Endoscopic submucosal dissection for early gastric cancer performed by supervised residents: assessment of feasibility and learning curve.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is feasible as a treatment for early gastric cancer (EGC) when it is performed by an experienced endoscopist. We investigated whether it was feasible for novice endoscopists to perform ESD for EGC, and how difficult it was to learn the procedure. METHODS: This case series study was performed in a cancer referral center. Three resident endoscopists, who had already learned basic procedures, performed ESD under supervision for 30 consecutive lesions, and their procedures were analyzed. The procedure was divided for assessment into (i) mucosal incision and (ii) submucosal dissection by completion of the circumferential mucosal cut. An insulated-tip knife was used for mucosal incision and submucosal dissection. A total of 90 mucosal EGCs (< or = 2 cm) without ulcers or scars in 87 patients were included. Outcomes were: rates of complete resection, complications, and self-completion; operation time; learning curve; and reasons for change of supervisor as an indicator of difficulty. RESULTS: Among the 90 procedures, there was a good overall complete resection rate of 93 %, with an acceptable complication rate of 4.4 %; the complications were delayed hemorrhage in two patients, and perforations in another two patients that were repaired successfully by endoscopic clipping. The self-completion rate and operation time were significantly worse for submucosal dissection than for mucosal incision. Two of the three operators showed a flat learning curve for submucosal dissection. Difficulty with the procedure was related mainly to uncontrollable hemorrhage. CONCLUSIONS: With appropriate supervision, gastric ESD by residents is feasible, with equivalent complete resection rates and acceptable complication rates compared with those of experienced endoscopists, although there was difficulty in achieving sufficient self-completion rates in submucosal dissection. Better control of bleeding during submucosal dissection may be a key to improving the procedure.

Physiological characteristics of diabetic neuropathy in sucrose-fed Otsuka Long-Evans Tokushima fatty rats.

Diabetic neuropathy is a very common complication of diabetes mellitus, and animal studies have contributed tremendously to its understanding. The aim of this study was to estimate the neuropathic alterations in the Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus. For this purpose, four groups of animals were used: untreated OLETF rats, sucrose-fed for 2 months OLETF rats, untreated Long-Evans Tokushima Otsuka (LETO) nondiabetic rats as genetic controls of OLETF, and sucrose-fed LETO rats. All were examined at baseline, at the end of the sucrose treatment, and during a washout period. The following parameters were evaluated: motor nerve conduction velocity (MNCV), sensitivity to noxious thermal and mechanical stimuli using the tail-flick (TF) and tail-pressure (TP) tests, and blood glucose (BG) and HbA1c levels. Our results showed that BG and HbA1c were significantly higher in OLETF rats when compared with those in control LETO rats. Sucrose caused remarkable increase of BG and HbA1c in the OLETF rats, but not in the sucrose-fed LETO rats. MNCV and thermal nociception significantly decreased in OLETF rats in their 10th month, while the values of the TP test did not differ compared with those from LETO rats. Sucrose administration significantly decreased the MNCV, and increased the pain threshold evaluated by the TF and TP tests, compared with those in the control OLETF rats. The studied parameters were not significantly altered in sucrose-fed LETO rats. In conclusion, our findings show that signs of diabetic neuropathy appear late in the individual development of the OLETF rats, and MNCV and thermal nociception are selectively affected in this strain. Sucrose deteriorated the diabetic state, decreased MNCV, and caused thermal and mechanical hypoalgesia.

Impaired heart function and noradrenaline release after ischaemia in stroke-prone spontaneously hypertensive rats.

1. Stroke-prone spontaneously hypertensive rats (SHRSP) are a strain of rat that exhibit severely high blood pressure and stroke attacks at an early age, but their heart function in vitro has seldom been studied in detail. Although the activity of the sympathetic nervous system is known to increase after myocardial ischaemia, there is little information about the cardiac release of noradrenaline (NA) associated with heart function after ischaemia in SHRSP. The aim of the present study was to examine heart function and cardiac NA release after ischaemia in SHRSP. 2. Isolated hearts of 4- and 8-month-old SHRSP and age-matched Wistar-Kyoto (WKY) rats were perfused in a working heart preparation and were subjected to 30 min ischaemia followed by 30 min reperfusion. Heart function and coronary flow were monitored throughout the experiment. Coronary effluent was collected for determination of NA using high-performance liquid chromatography coupled with electrochemical detection. 3. Under baseline conditions, cardiac output of 4-month-old SHRSP was slightly but significantly decreased compared with that of WKY rats (P < 0.05), although coronary flow was maintained normally at this age. Eight-month-old SHRSP showed a further impairment of systolic heart function, with lower coronary flow and higher coronary vascular resistance under baseline conditions. Elevated left ventricular end-diastolic pressure was evident in SHRSP at both ages before ischaemia. Heart function was severely damaged after 30 min global ischaemia in SHRSP from both age groups. Stroke-prone spontaneously hypertensive rats also showed lower coronary flow and higher coronary vascular resistance during reperfusion. 4. Coronary NA was not detectable in WKY rats or SHRSP at 4 months of age under baseline conditions. In 8-month-old SHRSP, pre-ischaemic NA release was significantly higher than that in age-matched WKY rat controls. The concentration of NA in the coronary effluent of SHRSP during reperfusion was also significantly higher than that of WKY rats at both ages. 5. These data demonstrate that SHRSP have early impairment of both systolic and diastolic heart function compared with WKY rats. Severe damage of heart function and coronary flow after ischaemia in SHRSP was accompanied with an increased release of NA, which may play a harmful role in heart function impairment in SHRSP after ischaemia.

Role of ATP and related purine compounds on urethral relaxation in male rabbits.

BACKGROUND: Non-adrenergic, non-cholinergic (NANC) relaxation evoked by electrical field stimulation (EFS) has been observed in the urethra, with nitric oxide (NO) considered the agent most probably mediating this effect. However, Burnstock's purinergic hypothesis suggests that ATP and related purine compounds are neurotransmitters in NANC relaxation, although the physiological and pharmacological effects of ATP and related purine compounds in the urethra have been little studied. METHODS: The effects of ATP and related purine compounds, NG-nitro-L-arginine (NOARG; an inhibitor of nitric oxide synthesis from L-arginine), calcitonin gene-related peptide (CGRP), substance P and vasoactive intestinal polypeptide (VIP) on relaxation and smooth muscle tension induced by electrical field stimulation (EFS) were studied in isolated male rabbit circular urethral smooth muscle (functional study). In addition, the outflow of ATP elicited by EFS was measured using the luciferase technique (superfusion study). All experiments were performed in the presence of guanethidine (3 x 10(-3) mol/L) and atropine (10(-6) mol/L). RESULTS: In preparations contracted with U46619, a prostaglandin peroxidase inhibitor, ATP had almost no effect on EFS-induced relaxation; however, suramin, a non-selective P2Y-purinoceptor antagonist, and NOARG each markedly attenuated this relaxation in a concentration-dependent manner. ATP and related purine compounds (adenosine, AMP and ADP) each reduced U46619-induced tonic contraction in a concentration-dependent manner. The potencies of the relaxant effects of ATP and these purine compounds were almost the same. In preparations contracted with U46619, CGRP and substance P had no effect on tonic contraction, but VIP reduced tonic contraction in a concentration-dependent manner. In the superfusion study, the outflow of ATP into the superfusate was markedly increased by EFS. When NOARG or prazosin was added to the superfusate, the increase in outflow of ATP was unchanged, but when suramin was added to the superfusate, no increase in outflow of ATP was observed. CONCLUSIONS: These findings suggest that P2Y-purinoceptors exist in the male rabbit urethra, and that ATP and related purine compounds may play a role in non-adrenergic, non-cholinergic neurotransmission. Consequently, the pathways mediating urethral relaxation by ATP, NO and VIP may be different.

Synthesis of novel dioxane nucleosides having two bases, physico-chemical properties, and their biological activities.

Novel dioxane nucleosides having two bases, 2(R)-(5-fluorouracil-1-yl)-5(R)-hydroxymethyl-3(R)-(uracil-1-yl)-1,4-dioxane (7a) and 2(S)-(5-fluorouracil-1-yl)-5(R)-hydroxymethyl-3(R)-(uracil-1-yl)-1,4-dioxane (7b) were synthesized from uridine to develop a new category of nucleoside for therapeutic use. Some derivative of precursors of the nucleoside were also synthesized and several compounds synthesized were tested antitumor activity using human gastric cancer cell lines in culture.

[The adrenoceptor and calcitionin-gene related peptide receptor in the striated urethral sphincter in male rabbit].

BACKGROUND: The objective of this study is to analyze the adrenoceptor and calcitonin-gene related peptide receptor in the isolated striated urethral sphincter from a male rabbit. METHODS: The striated urethral sphincter preparations were suspended in 2ml tissue chamber filled with Krebs Ringer solution, and the changes of isometric twitch contraction induced by electrical field stimulation (EFS-contraction) were recorded in the presence of 3-isobutyl-1-methyl-xanthine (IBMX, 10(-5) M). RESULTS: The EFS-contraction was almost completely attenuated by tetrodotoxin (TTX, 10(7) M), vecronium (10(-4) M) and suxamethonium (10(-4) M). Norepinephrine (NE, 10(-8) M-10(-4) M) did not affect the EFS-contraction, but increased the tonic contraction in a dose-dependent manner. The tonic contractions induced by NE was significantly blocked by phentolamine (10(-6) M). Clonidine (10(-7) M), yohimbin (10(-7) M) and propranolol (10(-9) M-10(-6) M) did not affect the EFS-contraction. Isoproterenol (10(-9) M-10(-6) M) did not reduce the carbachol (10(-5) M) induced tonic contraction. Calcitonin-gene related paptide (CGRP, 10(-7) M-3 x 10(-6) M) did not affect the EFS-contraction and did not increase the tonic contraction. CONCLUSION: These results suggested that alpha 1-adrenoceptors of the striated urethral sphincter play a role to modulate the resting tension level, but alpha 2-adrenoceptors, beta-adrenoceptors and CGRP receptors play no role in this regard.

Changes of endothelial functions in the coronary artery after chronic nitroarginine feeding.

1. The effects of chronic NG-nitro-L-arginine (LNA) feeding on the endothelial function in isolated coronary arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto (WKY) rats were studied. 2. A diet containing LNA (0.02%) was given to male SHRSP and WKY at 6 weeks of age and the coronary arteries were dissected on the 10th day of feeding. 3. In the SHRSP and WKY fed the LNA-free diet, acetylcholine (ACh) relaxed the precontracted ring segments of the coronary artery with intact endothelium in a dose-dependent manner. The reactivity was stronger in the WKY than in the SHRSP. However, the ACh-induced relaxation after the LNA-feeding was significantly stronger in the coronary arteries from the WKY than in those from the SHRSP. 4. The relaxation induced by the calcitonin gene-related peptide (CGRP) was endothelium-dependent and endothelium-independent. The degree of the response in the rats fed the LNA-containing diet was not significantly different from that in the rats fed the LNA-free diet. 5. The vasodilator response induced by sodium nitroprusside (SNP) was dose-dependent and similar in the rats fed the LNA containing diet and the LNA-free diet. 6. These findings indicate that chronic LNA feeding markedly impaired the endothelial nitric oxide formation in the coronary artery from young SHRSP.

[Traumatic bilateral MLF syndrome--a case report].

A case of traumatic bilateral medial longitudinal fasciculus (MLF) syndrome is reported. An 18-year-old man who had been struck on the occipital region in a traffic accident was admitted to our center. On admission, the consciousness evaluated by the Japan Coma Scale was 30. Skull X-ray film revealed a linear skull fracture of the left occipital bone. CT scan showed subdural hematoma in the right frontotemporal region, contusion of bilateral frontal lobes and the left cerebellar hemisphere, subarachnoid hemorrhage, and pneumoce phalus. Two weeks after the injury, his consciousness improved and he was diagnosed as having bilateral MLF syndrome. Barbiturate, dehydration and steroid therapy were added to for intracranial hemorrhage. One month later, MLF syndrome improved and he was discharged without any neurological deficit.

The ionic mechanism of phenylephrine-induced rhythmic contractions in rabbit mesenteric arteries treated with ryanodine.

Phenylephrine induces endothelium-independent rhythmic contractions in ryanodine-treated rabbit mesenteric arteries. To elucidate the ionic mechanism of this rhythmic behaviour, rabbit mesenteric arterial rings were suspended in an organ chamber for isometric tension studies. Yohimbine, propranolol, and atropine had no effect on these contractions, minimizing the possibility that transmitter release from nerve terminals was involved. Additionally, the oscillatory contractions were not altered by diphenhydramine, cimetidine, and indomethacin, thus ruling out the involvement of histamine and prostaglandins. This oscillatory response was completely abolished after the removal of extracellular Ca2+, as well as after Ca2+ channel blockade by diltiazem or nifedipine. Sparteine and quinidine, Ca(2+)-activated K+ channel blockade by diltiazem or nifedipine. Sparteine and quinidine, Ca(2+)-activated K+ channel antagonists, also abolished the oscillation. In contrast, tetraethylammonium and 3,4-diaminopyridine, voltage-dependent K+ channel antagonists, augmented the response. Glibenclamide, an antagonist of the ATP-sensitive K+ channel, had no effect on the rhythmic contractions. These results suggest that the rhythmic contractions observed in rabbit mesenteric arteries after ryanodine treatment were caused by the movement of Ca2+ and K+ across the plasmalemma via the voltage-dependent Ca2+ channel and the Ca(2+)-activated K+ channel, respectively.

Relaxant response of isolated basilar arteries to calcitonin gene-related peptide in stroke-prone spontaneously hypertensive rats.

The relaxant effects of calcitonin gene-related peptide (CGRP) and other drugs were compared in basilar artery rings obtained from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY). In addition, the relaxant effect of CGRP on basilar arteries from spontaneously hypertensive rats (SHR) was examined. Relaxation induced by CGRP was independent of the presence of endothelium, and it was markedly increased in SHRSP when compared to WKY. In contrast, acetylcholine-induced relaxation was endothelium-dependent and did not differ between the two groups. Enhanced CGRP-induced relaxation was also found in SHR when compared to WKY. However, the relaxant response was greater in SHRSP than in SHR. No significant differences were found in the relaxation induced by isoproterenol, forskolin, dibutyryl cyclic AMP, and 3-isobutyl-1-methylxanthine in endothelium-rubbed arteries of WKY and SHRSP. These results suggest that CGRP produces endothelium-independent relaxation in the rat basilar artery, and that the enhanced CGRP-induced relaxation found in SHRSP may not be associated with alterations of vasodilation mediated by cyclic AMP.

The role of endothelium in the phenylephrine-induced oscillatory responses of rabbit mesenteric arteries.

Phenylephrine-induced oscillatory contractions in rabbit mesenteric arteries were investigated in vitro. Adrenergic, cholinergic, or histamine antagonists as well as cyclooxygenase and lipoxygenase inhibitors had no effect on this phenylephrine-induced oscillation. The removal of extracellular calcium ions or treatment with a calcium antagonist reduced the amplitude and frequency of the oscillation. Removal of the endothelium or treatment with inhibitors of the synthesis or the target enzyme of endothelium-derived relaxing factor (EDRF) also reduced the amplitude and frequency of the oscillation. In a perfusion bioassay, the perfusate from an endothelium-intact arterial segment induced oscillation of an endothelium-denuded arterial ring recipient. These results suggest that phenylephrine-induced oscillation is mediated by an endothelium-derived factor such as EDRF and depends on the influx of extracellular calcium ions.

A possible mechanism of infertility by acute cadmium intoxication.

A possible mechanism of infertility by Cd was investigated from the standpoint of influence of Cd on the contractile responses of isolated seminal vesicle from guinea pigs to K, acetylcholine, noradrenaline, Ba and Ca by using the Magnus method. Cd inhibited the contractile responses to the contractile agents tested in a dose-dependent manner. Cd showed the preferential inhibition against the contractile responses to K and Ca. The inhibitory effect of Cd on the contractile responses to noradrenaline and acetylcholine was hardly removed. The effect of Cd was inhibited by the thiol compounds, glutathione and thiola. The active mechanism of Cd was discussed in relation to Ca mobilization.

Recording of the fourth heart sound by the signal averaging method. Preliminary report.

The fourth heart sound was clearly recorded by using the signal averaging method. Furthermore, the simultaneous recording of the Doppler signal with the fourth heart sound was performed. Thus, it was demonstrated that the Doppler signal started after the P wave and followed by the fourth heart sound. In 2 cases, the effect of the double Master's test and taking a bath was studied on the computer averaged phonocardiogram. After the exercise, the amplitude of the fourth heart sound was increased, whereas after taking a bath it was almost unchanged. The above results show that the simultaneous recordings of a computer averaged phonocardiogram and Doppler signal that is associated with cardiac activity can greatly facilitate the interpretation of small vibrations such as the fourth heart sound.

An investigation of spontaneous potentials recorded from the smooth-muscle cells of the guinea-pig seminal vesicle.

1. A spontaneous discharge of small potentials from smooth muscle cells of the guinea-pig seminal vesicle has been described. The mean amplitude, frequency and duration of the potentials were 0.9 mV, 12.2/min, and 92 msec, respectively. Occasionally, large potentials of 5-7 mV were recorded.2. The frequency of spontaneous potentials was enhanced by about twofold in 15 mM potassium-Krebs solution. Removal of calcium from the perfusing solution, or adding excess magnesium (12 mM) suppressed the rate of these potentials. Cobalt (2.5 mM) did not affect them but blocked excitatory junction potentials evoked by the hypogastric nerve stimulation.3. The spontaneous potentials were unaffected by atropine. Their rate and amplitude were reversibly reduced in the presence of high concentrations of phentolamine (10(-4) but not by 10(-5) g/ml.). Guanethidine enhanced the frequency initially (5 min), but subsequently the control rate was not appreciably changed, even after 20 min of guanethidine perfusion.4. After post-ganglionic denervation or reserpine treatment, the frequency of discharge of spontaneous potentials was reduced, without any effect on amplitude.5. The properties of the spontaneous potentials recorded from the smooth muscle cells of the seminal vesicle are similar to those reported for the vas deferens. They appear to be due to an interaction between noradrenaline released from sympathetic nerve endings and the smooth-muscle cell membrane. Present experiments cannot completely rule out the possibility that another transmitter in addition to noradrenaline may be released at this neuroaffector junction.

Modification by ouabain of the electrical and mechanical effects of acetylcholine in isolated rabbit atria.

1. Left atrial preparations isolated from rabbits were stimulated electrically at frequencies between 6 and 240/min. Tension-frequency curves were obtained from control preparations and preparations treated with ouabain and acetylcholine. Transmembrane potentials were recorded from single cells of the left atrium stimulated at different frequencies.2. The tension-frequency curve was moved downwards by acetylcholine (10(-6) g/ml). Ouabain (10(-6) g/ml) caused characteristic alterations in the tension-frequency relationship, enhancing the contractile tension at low but not high frequencies. The negative inotropic effect of acetylcholine was reduced by treatment with ouabain.3. Action potential durations were significantly influenced by alterations in frequency of contraction. The 10% duration increased with frequency within the range between 6 and 60/min but decreased at frequencies higher than 120/min. The 50% duration increased with frequency between 6 and 120/min but decreased at frequencies higher than 180/min. The dependence of the 50% duration upon frequency paralleled that of contractile tension. The 90% duration, the overshoot and the resting potential were not affected by frequency of contraction.4. Acetylcholine (10(-6) g/ml) shifted the 10%, 50% and 90% duration-frequency curves downwards, but did not significantly alter the overshoot and the resting potential. Ouabain (10(-6) g/ml) shifted the duration-frequency curves downwards and also reduced the size of the overshoot and the resting potential. Treatment of atrial preparations with 10(-6) g/ml ouabain potentiated the membrane effects of acetylcholine.5. The inhibition by ouabain of the negative inotropic effect of acetylcholine did not appear to be due to antagonism at the receptor level, but to interference with the mechanisms responsible for the mechanical events.