose from baseline (exendin-4, 1.5 +/- 0.3 vs. saline, 2.2 +/- 0.3 mmol/l, P < 0.05). Gastric emptying was delayed, as measured by the paracetamol absorption method. Volunteers consumed 19% fewer calories at a free-choice buffet lunch with exendin-4 (exendin-4, 867 +/- 79 vs. saline 1,075 +/- 93 kcal, P = 0.012), without reported side effects. Thus our results are in accord with the possibility that exendin-4 may be a potential treatment for type 2 diabetes, particularly for obese patients, because it acts to reduce plasma glucose at least partly by a delay in gastric emptying, as well as by reducing calorie intake.
Acetaminophen↗
Oxyntomodulin inhibits food intake in the rat.
Oxyntomodulin is derived from proglucagon processing in the intestine and the central nervous system. To date, no role in the central nervous system has been demonstrated. We report here that oxyntomodulin inhibits refeeding when injected intracerebroventricularly and into the hypothalamic paraventricular nucleus of 24-h fasted rats [intracerebroventricularly and into the paraventricular nucleus, 1 h, oxyntomodulin (1 nmol), 3.1 +/- 0.5 g; saline, 6.2 +/- 0.4 g; P < 0.005]. In addition, oxyntomodulin inhibits food intake in nonfasted rats injected at the onset of the dark phase (intracerebroventricularly, 1 h: oxyntomodulin, 3 nmol, 1.1 +/- 0.19 g vs. saline, 2.3 +/- 0.2 g; P < 0.05). This effect of oxyntomodulin on feeding is of a similar time course and magnitude as that of an equimolar dose of glucagon-like peptide-1. Other proglucagon-derived products investigated [glucagon, glicentin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol), and spacer peptide-1 (intracerebroventricularly and into the paraventricular nucleus, 3 nmol)] had no effect on feeding at any time point examined. The anorectic effect of oxyntomodulin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol) was blocked when it was coadministered with the glucagon-like peptide-1 receptor antagonist, exendin-(9-39) (intracerebroventricularly, 100 nmol; into the paraventricular nucleus, 10 nmol). However, oxyntomodulin has a lower affinity for the glucagon-like peptide-1 receptor compared with glucagon-like peptide-1 (IC(50): oxyntomodulin, 8.2 nM; glucagon-like peptide-1, 0.16 nM). One explanation for this is that there might be an oxyntomodulin receptor to which exendin-(9-39) can also bind and act as an antagonist.
Animals↗
Cocaine- and amphetamine-regulated transcript, glucagon-like peptide-1 and corticotrophin releasing factor inhibit feeding via agouti-related protein independent pathways in the rat.
The melanocortin-4 receptor (MC4-R) appears to be an important downstream mediator of the action of leptin. We examined to what extent the anorectic effects of cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1) and corticotrophin releasing factor (CRF) might be mediated via MC4-R. alpha-Melanocyte stimulating hormone (alpha-MSH), the MC4-R agonist, administered intracerebroventricularly (ICV) at a dose of 1 nmol reduced food intake by approximately half. Agouti-related protein (Agrp) (83-132), a biologically active fragment of the endogenous MC4-R antagonist, administered ICV at a dose of 1 nmol completely blocked the anorectic effect of 1 nmol alpha-MSH. CART (55-102) (0.2 nmol), GLP-1 (3 nmol) and CRF (0.3 nmol) produced a reduction in feeding of approximately the same magnitude as 1 nmol alpha-MSH. Agrp (83-132) (1 nmol) administered ICV did not block the anorectic effects of CART (55-102) (1 h food intake, 0.2 nmol CART (55-102), 2.7+/-0.8 g vs. CART (55-102)+Agrp (83-132), 2.6+/-0.6 g, P=0.87; saline control 5.4+/-0.3 g, P<0.001 vs. both groups). Agrp (83-132) also did not block the anorectic effects of GLP-1 or CRF (1 h food intake, 0.3 nmol CRF, 0.7+/-0.3 g vs. CRF+Agrp (83-132), 0.7+/-0.3 g, P=0.91; 3 nmol GLP-1, 1.9+/-0.4 g vs. GLP-1+Agrp (83-132), 1.1+/-0. 5 g, P=0.23; saline control 5.0+/-0.6 g, P<0.001 vs. all four groups). Thus, as previous data suggests, GLP-1 and CRF do not appear to reduce food intake predominantly via MC4-R, we here demonstrate for the first time that CART, in addition to GLP-1 and CRF primarily acts via Agrp independent pathways.
Agouti-Related Protein↗
Role of a defunctioning stoma in the management of large bowel Crohn's disease.
BACKGROUND: The faecal stream plays a significant role in the pathogenesis of Crohn's disease. This retrospective study aimed to assess the effect of faecal diversion on the natural history of refractory Crohn's colitis (RCC) and severe perianal disease (PAD). METHODS: All patients undergoing a defunctioning stoma without resection for RCC or PAD between 1970 and 1997 were studied. Indications for surgery, acute clinical response, subsequent outcome and stoma rates were recorded. RESULTS: Some 73 patients underwent a defunctioning stoma (55 RCC and 18 PAD). Acute remission was achieved in 63 patients (48 RCC, 15 PAD). Twenty-nine patients had subsequent closure of the defunctioning stoma (25 of 48 acute responders with RCC and four of 15 acute responders with PAD). Eleven patients with RCC and two with PAD achieved good long-term function without disease relapse (median follow-up 36 months). Overall 52 patients have undergone proctocolectomy or remain with a defunctioning stoma (37 with RCC and 15 with PAD). CONCLUSION: Faecal diversion is associated with acute clinical remission in the majority of patients with RCC and PAD, but sustained benefit occurs less often. For selected patients, diversionary surgery alone offers a realistic alternative to major bowel resection.
Adult↗
Diet-induced change in fatty acid composition of plasma triacylglycerols is not associated with change in glucagon-like peptide 1 or insulin sensitivity in people with type 2 diabetes.
BACKGROUND: Polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) have been shown to positively affect blood lipids; however, their comparative effects on insulin sensitivity are unclear. OBJECTIVE: Our objective was to investigate whether chronic intake of MUFAs or PUFAs improves insulin sensitivity in people with type 2 diabetes via stimulation of the endogenous gut hormone glucagon-like peptide 1 [7-36] amide (GLP-1). DESIGN: Nine overweight people with type 2 diabetes received isoenergetic high-MUFA (20.3 +/- 3.5% of total energy) or high-PUFA (13.4 +/- 1. 3%) diets for 24 d in a randomized, double-blind crossover design. RESULTS: Weight and glycemic control remained stable throughout the study. Despite a significant change in the plasma triacylglycerol linoleic-oleic acid ratio (L:O) with both diets (MUFA: from 0.46 +/- 0.03 to 0.29 +/- 0.02, P: < 0.005; PUFA: from 0.36 +/- 0.04 to 0.56 +/- 0.05, P: < 0.05) and the phospholipid L:O (1.7 +/- 0.1 to 2.0 +/- 0.3; P: = 0.04) during consumption of the PUFA diet, this change was not associated with a change in insulin sensitivity, measured by the short-insulin-tolerance test. There was a significant reduction in the ratio of total to HDL cholesterol during consumption of the PUFA diet (5.2 +/- 0.4 compared with 4.7 +/- 0.3; P: = 0.005) but no change with the MUFA diet. There was no change in the fasting or postprandial incremental area under the curve in response to an identical standard test meal for glucose, insulin, triacylglycerol, nonesterified fatty acids, or GLP-1. CONCLUSIONS: Over the 3-wk intervention period, diet-induced change in the triacylglycerol or phospholipid L:O was not associated with either increased stimulation of GLP-1 or a change in insulin sensitivity in people with type 2 diabetes.
Blood Glucose↗
The differential effects of galanin-(1-30) and -(3-30) on anterior pituitary hormone secretion in vivo in humans.
Intravenous injection of galanin increases plasma growth hormone (GH) and prolactin (PRL) concentrations. In the rat, the effects of galanin on GH appear to be mediated via the hypothalamic galanin receptor GAL-R(1), at which galanin-(3-29) is inactive. In contrast, the effect of galanin on PRL is mediated via the pituitary-specific galanin receptor GAL-R(W), at which galanin-(3-29) is fully active. We investigated the effects of an intravenous infusion of human galanin (hGAL)-(1-30) and -(3-30) on anterior pituitary hormone levels in healthy females. Subjects were infused with saline, hGAL-(1-30) (80 pmol. kg(-1). min(-1)), and hGAL-(3-30) (600 pmol. kg(-1). min(-1)) and with boluses of gonadotropin-releasing hormone, thyrotropin-releasing hormone, and growth hormone-releasing hormone (GHRH). Both hGAL-(1-30) and -(3-30) potentiated the rise in GHRH-stimulated GH levels [area under the curve (AUC), saline, 2,810 +/- 500 vs. hGAL-(1-30), 4,660 +/- 737, P < 0.01; vs. hGAL-(3-30), 6, 870 +/- 1,550 ng. min. ml(-1), P < 0.01]. In contrast to hGAL-(1-30), hGAL-(3-30) had no effect on basal GH levels (AUC, saline, -110 +/- 88 vs. hGAL 1-30, 960 +/- 280, P < 0.002; vs. hGAL-(3-30), 110 +/- 54 ng. min. ml(-1), P = not significant). These data suggest that the effects of galanin on basal and stimulated GH release are mediated via different receptor subtypes and that the human equivalent of GAL-R(W) may exist.
Adult↗
The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.
Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.
Agouti-Related Protein↗
Neuropeptide Y in the sheep fetus: effects of acute hypoxemia and dexamethasone during late gestation.
Plasma concentrations of neuropeptide Y (NPY) were measured in pregnant ewes and their fetuses under basal conditions and in response to acute hypoxemia during late gestation. The effects of fetal treatment with dexamethasone on these NPY responses were also examined. Under general anesthesia, 10 Welsh Mountain ewes and their fetuses were chronically instrumented between 117-120 days gestation (dGA; term is approximately 145 dGA) with vascular and amniotic catheters, and an ultrasonic probe around a femoral artery of each fetus. At 124 dGA, five fetuses were continuously infused i.v. with dexamethasone for 48 h at a rate of 1.73 +/- 0.16 microg x kg(-1) x h(-1) while the remaining five fetuses received vehicle at the same rate. At 126 dGA, 45 h from the onset of either infusion, 1 h of materno-fetal hypoxemia was induced by reducing maternal FiO2. During normoxia, maternal plasma NPY concentrations were three times those measured in fetal plasma in both groups. During hypoxemia, PaO2 fell to similar levels in the control and dexamethasone-treated groups in both mothers and fetuses. In control animals, there was a significant increase in the NPY concentration in fetal, but not maternal, plasma during hypoxemia. Fetal treatment with dexamethasone significantly enhanced the fetal NPY response to acute hypoxemia but had no effects on basal NPY levels in the fetal or maternal plasma or on the maternal response to acute hypoxemia. These data show: 1) differences between the maternal and fetal plasma NPY response to maternal inhalation hypoxia; 2) that NPY may play a role in mediating fetal defense responses to acute hypoxemia; and 3) that fetal exposure to glucocorticoids modifies the fetal plasma NPY response to acute hypoxemia.
Animals↗
Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone.
The melanocortin-4 receptor (MC4R) in the hypothalamus is thought to be important in physiological regulation of food intake. We investigated which hypothalamic areas known to express MC4R are involved in the regulation of feeding by using alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous MC4R agonist, and agouti-related peptide (Agrp), an endogenous MC4R antagonist. Cannulae were inserted into the rat hypothalamic paraventricular (PVN), arcuate (Arc), dorsomedial (DMN), and ventromedial (VMN) nuclei; the medial preoptic (MPO), anterior hypothalamic (AHA), and lateral hypothalamic (LHA) areas; and the extrahypothalamic central nucleus of the amygdala (CeA). Agrp (83-132) (0.1 nmol) and [Nle4, D-Phe7]alpha(-MSH (NDP-MSH) (0.1 nmol), a stable alpha-MSH analog, were administered to fed and fasted rats, respectively. The PVN, DMN, and MPO were the areas with the greatest response to Agrp and NDP-MSH. At 8 h postinjection, Agrp increased feeding in the PVN by 218 +/- 23% (P < 0.005), in the DMN by 268 +/- 42% (P < 0.005), and in the MPO by 236 +/- 31% (P < 0.01) compared with a saline control group for each nucleus. NDP-MSH decreased food intake in the PVN by 52 +/- 6% (P < 0.005), in the DMN by 44 +/- 6% (P < 0.0001), and in the MPO by 55 +/- 6% (P < 0.0001) at 1 h postinjection. Injection into the AHA and CeA resulted in smaller alterations in food intake. No changes in feeding were seen after the administration of Agrp into the Arc, LHA, or VMN, but NDP-MSH suppressed food intake in the Arc and LHA. This study indicates that the hypothalamic nuclei expressing MC4R vary in their sensitivity to Agrp and alpha-MSH with regard to their effect on feeding.
Agouti-Related Protein↗
The cutaneous vasoconstrictor response to venous stasis is normal in subjects with primary Raynaud's disease.
In control subjects and in subjects with primary Raynaud's disease, sudden sound or a mild cool stimulus evokes the pattern of alerting response that includes cutaneous vasoconstriction but vasodilatation in forearm muscle. In control subjects, response habituates on repetition of these stimuli both within experimental sessions and over successive days. However, in subjects with primary Raynaud's disease, the cutaneous vasoconstriction and the muscle vasodilatation persist. We have now tested whether a similar disparity exists for the cutaneous vasoconstriction evoked by venous stasis, a response considered to be a veno-arteriolar reflex mediated by sympathetic fibers, but not requiring transmission through the spinal cord. In 10 subjects with primary Raynaud's disease and in 10 matched controls, a sphygmomanometer cuff on the left arm was inflated to 40 mm Hg for 2 minutes, five times on each of three experimental sessions on days 1, 3, and 5. Cutaneous red cell flux (RCF) was recorded from the pulp and dorsum of the left index finger by using a laser Doppler meter; digital vascular conductance (DCVC) was computed as RCF divided by arterial pressure. The first venous stasis, in session 1, evoked a decrease in pulp and dorsum DCVC in the control and primary Raynaud's subjects. There were no differences between the groups in the magnitudes or durations of these responses. Within session 1, the magnitude of the decrease in DCVC diminished on repetition of venous stasis in the dorsum in controls and in the pulp in primary Raynaud's subjects. We propose these effects reflected the similar reductions in baseline DCVC over time; there was no change in the duration of the responses. Repetition of venous stasis had similar effects in both groups of subjects within sessions 2 and 3. Further, judging from the mean of the responses evoked in each Session the decreases evoked in pulp and dorsum DCVC by venous stasis were fully consistent in magnitude and duration over the three sessions in both groups. These results indicate that the direct constrictor influence of sympathetic fibers upon cutaneous blood vessels is similar in magnitude and similarly reproducible in controls and subjects with primary Raynaud's disease. This reinforces our view that the lack of habituation of the cutaneous vasoconstrictor component of the alerting response in subjects with primary Raynaud's disease reflects impairment of the central neural process of habituation, rather than a peripheral phenomenon, and that this lack of habituation predisposes these subjects to vasospasm.
Adult↗
The incretins--outdated terminology in man?
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Animals↗
Diversion colitis--new light through old windows.
Diversion proctocolitis is an iatrogenic disorder caused by surgical diversion of the faecal stream away from the colorectal mucosa. Such surgery may be necessary in cases of tumour, trauma or inflammatory conditions of the colorectum. Histopathological change is characterized by a chronic lymphoplasmacytic inflammatory infiltrate, and the hallmark feature, lymphoid follicular hyperplasia. Histological appearances are determined by the disease state of the colonic mucosa prior to faecal diversion. Macroscopic appearances may vary considerably, but often include aphthoid ulceration. The exact pathogenesis of the condition remains unclear, but the removal of short-chain fatty acids, present in the faecal stream, is considered an important aetiological factor. Current research areas, including the microbiology and cellular kinetics of diversion colitis, are discussed along with clinical features and treatments.
Bacteria↗
Peptides as drugs.
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Anti-Bacterial Agents↗
Ileal pouch-anal anastomosis for Crohn's disease.
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Colitis, Ulcerative↗
Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat.
Central nervous system glucagon-like peptide-1-(7-36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (i.c.v.) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9-39), affects food intake and body weight. Daily i.c.v. injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 +/- 5 g (P < 0.02 compared with saline-injected controls). Daily i.c.v. administration of 30 nmol exendin-(9-39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 +/- 2 g (P < 0.02 compared with saline-injected controls). Twice daily i.c.v. injections of 30 nmol exendin-(9-39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 +/- 4 g compared with 14 +/- 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to i.c.v. GLP-1 or exendin-(9-39). GLP-1 may thus be involved in the regulation of body weight in the rat.
Animals↗