Analysis of VH gene rearrangement and somatic hypermutation in Sjogren's syndrome and IgG4-related sclerosing sialadenitis.

IgG4-related sclerosing sialadenitis is currently considered as an autoimmune disease distinct from Sjogren's syndrome (SS) and responds extremely well to steroid therapy. To further elucidate the characteristics of IgG4-related sclerosing sialadenitis, we analysed VH fragments of IgH genes and their somatic hypermutation in SS (n = 3) and IgG4-related sclerosing sialadenitis (n = 3), using sialolithiasis (n = 3) as a non-autoimmune control. DNA was extracted from the affected inflammatory lesions. After PCR amplification of rearranged IgH genes, at least 50 clones per case (more than 500 clones in total) were sequenced for VH fragments. Monoclonal IgH rearrangement was not detected in any cases examined. When compared with sialolithiasis, there was no VH family or VH fragment specific to SS or IgG4-related sclerosing sialadenitis. However, rates of unmutated VH fragments in SS (30%) and IgG4-related sclerosing sialadenitis (39%) were higher than that in sialolithiasis (14%) with statistical significance (P = 0.0005 and P < 0.0001, respectively). This finding suggests that some autoantibodies encoded by germline or less mutated VH genes may fail to be eliminated and could play a role in the development of SS and IgG4-related sclerosing sialadenitis.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK.

Citrin deficiency is a disorder with two phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult-onset type II citrullinaemia (CTLN2). NICCD presents in the first few weeks of life with prolonged cholestasis and metabolic abnormalities including aminoacidaemia (notably citrulline, tyrosine, threonine, arginine and methionine) and galactosuria. Symptoms resolve within the first year of life, thus making a diagnosis difficult after this time. Although patients subsequently remain generally healthy, some may develop more severe symptoms of CTLN2, characterized by neurological changes, one or more decades later. To date more than 400 cases have been reported, almost all from East Asia (mainly Japan). Here we describe the first two cases of NICCD in infants from the UK, one of caucasian origin and one of Pakistani origin. Both showed typical clinical and biochemical changes with a diagnosis confirmed by the presence of previously unreported mutations in the SLC25A13 gene. The presence of citrin deficiency in other ethnic groups means that NICCD needs to be considered in the diagnosis of any neonate with an unexplained cholestasis. We discuss both the difficulties in diagnosing these patients in populations where very few DNA mutations have been identified and the problems faced in the management of these patients. These findings also raise the possibility of adults with CTLN2 in whom a diagnosis has yet to be made.

Standard steroid treatment for autoimmune pancreatitis.

OBJECTIVE: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP). METHODS: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse. RESULTS: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p<0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them. CONCLUSIONS: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

Interaction of edrophonium with muscarinic acetylcholine M2 and M3 receptors.

BACKGROUND: It has been reported that edrophonium can antagonize the negative chronotropic effect of carbachol. This study was undertaken to evaluate in detail the interaction of edrophonium with muscarinic Mz and M3 receptors. METHODS: A functional study was conducted to evaluate the effects of edrophonium on the concentration-response curves for the negative chronotropic effect and the bronchoconstricting effect of carbachol in spontaneously beating right atria and tracheas of guinea pigs. An electrophysiologic study was conducted to compare the effects of edrophonium on carbachol-, guanosine triphosphate (GTP)gama S-, and adenosine-induced outward K+ currents in guinea pig atrial cells by whole cell voltage clamp technique. A radioligand binding study was conducted to examine the effects of edrophonium on specific [3HIN-methylscopolamine (NMS) binding to guinea pig atrial (M2) and submandibular gland (M3) membrane preparations, and on atropine-induced dissociation of [3H]NMS. RESULTS: Edrophonium shifted rightward the concentration-response curves for the negative chronotropic and bronchoconstricting effects of carbachol in a competitive manner. The pA2 values for cardiac and tracheal muscarinic receptors were 4.61 and 4.03, respectively. Edrophonium abolished the carbachol-induced outward current without affecting the GTPgamma S- and adenosine-induced currents in the atrial cells. Edrophonium inhibited [3H]NMS binding to M2 and M3 receptors in a concentration-dependent manner. The pseudo-Hill coefficient values and apparent dissociation constants of edrophonium for M2 and M3 receptors were 1.02 and 1.07 and 21 and 34 microM, respectively. Edrophonium also changed dissociation constant values of [3H]NMS without affecting its maximum binding capacities. CONCLUSION: Edrophonium binds to muscarinic M2 and M3 receptors nonselectively, and acts as a competitive antagonist.

[Pretreatment of acid-induced lung injury with specific neutrophil elastase inhibitor ONO-5046 did not exasperate the subsequent bacterial lung infection by Pseudomonas aeruginosa].

Patients with acid lung injuries are at high risk for bacterial pulmonary infections which commonly occur several days after the acid aspiration. We reported that a specific neutrophil elastase inhibitor ONO-5046 inhibited the multi-organ injury caused by acid-instillation into the lung. In this study, we evaluated the effect of ONO-5046 on lung infection by Pseudomonas aeruginosa (PAO-1:Ps.) following acid-induced lung injury in rat lungs. Animals received 0.2 ml of hydrochloric acid (pH = 1) into the right lungs. Pretreated animals were administered ONO-5046 (30 mg.kg-1) i.v. 15 min. before acid instillation. Other groups received vehicle (saline). Twenty four hours later, they were instilled with 0.1 ml of Ps. 1 x 10(8) cfu into the left lungs. Four hours after bacterial challenge, the animals were deeply anesthetized and killed. Bronchoalveolar lavage was done on each lung separately to evaluate neutrophil elastase activity, neutrophil number and protein permeability of lung endothelium and epithelium. The numbers of Ps. in the lungs were measured. In the Ps.-instilled lung, the number of Ps. or the protein permeability was not increased with ONO-5046 pretreatment compared with those in the untreated group. Pretreatment inhibited the exasperation of the protein permeability indirectly caused by Ps. infection in the acid-instilled lung. It was indicated that ONO-5046 could inhibit the indirect lung injury caused by acid-instillation into the lung without aggravating the subsequent bacterial infection.

[Continuous monitoring of hemoglobin oxygen saturation of the hepatic vein in patients undergoing laparoscopic cholecystectomy].

We monitored of hemoglobin oxygen saturation of the hepatic vein (ShvO2) continuously in 6 patients undergoing laparoscopic cholecystectomy under inhalation anesthesia only, and in 6 patients under combined epidural and inhalation anesthesia. In inhalation anesthesia only group, arterial blood pressure increased and ShvO2 values decreased immediately after intraperitoneal insufflation with CO2, demonstrating the mean lowest ShvO2 value of 25 percent. In combined anesthesia group, arterial blood pressure and ShvO2 values were unchanged after the intraperitoneal insufflation compared with values obtained before the insufflation. The results indicate that hepatic blood flow may be better preserved with combined epidural and inhalation anesthesia than with inhalation anesthesia only, suggesting that sympathetic block by epidural anesthesia may contribute to this favorable effect on ShvO2.

Dynorphins directly inhibit neuronal nicotinic acetylcholine receptors in PC12 cells.

The authors have previously reported that dynorphin A (1-17), an endogenous kappa opioid agonist, inhibits the current mediated through neuronal nicotinic acetylcholine receptors (nAChRs) without the involvement of opioid receptors or G-proteins. We have further characterized this action to elucidate the mechanisms. The nicotine-induced current was studied in PC12 cells using patch-clamp techniques. In the whole-cell configuration, four kinds of dynorphins with different lengths, dynorphin A (1-17) (1-13) (2-13) and (1-8), similarly inhibited the nicotine-induced inward current at 1 microM and accelerated the current decay. The inhibition by dynorphin A (1-17) was not antagonized by the increasing concentrations of nicotine. The current-voltage relationship revealed that dynorphin's inhibition was voltage independent at the membrane potentials from -30 to -70 mV. The inhibition was not affected by pretreatment with pertussis toxin (PTX) or inclusion of staurosporine into the pipette solution. The inhibitory effect of dynorphin A (1-17) was well preserved in the outside-out patch configuration. Analysis of the nicotine-induced noise and single-channel kinetics revealed that dynorphin A(1-17) reduced open time without changing the amplitude of the unitary current. We found that the inhibitory effect on neuronal nAChRs is shared by all four dynorphins studied. The inhibition appears to be non-competitive and voltage independent. The outside-out recording together with other experiments indicated that a major part of this inhibition is not mediated through cytoplasmic messengers, but based on the direct action of dynorphins on neuronal nAChRs leading to the reduction of open time.

NOx- concentrations in the rat hippocampus and striatum have no direct relationship to anaesthesia induced by ketamine.

Using microdialysis, we have examined the effects of ketamine on concentrations of total nitric oxide oxidation products (NOx-) in the rat hippocampus and striatum in vivo to investigate the relationship between anaesthesia and NOx- production in the brain. Ketamine 25, 50 and 100 mg kg-1 i.p. increased NOx- concentrations to mean 125 (SD 13)%, 165 (11)% and 193 (13)% of basal, respectively, in the hippocampus and to 122 (12)%, 147 (7)% and 177 (14)% of basal in the striatum. Local perfusion with ketamine 50 and 100 mumol litre-1 into the hippocampus or striatum increased NOx- concentrations to 212 (32)% and 291 (17)% of basal, respectively, in the hippocampus and to 148 (20)% and 201 (18)% of basal in the striatum. Ketamine 50 and 100 mg kg-1 i.p. caused dose-dependent prolongation of loss of the righting reflex (LRR) and 100 mg kg-1 i.p. also caused loss of the corneal reflex (LCR). Local perfusion of ketamine did not provoke LRR or LCR. Inhibition of NOS by L-NAME 100 mg kg-1 i.p. decreased hippocampal NOx- concentrations to 58 (7)% of basal and did not provoke LRR or LCR. Although the effect of ketamine-induced increases in hippocampal NOx- concentrations was significantly depressed by L-NAME, LRR was not affected. These data imply that NOx- concentrations in the hippocampus or striatum have no direct relationship to the anaesthetic efficacy of ketamine, although this requires further investigation.

Age-related modifications of effects of ketamine and propofol on rat hippocampal acetylcholine release studied by in vivo brain microdialysis.

BACKGROUND: We sometimes encounter impairment of learning and memory after general anesthesia in elderly patients. The aim of this study was to examine age-related modifications of the effects of ketamine and propofol on rat hippocampal acetylcholine (ACh) release because hippocampal cholinergic neurons are supposed to be involved in learning and memory. METHODS: The experiments were performed on male Wistar young rats (2 months old) and old rats (18 months old), using in vivo brain microdialysis technique under freely moving condition. After initial sampling of three collections, test drugs were administered. The ACh release was determined by the HPLC-ECD method. RESULTS: In old rats, the hippocampal basal ACh release was significantly lower than in young rats. Ketamine (25 and 50 mg kg(-1) i.p.) increased and propofol (25 and 50 mg kg(-1) i.p.) decreased the hippocampal ACh release in both young and old rats. Furthermore, ketamine 50 mg kg(-1) i.p. (anesthetic dose) produced facilitatory effects on the hippocampal ACh release in young rats (193% of the basal release), while in old rats the same dose of ketamine i.p. produced more pronounced facilitatory effects on the hippocampal ACh release (317% of the basal release). On the other hand, propofol 50 mg kg(-1) i.p. (anesthetic dose) produced inhibitory effects on the hippocampal ACh release in young rats (56% of control) and in old rats (77% of control). Although the maximal inhibitory peak effects of propofol 50 mg kg(-1) i.p. did not differ significantly between young rats and old rats, decrease of the hippocampal ACh release in old rats persisted longer than in young rats. CONCLUSION: Ketamine produced more pronounced facilitatory effects on the hippocampal ACh release in old rats, as compared with young rats. On the other hand, propofol has inhibitory effects on the hippocampal ACh release in young and old rats. The aging process may suppress the ability to recover from the inhibitory anesthetic state induced by propofol.

An L-dopaergic relay from the posterior hypothalamic nucleus to the rostral ventrolateral medulla and its cardiovascular function in anesthetized rats.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter in the central nervous system [Misu Y. et al. (1996) Prog. Neurobiol. 49, 415-454]. Herein, we attempt to clarify whether lesions in the posterior hypothalamic nucleus decrease the tissue content of L-DOPA in the rostral ventrolateral medulla. We also attempt to clarify whether or not endogenous L-DOPA is evoked by electrical stimulation of the posterior hypothalamic nucleus. It is possible that evoked L-DOPA functions as a transmitter candidate to activate pressor sites of the rostral ventrolateral medulla in anesthetized rats. Electrolytic lesions were made in the bilateral posterior hypothalamic nucleus by a monopolar direct current of 2 mA for 10 s, 10 days before measurements. The effect of the lesions was to selectively decrease the tissue content of L-DOPA by one-half in the right rostral ventrolateral medulla. Decreases in the amounts of dopamine, noradrenaline or adrenaline were not observed. Decreases were also not evident in the right caudal ventrolateral medulla. During microdialysis of the right rostral ventrolateral medulla, extracellular basal levels of L-DOPA and three types of catecholamine were consistently detectable by high-performance liquid chromatography with electrochemical detection. Tetrodotoxin (1 microM) perfused into the right rostral ventrolateral medulla gradually decreased basal levels of L-DOPA by 25%; it decreased basal levels of noradrenaline and adrenaline by 25-30% and dopamine levels by 40%. Intensive electrical stimulation of the ipsilateral posterior hypothalamic nucleus (50 Hz, 0.3 mA, 0.1 ms duration, twice for 5 min at an interval of 5 min) selectively caused the release of L-DOPA in a repetitive and constant manner. The stimulation was accompanied by hypertension and tachycardia. However, catecholamines were not released. Tetrodotoxin suppressed the release of L-DOPA, but partially inhibited hypertension with only a slight inhibition of tachycardia evoked by stimulation of the posterior hypothalamic nucleus. L-DOPA methyl ester, a competitive L-DOPA antagonist, was bilaterally microinjected into pressor sites of the rostral ventrolateral medulla at 1.5 microg x 2 and 3 microg x 2. The antagonist dose-dependently and consistently antagonized pressor and tachycardiac responses to mild transient stimulation of the unilateral posterior hypothalamic nucleus (33 Hz, 0.2 mA, 0.1 ms duration, for 10 s). In addition, the antagonist alone (3 microg x 2) elicited hypotension and bradycardia. These results show that an L-DOPAergic relay may project from the posterior hypothalamic nucleus directly to pressor sites of the rostral ventrolateral medulla and/or indirectly to certain neurons near pressor sites in microcircuits of the same region. When released, L-DOPA appears to function tonically to activate pressor sites; it also appears to be involved in the maintenance and regulation of blood pressure and heart rate.

Comparison of the effects of convulsant and depressant barbiturate stereoisomers on AMPA-type glutamate receptors.

BACKGROUND: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. METHOD: The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. RESULTS: Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. CONCLUSIONS: Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

Retinal artery air embolism in dogs: fluorescein angiographic evaluation of effects of hypotension and hemodilution.

UNLABELLED: Cerebral air embolism can cause cerebral complications after open heart surgery. The duration of cerebral artery occlusion by air embolism is thought to vary depending on the conditions. However, no study has evaluated factors affecting the duration of occlusion. In this study, we examined the effects of blood pressure and hemodilution on the duration of retinal artery occlusion caused by air embolism in dogs. The duration of retinal artery occlusion caused by the injection of 0.6 mL of air into the common carotid artery was measured by fluorescein angiography and compared among the following three periods: a control period, during which the mean blood pressure (MBP) was maintained at 80 mm Hg; a hypotension period, during which MBP was decreased to 60 mm Hg by exsanguination; and a hypotension plus hemodilution period, during which an additional exchange of blood with hydroxyethyl starch solution was performed and MBP was maintained at 60 mm Hg. When MBP was lowered from 80 to 60 mm Hg, the duration of retinal artery occlusion was prolonged from 34+/-39 to 166+/-90 s (P < 0.01). In dogs with MBP of 60 mm Hg, hemodilution (12.0+/-0.9 to 7.3+/-0.5 g/dL hemoglobin concentration) shortened the duration from 166+/-90 to 75+/-50 s (P < 0.05). Our results demonstrate that hypotension prolongs and hemodilution shortens the duration of retinal artery occlusion caused by air embolism. IMPLICATIONS: We evaluated the effects of blood pressure and hemodilution on the duration of retinal artery occlusion caused by air embolism by retinal fluorescein angiography. Hypotension prolonged and hemodilution shortened the duration of retinal artery occlusion caused by air embolism.

Intraoperative management for removal of tumor thrombus in the inferior vena cava or the right atrium with multiplane transesophageal echocardiography.

BACKGROUND: To investigate the role and impact of multiplane transesophageal echocardiography during thrombectomy in the inferior vena cava or the right atrium. EXPERIMENTAL DESIGN: Retrospective. SETTING: A university hospital. PARTICIPANTS: Four patients who underwent removal of tumor thrombus in the inferior vena cava (IVC) or the right atrium. INTERVENTIONS: The medical records of 4 patients and videotapes of these intraoperative transesophageal echocardiography examinations were reviewed. RESULTS: Before thrombectomy, multiplane transesophageal echocardiography (MTEE) provided excellent IVC long axis view, which offered precise recognition of the cephalic extent of tumor, extent of caval occlusion, characterization of the tumor head. During surgery, MTEE could provide continuous monitoring of cardiac function, cardiac volume, and pulmonary embolism. Moreover, MTEE could provide the useful images of a cannula or the caval occlusion balloon catheter, which facilitated removal of neoplasm extending into the IVC. CONCLUSIONS: We presented four surgical cases, in which the removal of the tumor extended into the inferior vena cava or the right atrium using MTEE. MTEE could provide valuable information such as excellent images of the tumor, cardiac function, the position of a cannula or the caval occlusion balloon catheter. These findings could improve the anesthetic management of the patients, as well as the surgical approach and technical maneuvers, and facilitate removal of neoplasm into the IVC.

Involvement of barium-sensitive K+ channels in endothelium-dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds.

1. We examined the vasodilatory effect of hypercapnia in the rat isolated mesenteric vascular bed. The preparation was perfused constantly (5 ml min(-1) with oxygenated Krebs-Ringer solution, and the perfusion pressure was measured. In order to keep the extracellular pH (pHe) constant (around 7.35) against a change in CO2, adequate amounts of NaHCO3 were added to Krebs-Ringer solution. 2. In the endothelium intact preparations, an increase in CO2 from 2.5% to 10% in increments of 2.5% decreased the 10 microM phenylephrine (PE)-produced increase in the perfusion pressure in a concentration-dependent manner. Denudation of the endothelium by CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulphonate) (5 mg l(-1), 90 s perfusion) abolished the vasodilatory effect of hypercapnia. 3. An increase in CO2 from 5% to 10% reduced the increases in the perfusion pressure produced by 10 microM PE and 400 nM U-46619 by 48% and 44%, respectively. NG-monomethyl-L-arginine (100 microM) and indomethacin (10 microM) did not affect the vasodilatory effect of hypercapnia, whereas the vasodilatory response of the preparation to hypercapnia disappeared when the preparation was contracted by 60 mM K+ instead of PE or U-46619. 4. The vasodilatory effect of hypercapnia observed in the PE- or U-46619-precontracted preparation was affected by neither tetraethylammonium (1 mM), apamin (500 microM), glibenclamide (10 microM), nor 4-aminopyridine (1.5 mM). On the other hand, pretreatment with Ba2+ at a concentration of 0.3 mM abolished the hypercapnia-produced vasodilation. 5. An increase in the concentration of K+ in Krebs-Ringer solution from 4.5 mM to 12.5 mM in increments of 2 mM reduced the PE-produced increase in the perfusion pressure in a concentration-dependent manner. Pretreatment of the preparations with not only Ba2+ (0.3 mM) but also CHAPS abolished the vasodilatory effect of K+. 6. The results suggest that an increase in CO2 produces vasodilation by an endothelium-dependent mechanism in the rat mesenteric vascular bed. The membrane hyperpolarization of the endothelial cell by an activation of the inward rectifier K+ channel seems to be the mechanism underlying the hypercapnia-produced vasodilation. Neither nitric oxide nor prostaglandins are involved in this response.

In vivo effects of propofol on acetylcholine release from the frontal cortex, hippocampus and striatum studied by intracerebral microdialysis in freely moving rats.

Using in vivo microdialysis, we have investigated the effects of propofol on acetylcholine (ACh) release from various regions of the rat brain. Propofol 25 and 50 mg kg-1 i.p. decreased basal ACh release from the frontal cortex by 70% and 85%, respectively. Propofol 25 and 50 mg kg-1 i.p. decreased basal ACh release from the hippocampus by 47% and 72%, respectively. However, in rat striatum, propofol 25 mg kg-1 i.p. did not affect basal ACh release and 50 mg kg-1 i.p. produced slight inhibition of basal ACh release (by 19%) only in the second sample after i.p. injection. In addition, we also examined the pharmacological mechanisms mediating the interaction between propofol and a gamma-aminobutyric acid A (GABAA) receptor complex. In the rat hippocampus, local application of bicuculline 1 mumol litre-1, a GABAA receptor antagonist, significantly antagonized the inhibitory effects of propofol 50 mg kg-1 i.p. on basal ACh release. In the rat frontal cortex, local application of bicuculline 1 mumol litre-1 did not antagonize the inhibitory effects of propofol 50 mg kg-1 i.p. on basal ACh release, while systemic application of bicuculline 1 mg kg-1 i.p. significantly antagonized the inhibitory effects of propofol 50 mg kg-1 i.p. These results suggest that propofol has powerful depressant effects on ACh release from the rat frontal cortex and hippocampus but not from the striatum, indicating that propofol has a "region-selective" anaesthetic action. Further, these results suggest that the inhibitory effects of propofol in the rat hippocampus may involve "intra" hippocampal GABAA receptors while the inhibitory effects in the rat frontal cortex may be mediated by GABAA receptors other than "intra" frontal cortex GABAA receptors.

Nephrotoxic serum-induced nephritis in Wistar-Kyoto rats: a model to evaluate antinephritic agents.

We investigated nephrotoxic serum (NTS)-induced glomerulonephritis in Wistar-Kyoto (WKY) rats as a model to evaluate antinephritic agents. WKY rats required only a small amount of NTS to induce crescentic glomerulonephritis and the rats progressively lost their renal function in a few weeks. In a comparative study with WKY and Sprague-Dawley (SD) rats, WKY rats showed a normal distribution pattern in the severity of proteinuria with a small variance. While SD rats needed a much higher amount of NTS to exhibit a comparable proteinuria which was not normal and had a large variance. The effects of clinically available antinephritic drugs, methylprednisolone, cyclophosphamide and cyclosporin A, were studied in both strains. In WKY rats, these drugs significantly inhibited the proteinuria, glomerular histological changes and decrease in creatinine clearance. On the other hand, such significant inhibitory effects on proteinuria were not observed with any of these drugs in SD rats. In conclusion, NTS nephritis in WKY rats may prove to be a useful model for studying antinephritic agents.

Retroperitoneal malignant fibrous histiocytoma causing variegated colonic lesions.

A 68-year-old man visited our hospital because of heartburn. A firm mass was palpated in the left upper abdominal quadrant. Ultrasonography and computed tomography revealed a large left sided retroperitoneal tumor. A barium enema examination showed shallow irregularly depressed or elevated lesions. Colonoscopy revealed an irregularly shaped ulcer and multiple submucosal masses suggesting invasion by an extrinsic malignant tumor. Although colonoscopic biopsy was negative, a resected tumor was histologically diagnosed as a malignant fibrous histiocytoma (MFH). When such varigated lesions are detected in the colon, MFH should be considered, and an attempt to sample the submucosal layer may be necessary.

ATP-induced ventricular asystole and hypotension during endovascular stenting surgery.

PURPOSE: To describe four cases of endoluminal stenting surgery in which adenosine 5'-triphosphate (ATP) was used to arrest the heart for accurate placement of the stent-graft. CLINICAL FEATURES: Four patients with descending thoracic aortic aneurysm were anaesthetized for deployment of a self-expanding stent-graft. Maintenance of general anaesthesia was performed with isoflurane and nitrous oxide in three patients, and with fentanyl and propofol in another. An initial trial of 20 mg ATP was administered via a central venous catheter as rapidly as possible, and produced third degree AV block of 8 +/- 1.7 sec and 59.7 +/- 17.5 sec hypotension, mean blood pressure < 60 mmHg, in three patients. The time to onset of AV block was 15.7 +/- 6.7 sec. In these patients, deployment of the stent-graft was performed during ventricular asystole produced by 30 mg ATP, which produced 16.3 +/- 2.1 sec third and second degree AV block. In one patient anaesthetized with fentanyl and propofol, 20 mg ATP did not change AV conduction. However, after 10 mg edrophonium, 20 mg ATP produced 9 sec third degree AV block. In all cases, heart rate and PQ interval were restored to the pre-drug control level within 50 sec after the commencement of AV block. There were no clinical complications related to this procedure in any patient. CONCLUSION: ATP is a convenient and suitable agent to produce transient ventricular asystole for the precise deployment of a self-expanding stent-graft. Co-administration of a parasympathomimetic agent might potentiate the inhibitory effect of ATP on AV conduction.

Involvement of angiotensin II in development of spontaneous nephrosis in Dahl salt-sensitive rats.

We investigated the effect of angiotensin-converting enzyme inhibition on spontaneous nephrosis in Dahl salt-sensitive (Dahl/S) rats. Dahl/S rats fed on a normal sodium diet spontaneously developed nephrosis and mild hypertension from a young age. In young Dahl/S rats, an angiotensin-converting enzyme inhibitor, imidapril, attenuated the development of proteinuria accompanied by a decrease in blood pressure. Methylprednisolone, a potent therapeutic agent for proteinuria, did not affect the development of nephrosis. An angiotensin AT1 receptor antagonist, losartan, but not a Ca2+ channel blocker, verapamil, inhibited the development of nephrosis while both agents decreased blood pressure to a similar extent as imidapril. In mature Dahl/S rats, imidapril suppressed not only the development of proteinuria but also the glomerular lesions. It is concluded that the development of spontaneous nephrosis in Dahl/S rats is mediated by angiotensin II.