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Merry-go-round? Egg recording during centrifuge and rotating chair induced vestibular stimulation
April 1 9 9 5
• I N H I B I T I O N OF G A S T R I C E M P T Y I N G BY P E R I P H E R A L INTERLEUKIN-11~ IN RATS: MEDIATION T H R O U G H DIFFERENT MECHANISMS I N V O L V I N G C H O L E C Y S T O K I N I N (CCK) AND NITRIC OXIDE (NO). K. Kubo, A. Uehara, E. Shoji, S.B. Santos, T. Kubota, Y. Watanahe, T. Nozu, M. Moriya, F. Shaku, K. Harada, Y. Kohgo. Dept. of Internal Medicine (III), Asahikawa Medical College, Asahikawa, Hokkaldo 078, Japan It is now well-documented that interleukin-1 (IL-I), a cytokine mainly produced by the immune system, is involved in the regulation of gastric functions and inthe maintenance of mucosal integrity (Ann NY Acad Sci 697: 260-268, 1993). Along these lines, it has been reported that IL-I delays gastric emptying in rats; however, the mechanism for the IL- l-induced inhibition of gastric emptying is poorly Understood. In the present study, we investigated by what mechanism IL-1 suppressed gastric emptying, using male Sprague-Dawley rats weighing about 220 g. Since it is known that gastric emptying of solid and liquid meals are regulated by different mechanisms, we evaluated the effects of IL- 1 on the gastric emptying of liquid and solid meals, separately. Gastric emptying of a liquid meal was measured with the methylcellulose phenol red method using 24-hr fasted rats, while emptying of a solid meal was assessed by determining changes in the weight of gastric contents in rats fed ad libitum before and 5 hr after 1L- 1 or saline injection. The intraperitoneal (ip) injection of human recombinant IL-II3 (4 lttg/kg, Otsuka Pharmaceutical Co., Japan) significantly suppressed both solid and liquid emptying by 85.9 % and 56.3 %, respectively. The lL-l-induced inhibition of solid emptying was, however, completely abolished by pretreatment with intravenous (iv) Na-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg), a NO synthase inhibitor, but not by iv lorglumide (4 mg/kg), a type A ch01ecystokinin (CCK) receptor antagonist, or ip indomethacin (5 mg/kg), a blocker of prostaglandin (PG) biosynthesis. In contrast, the inhibitory action of IL- 1 on liquid emptying was totally reserved by lorghimide or indomethacin, whereas L-NAME was without effect. Taken together, the present findings clearly demonstrate for the first time that the inhibition by IL- 1 of solid emptying is NO-dependent and CCK- and PG-independent, while the suppression of liquid emptying is NO-independent and CCK- and PG-dependent. Since ip IL-1 stimulates the secretion of corticotropin-releasing factor (CRF) in the brain by a central PG dependent pathway and CRF elevates plasma CCK levels, the inhibition by IL-1 of liquid emptying appears to involve the PG-CRF-CCK pathway. On the other hand, IL- I may act directly on the gastric smooth muscle to activate NO production, which in turn delays solid meal emptying.
• REDUCED VARIABILITY OF GASTRIC MYOELECTRICAL ACTIVITY AND HEART RATE IN AUTONOMIC NEUROPATHY. R.Kuhlbusch, P.Zacchi-Deutschbein, *A.Pour-Mirza, *D.Ziegler, P.Auer, D.H~iussinger, P.Enck. University Dept. of Gastroenterology and *Diabetes Research Institute, D0sseldorf, Germany We have previously shown that the stomach exhibits freqUency alterations of the dominant frequency of myoelectric activity, but it remains unclear whether this is of clinical relevance similar to reduced heart rate variability in diabetic autonomic neuropathy. Methods: Electrogastrography (EGG) as well as ECG were recorded in 10 healthy volunteers under fasting conditions and after a meal for 90 minutes, and in 8 patients (44.2 years, 6 females) with autonomic neuropathy due to insulin-dependent diabetes (n=7) or HIV, all of which had clinical symptoms of gastroparesis. Delayed gastric emptying was confirmed in 5 patients by scintigraphy. EGG (Synectics Medical, Sweden) was analyzed for frequency variation of the dominant frequency (0.015 to 0.15 Hz), expressed as coefficient of variation (CV) during fasting and postprandially. ECG was analyzed for R-R-interval variation (CV) under resting and deep breathing conditions using a ProSciCard system (MediSyst, Linden, Germany). Results: 1) All but one control subjects exhibited regular variability of the dominant EGG frequency with a CV of 26.3 _+.10.5 % and 27.3 + 5.3 % (range: 17 - 35 %), pre and postprandially, respectively. There was a significant inverse relationship between the pre- and postprandial EGG variability (r=-.81, p<0.01). 2) Patients had a significantly (p<0.05) reduced CV of gastric activity (18.0 + 14.0 o~) as compared to controls, and in 6/8 it ranged between 0 and 17 %. 3) Five patients but only one of the control subjects showed pathologically reduced variability of heart rate during rest or with deep respiration (rest: 4.2 + 3.6 vs. 6.3 _+2.3 %; deep respiration: 4.4 + 3.0 vs 7.0 + 3.5 %, respectively. 4) Four patients had a reduced CV of heart and stomach activity. Conclusion: Variability of gastric myoelectrical activity may be a very specific clinical indicator of intestinal autonomic neuropathy in diabetes and other conditions. (Supported by a grant from the Deutsche Forschungsgemeinschaff, En 50/10).
M o t i l i t y and Nerve-Gut Interactions
A633
MERRY-GO-ROUND ? EGG RECORDING DURING CENTRIFUGE AND ROTATING CHAIR INDUCED VESTIBULAR STIMULATION. R.Kuhlbusch, P.Zacchi-Deutschbein, J.Kugler, *L.Vogt, *C.Drummer, P.Enck, D0sseldorf University Hospitals, Dept. of Gastroenterology and *German Aerospace Research Establishment (DLR), Cologne, Germany While vection (illusory motion)-induced nausea and vomiting has been shown to be associated with electrogastrographic dysrhythmias, this has not yet been investigated in vestibular stimulation-induced motion sickness. Method=: Eight healthy volunteers participated in two studies. A) Centrifuge stimulation with 3-g acceleration for ten minutes in both supine (+Gx) and prone (-Gx) position in randomized sequence, preceeded, seperated and followed by 10 minutes of rest in the same condition. B) Coriolis stimulation in a rotating chair, alternating 1-minute periods of rotation (60 degrees/sec) during which the subjects bended forward or moved upright every 10 sec, with 1-minute periods of rest for a total of 10 minutes, preceeded and followed by 10 minutes of resting. Under all conditions, EGG was recorded continously through an ambulatory device (Synectics Medical, Sweden), and blood samples for cortisol and ratings of malaise on a standardized (Graybiel) scale were taken prior, during and 20 min post stimulation. EGG data were analyzed for change in the dominant gastric frequency and compared between conditions (before and after stimulation), as well as correlated to cortisol levels and subjective symptoms (n.s.= not significant). Results: All but 2 subjects exhibited symptoms of nausea during both stimulation paradigms, but its degree varied significantly between subjects and was more pronounced with the rotating chair. The dominant frequency changed from baseline 3.06 + 035 and 3.14 + 0.43 cpm (centrifuge, prone and supine, respectively) and 2.94 + 0.16 cpm (rotating chair) to 4.04 + 2.4 (n.s.), 3.94 + 2.03 (n.s.), and 3.49 + 0.62 cpm (p=0.025), respectively. They did not completely return to baseline afterwards (3.41 +_0.73, 3.43 _+ 1.01 and 3.21 +_ 0.46 epm, respectively). Simultaneously, serum cortisol rose from 10.34 + 5.53 to 17.55 + 7.77 ug/dl (centrifuge, n.s.) and from 13.0 + 4.3 to 27.5 + 3.89 ug/dl (rotating chair, p<0.01). No significant association was found between the EGG changes of the dominant frequency and subjective symptom ratings, but malaise during rotation in the chair was significantly (p=0.023) correlated to cortisol levels 20 minutes later. Conclusion: Vestibular stimulation reliably induces symptoms of nausea, but this seems only marginally be reflected in the EGG changes seen during and after stimulation, presumably because of confounding stress effects. (Supported by DFG En 50/10).
CAN N O N - H I S T O L O G I C A L TECHNIQUES PREDICT VISCERAL M Y O P A T H I E S / N E U R O P A T H I E S ?
A Kumar, TL Abell, G Voeller, P Dean, B Waters, BO Familoni; Dept of Medicine, Surgery & Biomedicial Engineering; U T Memphis; Dept of Pathology; Baptist Memorial Hospital; Dept of Electrical Engineering, University of Memphis INTRODUCTION: Patients with intractable nausea and vomiting continue to present difficult diagnostic and management problems for the clinician. Lacking proven non-invasive diagnostic studies, some patients require diagnostic small bowel biopsies, often done at the time of placement. We studied the ability of two non-invasive studies 8 radionuclide small bowel transit, and serum auto-antibodies, to predict the presence or absence of specific histological abnormalities of small bowel. PATIENTS: 40 patients (5 male, 35 female mean age of 39 years) with intractable nausea, vomiting and abdominal pain (refractory to all standard and investigational drugs) were studied prospectively. METHODS: Full-thickness small intestinal biopsies were obtained of at the time of laparotomy (or laparoscopy) and stained with H&E stain, as well as silver stains of the myenteric plexus. Patients were classified as: myopathy (MYO), neuropathy (NEURO) or neither (NORM). Auto-antibodies were measured in serum by western blot, and a total antibody score (ABS = (sum presence of antibodies intensity was calculated, normal <3). Radionuclide small bowel transit (SBT) was defined as delayed for solids if > 163 minutes, delayed for liquids if -> 209 minutes. Fishers exact test was used for statistical analysis, RESULTS: There were 13 patients with normal histology years.Histrology reveals; 13 patients were NORM, 11 MYO and 16 NEURO. Abnormal ABS (b>_3) were present in 63% of NORM, 45% ofMYO and 37% of NEURO. Specific autoantibodies for MYO versus NEURO were: p33 (1/11 vs 4/16), p50 (3/11 vs 4/16), p60 (4/t 1 vs 5/16), p68 (6/11 vs 7/16), p70 (5/11 vs 9/16), and p105 (6/11 vs 4/16) but these did not distinguish myopathy from neuropathy (p > 0.05). Solid SBT was abnormal in 6/11 NEURO, 1/2 MYO, 3/6 NORM and liquid SBT was abnormal in 5/10 NEURO, 2/2 MYO, 1/5 NORM either solid and/or liquid SBT was abnormal in 6/10 NEURO, 2/2 MYO and 4/6 NORM. The combination of abnormal SBT and abnormal ABS predicted abnormalities in 75% of NEURO and 55% of MYO, but also 73% of NORM patients. CONCLUSIONS: Specific histological small bowel abnormalities could not be predicted by two non-invasive studies: radionuelide transit studies or serum auto-antibodies. Further research is needed to develop non-invasive techniques to distinguish small bowel myopathies and neuropathies from normal. Until then, patients with intractable symptoms will continue to require tissue diagnosis, currently obtainable only by laparotomy or laparoscopy.
• I N H I B I T I O N OF G A S T R I C E M P T Y I N G BY P E R I P H E R A L INTERLEUKIN-11~ IN RATS: MEDIATION T H R O U G H DIFFERENT MECHANISMS I N V O L V I N G C H O L E C Y S T O K I N I N (CCK) AND NITRIC OXIDE (NO). K. Kubo, A. Uehara, E. Shoji, S.B. Santos, T. Kubota, Y. Watanahe, T. Nozu, M. Moriya, F. Shaku, K. Harada, Y. Kohgo. Dept. of Internal Medicine (III), Asahikawa Medical College, Asahikawa, Hokkaldo 078, Japan It is now well-documented that interleukin-1 (IL-I), a cytokine mainly produced by the immune system, is involved in the regulation of gastric functions and inthe maintenance of mucosal integrity (Ann NY Acad Sci 697: 260-268, 1993). Along these lines, it has been reported that IL-I delays gastric emptying in rats; however, the mechanism for the IL- l-induced inhibition of gastric emptying is poorly Understood. In the present study, we investigated by what mechanism IL-1 suppressed gastric emptying, using male Sprague-Dawley rats weighing about 220 g. Since it is known that gastric emptying of solid and liquid meals are regulated by different mechanisms, we evaluated the effects of IL- 1 on the gastric emptying of liquid and solid meals, separately. Gastric emptying of a liquid meal was measured with the methylcellulose phenol red method using 24-hr fasted rats, while emptying of a solid meal was assessed by determining changes in the weight of gastric contents in rats fed ad libitum before and 5 hr after 1L- 1 or saline injection. The intraperitoneal (ip) injection of human recombinant IL-II3 (4 lttg/kg, Otsuka Pharmaceutical Co., Japan) significantly suppressed both solid and liquid emptying by 85.9 % and 56.3 %, respectively. The lL-l-induced inhibition of solid emptying was, however, completely abolished by pretreatment with intravenous (iv) Na-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg), a NO synthase inhibitor, but not by iv lorglumide (4 mg/kg), a type A ch01ecystokinin (CCK) receptor antagonist, or ip indomethacin (5 mg/kg), a blocker of prostaglandin (PG) biosynthesis. In contrast, the inhibitory action of IL- 1 on liquid emptying was totally reserved by lorghimide or indomethacin, whereas L-NAME was without effect. Taken together, the present findings clearly demonstrate for the first time that the inhibition by IL- 1 of solid emptying is NO-dependent and CCK- and PG-independent, while the suppression of liquid emptying is NO-independent and CCK- and PG-dependent. Since ip IL-1 stimulates the secretion of corticotropin-releasing factor (CRF) in the brain by a central PG dependent pathway and CRF elevates plasma CCK levels, the inhibition by IL-1 of liquid emptying appears to involve the PG-CRF-CCK pathway. On the other hand, IL- I may act directly on the gastric smooth muscle to activate NO production, which in turn delays solid meal emptying.
• REDUCED VARIABILITY OF GASTRIC MYOELECTRICAL ACTIVITY AND HEART RATE IN AUTONOMIC NEUROPATHY. R.Kuhlbusch, P.Zacchi-Deutschbein, *A.Pour-Mirza, *D.Ziegler, P.Auer, D.H~iussinger, P.Enck. University Dept. of Gastroenterology and *Diabetes Research Institute, D0sseldorf, Germany We have previously shown that the stomach exhibits freqUency alterations of the dominant frequency of myoelectric activity, but it remains unclear whether this is of clinical relevance similar to reduced heart rate variability in diabetic autonomic neuropathy. Methods: Electrogastrography (EGG) as well as ECG were recorded in 10 healthy volunteers under fasting conditions and after a meal for 90 minutes, and in 8 patients (44.2 years, 6 females) with autonomic neuropathy due to insulin-dependent diabetes (n=7) or HIV, all of which had clinical symptoms of gastroparesis. Delayed gastric emptying was confirmed in 5 patients by scintigraphy. EGG (Synectics Medical, Sweden) was analyzed for frequency variation of the dominant frequency (0.015 to 0.15 Hz), expressed as coefficient of variation (CV) during fasting and postprandially. ECG was analyzed for R-R-interval variation (CV) under resting and deep breathing conditions using a ProSciCard system (MediSyst, Linden, Germany). Results: 1) All but one control subjects exhibited regular variability of the dominant EGG frequency with a CV of 26.3 _+.10.5 % and 27.3 + 5.3 % (range: 17 - 35 %), pre and postprandially, respectively. There was a significant inverse relationship between the pre- and postprandial EGG variability (r=-.81, p<0.01). 2) Patients had a significantly (p<0.05) reduced CV of gastric activity (18.0 + 14.0 o~) as compared to controls, and in 6/8 it ranged between 0 and 17 %. 3) Five patients but only one of the control subjects showed pathologically reduced variability of heart rate during rest or with deep respiration (rest: 4.2 + 3.6 vs. 6.3 _+2.3 %; deep respiration: 4.4 + 3.0 vs 7.0 + 3.5 %, respectively. 4) Four patients had a reduced CV of heart and stomach activity. Conclusion: Variability of gastric myoelectrical activity may be a very specific clinical indicator of intestinal autonomic neuropathy in diabetes and other conditions. (Supported by a grant from the Deutsche Forschungsgemeinschaff, En 50/10).
M o t i l i t y and Nerve-Gut Interactions
A633
MERRY-GO-ROUND ? EGG RECORDING DURING CENTRIFUGE AND ROTATING CHAIR INDUCED VESTIBULAR STIMULATION. R.Kuhlbusch, P.Zacchi-Deutschbein, J.Kugler, *L.Vogt, *C.Drummer, P.Enck, D0sseldorf University Hospitals, Dept. of Gastroenterology and *German Aerospace Research Establishment (DLR), Cologne, Germany While vection (illusory motion)-induced nausea and vomiting has been shown to be associated with electrogastrographic dysrhythmias, this has not yet been investigated in vestibular stimulation-induced motion sickness. Method=: Eight healthy volunteers participated in two studies. A) Centrifuge stimulation with 3-g acceleration for ten minutes in both supine (+Gx) and prone (-Gx) position in randomized sequence, preceeded, seperated and followed by 10 minutes of rest in the same condition. B) Coriolis stimulation in a rotating chair, alternating 1-minute periods of rotation (60 degrees/sec) during which the subjects bended forward or moved upright every 10 sec, with 1-minute periods of rest for a total of 10 minutes, preceeded and followed by 10 minutes of resting. Under all conditions, EGG was recorded continously through an ambulatory device (Synectics Medical, Sweden), and blood samples for cortisol and ratings of malaise on a standardized (Graybiel) scale were taken prior, during and 20 min post stimulation. EGG data were analyzed for change in the dominant gastric frequency and compared between conditions (before and after stimulation), as well as correlated to cortisol levels and subjective symptoms (n.s.= not significant). Results: All but 2 subjects exhibited symptoms of nausea during both stimulation paradigms, but its degree varied significantly between subjects and was more pronounced with the rotating chair. The dominant frequency changed from baseline 3.06 + 035 and 3.14 + 0.43 cpm (centrifuge, prone and supine, respectively) and 2.94 + 0.16 cpm (rotating chair) to 4.04 + 2.4 (n.s.), 3.94 + 2.03 (n.s.), and 3.49 + 0.62 cpm (p=0.025), respectively. They did not completely return to baseline afterwards (3.41 +_0.73, 3.43 _+ 1.01 and 3.21 +_ 0.46 epm, respectively). Simultaneously, serum cortisol rose from 10.34 + 5.53 to 17.55 + 7.77 ug/dl (centrifuge, n.s.) and from 13.0 + 4.3 to 27.5 + 3.89 ug/dl (rotating chair, p<0.01). No significant association was found between the EGG changes of the dominant frequency and subjective symptom ratings, but malaise during rotation in the chair was significantly (p=0.023) correlated to cortisol levels 20 minutes later. Conclusion: Vestibular stimulation reliably induces symptoms of nausea, but this seems only marginally be reflected in the EGG changes seen during and after stimulation, presumably because of confounding stress effects. (Supported by DFG En 50/10).
CAN N O N - H I S T O L O G I C A L TECHNIQUES PREDICT VISCERAL M Y O P A T H I E S / N E U R O P A T H I E S ?
A Kumar, TL Abell, G Voeller, P Dean, B Waters, BO Familoni; Dept of Medicine, Surgery & Biomedicial Engineering; U T Memphis; Dept of Pathology; Baptist Memorial Hospital; Dept of Electrical Engineering, University of Memphis INTRODUCTION: Patients with intractable nausea and vomiting continue to present difficult diagnostic and management problems for the clinician. Lacking proven non-invasive diagnostic studies, some patients require diagnostic small bowel biopsies, often done at the time of placement. We studied the ability of two non-invasive studies 8 radionuclide small bowel transit, and serum auto-antibodies, to predict the presence or absence of specific histological abnormalities of small bowel. PATIENTS: 40 patients (5 male, 35 female mean age of 39 years) with intractable nausea, vomiting and abdominal pain (refractory to all standard and investigational drugs) were studied prospectively. METHODS: Full-thickness small intestinal biopsies were obtained of at the time of laparotomy (or laparoscopy) and stained with H&E stain, as well as silver stains of the myenteric plexus. Patients were classified as: myopathy (MYO), neuropathy (NEURO) or neither (NORM). Auto-antibodies were measured in serum by western blot, and a total antibody score (ABS = (sum presence of antibodies intensity was calculated, normal <3). Radionuclide small bowel transit (SBT) was defined as delayed for solids if > 163 minutes, delayed for liquids if -> 209 minutes. Fishers exact test was used for statistical analysis, RESULTS: There were 13 patients with normal histology years.Histrology reveals; 13 patients were NORM, 11 MYO and 16 NEURO. Abnormal ABS (b>_3) were present in 63% of NORM, 45% ofMYO and 37% of NEURO. Specific autoantibodies for MYO versus NEURO were: p33 (1/11 vs 4/16), p50 (3/11 vs 4/16), p60 (4/t 1 vs 5/16), p68 (6/11 vs 7/16), p70 (5/11 vs 9/16), and p105 (6/11 vs 4/16) but these did not distinguish myopathy from neuropathy (p > 0.05). Solid SBT was abnormal in 6/11 NEURO, 1/2 MYO, 3/6 NORM and liquid SBT was abnormal in 5/10 NEURO, 2/2 MYO, 1/5 NORM either solid and/or liquid SBT was abnormal in 6/10 NEURO, 2/2 MYO and 4/6 NORM. The combination of abnormal SBT and abnormal ABS predicted abnormalities in 75% of NEURO and 55% of MYO, but also 73% of NORM patients. CONCLUSIONS: Specific histological small bowel abnormalities could not be predicted by two non-invasive studies: radionuelide transit studies or serum auto-antibodies. Further research is needed to develop non-invasive techniques to distinguish small bowel myopathies and neuropathies from normal. Until then, patients with intractable symptoms will continue to require tissue diagnosis, currently obtainable only by laparotomy or laparoscopy.