Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system.

PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer. PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system. RESULTS: Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P =.61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays. CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.

Health-related quality of life and health care costs in severe, refractory irritable bowel syndrome.

BACKGROUND: The irritable bowel syndrome (IBS) may lead to considerable impairment of health-related quality of life and high health care costs. It is not clear whether these poor outcomes directly result from severe bowel symptoms or reflect a coexisting psychiatric disorder. OBJECTIVE: To determine whether bowel symptom severity and psychological symptoms directly influence health-related quality of life and health care costs. DESIGN: Cross-sectional survey. SETTING: Secondary and tertiary gastroenterology clinics. PATIENTS: 257 patients with severe IBS who did not respond to usual treatments and were recruited for a trial of psychological treatment. MEASUREMENTS: Predictors were abdominal pain, entries in a diary of 10 IBS symptoms, and measures of psychological symptoms. Outcomes were inability to work, health-related quality of life (measured by Medical Outcomes Survey 36-item short-form questionnaire [SF-36] physical component summary scores), and health care and productivity costs. Predictor and outcome measures were compared by using multiple regression and logistic regression analyses. RESULTS: Abdominal pain occurred on average 24 days per month and activities were restricted on 145 days of the previous 12 months. The mean (+/-SD) Hamilton depression score was 11.3 +/- 6.1. The SF-36 physical component summary score was low (37.7 +/- 10.6), and the patients had incurred high health care costs ($1743 +/- $2263) over the previous year. Global severity and somatization scores on the Symptom Checklist 90 Revised, abdominal pain, and Hamilton depression scores independently contributed to the physical component score of the SF-36 (adjusted R(2) = 35.2%), but only psychological scores were associated with disability due to ill health. These variables did not accurately predict health care or other costs (adjusted R(2) = 9.3%). History of sexual abuse was not an independent predictor of outcome. CONCLUSIONS: Both abdominal and psychological symptoms are independently associated with impaired health-related quality of life in patients with severe IBS. Optimal treatment is likely to require a holistic approach. Since health care and loss of productivity costs are not clearly associated with these symptoms, alleviation of them will not necessarily lead to reduced costs.

Harnessing the patient's powers of recovery: the role of the psychotherapies in the irritable bowel syndrome.

The aim of this chapter is to provide a clear and balanced account of the role of the various forms of psychotherapy in the irritable bowel syndrome (IBS). It commences with an account of the philosophical basis for psychotherapy, attempting to integrate the concepts of autonomic arousal, repression, conversion and a developmental disorder of thinking and emotional expression. These concepts are used to explain why separation and loss can lead to the development of IBS and how the gut is such an important vehicle for emotional expression. Against this background the role and philosophy of relaxation therapy, hypnotherapy, biofeedback, cognitive behavioural therapy and analytical psychotherapy are discussed. These therapies describe a philosophical approach that is quite different from biomedical treatments in that it attempts to harness the patient's own powers for recovery. For that reason the efficacy of psychotherapies cannot be evaluated by randomized controlled trials. Psychotherapies rely on the relationship between therapist and patient and vary according to whether the locus of responsibility lies mainly with the therapist or mainly with the patient. Different patients may well require different therapies.

Pronounced cytoplasmic pH gradients are not required for tip growth in plant and fungal cells.

The existence of pronounced cytoplasmic pH gradients within the apices of tip-growing cells, and the role of cytoplasmic pH in regulating tip growth, were investigated in three different cell types: vegetative hyphae of Neurospora crassa; pollen tubes of Agapanthus umbellatus; and rhizoids of Dryopteris affinis gametophytes. Examination of cytoplasmic pH in growing cells was performed by simultaneous, dual emission confocal ratio imaging of the pH-sensitive probe carboxy SNARF-1. Considerable attention was paid to the fine tuning of dye loading and imaging parameters to minimise cellular perturbation and assess the extent of dye partitioning into organelles. With optimal conditions, cytoplasmic pH was measured routinely with a precision of between +/-0.03 and +/-0.06 of a pH unit and a spatial resolution of 2.3 microm2. Based on in vitro calibration, estimated values of mean cytoplasmic pH for cells loaded with dye-ester were between 7.15 and 7.25 for the three cell types. After pressure injecting Neurospora hyphae with dextran-conjugated dye, however, the mean cytoplasmic pH was estimated to be 7.57. Dextran dyes are believed to give a better estimate of cytoplasmic pH because of their superior localisation and retention within the cytosol. No significant cytoplasmic pH gradient (delta pH of >0.1 unit) was observed within the apical 50 microm in growing cells of any of the three cell types. Acidification or alkalinisation of the cytoplasm in Neurospora hyphae, using a cell permeant weak acid (propionic acid at pH 7.0) or weak base (trimethylamine at pH 8.0), slowed down but did not abolish growth. However, similar manipulation of the cytoplasmic pH of Agapanthus pollen tubes and Dryopteris rhizoids completely inhibited growth. Modification of external pH affected the growth pattern of all cell types. In hyphae and pollen tubes, changes in external pH were found to have a small transient effect on cytoplasmic pH but the cells rapidly readjusted towards their original pH. Our results suggest that pronounced longitudinal gradients in cytoplasmic pH are not essential for the regulation of tip growth.

The effect of oral vancomycin on chronic idiopathic constipation.

BACKGROUND: A case study reporting the efficacy of oral vancomycin in a patient with chronic idiopathic constipation prompted this prospective trial of oral vancomycin in eight female patients (aged 21-61 years) with severe constipation resistant to the action of dietary fibre. METHODS: The trial was divided into two consecutive 14-day periods. During the first period, each patient was given ispaghula, 3.5 g twice a day, and during the subsequent period they took 250 mg vancomycin t.d.s. per os, as well as the fibre supplement. During both periods they collected stools and recorded daily bowel symptoms (stool frequency, straining, stool consistency, subjective stool volume) in a diary. At the end of each period whole gut transit time and the breath hydrogen response to a standard meal, giving oro-caecal transit time, were measured along with gastrointestinal symptoms which were assessed on visual analogue scales. RESULTS: Vancomycin caused a significant improvement in stool frequency, consistency, ease of defecation and the amount of stool patients felt they produced (all P < 0.05), but objective measures of daily stool weight and whole gut or oro-caecal transit time were not significantly different. Basal breath hydrogen levels were higher after vancomycin treatment in seven out of eight patients. One patient experienced a complete remission of symptoms when she took vancomycin and remains in remission after 14 months. This patient showed no elevation in basal breath hydrogen level. CONCLUSION: Although this study does not support the use of vancomycin for most patients with constipation, the results suggest that modification of the intraluminal flora may be of value in the treatment of the occasional case of idiopathic constipation.

Investigation of mode of action of biofeedback in treatment of fecal incontinence.

A study was carried out in 25 incontinent patients to evaluate some of the factors thought to be responsible for the success of retraining for fecal incontinence. Subjects were initially allocated to one of two groups; one group was trained to perceive small rectal volumes (active retraining), the other group carried out the same maneuvers but were not given any information or instruction. Active sensory retraining reduced the sensory threshold from 32 +/- 8 to 7 +/- 2 ml (P less than 0.001), corrected any sensory delay that was present (P less than 0.004), and reduced the frequency of incontinence from 5 +/- 1 to 1 +/- 1 episodes per week (P less than 0.01). Sham retraining caused a modest reduction in the sensory threshold (from 29 +/- 9 to 20 +/- 8; P less than 0.05) but did not significantly reduce the frequency of incontinence. Subsequent strength and coordination training did not significantly improve continence, although at the end of the study, 50% of patients had no incontinent episodes at all and 76% of patients had reduced the frequency of incontinence episodes by more than 75%. This improvement in continence was not associated with any change in sphincter pressures or in the continence to rectally infused saline but was associated with significant improvements in rectal sensation. The functional improvement was sustained over a period of two years in 16 of the 22 patients available for follow-up. In conclusion, the results support the use of retraining in the management of fecal incontinence and suggest that retraining may work by enhancing rectal sensitivity and instilling confidence.

Control of defecation in patients with spinal injuries by stimulation of sacral anterior nerve roots.

OBJECTIVE: To observe the effects of stimulation of the sacral anterior roots on anorectal and low colonic pressures and to programme implanted stimulators to produce defecation. DESIGN: Prospective study of 12 consecutive patients. SETTING: Spinal injuries unit and university gastrointestinal physiology department. PATIENTS: 12 Patients with complete supraconal spinal cord lesions. Their injuries had been sustained at least two years before the study. INTERVENTIONS: A Brindley-Finetech intradural sacral anterior root stimulator was implanted in all patients. Three months postoperatively the stimulator settings were adjusted after measurement of simultaneous anorectal and low colonic pressures. MAIN OUTCOME MEASURES: Full defecation. RESULTS: Six patients achieved complete rectal evacuation of faeces using the implant and subsequently did not require manual help for defecation. For all but one of the patients the total time taken to complete defecation was reduced, and all were free from constipation, the most prevalent gastrointestinal symptom in patients with spinal injuries. CONCLUSIONS: Sacral anterior root stimulators can be programmed to achieve complete unassisted defecation and can considerably improve the quality of life of patients with spinal injuries.

Effect of coffee on distal colon function.

Ninety nine healthy young volunteers (58 men, 34 women, aged 17-27 years) answered a questionnaire concerning their bowel habit with particular reference to the effects of beverages. Twenty nine per cent (63% women) claimed that coffee induced a desire to defecate. The rectosigmoid motor responses to black, unsweetened coffee were then investigated by multiport manometry in 14 healthy-subjects (12 men, two women, eight of whom claimed coffee caused a desire to defecate (responders). Results revealed an increase in motility index within four minutes after ingestion of both regular and decaffeinated coffee (p less than 0.05) in the eight responders, but not in the six non-responders. The increase in rectosigmoid motility induced by coffee lasted at least 30 minutes. There was no increase in the motility index in any subject after a drink of hot water. These results suggest that drinking coffee can stimulate a motor response of the distal colon in some normal people.

A comparative study of the effects on colon function caused by feeding ispaghula husk and polydextrose.

Polydextrose is a new soluble food ingredient which cannot be digested by intestinal enzymes and so may affect colonic function. Studies in healthy volunteers compared the effects of diet supplementation with 30 g/day polydextrose, a standard dose of 7 g/day ispaghula and two mixtures containing 2 g/day ispaghula with either 30 g/day polydextrose or 10 g/day polydextrose with a control period. During the 10-day periods, the mass, frequency and consistency of faeces were assessed as well as the whole-gut transit time, ease of defaecation, flatulence and palatability of the preparations. All preparations significantly increased the weekly faecal mass above control values (P less than 0.05) but there were no significant differences between the preparations. Transit time and stool frequency were not affected significantly by any of the preparations (P greater than 0.05). Both preparations supplying 30 g/day polydextrose softened stool consistency equally but the other preparations had no effect. All preparations caused flatulence and other gas-related problems but polydextrose caused more than ispaghula, even at the lowest dose of 10 g/day. More volunteers preferred taking the polydextrose drinks than the sachets of ispaghula which formed a viscous drink with water. Despite superior palatability and equally effective stool bulking, polydextrose is unlikely to be an alternative laxative to ispaghula because of the unacceptable levels of flatulence.

The relation between bacterial degradation of viscous polysaccharides and stool output in human beings.

1. The relation between bacterial degradation of three viscous polysaccharides (guar gum, ispaghula and xanthan gum) by colonic bacteria in vitro and their effects on colonic function were investigated by comparing the results of anaerobic in vitro incubations with fresh faeces from seven healthy volunteers (measuring viscosity, pH and gas production) with the effects of feeding all three polysaccharides to the same volunteers for 1 week each (14-15 g/d) on faecal mass and whole-gut transit time. 2. Guar gum was rapidly fermented in vitro by faecal bacteria from all volunteers with concomitant loss of viscosity, reduction in pH and generation of gases. Ispaghula maintained its viscosity during incubation, but the pH fell significantly. The results of xanthan gum incubations showed considerable individual variation. 3. Only ispaghula significantly increased faecal mass, whilst none of the gums significantly affected stool frequency or transit time. Statistical analysis of the pooled results showed that although transit time and faecal output were inversely related, feeding viscous polysaccharides could influence these indices independently. Stool frequency was significantly correlated with the transit time, but not the faecal output. 4. Transit time was reduced by gum feeding to a significantly greater extent in those subjects whose faecal bacteria reduced or removed the viscosity of that gum, than in those subjects where the viscosity was maintained. In contrast, there was a smaller increase in faecal mass when the viscosity of the appropriate cultures was removed than when it was maintained or reduced. Increases in stool frequency were significantly associated with hydrogen production from in vitro cultures.

The effect of guar gum on the distribution of a radiolabelled meal in the gastrointestinal tract of the rat.

1. The effect of addition of guar gum (5 and 10 g/l) to a radiolabelled, homogenized, baked-bean test meal on the distribution of that meal in the gastrointestinal tract was investigated in groups of male rats killed at 25, 50, 100, 200, 300 and 400 min after gavage. 2. Addition of 5 and 10 g guar gum/l significantly increased the proportion of the meal remaining in the stomach at 25 and 50 min after gavage (P less than 0.01). 3. The heads of the control meal and meals containing guar gum reached the distal intestine within 25 min after gavage but radioactivity was not observed in the caecum until 100 min after administration of each of the meals. Addition of guar gum (5 and 10 g/l) delayed caecal filling even though the head of each meal reached the caecum at the same time after gavage. 4. The geometric centres of guar-gum-containing meals were proximal to that of the control meal at all times after gavage. 5. The observed delay in the passage of a guar-gum-containing meal through the stomach and small intestine is probably due to the viscous nature of the meal resisting the propulsive and mixing effects of the gastrointestinal contractions, thereby reducing access of the glucose to the absorptive epithelium. This could contribute to the observed reductions in postprandial glycaemia seen in previous studies after incorporating guar gum into a meal.

Regulation of gastric emptying by ileal nutrients in humans.

Studies were carried out in 25 healthy male volunteers to investigate the effect of ileal infusion of solutions of different nutrient composition and osmolality on the profiles of a radiolabeled solid meal emptying from the stomach. Ileal infusion of a 50% corn oil emulsion or a 20% oleic acid emulsion slowed the rate of gastric emptying compared with ileal infusion of isotonic saline (0.9%). In contrast, infusion of either hypertonic saline (430 mosmol), distilled water, or isotonic solutions containing protein hydrolysate (8 g%) or glucose (50 mM) had no effect on the gastric emptying profile. These experiments support the hypothesis that the presence of unabsorbed lipid or fatty acids in the distal small intestine may delay gastric emptying, but suggest that sugars and proteins are ineffective. As infusion of both protein hydrolysates and lipid into the ileum can delay small bowel transit in humans, the data suggest that ileal regulation of gastric emptying and small bowel transit may be mediated by different mechanisms.

Adaptation of hydrogen analysis to measure stomach to caecum transit time in the rat.

Excreted hydrogen analysis was used to measure stomach to caecum transit time of the head of a test meal in 120 rats fed by gavage. Results were compared with the distribution of a labelled test meal in the gastrointestinal tract of rats killed at different time intervals after gavage. Values for stomach to caecum transit were compatible with the distribution of labelled meals in 91% of animals, although in the remainder the hydrogen concentration had not risen even though food residues were in the caecum when the animals were killed. The technique gave reproducible results; the coefficients of variation for four studies carried out in each of six animals varied between 4 and 14%. A meal consisting of homogenised baked beans had a significantly shorter stomach to caecum transit time (88.1 +/- 4.5 min; mean +/- SE; n = 21; p less than 0.001) than an equivalent volume of Complan/lactulose (180.9 +/- 8.7 min; n = 13). This technique was used to investigate the effect of ileal infusion of a fat emulsion (20% Intralipid) via a chronically implanted intestinal cannula on the stomach to caecum transit time of a bean meal, in a series of paired studies carried out in six rats. Stomach to caecum transit time was significantly delayed during ileal infusion of 20% Intralipid compared with the control infusion of an isotonic saline solution (218.3 +/- 21 min v 106.7 +/- 33 min Intralipid v saline; n = 6; p less than 0.001).

Effect of ileal and intravenous infusions of fat emulsions on feeding and satiety in human volunteers.

The effect of ileal infusion of a lipid emulsion, containing 50% corn oil and 3% albumen, on food intake and satiety was measured in paired experiments carried out in 6 healthy volunteers. Subjects ate for shorter periods of time during ileal infusions of fat emulsion compared with control infusions of albumen and saline (25 +/- 1 vs. 32 +/- 3 min, mean +/- SEM) and consumed a smaller amount of food (670 +/- 23 g vs. 884 +/- 89 g) and energy (1016 +/- 79 kcal vs. 1591 +/- 228 kcal). The quantity of liquid drunk and the rates of eating and drinking were not significantly affected by the infusion of fat emulsion. In a further series of experiments carried out in 5 normal volunteers, ileal infusion of corn oil emulsions delayed gastric emptying compared with ileal infusion of albumen and saline (t1/2 = 203 +/- 48 vs. 68 +/- 12 min, p less than 0.02). The possibility that the observed reductions in food intake were related to the effect of absorbed fat was investigated in 6 healthy volunteers during intravenous infusion of either fat emulsion or isosmotic saline. Food intake was not affected by intravenous infusion of lipid. Our results suggest that lipid may interact with ileal receptors to induce early satiety and reduce the amount of food consumed. The earlier inhibition of food intake during lipid infusion is perhaps best explained by early gastric distention caused by delayed gastric emptying, though the data would not exclude the release of an ileal mechanism, which has a direct action on the satiety centers.

The effect of ispaghula (Fybogel and Metamucil) and guar gum on glucose tolerance in man.

The effects of incorporating Fybogel (3.5 and 7 g doses), Metamucil (7 g) or guar gum (2.5 and 14.5 g doses) in a drink containing 50 g glucose on plasma glucose, plasma insulin and gastric emptying were studied in thirty-eight normal volunteers. In addition, the effects of Fybogel (7 g) on glucose tolerance, plasma insulin and gastric emptying were measured in fourteen non-insulin-dependent diabetics. Both doses of guar gum significantly lowered plasma glucose and plasma insulin responses to the oral glucose load in normal subjects, although 14.5 g guar gum did not delay the half-time for gastric emptying. Neither Fybogel nor Metamucil had significant effects on plasma glucose responses in normal subjects. In addition, Fybogel (at either dose) had no significant effects on plasma insulin levels, or on gastric emptying in normal subjects or on plasma glucose and insulin responses in diabetic patients. The viscosity of ispaghula solutions ( Fybogel ) was lower than that of guar gum solutions.

Role of anorectal sensation in preserving continence.

The role of anal sensation in preserving continence was studied in nine healthy volunteers. Objective assessment of sphincter function by manometry and rectal saline infusion was carried out during topical anaesthesia of the anal canal using 5% lignocaine gel and during lubrication with the same amount of inert gel. Anaesthesia successfully abolished anal sensation and reduced both the amplitude and duration of the voluntary squeeze. Basal pressure was unaffected, but the rectal volume required to produce a sustained internal sphincter relaxation was increased. Saline continence was not impaired. Indeed, two subjects, who were previously unable to retain the full 1500 ml of rectally infused saline, did so when the anal canal was anaesthetised. Our findings suggest that anal sensation is not a critical factor in preserving continence. This implies that the incontinence experienced after anorectal surgery or neuropathy cannot be explained by lack of anal sensation alone.