The future of intestinal pacing.

Pacing the human heart, first done in 1952, is commonly used today. Pacing the canine stomach and small intestine has also been accomplished and has been used to treat a variety of disease models, including dumping, the short bowel syndrome, gastroparesis, the Roux stasis syndrome, and tachygastria. In contrast, pacing the human stomach and small intestine has not progressed as far. Pacing of these organs in man has only been done for short intervals. Moreover, no clear-cut therapeutic applications have as yet emerged. Nonetheless, pacing holds promise as a future therapeutic modality for a variety of disorders of the human stomach and small bowel.

Gastric acid secretion and vitamin B12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity.

OBJECTIVE: This study sought to determine the basal and peak-stimulated acid secretion from the proximal gastric pouch and its relationship to absorption of free and food-bound vitamin B12 after gastric bypass for morbid obesity. SUMMARY BACKGROUND DATA: Gastric bypass can be performed safely and provides acceptable weight loss, but concerns remain about possible long-term complications such as vitamin B12 malabsorption. The authors hypothesized that by constructing a small pouch of gastric cardia, acid secretion into the pouch would be low, leading to maldigestion of food-bound vitamin B12 with subsequent malabsorption. METHODS: Basal and pentagastrin-stimulated peak acid outputs from the proximal gastric pouch were measured in ten patients after vertical Roux-en-Y gastric bypass using a perfused orogastric tube technique. Absorption of free and food-bound 57Co-vitamin B12 was evaluated separately using 24-hour urinary excretion. RESULTS: Basal (mEq/hr, mean +/- standard error of the mean [SEM]) and peak-stimulated (mEq/30 min) acid secretions from the proximal gastric pouch were markedly decreased compared to those for age- and sex-matched hospital control subjects (0.01 +/- 0.01 vs. 4.97 +/- 0.66 and 0.08 +/- 0.04 vs. 12.11 +/- 1.34, respectively; p < 0.001 for each). While absorption of free vitamin B12 was not statistically different from that of control subjects (11 +/- 2 vs. 15 +/- 2%; p > 0.05), absorption of food-bound vitamin B12 was decreased (0.8 +/- 0.2 vs. 3.7 +/- 0.5%; p < 0.01). CONCLUSIONS: After vertical Roux-en-Y gastric bypass for morbid obesity, acid secretion is virtually absent and food-bound vitamin B12 is maldigested and subsequently malabsorbed. The results of this study suggest that postoperative vitamin B12 supplementation is important and can be achieved with either monthly parenteral vitamin B12 or daily oral crystalline preparations.

Effects of bright light on mood in normal elderly women.

Reduced light appears to be a key factor in seasonal affective disorder (SAD). This study asks whether the reduced levels of light experienced by elderly persons might result in depression and other SAD symptoms, and how normal elderly persons might respond to bright light interventions similar to those used to treat SAD. In interviews with 140 senior citizens, we found virtually no seasonal variation in mood and behavior and very little depressed affect. Seventeen of these seniors who had good mental and physical health, with no major eye problems, participated in a crossover study of the effects of bright light on both positive and negative affect and sleep. Although sleep did not appear to be affected, the bright light intervention tended to make these normal elderly persons feel worse--more irritable, anxious, and agitated. These findings confirm earlier reports that bright light is not beneficial for normal individuals who are unaffected by seasonal changes.

The selection of cases for randomised trials: a registry survey of concurrent trial and non-trial patients. The British Stomach Cancer Group.

A randomised trial of adjuvant chemotherapy vs placebo in operable stomach cancer recruited 249 patients from the West Midlands Region between 1976-1980. A Cancer Registry survey identified a further 1261 suitable concurrent cases. Trial patients were compared with the 960 non-trial cases from participating Districts. Only 493 (51%) non-trial cases passed all of the prospective trial selection criteria for entry. Stage and fitness caused the majority of exclusions and were also highly prognostic. A univariate analysis comparing eligible patients with the trial showed the two groups to be balanced for the significant independent prognostic factors of the trial. However, differences in patient age and the surgery performed indicate that recruitment may have been influenced by unknown selection factors. This survey highlights the difficulty of retrospective selection and confirms the need for randomised controls. Data available from specialist Registries may be used to help develop new protocols and to verify and extend trial results.

The Roux stasis syndrome. Treatment by pacing and prevention by use of an 'uncut' Roux limb.

Ectopic pacemakers in the Roux limb are associated with delayed gastric emptying after Roux gastrectomy. The aim herein was to suppress the ectopic pacemakers by electrical pacing or to prevent them by maintaining enteric myoneural continuity with an "uncut" Roux limb, and so improve the delayed emptying. Among eight dogs with truncal vagotomy and Roux hemigastrectomy, four dogs had a pacing electrode applied to the proximal end of the Roux limb. The other four dogs had a gastrojejunostomy to an uncut Roux limb. In them, the afferent jejunal limb was occluded by staples but not divided, and a diverting jejuno-jejunostomy was performed. Roux pacing and the uncut Roux operation abolished ectopic pacemakers in the Roux limb and speeded the slow gastric emptying present in unpaced control tests. At autopsy, however, dehiscences were found in the staple line in the dogs with the uncut Roux procedures. In conclusion, electrical pacing and the uncut Roux limb show promise as techniques to prevent ectopic jejunal pacemakers and gastric stasis after Roux gastrectomy. Both must be improved before they can be used in patients.

West Midlands Oncology Association trial of adjuvant chemotherapy in node-negative breast cancer.

Between 1976 and 1984, 574 patients with operable breast cancer and histologically negative axillary lymph nodes were randomly assigned after mastectomy to receive either no further treatment or chemotherapy with oral LMF (fluorouracil, 500 mg, methotrexate, 25 mg, and chlorambucil, 10 mg, on day 1; fluorouracil, 500 mg, and chlorambucil, 10 mg, on day 2). There is no overall survival or relapse-free survival benefit at a median follow-up of 10 years and 8 years, respectively. There are significantly more local relapses in the control group (P less than .01), but an excess of distant relapses in the treated group is not statistically significant (P = .24). A positive treatment effect in small tumors (relapse-free survival, odds ratio = 0.55, P = .01) and a negative effect in progesterone receptor-positive tumors (survival, odds ratios = 2.04, P = .04) is probably ascribable to chance. Analysis of various prognostic factors shows that tumor size and histological grade have a clear effect on both relapse-free interval and survival.

Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome.

Bright light has recently been shown to have phase-shifting effects on human circadian rhythms. In this study we applied this effect to 20 patients with delayed sleep phase syndrome (DSPS) who were unable to fall asleep at conventional clock times and had a problem staying alert in the morning. In a controlled treatment study, we found that 2 h of bright light exposure in the morning together with light restriction in the evening successfully phase advanced circadian rhythms of core body temperature and multiple sleep latencies in these patients. This finding corroborates the importance of light for entraining human circadian rhythms.

Effects of light treatment on core body temperature in seasonal affective disorder.

Abnormalities in circadian rhythms of core body temperature have been reported previously in depressed patients. In this study, we compared the temperature rhythms of 10 depressed seasonal affective disorder (SAD) patients with winter depression with those of 12 normal controls and evaluated the effects of bright light on temperature in SAD. Unlike previous studies of depressed patients, the temperature curves of the patients and normal controls during the off-light condition were nearly identical. We found a significant difference in amplitude between the patients in the untreated and light-treated conditions. Although there was no systematic difference in circadian phase across groups or treatment conditions, we present preliminary evidence that suggests that phase-typed subgroups may be present in the population distinguished by their treatment responses.

West Midlands Oncology Association trials of adjuvant chemotherapy in operable breast cancer: results after a median follow-up of 7 years. II. Patients without involved axillary lymph nodes.

The aim of this study was to test the effectiveness of a regimen of combination chemotherapy when given as an adjuvant treatment after mastectomy to patients with histologically negative axillary lymph nodes. A total of 574 patients with cancer of the breast and no involvement of axillary lymph nodes were randomised, after simple mastectomy with axillary sampling, to receive either no adjuvant treatment or oral fluorouracil 500 mg, methotrexate 25 mg and chlorambucil 10 mg p.o. on day 1 and fluorouracil 500 mg and chlorambucil 10 mg p.o. on day 2 (LMF) every 21 days for eight cycles. Randomisation was stratified according to menopausal status and tumour size. Treatment was started within 14 days of surgery in 97% of patients. Ninety per cent of patients received eight cycles of chemotherapy with no dose reduction. At a median follow-up of 7 years, there was no evidence that relapse-free or overall survival time were influenced by treatment.

Surgical therapy of the short bowel syndrome.

Patients with the short bowel syndrome should be managed initially by giving total parenteral nutrition and by maximizing the function of the remaining intestine. Enteral feedings should be instituted as soon as the patient stabilizes, usually after 2 to 4 weeks. The gastric hypersecretion that accompanies the syndrome can usually be controlled with an H2-receptor blocker. In those patients who fail to recover adequate digestion and absorption after 6 months to 1 year, operations to improve absorption should be considered. The reversed intestinal segment and the intestinal lengthening procedures are most often employed, but neither type of operation can be recommended without reservation. Newer procedures, such as growing new intestinal mucosa on serosal patches, intestinal pacing, and intestinal transplantation may play a role in future therapies. At present, long-term parenteral nutrition remains the cornerstone of therapy.

Adjuvant chemotherapy in operable gastric cancer. 5 year follow-up of first British Stomach Cancer Group trial.

411 patients were entered into a prospective, randomised controlled trial of adjuvant chemotherapy after gastrectomy for adenocarcinoma. After a follow-up of at least 5 1/2 years there has been no survival advantage for those receiving adjuvant 5-fluorouracil and mitomycin C with or without an induction course of 5-fluorouracil, vincristine, cyclophosphamide, and methotrexate compared with those undergoing surgery only. There have been 366 deaths, including 22 from treatment-related conditions. A multivariate analysis of prognostic factors demonstrated that stage of disease, nodal and resection margin involvement, and the presence of residual disease are significant determinants of survival. Weight loss before surgery had a significant independent influence on survival. The combination of preoperative symptoms and intraoperative findings may be used to select patients for radical or palliative procedures.

Enhancing the anti-dumping effect of Roux gastrojejunostomy with intestinal pacing.

We wondered whether Roux gastrojejunostomy alone or with intestinal pacing would slow gastric emptying and ameliorate the dumping syndrome after truncal vagotomy and subtotal distal gastrectomy. In five conscious dogs with vagotomy and distal gastrectomy, the Roux loop alone slowed gastric emptying of 100 ml 5% glucose instillates, but not of 100 ml 25% glucose instillates, while pacing the loop backwards slowed emptying of both. Pacing also decreased the postcibal hemoconcentration and hyperglycemia found after the 25% instillates. However, pacing did not alter the postprandial hyper-GIP-emia (gastric inhibitory peptide) and hyperinsulinemia found in Roux gastrectomy dogs, suggesting that pacing worked by slowing emptying of glucose rather than by releasing enteric hormones. Although pacing did not stimulate jejunal action potentials (contractions), the greater the number of action potentials occurring during pacing, the more the slowing (r = .738, p less than .001). We concluded that the combination of Roux gastrojejunostomy and pacing ameliorated postgastrectomy dumping in dogs. The tests provide a basis for treating humans with postgastrectomy dumping.

Intestinal pacing for canine postgastrectomy dumping.

Our aim was to determine whether or not postprandial retrograde duodenal pacing would abolish the canine postgastrectomy dumping syndrome. Five dogs underwent truncal vagotomy, distal hemigastrectomy, gastroduodenostomy, and circumferential proximal duodenal myotomy to facilitate pacing. Bipolar stimulating electrodes from an implanted pacing unit were attached to the bowel 35 cm distal to the gastroduodenostomy, and six monopolar recording electrodes were applied at 5-cm intervals proximal to the pacing electrodes. After recovery, gastric emptying was assessed in the fasted conscious dogs using 300-ml gastric instillates of 25% dextrose marked with [14C]polyethylene glycol, while pulse, hematocrit, and defecation were monitored. Each dog underwent five tests with and five tests without retrograde duodenal pacing. Without pacing, the dogs emptied a mean +/- SEM of 237 +/- 14 ml of the instillate by 20 min and developed tachycardia (change in pulse, 45 +/- 4), hemoconcentration (change in hematocrit, 8 +/- 1), and diarrhea in 13 of 25 tests. Retrograde duodenal pacing slowed gastric emptying (157 +/- 20 ml, p less than 0.05) and minimized the adverse cardiovascular sequelae (change in pulse, 25 +/- 5, change in hematocrit, 6 +/- 1; p less than 0.05) and the diarrhea (only 2 of 25 tests, p less than 0.01). We concluded that intestinal pacing ameliorated the postgastrectomy dumping syndrome in dogs. Such an approach may be applicable to humans.

Suppression of IgE antibody production in sensitized mice and rats by tolerogenic conjugates of synthetic hydrophilic polymers with antigen or hapten: effect on antigen-induced histamine release from peritoneal mast cells.

IgE antibodies were produced in mice and rats by immunization with ragweed pollen extract (RAG) or dinitrophenylated ovalbumin (DNP3-OA). Treatment of these animals with tolerogenic conjugates of (i) the antigen (RAG or OA) with monomethoxypolyethylene glycol (mPEG), or (ii) DNP with polyvinyl alcohol (DNP-PVA) resulted, within 7-14 days, in a fall in circulating IgE antibodies and in mast cell sensitivity, as assessed by the radioallergosorbent test (RAST) and in the in vitro antigen-induced histamine release (HR) test, respectively. The reduction in responsiveness was more marked in mice than rats; 10 days after a booster immunization, the IgE antibody titres in the RAG-mPEG-treated group of mice were approximately 10-fold lower than in the saline-treated group, with a 100-fold difference in cell sensitivity. DNP-PVA treatment of mice produced a more than 10-fold reduction in IgE anti-DNP titres with a substantial reduction in histamine release.

Electrical pacing for short bowel syndrome.

In five dogs, the abroad two-thirds of the small intestine were removed, and a jejunocolostomy was performed to create the short bowel syndrome. Electrodes were affixed to the remaining proximal part of the small intestine for recording and to the distal part of the small intestine for stimulating. A comparison was made between 15 day periods in which feedings were followed by either four hours of retrograde electrical pacing or no pacing. Daily weight loss was less during the periods of pacing in each dog than during the periods of no pacing. Retrograde electrical pacing of the small intestine decreased weight loss in dogs with the short bowel syndrome.