Ryouichi Tomita

Role of Nitric Oxide in the Colon of Patients With Slow-Transit Constipation

AbstractPURPOSE: The cause of dysmotility in patients with slow-transit constipation is unknown. Nitric oxide has recently been shown to be a neurotransmitter in the nonadrenergic, noncholinergic inhibitory nerves of the human gut. To clarify the physiologic significance of nitric oxide in the colon of patients with slow-transit constipation, we investigated the enteric nerve responses in lesional and normal bowel segments derived from patients with slow-transit constipation and patients who underwent colon resection for colonic cancers. METHODS: Twenty-six preparations were taken from colonic lesions in eight patients with slow-transit constipation (2 men; age, 23 to 69 (mean, 44.8) years). Forty-two preparations were taken from the normal colons of 14 patients with colonic cancer (8 men; age, 40 to 66 (mean, 52.4) years). A mechanographic technique was used to evaluate in vitro muscle responses to electric field stimulation before and after treatment with various autonomic nerve blockers, NG-nitro-L-arginine, and L-arginine. RESULTS: The colons of patients with slow-transit constipation were more strongly innervated by nonadrenergic, noncholinergic inhibitory nerves than were normal colons (P <0.05). Nitric oxide was found to act on both normal and slow-transit constipation colons. The colons of patients with slow-transit constipation were more strongly innervated by nitric oxide nerves than were normal colons (P < 0.01). Responses to electric field stimulation were the same in each case among the normal colons and were also the same in each case among the slow-transit constipation colons. CONCLUSION: These findings suggest that an increase of nitric oxide mediates nonadrenergic, noncholinergic inhibitory nerves and plays an important role in the dysmotility observed in the colons of patients with slow-transit constipation.

Pathophysiological studies on the relationship between postgastrectomy syndrome and gastric emptying function at 5 years after pylorus-preserving distal gastrectomy for early gastric cancer.

Pylorus-preserving distal gastrectomy (PPG) has frequently been performed on patients with early gastric cancer in Japan to prevent the postgastrectomy syndrome seen after conventional distal gastrectomy (CDG). The long-term postoperative quality of life (QOL) and gastric emptying function in patients after PPG has not been assessed in detail. To clarify the usefulness of PPG for treating early gastric cancer we investigated the relation between postgastrectomy syndrome and gastric emptying function 5 years after PPG and then compared the results with those 5 years after CDG. Altogether, 32 patients who underwent curative gastrectomy at our clinic for early gastric cancer (submucosal cancer without lymph node metastasis) were studied. Ten subjects who underwent PPG with D2 lymphadenectomy without preserving the hepatic and pyloric branches of the vagal nerve [group A: eight men, two women; age 33–70 years (mean 60.7 years)] were interviewed and asked about appetite, weight loss, epigastric fullness, reflux esophagitis, and early dumping syndrome. They were compared with patients after CDG [group B: 36–72 years (mean 63.6 years)]. Esophagogastric endoscopy, abdominal ultrasonography, and gastric emptying function were also studied. The gastric emptying time of a semisolid diet was measured with a radioisotope method using 99mTc-labeled rice gruel; the gastric emptying time of a liquid diet was measured with the acetaminophen method using orange juice. The control subjects (group C) consisted of 18 healthy volunteers (10 men, 8 women) without gastrointestinal symptoms aged 38 to 68 years (mean 60.8 years). The following results were obtained: PPG (group A) alleviated postoperative gastrointestinal symptoms such as appetite loss, reflux esophagitis, early dumping syndrome, lost body weight, endoscopic reflux esophagitis, endoscopic gastritis in the remnant stomach, and postogastrectomy cholecystolithiasis better than did CDG (group B). The only weak point with the PPG procedure was that it produced a feeling of epigastric fullness. The pattern of the gastric emptying curve for the semisolid diet was almost the same among groups A, B, and C, although delayed gastric emptying was clearly more frequent in group A than in group B or C (p < 0.05). Gastric emptying with the liquid diet in group B was significantly faster than that in groups A and C (p < 0.01). Gastric emptying in groups A and C was similar. These results showed that PPG improved the postoperative QOL, but the delayed emptying of semisolid diet after PPG led to a feeling of epigastric fullness after meals due to retention of contents in the residual stomach. Epigastric fullness after meals continued in many patients after PPG. Thus the only disadvantage of the PPG procedure is the sensation of epigastric fullness and gastric stasis due to delayed gastric emptying of a semisolid diet.

Physiologic effects of cisapride on gastric emptying after pylorus-preserving gastrectomy for early gastric cancer.

Abstract. Pylorus-preserving gastrectomy (PPG) has been considered reasonable reduction surgery. However, even patients in whom more than 1 year passed after surgery frequently have a feeling of gastric fullness after meals and long-term retention of foods in the residual stomach. To treat this syndrome, cisapride has been administered. We studied the emptying time of a semisolid diet (radioisotope method using 99m Tc-tin colloid-labeled rice gruel) and the emptying time of a fluid diet (acetaminophen method with orange juice) before and after oral administration of cisapride (15 mg/day for 1 month) in 14 patients (10 men, 4 women; 32–70 years old, average 60.6 years) who underwent PPG (Billroth I procedure, D 2 lymph node dissection, curability A) for treatment of early gastric cancer. Ten healthy volunteers without gastrointestinal symptoms and digestive diseases (7 men, 3 women; 28–61 years old, average 49.8 years) were enrolled as controls. The results showed obviously delayed emptying time of the semisolid diet before administration of cisapride in patients with PPG compared with that of the control group, whereas the emptying curves for the fluid diet showed an almost normal pattern. One month after the start of cisapride administration the emptying time of the semisolid diet was improved, and the emptying curves were close to the patterns in the control group. Emptying of the fluid diet was slightly accelerated compared with that before administration of cisapride, and the emptying curves showed almost the same pattern as in the control group. A postgastrectomy symptom, “gastric fullness,” after PPG was alleviated by cisapride. These results showed that cisapride improved delayed emptying of a semisolid diet after PPG and prevented the feeling of gastric fullness after meals due to retention in the residual stomach.

Studies on gastrointestinal hormone and jejunal interdigestive migrating motor complex in patients with or without early dumping syndrome after total gastrectomy with Roux-en-Y reconstruction for early gastric cancer.

BACKGROUND There has been no report concerning fasting Roux limb motilities and gut hormone in patients with early dumping syndrome (EDS) after total gastrectomy with Roux-en-Y reconstruction. The present study investigated interdigestive migrating motor complex, phase III (IMMC-pIII) in the Roux limb, changes in the plasma gut hormone levels, and the relationships among those parameters and EDS. METHODS Forty-eight patients (35 men, 13 women; aged 33 to 69 years, mean, 59.8) 1.5 to 2.0 years (mean 1 year, 8 months) after total gastrectomy with Roux-en-Y reconstruction for early gastric cancer were allocated to two groups based on the presence or absence of EDS. The occurrence of IMMC-pIII was compared and changes in the plasma levels of both motilin (MT) and somatostatin (SOM) were monitored. RESULTS None of the patients with EDS (n = 8) were recognized as having IMMC-pIII. In the IMMC-pIII positive group, MT and SOM increased sequentially from phase I through IMMC-pIII. In the IMMC-pIII negative group, MT and SOM were significantly lower than in the IMMC-pIII positive group during phases I, II, and IMMC-pIII (P <0.05, P <0.01, P <0.01, respectively). CONCLUSIONS There is an absence of IMMC-pIII in patients with EDS, and both MT and SOM might be necessary for IMMC-pIII generation.

Role of Nitric Oxide in the Colon of Patients with Ulcerative Colitis

Abstract. The cause of impaired motility, such as diarrhea and toxic megacolon, in patients with ulcerative colitis (UC) is unknown. Nitric oxide (NO) has been shown to be a neurotransmitter in the nonadrenergic noncholinergic (NANC) inhibitory nerves in the human gut. To assess the physiologic significance of NO in the colon of patients with UC, we investigated enteric nerve responses on lesional and normal bowel segments derived from patients with ulcerative colitis (n= 6) and patients who underwent colon resection for colonic cancers (n= 10). A mechanographic technique was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, includingNG-nitro-l-arginine (l-NNA) and l-arginine. The results showed that (1) NANC inhibitory nerves were found to act on both normal colon and UC colon; (2) the colon with UC was more strongly innervated by NANC inhibitory nerves than the normal colon; (3) l-NNA concentration-dependently inhibited the relaxation in response to EFS in the colon of both normal and UC colon; and (4) this inhibitory effect in the colon of both normal and UC patients was reversed by l-arginine; (5) NO acts more strongly in the UC colon than the normal colon. These findings suggest that NANC inhibitory nerves play an important role in the impaired motility observed in patients with UC and that NO plays an important role as a neurotransmitter in NANC inhibitory nerves of human colon.

Increased IL‑17 production correlates with immunosuppression involving myeloid‑derived suppressor cells and nutritional impairment in patients with various gastrointestinal cancers

Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cell mechanisms mediating this relationship have not been elucidated. Th17 cells, which produce the proinflammatory cytokine interleukin 17 (IL-17), have been recognized as one of the key factors in the regulation of inflammatory bowel disease and rheumatoid arthritis. This study demonstrated that, in patients with various types of gastrointestinal cancer, IL-17 production was correlated with myeloid-derived suppressor cell (MDSC) levels and with markers for nutritional impairment, immune suppression and chronic inflammation. IL-17 was significantly higher in patients with various types of gastrointestinal cancer compared to normal volunteers. In addition, IL-17 levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio (NLR) and significantly inversely correlated with cell-mediated immune response indicators [lymphocyte phytohemagglutinin (PHA)-blastogenesis and IL-12 induction] and patient nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism contributing to disease progression through enhancement of immune suppression or cachexia. Controlling the activation of Th17 cells may prove to be a valuable strategy for the treatment of gastrointestinal cancer patients.

Utility of Mobilization of the Right Colon and the Root of the Mesentery for Avoiding Vein Grafting During Reconstruction of the Portal Vein

A radical operation for pancreatoduodenal cancer often involves resection and reconstruction of the portal vein. For segment resection of up to 4 to 5 cm of the portal vein, reconstruction can be easily done with an end-toend anastomosis without grafting. Reconstruction of longer segments requires the use of an autologous venous graft or a synthetic vascular graft. But autologous venous grafts are complicated to procure and often bring about a functional impairment after their removal; artificial vessel grafts have problems in longterm patency and easy infectability. In this article, we describe a simple procedure for vascular reconstruction without grafting after wide (6 to 10 cm) resection of the portal vein. In our simple technique, only complete mobilization of the right colon and the root of the mesentery are required in addition to the ordinary procedure.

ROLE OF NON-ADRENERGIC NON-CHOLINERGIC INHIBITORY NERVES IN THE COLON OF PATIENTS WITH ULCERATIVE COLITIS

Abstract: The cause of impaired colonic motility in patients with ulcerative colitis (UC) is unknown. The non-adrenergic non-cholinergic (NANC) inhibitory nervous system is one of the most important factors in the enteric nervous system of human gut. To assess the physiological significance of NANC inhibitory nerves in the colon of patients with UC, we investigated the enteric nerve responses of colonic tissues from patients with this disease. Colonic tissues were obtained from the lesional sigmoid colons of six patients with UC. Normal sigmoid colonic tissues obtained from ten patients with colonic cancer were used as controls. A mechanographic technique was used to evaluate in-vitro muscle responses to the electrical field stimulation (EFS) of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers. NANC inhibitory nerves were found to act on both normal colon and the lesional colon of patients with UC, but colon with UC was more strongly innervated by NANC inhibitory nerves than was the normal colon. These findings suggest that NANC inhibitory nerves play an important role in the impaired motility observed in the colon of patients with UC.

The role of motilin and cisapride in the enteric nervous system of the lower esophageal sphincter in humans.

To assess the pharmacophysiological significance of the enteric nervous system and the responses of the human lower esophageal sphincter (LES) to motilin and cisapride, the mechanical responses of esophgeal tissues from six patients with esophageal cancer and seven patients with gastric cancer were investigated. Circular muscle reactions were recorded to evaluate the in vitro esophageal responses to electrical field stimulation (EFS), motilin, and cisapride, evoking the adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers. The findings of this study revealed that: cholinergic nerves are mainly involved in the regulation of enteric nerves in the steady state, while nonadrenergic non-cholinergic (NANC) inhibitory nerves also exist; motilin may act both via nerves and also directly on the LES smooth muscle; and cisapride releases acetylcholine from the end of the postganglionic fiber of the cholinergic nerve in human LES thereby inducing contraction of the LES. These results suggest that cholinergic and NANC inhibitory nerves play an important role in human LES, and that motilin and cisapride is clinically useful for improving the impaired LES of patients with gastroesophageal reflux.

Relationship between nitric oxide and non-adrenergic non-cholinergic inhibitory nerves in human lower esophageal sphincter

Nitric oxide (NO) has recently been shown to be a neurotransmitter in the non-adrenergic non-cholinergic (NANC) inhibitory nerves in the gastrointestinal tract. To clarify the the role of NO in the human lower esophageal sphincter (LES), enteric nerve responses in lower esophageal tissue specimens obtained from patients with esophageal cancer (n=7) and patients with gastric cancer (n=6) were investigated. A mechanographic technique was used to evaluate in vitro LES muscle responses to electrical field stimulation (EFS) of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, including NG-nitro-L-arginine (L-NNA) and L-arginine. Findings were: (1) Cholinergic nerves were those mainly involved in the regulation of enteric nerve responses to EFS in the steady state, and NANC inhibitory nerves acted on the LES; (2) L-NNA concentration-dependently inhibited the relaxation in response to EFS in the LES; and (3) this inhibitory effect in the LES was reversed by L-arginine. These findings suggest that cholinergic and NANC inhibitory nerves play important roles in regulating contraction and relaxation of the human LES, and that NO plays an important role as a neurotransmitter in NANC inhibitory nerves of the human LES.