Acupuncture for hot flashes in patients with prostate cancer.

OBJECTIVES: To determine the effect of acupuncture on hot flash frequency and intensity, quality of life, and sleep quality in patients undergoing hormonal therapy for prostate cancer. Hot flashes are a common adverse effect of hormonal therapy for prostate cancer. METHODS: Men who had a hot flash score > 4 who were receiving androgen deprivation therapy for prostate cancer underwent acupuncture with electrostimulation biweekly for 4 weeks, then weekly for 6 weeks, using a predefined treatment plan. The primary endpoint was a 50% reduction in the hot flash score after 4 weeks of therapy, calculated from the patients' daily hot flash diaries. The hot flash-related quality of life and sleep quality and biomarkers potentially related to hot flashes, including serotonin, calcitonin gene-related peptide, and urinary 5-hydroxyindoleacetic acid, were examined. RESULTS: A total of 25 men were enrolled from September 2003 to April 2007. Of these, 22 were eligible and evaluable. After 4 weeks, 9 (41%, 95% confidence interval 21%-64%) of 22 patients had had a > 50% reduction in the hot flash score. Of the 22 patients, 12 (55%, 95% confidence interval 32%-76%) met this response definition at any point during the therapy course. No patient had a significant increase in hot flash score during therapy. A reduced hot flash score was associated with improvement in the hot flash-related quality of life and sleep quality. CONCLUSIONS: Multiple placebo-controlled trials have demonstrated a 25% response rate to placebo treatment for hot flashes. Of the 22 patients, 41% had responded by week 4 and 55% overall in the present pilot study, providing evidence of a potentially meaningful benefit. Additional studies of acupuncture for hot flashes in this population are warranted.

NSAID prescribing precautions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used, but have risks associated with their use, including significant upper gastrointestinal tract bleeding. Older persons, persons taking anticoagulants, and persons with a history of upper gastrointestinal tract bleeding associated with NSAIDs are at especially high risk. Although aspirin is cardioprotective, other NSAIDs can worsen congestive heart failure, can increase blood pressure, and are related to adverse cardiovascular events, such as myocardial infarction and ischemia. Cyclooxygenase-2 inhibitors have been associated with increased risk of myocardial infarction; however, the only cyclooxygenase-2 inhibitor still available in the United States, celecoxib, seems to be safer in this regard. Hepatic damage from NSAIDs is rare, but these medications should not be used in persons with cirrhotic liver diseases because bleeding problems and renal failure are more likely. Care should be used when prescribing NSAIDs in persons taking anticoagulants and in those with platelet dysfunction, as well as immediately before surgery. Potential central nervous system effects include aseptic meningitis, psychosis, and tinnitus. Asthma may be induced or exacerbated by NSAIDs. Although most NSAIDs are likely safe in pregnancy, they should be avoided in the last six to eight weeks of pregnancy to prevent prolonged gestation from inhibition of prostaglandin synthesis, premature closure of the ductus arteriosus, and maternal and fetal complications from antiplatelet activity. Ibuprofen, indomethacin, and naproxen are safe in breastfeeding women. Care should be taken to prevent accidental NSAID overdose in children by educating parents about correct dosing and storage in childproof containers.

Effects of intravenous fructose on gastric emptying and antropyloroduodenal motility in healthy subjects.

Gastric emptying (GE) of glucose is regulated closely, not only as a result of inhibitory feedback arising from the small intestine, but also because of the resulting hyperglycemia. Fructose is used widely in the diabetic diet and is known to empty from the stomach slightly faster than glucose but substantially slower than water. The aims of this study were to determine whether intravenous (iv) fructose affects GE and antropyloroduodenal motility and how any effects compare to those induced by iv glucose. Six healthy males (age: 26.7 +/- 3.8 yr) underwent concurrent measurements of GE of a solid meal (100 g ground beef labeled with 20 MBq (99m)Tc-sulfur colloid) and antropyloroduodenal motility on three separate days in randomized order during iv infusion of either fructose (0.5 g/kg), glucose (0.5 g/kg), or isotonic saline for 20 min. GE (scintigraphy), antropyloroduodenal motility (manometry), and blood glucose (glucometer) were measured for 120 min. There was a rise in blood glucose (P < 0.001) after iv glucose (peak 16.4 +/- 0.6 mmol/l) but not after fructose or saline. Intravenous glucose and fructose both slowed GE substantially (P < 0.005 for both), without any significant difference between them. Between t = 0 and 30 min, the number of antral pressure waves was less after both glucose and fructose (P < 0.002 for both) than saline, and there were more isolated pyloric pressure waves during iv glucose (P = 0.003) compared with fructose and saline (P = NS for both) infusions. In conclusion, iv fructose slows GE and modulates gastric motility in healthy subjects, and the magnitude of slowing of GE is comparable to that induced by iv glucose.

Integration of acupuncture into family medicine teaching clinics.

OBJECTIVES: As growing numbers of patients use complementary and alternative medicine (CAM), improvement is needed in communication between providers of CAM and allopathic medicine. This study describes collaborative acupuncture clinics (CACs) run by providers from Oregon Health and Science University (OHSU) and the Oregon College of Oriental Medicine (OCOM) in the setting of family medicine teaching clinics. It examines patient demographics, quality of education for medical learners, referral practices of primary care physicians (PCPs), and quality of communication between acupuncturists and PCPs at these clinics. DESIGN: Demographic data were abstracted from electronic medical records of patients treated at least three times in the CACs between 2006 and 2007. A survey on quality of education at the CACs was given to acupuncture interns, medical students, and acupuncture supervisors. A separate survey collected information from PCPs at the family medicine clinics regarding referral practices to acupuncture and quality of communication between PCPs and acupuncturists. RESULTS: Of the 96 patients seen at the clinics, 74% were female, 76% were European-American, and the mean age was 45.9 years. Sixty-one percent (61%) of patients were insured through private insurance, 31.3% had Medicare or Medicaid, and 7.3% did not have insurance. Most of the 51 acupuncture providers who responded were satisfied with the quality of education at the CACs. Eighty percent of responding PCPs had referred at least one patient to the CACs. The majority of referrals was for a pain condition. Most PCPs would find a summary of the acupuncture visit helpful. Referral practices to different modalities were most influenced by patient interest and physician's belief in whether or not the modality would help. CONCLUSIONS: Demographics of patients at the CACs were comparable to those of patients seen in other acupuncture clinics. The collaborative structure of the CACs allowed for a unique learning experience and improved communication between providers of CAM and conventional medicine.

Transient, early release of glucagon-like peptide-1 during low rates of intraduodenal glucose delivery.

CONTEXT: The "incretin" hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), account for some 60% of the stimulation of insulin by oral glucose, but the determinants of their secretion from the small intestine are poorly understood. Cells which release GIP (K cells) are localized to the proximal small intestine, while GLP-1 releasing cells (L cells) predominate in the distal gut. It has been suggested that a threshold rate of duodenal glucose delivery (approximately 1.8 kcal/min) needs to be exceeded for stimulation of GLP-1. OBJECTIVE: To determine whether a low intraduodenal glucose load (1 kcal/min) has the capacity to stimulate GLP-1, and if so, the characteristics of the response. DESIGN: Retrospective analysis of all studies in our laboratory involving healthy humans administered intraduodenal glucose at 1 kcal/min for 120 min. SETTING: Clinical research laboratory. PARTICIPANTS: 27 healthy subjects (24 male; age 36+/-3 years; BMI 25.2+/-0.7 kg/m(2)). MAIN OUTCOME MEASURES: Plasma GLP-1, GIP, insulin, and blood glucose concentrations, reported as mean+/-SEM. RESULTS: During intraduodenal glucose, plasma GLP-1 increased at 15 and 30 min (P<0.001 for both) and returned to baseline thereafter. In contrast, there were sustained increases in plasma GIP (P<0.001), insulin (P<0.001), and blood glucose (P<0.001). CONCLUSION: In healthy subjects, there is early, transient stimulation of GLP-1 by glucose loads hitherto believed to be "sub-threshold". The mechanisms underlying this effect, which could be attributed to initially rapid transit to jejunal L cells, or a duodeno-jejunoileal neural or hormonal loop, remain to be determined.

Effects of lipase inhibition on gastric emptying and alcohol absorption in healthy subjects.

The rate of alcohol absorption is dependent on gastric emptying (GE). As the slowing of GE by fat is dependent on lipolysis, orlistat may increase the rise in blood alcohol when alcohol is consumed with, or after, fat. The aim of the study was to evaluate the effects of orlistat on GE and blood alcohol after an alcohol-containing drink following a fat 'preload', in healthy subjects. Ten healthy males consumed 120 ml cream with or without 120 mg orlistat, 30 min before an alcohol-containing drink labelled with 20 MBq [(99 m)Tc]sulfur colloid on 2 d. GE, plasma alcohol and blood glucose were measured. GE was slightly faster with orlistat (P<0.05) compared with control. Plasma alcohol at 15 min was slightly higher with orlistat (0.034 (SEM 0.006) g/100 ml) v. control (0.029 (SEM 0.005) g/100 ml) (P<0.05), but there was no effect on the area under the curve 0-240 min. The increase in blood glucose was greater with orlistat, for example, at 15 min (1.07 (SEM 0.2) mmol/l) v. control (0.75 (SEM 0.2) mmol/l) (P=0.05). The rise in blood glucose and plasma alcohol were related (for example, at 15 min r 0.49; P=0.03). In conclusion, lipase inhibition accelerates GE of an alcohol-containing drink following a fat 'preload' with a minor increase in the initial rise in plasma alcohol.

Effects of posture on gastric emptying, transpyloric flow, and hunger after a glucose drink in healthy humans.

Previous studies suggest that posture has relatively little effect on gastric emptying of high-nutrient liquids; these studies have, however, only assessed overall rates of gastric emptying, whereas gastric emptying is known to be predominantly a pulsatile phenomenon. In healthy subjects perceptions of appetite, such as hunger, are inversely related to antral area and content; hence, changes in intragastric meal distribution induced by posture may affect appetite. Gastric emptying is a major determinant of postprandial glycemia. The aims of this study were to evaluate the effects of posture on patterns of transpyloric flow (TF), gastric emptying (GE), antral area (AA), hunger, and the glycemic response to oral glucose. Eight healthy young subjects (five males, three females; mean age, 24.0 +/- 2.4 years; BMI, 21.2 +/- 0.6 kg/m2) were studied twice in random order, once in the sitting position and once in the lying (supine) position. After consuming 600 ml water with 75 g glucose, labeled with 20 MBq 99mTc-sulfur colloid, subjects had simultaneous measurements of (i) TF during consumption of the drink by Doppler ultrasonography, (ii) GE with scintigraphy, (iii) AA at t = -5 and t = 30 min by ultrasonography, and (iv) perceptions of appetite with a visual analogue scale. During drink ingestion TF was greater in the sitting, compared with the lying, position (586 +/- 170 vs. 177 +/- 65 [cm/sec] x sec; P < 0.05). Posture affected intragastric distribution; more of the drink was retained in the distal stomach in the sitting position (e.g., at 30 min: sitting, 29 +/- 3%, vs. lying, 12 +/- 3%; P < 0.0001) but had no effect on the overall rate of GE or the blood glucose response. AA at t = 30 min (P < 0.005) was greater in the sitting position; there was an inverse relationship between hunger and AA at 30 min (r = -0.53, P < 0.05). We conclude that posture influences initial TF and intragastric distribution, but not the overall rate of GE of, or the glycemic response to, a large-volume nutrient liquid. The increases in AA and content in the sitting position are associated with a reduction in hunger.

The release of GLP-1 and ghrelin, but not GIP and CCK, by glucose is dependent upon the length of small intestine exposed.

Previous observations suggest that glucagon-like peptide-1 (GLP-1) is released into the bloodstream only when dietary carbohydrate enters the duodenum at rates that exceed the absorptive capacity of the proximal small intestine to contact GLP-1 bearing mucosa in more distal bowel. The aims of this study were to determine the effects of modifying the length of small intestine exposed to glucose on plasma concentrations of GLP-1 and also glucose-dependent insulinotropic peptide (GIP), insulin, cholecystokinin (CCK) and ghrelin, and antropyloric pressures. Glucose was infused at 3.5 kcal/min into the duodenum of eight healthy males (age 18-59 yr) over 60 min on the first day into an isolated 60-cm segment of the proximal small intestine ("short-segment infusion"); on the second day, the same amount of glucose was infused with access to the entire small intestine ("long-segment infusion"). Plasma GLP-1 increased and ghrelin decreased (P < 0.05 for both) during the long-, but not the short-, segment infusion. By contrast, increases in plasma CCK and GIP did not differ between days. The rises in blood glucose and plasma insulin were greater during the long- than during the short-segment infusion (P < 0.05). During the long- but not the short-segment infusion, antral pressure waves (PWs) were suppressed (P < 0.05). Isolated pyloric PWs and basal pyloric pressure were stimulated on both days. In conclusion, the release of GLP-1 and ghrelin, but not CCK and GIP, is dependent upon >60 cm of the intestine being exposed to glucose.

Postprandial hypotension - novel insights into pathophysiology and therapeutic implications.

Postprandial hypotension is a frequent disorder, occurring in approximately 40% of nursing-home residents, and represents a major cause of morbidity and mortality. Current approaches to management are suboptimal. While it has been generally assumed that ingestion of carbohydrate has the greatest effect, the fall in blood pressure (BP) does not appear to be mediated by the consequent elevations in blood glucose and insulin. Moreover, there is evidence that fat may decrease BP to a comparable extent to carbohydrate, although onset of the response may be slower, and that the response is affected by the type of carbohydrate. It has recently been established that the rate of nutrient delivery from the stomach into the small intestine is an important determinant of the hypotensive response to carbohydrate, so that the magnitude of the fall in BP and rise in heart rate is greater when gastric emptying is relatively more rapid. In both healthy elderly subjects and patients with type 2 diabetes, the fall in BP is attenuated when gastric emptying and small intestinal carbohydrate absorption are slowed by dietary (e.g. guar) or pharmacological (e.g. acarbose) means. Conversely, gastric distension attenuates the postprandial fall in BP. Strategies for the treatment of postprandial hypotension should, therefore, potentially be directed at (i) meal composition, particularly carbohydrate type and content, (ii) slowing gastric emptying and/or small intestinal carbohydrate absorption and/or (iii) increasing postprandial gastric distension.

Intraduodenal guar attenuates the fall in blood pressure induced by glucose in healthy older adults.

OBJECTIVES: Postprandial hypotension occurs frequently in older people and may result in syncope and falls. It has recently been established that the magnitude of the fall in blood pressure is related to the rate at which glucose enters the small intestine. We addressed the hypothesis that the fall in blood pressure induced by an intraduodenal glucose infusion is influenced by the interaction of glucose with the small intestinal absorptive epithelium. METHODS: Eight healthy older participants (four male, four female, age 70.3 +/- 3.4 years) were studied on two separate occasions, in single-blind, randomized order. Participants received an intraduodenal glucose infusion (3 kcal/min) with or without guar gum (4 g) for 60 minutes (0-60 minutes), followed by 0.9% saline intraduodenally for a further 60 minutes (60-120 minutes). Blood pressure and heart rate were measured every 3 minutes. Levels of blood glucose, plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependant insulinotropic-polypeptide (GIP) were also determined. RESULTS: Between t = 0 and t = 30 minutes, the magnitude of the fall in systolic blood pressure (p =.03) and increase in heart rate (p =.027) were lower after guar. The blood glucose (p =.009), plasma insulin (p =.027), plasma GLP-1 (p =.018), and GIP (p <.001) responses to intraduodenal glucose were attenuated by guar. CONCLUSIONS: In healthy older participants, the magnitude of the fall in systolic blood pressure and increase in heart rate induced by intraduodenal glucose are attenuated when the exposure of glucose to the small intestinal mucosa and subsequent glucose absorption is slowed by guar.

Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects.

The rate of gastric emptying of glucose-containing liquids is a major determinant of postprandial glycemia. The latter is also dependent on stimulation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Although overall emptying of glucose approximates 1-3 kcal/min, the "early phase" of gastric emptying is usually more rapid. We have evaluated the hypothesis that increased stimulation of incretin hormones and insulin by a more rapid initial rate of small intestinal glucose delivery would reduce the overall glycemic response to a standardized enteral glucose load. Twelve healthy subjects were studied on two separate days in which they received an intraduodenal (id) glucose infusion for 120 min. On one day, the infusion rate was variable, being more rapid (6 kcal/min) between t = 0 and 10 min and slower (0.55 kcal/min) between t = 10 and 120 min, whereas on the other day the rate was constant (1 kcal/min) from t = 0-120 min, i.e., on both days 120 kcal were given. Between t = 0 and 75 min, plasma insulin, GIP, and GLP-1 were higher with the variable infusion. Despite the increase in insulin and incretin hormones, blood glucose levels were also higher. Between t = 75 and 180 min, blood glucose and plasma insulin were lower with the variable infusion. There was no difference in the area under the curve 0-180 min for blood glucose. We conclude that stimulation of incretin hormone and insulin release by a more rapid initial rate of id glucose delivery does not lead to an overall reduction in glycemia in healthy subjects.

Effect of aging on transpyloric flow, gastric emptying, and intragastric distribution in healthy humans--impact on glycemia.

The aims of this study were to evaluate (i) the relationship between transpyloric flow (TF) assessed by Doppler ultrasonography and scintigraphy, (ii) the effects of healthy aging on TF and gastric emptying (GE), and (iii) the relationship between the glycemic response to oral glucose and TF. Ten healthy "young" (7 M, 3 F) and 8 "older" (4 M, 4 F), subjects had simultaneous measurements of TF, GE, and blood glucose after a 600-ml drink (75 g glucose labeled with 20 MBq 99mTc-sulfur colloid) while seated. TF measured by ultrasound was measured during drink ingestion and for 30 min thereafter. GE was measured scintigraphically for 180 min after drink ingestion. Blood glucose was measured before the drink and at regular intervals until 180 min. During drink ingestion, TF was greater (P < 0.05) and GE faster (retention at 60 min: 70.8+/-3.3 vs. 83.8+/-4.6%; P < 0.05) in young compared to older subjects. There was no difference in fasting blood glucose between the two groups but the magnitude of the rise in blood glucose was greater in the young compared to the older subjects; (at 15 min 2.4+/-0.3 vs. 1.5+/-0.5 mmol/L; P < 0.05). In contrast, after 90 min blood glucose concentrations were higher in the older subjects. There were significant relationships between the early blood glucose concentration and both TF (e.g., at 15 min: r = 0.56, P < 0.05) and GE (e.g., at 15 min: r = -0.51, P < 0.05). In conclusion, the results of this study indicate that (i) TF is initially less, and GE slower, in older compared to young subjects; (ii) the initial glycemic response to oral glucose is related to TF; and (iii) measurements of TF by ultrasound and scintigraphy correlate significantly.

Effects of drink volume and glucose load on gastric emptying and postprandial blood pressure in healthy older subjects.

Postprandial hypotension (PPH) occurs frequently in the elderly; the magnitude of the fall in blood pressure (BP) is related to the rate of glucose entry into the duodenum during intraduodenal glucose infusion and spontaneous gastric emptying (GE). It is unclear if glucose concentration affects the hypotensive response. Gastric distension may attenuate PPH; therefore, meal volume could influence the BP response. We aimed to determine the effects of 1) drink volume, 2) glucose concentration, and 3) glucose content on the BP and heart rate (HR) responses to oral glucose. Ten subjects (73.9 +/- 1.2 yr) had measurements of BP, GE, and blood glucose on 4 days after 1) 25 g glucose in 200 ml (12.5%), 2) 75 g glucose in 200 ml (37.5%), 3) 25 g glucose in 600 ml (4%), and 4) 75 g glucose in 600 ml (12.5%). GE, BP, HR, and blood glucose were measured for 180 min. After all drinks, duodenal glucose loads were similar in the first 60 min. Regardless of concentration, 600-ml (but not 200-ml) drinks initially increased BP, and in the first 30 min, systolic BP correlated (P < 0.01) with volume in both the proximal and total stomach. At the same concentration (12.5%), systolic BP fell more (P = 0.02) at the smaller volume; at the same volumes, there were no effects of concentration on BP. There was no difference in the glycemic response to drinks of identical glucose content. We conclude that 1) ingestion of glucose at a higher volume attenuates and 2) under constant duodenal load, glucose concentration (4-37%) does not affect the fall in BP.

Effect of variations in small intestinal glucose delivery on plasma glucose, insulin, and incretin hormones in healthy subjects and type 2 diabetes.

The determinants of postprandial blood glycemia are controversial. We assessed the effects of variations in the initial rate of small intestinal glucose delivery on blood glucose, plasma insulin, and incretin responses in both health and type 2 diabetes. Eight controls and eight patients with type 2 diabetes managed by diet alone underwent paired studies. On both days subjects received an intraduodenal glucose infusion (t = 0-120 min); on one day the infusion rate was variable, being more rapid initially (3 kcal/min) between t = 0 and 15 min and slower (0.71 kcal/min) subsequently (t = 15-120 min), whereas on the other day, the infusion rate was constant (1 kcal/min) from t = 0 to 120 min (i.e. on both days 120 kcal of glucose were administered). Between t = 0-180 min blood glucose, plasma insulin and plasma glucose-dependent insulin-releasing polypeptide were greater with the variable, compared with the constant, infusion. Between t = 0 and 30 min the magnitude of the rise in plasma glucagon-like peptide-1 was greater with the variable, compared with the constant infusion (P < 0.01, both groups). We conclude that modest variations in the initial rate of duodenal glucose entry may have profound effects on subsequent glycemic, insulin, and incretin responses.

Lipase inhibition attenuates the acute inhibitory effects of oral fat on food intake in healthy subjects.

The lipase inhibitor, orlistat, is used in the treatment of obesity and reduces fat absorption by about 30%. However, the mean weight loss induced by orlistat is less than expected for the degree of fat malabsorption. It was hypothesised that lipase inhibition with orlistat attenuates the suppressive effects of oral fat on subsequent energy intake in normal-weight subjects. Fourteen healthy, lean subjects (nine males, five females; aged 25 +/- 1.3 years) were studied twice, in a double-blind fashion. The subjects received a high-fat yoghurt 'preload' (males 400 g (2562 kJ); females 300 g (1923 kJ)), containing orlistat (120 mg) on one study day (and no orlistat on the other 'control' day), 30 min before ad libitum access to food and drinks; energy intake was assessed during the following 8 h. Blood samples were taken at regular intervals for the measurement of plasma cholecystokinin (CCK). Each subject performed a 3 d faecal fat collection following each study. Energy intake during the day was greater following orlistat (10,220 (SEM 928) kJ) v. control (9405 (SEM 824) kJ) (P=0.02). On both days plasma CCK increased (P<0.05) after the preload. Plasma CCK 20 min following ingestion of the preload was less after orlistat (4.1 (SEM 0.9) pmol/l) v. control (5.3 (SEM 0.9) pmol/l (P=0.028); however there was no difference in the area under the curve 0-510 min between the two study days. Fat excretion was greater following orlistat (1017 (SEM 168) kJ) v. control (484 (SEM 90) kJ) (P=0.004). In conclusion, in healthy, lean subjects the acute inhibitory effect of fat on subsequent energy intake is attenuated by orlistat and the increase in energy intake approximates the energy lost due to fat malabsorption.

Nutrition therapy for diabetic gastroparesis.

The management of diabetic gastroparesis often represents a significant clinical challenge in which the maintenance of nutrition is pivotal. Gastric emptying is delayed in 30% to 50% of patients with longstanding type 1 or type 2 diabetes and upper gastrointestinal symptoms also occur frequently. However, there is only a weak association between the presence of symptoms and delayed gastric emptying. Acute changes in blood glucose concentrations affect gastric motility in diabetes; hyperglycemia slows gastric emptying whereas hypoglycemia may accelerate it; blood glucose concentrations may also influence symptoms. It is now recognized that gastric emptying is a major determinant of postprandial glycemia and, therefore, there is considerable interest in the concept of modulating gastric emptying, by dietary or pharmacologic means, to optimize glycemic control in diabetes.

Idiopathic and Diabetic Gastroparesis.

The management of both diabetic and idiopathic gastroparesis often represents a substantial clinical challenge. In formulating recommendations for therapy, it should be recognized that these are based on less than optimal evidence; in particular, there are substantial deficiencies in current knowledge relating to the pathophysiology of gastroparesis, as well as the natural history of gastrointestinal symptoms, and the majority of pharmacologic trials have been short term and associated with methodologic limitations. Although the etiologic factors differ, the overall management principles are similar in the two conditions. Maintenance of adequate nutrition is pivotal, and parenteral nutrition may be required in severe cases associated with malnutrition. In patients with diabetes, rigorous attempts should be made to optimize glycemic control--hyperglycemia slows gastric emptying and may exacerbate symptoms and attenuate the effects of prokinetic drugs. Despite the relatively poor predictive value of symptoms, it is reasonable to suggest a trial of prokinetic therapy for about 4 weeks, rather than initially establishing the diagnosis by measurement of gastric emptying. However, it should be recognized that there is a substantial placebo response, a lack of evidence to support the cost effectiveness of such an approach, and that most patients will require prolonged therapy. In type 1 diabetic patients, prokinetic therapy may potentially benefit glycemic control, and this forms an additional rationale (albeit not established) for therapy. Some patients with diabetes and idiopathic gastroparesis with severe vomiting are unable to tolerate oral medication; in such cases subcutaneous metoclopramide may prove useful. Patients with intractable symptoms should be hospitalized and given intravenous erythromycin. The repertoire of prokinetic agents available in the United States is limited and includes metoclopramide, erythromycin, and cisapride (available by special program from its manufacturer); all of these drugs are associated with side effects. The use of metoclopramide may represent the first choice for chronic oral therapy, although it has been studied less comprehensively than cisapride. Combination therapy may be potentially more efficacious than the use of single agents. Dehydration and metabolic derangements should be corrected. The choice of chronic medical therapy should be individualized, taking factors such as age, presence of diabetes, concurrent medications, and comorbidities into account. In a small number of patients in whom medical treatment fails, surgery should be considered, and, if performed, done in a specialized center. A number of novel therapies, including gastric electrical stimulation, are currently being evaluated.

Effects of fat digestion on appetite, APD motility, and gut hormones in response to duodenal fat infusion in humans.

The presence of nutrients in the small intestine slows gastric emptying and suppresses appetite and food intake; these effects are partly mediated by the release of gut hormones, including CCK. We investigated the hypothesis that the modulation of antropyloroduodenal motility, suppression of appetite, and stimulation of CCK and glucagon-like peptide-1 secretion by intraduodenal fat are dependent on triglyceride hydrolysis by lipase. Sixteen healthy, young, lean men were studied twice in double-blind, randomized, crossover fashion. Ratings for appetite-related sensations, antropyloroduodenal motility, and plasma CCK and glucagon-like peptide-1 concentrations were measured during a 120-min duodenal infusion of a triglyceride emulsion (2.8 kcal/min) on one day with, on the other day without, 120 mg tetrahydrolipstatin, a potent lipase inhibitor. Immediately after the duodenal fat infusion, food intake at a buffet lunch was quantified. Lipase inhibition with tetrahydrolipstatin was associated with reductions in tonic and phasic pyloric pressures, increased numbers of isolated antral and duodenal pressure waves, and stimulation of antropyloroduodenal pressure-wave sequences (all P < 0.05). Scores for prospective consumption and food intake at lunch were greater, and nausea scores were slightly less, and the rises in plasma CCK and glucagon-like peptide-1 were abolished (all P < 0.05). In conclusion, lipase inhibition attenuates the effects of duodenal fat on antropyloroduodenal motility, appetite, and CCK and glucagon-like peptide-1 secretion.

Prognostic relevance of Fas (APO-1/CD95) ligand in human colorectal cancer.

OBJECTIVE: Fas ligand (FasL) is an important mediator of immune function and induces apoptosis by binding to its receptor Fas on sensitized cells. It has recently been shown that malignancies may express FasL and acquire immune privilege by inducing apoptosis of lymphocytes. Acquired resistance to Fas mediated apoptosis is known to be an early event in carcinogenesis. The aim of this study was to determine the extent of FasL expression in patients with colorectal cancer and examine its relationship with several prognostic pathological features and survival. DESIGN AND METHODS: Sixty-eight patients (median age 66 years) with colorectal cancer, whose diagnosis was made between 1988 and 1991 and in whom long-term follow-up was available, were evaluated. The tumours were of varying stages at diagnosis (eight Dukes' A, 28 Dukes' B, 23 Dukes' C and nine Dukes' D). The expression of FasL was detected immunohistochemically with a rabbit polyclonal IgG using the DAKO EnVision+ System. The specificity of FasL binding was confirmed by pre-incubation of the antibody with the immunizing peptide prior to staining. The relationship with several pathological features was determined using Kendall's tau-b correlation. Overall survival was estimated using the Kaplan-Meier product limit curves. Differences in observed survival were tested for statistical significance using the Mantel-Haenszel log rank test. Both the extent and intensity of staining were graded by a blinded observer. RESULTS: FasL was predominantly expressed in tumour epithelial cells in 88% of the cases. The positive staining of tumours varied in extent. FasL staining was higher in earlier Dukes' stage tumours in that the extent of FasL staining negatively correlated with Dukes' stage (Kendall tau-b = -0.22, P = 0.038). Consistent with this, the overall survival was better with a greater extent of FasL expression (log rank chi2 = 5.68, P = 0.017). There was a lower extent of FasL expression in mucinous adenocarcinomas (Kendall tau-b = 0.288, P = 0.01) and in those tumours with neural invasion (Kendall tau-b = -0.26, P = 0.03). No relationship was detected between FasL and tumour site, size, margin, differentiation, vascular invasion, necrosis or Crohn's-like reaction. CONCLUSIONS: FasL is widely expressed in colorectal cancers. This finding suggests that the extent of FasL expression in colorectal tumours is directly related to patients' survival.

Carbohydrate and satiety.

This review focuses on what is known about the effects of carbohydrate on food intake, the potential mechanisms mediating these effects, and the impact of different monosaccharides in humans. The inhibition of subsequent food intake associated with ingestion of carbohydrate appears to result primarily from gastrointestinal signals, including those generated by orosensory stimulation, gastric distension, and perhaps most importantly the interaction of nutrients with receptors in the small intestine. The latter is associated with the release of putative satiety hormones, including glucagon-like peptide-1 and amylin, and slowing of both gastric emptying and small intestinal transit (thereby prolonging gastric distension and increasing the time available for nutrient absorption). The effects of carbohydrate on food intake are dependent on the route of administration (i.e., oral, intragastric, or intraduodenal). Changes in blood glucose and insulin concentrations per se probably do not play a major role in the induction of satiety. Studies relating to the comparative effects of different monosaccharides/carbohydrates have yielded inconclusive results, probably in part owing to substantial differences in methodological approaches.