Programmed endoscopic follow-up examinations with eventual retreatment in patients locally injected for an acute or recent hemorrhage from a gastric or duodenal ulcer did not influence their outcome when compared to patients receiving only a second endoscopic intervention upon evidence for recurrent hemorrhage. Scheduled control endoscopies cannot be recommended after an initial successful endoscopic treatment of peptic ulcer bleeding when selection of the patients for second-look endoscopy is directed by the Forrest criteria.

SummaryTo evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35-74) were enrolled. 5-FU 2 g/m 2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m 2 as a 2 h infusion. Paclitaxel 175 mg/m 2 was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m 2 as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1-4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% Cl: 35.8-66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1-36+) and 14 months (range 2-36+), respectively. Neutropenia WHO III°/IV°occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III°/IV°toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment.

Sleep deprivation is an unpleasant burden of young hospital doctors during their medical training. It may disrupt the balance between coping strategies available to them and the professional demands encountered. Impaired medical care offered by sleep-deprived juniors may be a consequence. Valid research work on this subject is rare and surprisingly contradictory. Therefore, we evaluated the task-specific cognitive status and emotional condition of 40 young hospital doctors (27 men and 13 women, 29.9 +/- 2.9 years of age) at the University of Tuebingen, all of whom were in the beginning of their academic career. Subjects were tested twice acting as their own control, once at 8.00 am after a night off duty (OD) (at least 6 hours of uninterrupted sleep), and once at a similar time after a night on call (OC) being in the hospital for 24 hours. Standardized and reliable psychometric tests thought to represent daily routine medical function were performed. On-call activities were recorded by means of a sleep diary, whereas a questionnaire interrogated aspects of private and professional life. Neuropsychological function deteriorated significantly: number connection test (per cent of norms +/- SD, 103.2 +/- 9.8 OC vs 107.8 +/- 10.5 OD, F = 27.7, P < 0.001), things-to-do list (correct items +/- SD, 6.7 +/- 1.2 OC vs 7.4 +/- 1.5 OD, F = 12.7, P < 0.01), Vienna reaction timer (per cent of norms +/- SD, 95.6 +/- 9.0 OC vs 97.7 +/- 10.4 OD, F = 4.8, P < 0.05), Stroop test (T-values +/- SD, 59.7 +/- 6.3 OC vs 64.6 +/- 7.1 OD, F = 37.1, P < 0.001), ECG test (correct responses +/- SD, 38.3 +/- 7.3 OC vs 43.4 +/- 6.5 OD, F = 45.2, P < 0.001) and status of mood (T-value +/- SD, 60.3 +/- 9.0 OC vs 54.0 +/- 6.6 OD, F = 19.6, P < 0.001). Cognitive function and mood status of young hospital doctors after a night on call decrease considerably. In view of the special vulnerability of medical trainees to occupational stress all efforts are warranted to reduce sleep deprivation in the medical profession.

The effects of the nitric oxide donor nitroglycerin on gastric emptying and antropyloroduodenal motility were evaluated in nine healthy male subjects (ages 19–36 yr). Antropyloroduodenal pressures were recorded with a manometric assembly that had nine side holes spanning the antrum and proximal duodenum and a pyloric sleeve sensor; gastric emptying was quantified scintigraphically. In each subject, the emptying of 300 ml of 25% glucose labeled with99mTc was assessed on two separate days during intravenous infusion of either nitroglycerin (5 μg/min in 5% dextrose) or 5% dextrose (control). Studies were performed with the subject in the supine position; blood pressure and heart rate were monitored. Nitroglycerin had no significant effect on blood pressure or heart rate. Nitroglycerin slowed gastric emptying ( P < 0.02), and this was associated with greater retention of the drink in the proximal stomach ( P < 0.05). In both nitroglycerin and control studies, ingestion of the drink was associated with an increase in the number of isolated pyloric pressure waves ( P < 0.05) and antral pressure wave sequences ( P < 0.05). Nitroglycerin reduced the number of isolated pyloric pressure waves ( P < 0.05), basal pyloric pressure ( P < 0.05), and the number of antral pressure wave sequences ( P < 0.05), but not the total number of antral pressure waves. The rate of gastric emptying and the number of isolated pyloric pressure waves were inversely related during control ( P = 0.03) and nitroglycerin ( P < 0.05) infusions. We conclude that in normal subjects, 1) gastric emptying of 300 ml of 25% glucose is inversely related to the frequency of phasic pyloric pressure waves, and 2) nitroglycerin in a dose of 5 μg/min inhibits pyloric motility, alters the organization but not the number of antral pressure waves, and slows gastric emptying and intragastric distribution of 25% glucose.

Marked hyperglycemia (blood glucose ∼15 mmol/l) affects gastrointestinal motor function and modulates the perception of gastrointestinal sensations. The aims of this study were to evaluate the effects of mild hyperglycemia on the perception of, and motor responses to, duodenal distension. Paired studies were done in nine healthy volunteers, during euglycemia (∼4 mmol/l) and mild hyperglycemia (∼10 mmol/l), in randomized order, using a crossover design. Antropyloroduodenal pressures were recorded with a manometric, sleeve-side hole assembly, and proximal duodenal distensions were performed with a flaccid bag. Intrabag volumes were increased at 4-ml increments from 12 to 48 ml, each distension lasting for 2.5 min and separated by 10 min. Perception of the distensions and sensations of fullness, nausea, and hunger were evaluated. Perceptions of distension ( P < 0.001) and fullness ( P < 0.05) were greater and hunger less ( P < 0.001) during hyperglycemia compared with euglycemia. Proximal duodenal distension stimulated pyloric tone ( P < 0.01), isolated pyloric pressure waves ( P < 0.01), and duodenal pressure waves ( P< 0.01). Compared with euglycemia, hyperglycemia was associated with increases in pyloric tone ( P < 0.001), the frequency ( P < 0.05) and amplitude ( P < 0.01) of isolated pyloric pressure waves, and the frequency of duodenal pressure waves ( P < 0.001) in response to duodenal distension. Duodenal compliance was less ( P < 0.05) during hyperglycemia compared with euglycemia, but this did not account for the effects of hyperglycemia on perception. We conclude that both the perception of, and stimulation of pyloric and duodenal pressures by, duodenal distension are increased by mild hyperglycemia. These observations are consistent with the concept that the blood glucose concentration plays a role in the regulation of gastrointestinal motility and sensation.

To test the hypothesis that recurrent short-term hypoglycemic episodes may impair hormonal counterregulation, symptom awareness, and neurophysiological function during subsequent hypoglycemia, we examined two groups of IDDM patients (n = 18), neither of whom exhibited signs of autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed three days apart with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' awareness of and response to hypoglycemia was evaluated. In the intervention group (n = 11), three short-term hypoglycemic episodes preceded the second clamp study. Counterregulatory hormones increased significantly during hypoglycemia, but adrenaline (P < 0.03), cortisol (P < 0.01), and ACTH (albeit not significant) showed a blunted response after repetitive hypoglycemic events. In this group, the perception of hypoglycemic symptoms was significantly reduced and was most evident for the autonomic symptoms of sweating (P < 0.05), heart pounding (P < 0.01), and warmness (P < 0.03). The deterioration of neurophysiological function, as assessed from the middle latency auditory evoked potentials, was more pronounced in the intervention group (latency shift of the Pa component, P < 0.05). These data suggest that alterations of neuroendocrine counterregulation, symptom perception, and certain aspects of cerebral function may occur as a consequence of recurrent short-term hypoglycemic episodes. These adaptation phenomena may contribute to the increased incidence of severe hypoglycemia in IDDM patients on intensive insulin therapy.

Evidence for an intrinsic effect of insulin on the central nervous system is accumulating. To test the hypothesis that insulin per se may modulate neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus, we examined 27 patients without any sign of classical autonomic neuropathy or evidence of so-called hypoglycemia unawareness. We used the hyperinsulinemic (0.67 vs. 2.00 mU/kg.min), stepped hypoglycemic (5.6/3.5/2.4/2.0 mmol/L) clamp technique to assess the patient's awareness of and response to equivalent hypoglycemic stimuli under different degrees of physiological hyperinsulinemia (approximately 270 vs. approximately 810 pmol/L) after an overnight euglycemic clamp (5.6 mmol/L). Simultaneously, the patient's cerebral function was assessed from his electrophysiological activity and neuropsychological skills. Higher degrees of physiological hyperinsulinemia caused enhanced neuroendocrine response (adrenaline, P < 0.05; noradrenaline, P < 0.03; GH, P < 0.02; beta-endorphin, P < 0.03; ACTH, P = 0.12; cortisol, P = 0.06; PRL, P = 0.08) and symptom awareness (total symptoms, P < 0.04; autonomic symptoms, P < 0.02; neuroglycopenia symptoms, P < 0.05; sweating, P < 0.05; heart pounding, P < 0.02; trembling, P < 0.01; lack of concentration, P < 0.02) to occur. Deteriorations of electrophysiological activity (middle latency auditory-evoked potentials, P < 0.04; Pa peak latencies, P < 0.05; Pa-V interpeak latencies, P = 0.08) and neuropsychological skills (Stroop test, P < 0.05; trail making, P = 0.12) were more pronounced the higher the insulin level, but at similar blood glucose concentrations. We conclude that insulin-associated modulation of neuroendocrine counterregulation, hypoglycemia perception, and cerebral function may occur in insulin-dependent diabetes mellitus, which indicates an intrinsic effect of insulin on the human brain.

Both regimens are well tolerated and show activity in advanced pancreatic carcinoma. The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation.