Relaxant effect of omeprazole and lansoprazole in guinea pig gallbladder muscle strips in vitro

Background. The aim of this study was to investigate the role of omeprazole and lansoprazole, H⁺-K⁺ ATPase inhibitors, in gallbladder smooth muscle contractility in vitro. Methods. Gallbladder muscle strips obtained from guinea pigs were mounted in an organ bath. The responses of both precontracted strips and strips under basal tension to omeprazole and lansoprazole were determined. Results. Spontaneous contractile activity was blocked following omeprazole and lansoprazole administration. The agents also caused concentration-dependent relaxation in carbachol- and KCl-precontracted gallbladder muscle strips. Pretreatment with atropine (1µM), N^W-nitro l-arginine methyl ester (l-NAME; 30µM), indomethacin (10µM), ammonium chloride (7.5mM), sodium acetate (7.5mM), tetraethylammonium chloride (0.5mM), glibenclamide (1µM), 4-aminopyridine (0.1mM), or clotrimazole did not inhibit this relaxation. Gallbladder strips were placed in high-concentrtion potassium (80mM), calcium-free solution. The contraction produced with the addition of Ca²⁺ (2.5mM) was completely relaxed by omeprazole, lansoprazole, and nifedipine separately. Conclusions. These results demonstrate that omeprazole and lansoprazole have potent inhibitory effects on spontaneous contractions and cause dose-dependent relaxation in precontracted gallbladder smooth muscle strips of guinea pig in vitro. This effect could be due to blockade of the calcium channels.     

Lavage Administration of Dilute Surfactant in a Piglet Model of Meconium Aspiration

Maldistribution of exogenous surfactant may preclude any clinical response in acute lung injury associated with surfactant dysfunction. Our previous studies have shown the effectiveness of surfactant lavage after homogenous lung injury. The present study utilizes a histologically confirmed non-homogeneous lung injury model induced by saline lung-lavage followed by meconium injected into a mainstem bronchus. Piglets were then treated with Infasurf® or Exosurf® by lavage (I-LAVAGE, n=7; E-LAVAGE, n=5) or bolus (I-BOLUS, n=8; E-BOLUS, n=5), or went untreated (CONTROL, n=4). Lavage administration utilized a dilute surfactant (35 ml/kg; 4 mg phospholipid/ml) instilled into the lung, followed by gravity drainage. The retained doses of the respective surfactant in the lavage and bolus groups were similar. Results showed that the surfactant distribution was more uniform in the lavage groups compared to the bolus groups. Significant and consistent increases in PaO₂ were observed in the lavage groups compared to the bolus groups and the controls. PaO₂ (mmHg) at 240 min posttreatment: I-LAVAGE=297±54, E-LAVAGE= 280±57; I-BOLUS=139±31; E-BOLUS=152±29; C=119±73 (mean± SEM). Other improved pulmonary function parameters favored lavage administration. We conclude that better surfactant distribution achieved by lavage administration can be more effective than bolus administration in this type of non-homogeneous lung injury.     

Burden of musculoskeletal pain in Japan

Based on the prevalence of musculoskeletal pain in the context of interference with daily activities (IDA) and treatment for musculoskeletal disorders in the study population (n = 3188), we estimated the prevalence and years lived with disability (YLD) of musculoskeletal pain in Japan. The total of 42287 thousand (41.2%) of Japanese adult people was estimated to suffer from musculoskeletal pain. Among them, 9127 thousand was estimated to interfere with daily activities due to the pain. Overall YLD for musculoskeletal pain in Japan were estimated at 1297843.7 (1263.6 per 100000). The YLD for Pain without IDA were 33159.3 (32.3 per 100000) and the YLD for Pain with IDA were 1264684.4 (1231.3 per 100000). One-way sensitivity analysis showed that the YLD of musculoskeletal pain might increase to 4421844.0 (4305.2 per 100000) with the increased disability weight for Pain without IDA of 0.1, while they might inversely decrease to 1018875.0 (992.0 per 100000) with the increased treatment rate in Pain with IDA of 100%. Musculoskeletal pain imposes a substantial burden on the Japanese adult population. To allow the population to keep their health-related quality of life, health professionals should pay more attention to musculoskeletal pain and make positive efforts to improve prevention and control of musculoskeletal pain.     

Characteristics of ischaemic human myocardium: a transoesophageal echocardiographic and voltammetric microelectrode study

Delayed local myocardial power development (primary asynchrony) has been suggested as a marker of ischaemic ventricular dysfunction in humans. However, to prove this, microcirculatory perfusion, microcirculatory oxygenation, and intrinsic mechanical function of the same asynchronous myocardial segment should be studied simultaneously before and after revascularisation. We performed a prospective intraoperative study of 15 patients (age 67 [SD 5] years) at baseline and 30min after left anterior descending artery grafting. Local tissue perfusion and oxygenation of the anterior left ventricular wall were quantified with a voltammetric microelectrode technique. Transesophageal M-mode echocardiograms and simultaneous high-fidelity left ventricular pressure were measured. Eight patients showed primary asynchrony and 7 did not. Patients with primary asynchrony had local mechanical depression with lower resting values of myocardial work and peak power which increased with surgery. In this group, resting perfusion consistently increased with surgery (32.1 [13] to 54 [31]mlmin^–1 100g^–1, P < 0.05). In the remaining patients, local work and power were normal, and resting perfusion was consistently higher (90 [9]Mlmin^–1 100g^–1, P < 0.05 vs primary asynchrony), and fell with surgery. Local tissue oxygen tension was similar in both groups (38 vs 44mmHg) and did not change with surgery. In patients with chronic coronary artery disease, microcirculatory perfusion, but not pO₂, is reduced in regions showing primary asynchrony and impaired mechanical function. Abnormalities in both mechanical function and perfusion normalise within 30min of revascularisation. These data provide further evidence that primary asynchrony is not only a marker of chronic ischemic ventricular dysfunction, but is associated with a modified contraction pattern in which normal oxygen tension coexists with reduced perfusion.     

Effects of Piclamilast,a Selective Phosphodiesterase-4 Inhibitor,on Oxidative Burst of Sputum Cells From Mild Asthmatics and Stable COPD Patients

Oxidative stress associated with increased presence of neutrophils is an important feature of inflammatory airways diseases like asthma or chronic obstructive pulmonary disease. We studied the in vitro effect of piclamilast (RP73401), a selective phosphodiesterase (PDE)-4 inhibitor, compared to theophylline and prednisolone, on respiratory burst of sputum cells from mild asthmatics and COPD patients. Sputum cells were harvested from mild asthmatics and stable COPD patients and treated with piclamilast, theophylline or prednisolone. Respiratory burst was assessed by luminol-dependent chemoluminescence after stimulation with 10 M n-formyl-met-leu-phe (FMLP). Piclamilast inhibited FMLP-induced respiratory burst of sputum cells in a concentration-dependent manner (asthma: EC₅₀ approximately 100 nM, max. inhibition: 97.5±5% at 100 M; COPD: EC₅₀ approximately 1 M, max. inhibition: 70.6±4.5% at 100 M), whereas maximal inhibition observed with theophylline (asthma: max. inhib. 27±15%; COPD: 6±2%, both p < 0.05 vs. piclamilast) and prednisolone (asthma: 16±6%; COPD: 7.8±6.2%, both p < 0.05 vs. piclamilast) was weaker. Inhibition by piclamilast was largely reversed through pretreatment of cells with the adenylcyclase inhibitor SQ22536. We concluded that piclamilast, a selective PDE-4 inhibitor, attenuates the respiratory burst of sputum cells from mild asthmatics and COPD patients in vitro. These data underline the potential of PDE-4 inhibition as a novel therapeutic approach to inflammatory airway diseases like asthma or COPD.     

Block of HERG current expressed in HEK293 cells by the Na<Superscript>+</Superscript>-channel blocker cibenzoline

A Na⁺-channel blocker, cibenzoline, blocks the delayed rectifier potassium current (I_k), but its detailed action on the rapidly activating component (I_kr) of I_k encoded by the human ether-a-go-go-related gene (HERG) has not been clarified. We examined the effects of cibenzoline on stably expressed HERG current in HEK293 cells recorded by the patch-clamp technique of whole-cell configuration. Cibenzoline blocked HERG current expressed in HEK293 cells with IC₅₀ = 3.7 ± 0.963µM and Hill coefficient = 0.74 ± 0.12. Voltage-depended activation was shifted in a negative direction by cibenzoline. No block or minor block was induced at test depolarization of –40 to –30mV, and the block increased with depolarization reaching a plateau at 0mV without a further increase at positive voltages. Voltage-dependent activation of HERG currents became faster at negative test voltages but there were no changes at positive voltages after cibenzoline. No frequency-dependent block of HERG tail current by cibenzoline after equilibration was noted between 1.33 and 0.2Hz. Steady-state inactivation of the HERG current was shifted in a negative direction by 8mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the I_kr-like current reconstituted by HERG clone transfection with an IC₅₀ value comparable to therapeutic concentrations. Cibenzoline has a preferential affinity, at least, to the open state of the HERG channel with a rapid access to the binding site.     

Early Outcomes Following Alternative Treatment Strategies in the Management of the Acutely Ischemic Limb

The modem emergency management of the acutely ischemic limb has evolved considerably with the introduction of catheter-directed thrombolysis. Following preservation of life, the next goal of intervention in these emergency cases, whether with surgery or thrombolysis, is limb salvage. We report our own experience with both approaches in the early outcome of the emergency management of the acutely ischemic limb. This is a retrospective review of a tertiary-level vascular units experience. The inclusion criteria consisted of acute limb ischemia as defined by the guidelines of the Vascular Surgical Society of Great Britain and Ireland. Data acquisition used the hospitals inpatient enquiry system, and its operative and radiology databases. Analysis used the ² test and the Yates correction factor (p < 0.05). Patients: N=84. Events: 103. Median age: females, 82 yrs; males, 71 yrs. 17–91 yrs. Females vs. males > 70 years: ²=5.4, d.f.=1, 0.01 < p, 0.02) (²: p= 0.05). Seventy-one patients underwent preoperative angiography. Successful limb salvage was achieved in 75% of cases. Overall, the amputation and mortality rates were 16.5% and 13.1%, respectively. We initially treated 62% of events with surgery and 38% with thrombolysis. In those patients who underwent thrombolysis there, 31% went on to have reconstructive surgery. Thrombolytic treatment resulted in a limb salvage rate of 69%. Thrombolysis was discontinued in six cases due to complications. Significant differences in outcome were not demonstrable between the two treatment groups (²=1.1, d.f.=1, 0.5 < p < 0.1). Acute limb ischemia has significant morbidity and mortality rates. The use of catheter-directed thrombolysis offers the surgeon an alternative to emergency surgery. This approach does not demonstrate any increase in the rate of limb loss.     

Enhancement of EFS-induced contractions, by agmatine, in guinea pig gallbladder smooth muscle strips

Background Electrical field stimulation of gallbladder muscle strips produces frequency-dependent contractions by activating cholinergic nerves. The cholinergic motor function of the gallbladder and enteric system is also modulated by other mediators. The aim of this study was to investigate the role of agmatine, a ligand for alpha 2-adrenoceptors and imidazoline binding sites, in the cholinergic motor activity of guinea pig gallbladder smooth muscle.Methods Gallbladder muscle strips obtained from guinea pigs were subjected to electrical field stimulation (1–64Hz, 100V, 1-ms pulse width, and 10-s train duration). Frequency-response contractions of gallbladder muscle strips were traced before and after the addition of cumulative concentrations of agmatine (10^–5–10^–3M) to the tissue bath. The same set of experiments was repeated in the presence of different antagonists.Results Agmatine by itself did not produce any contractions in guinea pig gallbladder muscle strips, but significantly enhanced the contractile response produced by electrical field stimulation. Yohimbine (10^–6M), a selective alpha 2-adrenergic blocker, neither decreased nor increased the enhancement induced by agmatine. However, idazoxan (10^–4M), an alpha-receptor blocker and imidazoline receptor antagonist, abolished this enhanced contractile response. Pretreatment with N^W-nitro l-arginine methyl ester (l-NAME; 30µM), and indomethacin (10µM) did not inhibit the effect of agmatine.Conclusions Our findings indicate that agmatine has a modulator role in the electrical field stimulation-induced cholinergic contractions of guinea pig gallbladder smooth muscle strips, and this role could be mediated by imidazoline receptors. Receptor binding studies should be done to determine the presence of endogenous agmatine and imidazoline receptors in gallbladder smooth muscle.     

Hemophagocytic syndrome in ileum-origin B-cell lymphoma

A 56 year-old-man was admitted due to upper abdominal tumor and was diagnosed as having stage IVb diffuse B-cell malignant lymphoma that originally developed in the terminal ileum. The first and the second administrations of CHOP (cyclophosphamide, 750mg/m²; adriamycin, 50mg/m²; vincristine, 1.4mg/m²; and prednisolone, 100mg/day) therapy were effective; however, the third course of therapy was postponed because of an episode of massive hematochezia. After this episode, lymph nodes began to enlarge and progressive pancytopenia occurred. Bone marrow smear showed the proliferation of reactive histiocytic cells which phagocytized red blood cells, white blood cells, and platelets. B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) was diagnosed. This case is extremely rare because: (1) LAHS occurred in an ileum-origin B-cell lymphoma, and (2) LAHS developed during an interval after chemotherapy.     

The Role of Pleural Fluid-Serum Gradient of Tumor Necrosis Factor-α Concentration in Discrimination Between Complicated and Uncomplicated Parapneumonic Effusion

In a previous preliminary study an excess of tumor necrosis factor- (TNF) was found in pleural fluid of patients with complicated parapneumonic effusion (CPPE), and its levels in pleural fluid of these patients were shown to be significantly higher than those in patients with uncomplicated parapneumonic effusion (UCPPE). This larger population study was undertaken to investigate, for the first time, the role of pleural fluid-serum gradient of TNF (TNFgradient) in discrimination between UCPPE and CPPE. Using a commercially available high sensitivity ELISA kit, levels of TNF were measured in serum and pleural fluid of 51 patients with UCPPE and 30 patients with nonempyemic CPPE. The mean±SEM values of serum TNF (TNFserum), pleural fluid TNF (TNFpf), and TNFgradient in the UCPPE group were 6.65±0.48 pg/mL, 10.85±0.74 pg/mL, and 4.2±0.38 pg/mL respectively, and in the CPPE group they were 7.59±0.87 pg/mL, 54.02±5.43 pg/mL, and 46.43±5.34 pg/mL, respectively. While no significant difference was found between the two groups regarding levels of TNFserum (p=0.31), a highly significant difference between these two groups was found regarding levels of TNFpf and TNFgradient (p < 0.0001 for both variables). A significant correlation was found between levels of TNFserum and levels of TNFpf in the UCPPE group (r=0.89, p < 0.0001), but not in the CPPE group (r=0.18, p < 0.33). TNFgradient at an optimal cut-off level of 9.0 pg/mL was found to be a good marker for discrimination between UCPPE and CPPE (sensitivity, 96.7%, specificity, 98%, accuracy, 97.5%, and p < 0.0001). In conclusion, levels of TNFpf but not TNFserum are significantly higher in CPPEs than those in UCPPEs where TNFgradient at an optimal cut-off level of 9.0 pg/mL is a good marker for discrimination between UCPPE and CPPE.     

Interferon monotherapy for patients with chronic hepatitis C and normal serum aminotransferase levels at commencement of treatment

Background Approximately 30% of patients with chronic hepatitis C have normal serum alanine amino transferase (ALT) levels. While interferon (IFN) monotherapy is approved for patients with chronic hepatitis C infection, the effectiveness of such therapy for chronic hepatitis C patients with normal ALT levels at commencement of treatment remains poorly understood.Methods Ninety-four individuals (M/F, 54:40; median age, 46 years) with normal ALT levels (<50IU/l) at the commencement of treatment who were positive for both anti-hepatitis C virus (HCV) and serum HCV-RNA were studied. Among this group, 18 individuals (M/F, 9:9; median age, 50 years) had had persistently normal ALT levels for at least 3 months prior to treatment. All patients received their first course of IFN therapy in this study.Results Forty-three (45.7%) of 94 individuals had lost serum HCV-RNA at 6 months after cessation of therapy (complete response; CR). The proportion of patients with genotype 2a and HCV-RNA level over 1Meq/ml who showed CR was significantly lower in those with normal ALT levels than in those with elevated ALT levels (23.8% vs 55.6%; P = 0.0189). Two patients who had persistently normal ALT levels and HCV-RNA level over 1Meq/ml were nonresponders (NR) and had ALT flare-ups after IFN therapy. Patients with HCV-RNA levels of less than 1Meq/ml did not show differential responses based on ALT levels.Conclusions Our data suggest that IFN therapy is effective for patients with normal ALT levels and less than 1Meq/ml HCV-RNA. Thus, such patients should be considered for curative IFN therapy.     

Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice

Background d-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor- (TNF-) plays a pivotal role. We examined the effects of a highly selective adenosine A_2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure.Methods Mice were given an intraperitoneal dose of GalN (800mg/g body weight)/LPS (100ng/g body weight) with and without ATL-146e (0.01µg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF- levels in the serum were determined.Results The serum liver enzyme (ALT) level in vehicle-treated mice was 20960 ± 2800IU/ml and was reduced by 63% to 7800 ± 1670IU/ml by treatment with 0.01µg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF- and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12h from 65% to 13%.Conclusion The present findings suggest that the highly selective adenosine A_2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF- secretion.     

Microemboli at the Different Stages of Percutaneous Transluminal Carotid Angioplasty and Stenting in Patients with Post–carotid Endarterectomy Restenosis Compared to Primary Stenosis

Microembolization to cerebral arteries during percutaneous transluminal carotid angioplasty (PTCA) and stenting is well described, as well as different mural pathology in primary versus post–carotid endarterectomy (CEA) restenosis lesions. The purpose of this study is to investigate possible different patterns of embolization in regards to number and distribution of microembolic signals (high-intensity transient signals (HITS)) in patients with primary carotid stenosis and restenosis after CEA. We used transcranial Doppler (TCD) to monitor the ipsilateral middle cerebral artery (MCA) of 13 patients (13 procedures) with restenosis after CEA and six patients (seven procedures) with primary stenosis of the internal carotid artery (ICA) during PTCA and stenting. All the procedures were performed without protection devices. The total number of HITS recorded in all patients was 2692, including 1563 microemboli in patients with restenosis and 1129 in patients with primary stenosis. The mean number of microemboli per procedure was 120.2±65 and 161.3±70 (p=0.05) respectively. The average number of microembolic signals during the various stages of PTCA and stenting in the two groups was as follows: 1. Crossing the stenotic region with the guidewire and positioning the balloon inside the stenosis 33±6.9 and 73.4±9.4 (restenosis patients versus primary–stenosis patients, respectively, (p=0.011); 2. angioplasty, balloon inflation and deflation, 19.l±6.9 and 38.9±9.4 (restenosis versus primary lesions, respectively, p=0.09); 3. stent deployment, 39.5±6.9 and 27.3±9.4 (restenosis versus primary lesions, respectively, p=0.3); and 4. Post-stent dilatation, 29±6.9 and 21.7±9.4 (restenosis versus primary lesions, respectively, p=0.53). Microembolic signals are detected through all stages of PTCA and stenting in patients with primary or post-CEA-restenosis lesions. The number of HITS was significantly higher in patients with primary stenosis than with restenosis of ICA in stages prior to stenting. This probably stems from the difference in pathomorphologic structure between the lesions. There was no significant difference between groups during stent deployment and post-stent dilatation. The clinical significance of the phenomenon of microembolism during carotid stenting is still not clear, but our results suggest the importance of using protection devices to reduce the incidence of these events in both primary and post-CEA lesions.     

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.     

Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis

Background. 6-Mercaptopurine (6-MP) and azathioprine (AZA) have been used in patients with Crohn's disease (CD) and ulcerative colitis (UC) for reducing the dose of steroids and maintaining remission. However, some patients treated with 6-MP/AZA develop bone marrow suppression, one of the most serious side effects. The aim of this study was to evaluate the efficacy and safety of low-dose AZA (0.6–1.2mg/kg per day) for maintaining remission in patients with UC. We also investigated the relationship between bone marrow suppression and thiopurine methyltransferase (TPMT) mutation in the Japanese population. Methods. Study 1. To investigate the frequency of TPMT mutation, findings for 82 patients among 141 patients with UC or CD who were treated with AZA or 6-MP were analyzed retrospectively. Polymerase chain reaction (PCR) methods were used to analyze allele mutations of the TPMT gene. Study 2. A multicenter prospective trial was performed. The subjects were 22 patients with UC with presence of remission for 3 months or more. They were treated with 50mg/day of AZA, and we evaluated the remission rate at 6 months, adverse side effects, and changes in prednisone doses after the initiation of AZA. Results. Study 1. Seventy-four (91%) of the 82 patients analyzed had no TPMT mutation, 7 (8%) had one mutant allele, and 1 (1%) had two mutant alleles. Of the total of 141 patients, 4 (44%) of the 9 patients who were treated with 50mg/day of 6-MP or 100mg/day of AZA developed bone marrow suppression, although no mutation of TPMT was seen in any of these patients. On the other hand, 8 (6%) of the 132 patients who were treated with 30mg/day of 6-MP or 50mg/day of AZA developed bone marrow suppression. Seven of 8 patients (88%) who developed bone marrow suppression with a low dose of AZA had a mutant TPMT allele. Study 2. In the 17 patients who could continue taking low-dose AZA for 6 months, 15 (88%) maintained remission. Of 8 patients treated with low-dose prednisone (5–10mg/day), 3 patients (38%) could discontinue oral prednisone and 4 (50%) could reduce its dose. Six of the 22 patients (27%) had some adverse side effects. These side effects were ameliorated, or disappeared spontaneously, or disappeared with the discontinuation of AZA. Conclusions. A dose of 50mg/day of AZA is effective and safe for maintenance of remission in the Japanese population. Investigation of the TPMT allele may be useful for predicting the appearance of bone marrow suppression, when low-dose 6-MP or AZA is given.     

Burn injury sensitizes rat Kupffer cells via mechanisms dependent on gut-derived endotoxin

Background Bacterial translocation occurs after thermal injury in association with intestinal barrier loss. Recently, we found that sensitization of Kupffer cells involved gut-derived endotoxin; therefore, the purpose of this work was to study the mechanisms of sensitization of Kupffer cells in burn injury.Methods Rats received a 30% body surface area full-thickness steam burn 24h before experiments. Serum alanine aminotransferase (ALT) was measured to assess liver damage, and plasma endotoxin in the portal vein were measured. Kupffer cells were isolated 24h after the burn. Intracellular calcium ([Ca²⁺]_i) in Kupffer cells was measured using a microspectrofluorometer with the fluorescent indicator, fura-2, and tumor necrosis factor (TNF)- was measured by enzyme-linked immunosorbent assay (ELISA).Results Lipopolysaccharide (LPS)-induced mortality was increased by burn treatment. This increase was blocked by gadolinium chloride, a Kupffer-cell toxicant. Accordingly, Kupffer cells were involved in this system. The LPS-induced increase of ALT was upregulated by the burn injury. This increase was blocked by pretreatment with antibiotics. Endotoxin levels were increased to almost 300pg/ml (normal, <20pg/ml) in the portal veins of rats that received a burn. This increase was blunted by antibiotics. In Kupffer cells isolated from untreated control rats, [Ca²⁺]_i increased to 82 ± 7nM after the addition of LPS (100ng/ml). Levels were elevated twofold over control levels in the cells from rats with burn (174 ± 15nM). In addition, TNF- production by Kupffer cells isolated from rats with burn was increased fourfold over the based level. Sterilization of the gut with antibiotics completely blocked all effects of the burn on [Ca²⁺]_i and TNF- release.Conclusions Kupffer cells isolated from rats with burn exhibited sensitization to LPS, involving gut-derived endotoxin. It is concluded that burns sensitize Kupffer cells to LPS via mechanisms that are dependent on gut-derived endotoxin.     

Early effects of lafutidine or rabeprazole on intragastric acidity: which drug is more suitable for on-demand use?

Background Medication for the relief of heartburn should have the rapid onset of action required for on-demand use. We studied the inhibition of gastric acid secretion by lafutidine and rabeprazole, given in single doses to fasting and postprandial subjects.Methods A total of 22 healthy male, Helicobacter pylori-negative volunteers participated in this randomized, two-way crossover study. They were randomly assigned to receive a single oral dose of 10mg lafutidine or 20mg rabeprazole after fasting overnight (12 subjects, fasting study) or after eating a test meal (noodles, 364kcal; protein, 10.1g; fat, 16g; carbohydrates, 44.9g; NaCl, 1.1g; 10 subjects, postprandial study). Intragastric pH was monitored continuously for 6h after treatment. The other drug was given after a washout period of at least 7 days, and intragastric pH was similarly monitored.Results In the fasting study, lafutidine sustained pH at >3 and >4 during the second, third, fourth, fifth, and sixth hours of the study for significantly longer than rabeprazole. During the first 6h after treatment, lafutidine sustained pH at more than 2, 3, 3.5, 4, 5, 6, and 7 longer than rabeprazole. In the postprandial study, lafutidine sustained pH >3 and >4 for longer periods than rabeprazole during the third, fourth, fifth, and sixth hours of the study. During the first 6h after treatment, lafutidine sustained pH at more than 2, 3, 3.5, 4, 5, 6, and 7 longer than rabeprazole.Conclusions Lafutidine 10mg produces a prompter rise in intragastric pH than rabeprazole 20mg in fasting and postprandial Helicobacter pylori-negative male subjects.     

Efficacy of mizoribine treatment in patients with SjÖgren’s syndrome: an open pilot trial

The aim of this study was to evaluate the efficacy and safety of mizoribine in patients with SjÖgrens syndrome. Forty patients with sicca syndrome, whose conditions were definitely diagnosed as SjÖgrens syndrome, were given mizoribine orally at a dosage of 150mg/day for 12 months. The percentage change in salivary secretion after 3, 6, and 12 months of the therapy increased to +112.2% (P 0.001), +119.9% (P 0.01), and +147.3% (P 0.001), respectively, compared with the baseline. Serum IgG levels decreased significantly throughout the study, and the level was 1969.4 ± 620.0mg/dl after treatment for 12 months compared with the pretreatment value of 2094.3 ± 746.6mg/dl (P 0.05). The patients assessment of clinical signs and symptoms on a 10-cm visual analog scale improved significantly from 7.2 ± 2.3cm at the start of the treatment to 5.0 ± 1.9cm after 12 months (P 0.001). There was a similar improvement in the physicians assessment using the 10-cm visual analog scale: 7.1 ± 1.6cm at the start of the treatment and 5.2 ± 1.9cm after 12 months (P 0.001). With regard to safety, no serious adverse reactions were observed. Although a controlled study would be required to clarify the efficacy of mizoribine, these preliminary observations indicate its efficacy for ameliorating glandular symptoms through improvements in immune abnormalities in patients with SjÖgrens syndrome.     

Cyclooxygenase-2 mediates mucin secretion from epithelial cells of lipopolysaccharide-treated canine gallbladder

Biliary mucin was regarded as a major contributing factor in formation of pigment stones as well as cholesterol ones. The aim of this study was to elucidate the mechanism of biliary mucin secretion in canine gallbladder epithelial (CGBE) cells treated by lipopolysaccharides (LPS) with special reference to cyclooxygenase (COX) -2. Confluent CGBE cells were incubated with following compounds for 8, 12, and 24 hr: (1) serum-free medium, (2) serum-free medium containing LPS (100 m/ml), (3) serum-free medium containing LPS (100 m/ml) with NS-398 (10 M), and (4) serum-free medium containing LPS (100 m/ml) with indomethacin (10 M). Mucin assay and western blots for COX-1 and COX-2 were performed. Production of PGE₂, and cAMP was also measured. Mucin secretion increased with time. At 12 hr, mucin secretion increased to 200% of control (from 100 ± 5 to 200±45%, P < 0.05). LPS treatment significantly stimulated the COX-2 expression (P < 0.05). The productions of PGE₂ and cAMP were increased from 299±68 to 524±163 pg/mg (P < 0.05) and from 0.2±0.1 to 0.92±0.4 pmol/ml (P < 0.05), respectively. NS-398, which completely inhibited COX-2 expression, significantly suppressed the level of PGE₂ and cAMP as well as mucin secretion (P < 0.05). Indomethacin, which partially inhibited COX-2 expression, suppressed the production of PGE₂, but not cAMP and mucin secretion. In conclusion, our results suggested that the PGE₂ induced by COX-2 might play a role in mucin secretion from the gallbladder epithelium through the increment of cAMP.     

Changes in the peripheral eosinophil count in patients with acute eosinophilic myocarditis

In many cases, the diagnosis of eosinophilic myocarditis is suggested by an elevated peripheral blood eosinophil count. However, no detailed studies have been performed on the sequential changes in the initial peripheral blood eosinophil count over the course of the disease. We measured the peripheral blood eosinophil count at the time of presentation in eight patients with eosinophilic myocarditis proven by endomyocardial biopsy and intermittently thereafter. The eosinophil count at the time of onset was 500/mm³ in four patients, 500/mm³ but 1000/mm³ in three patients, and 1000/mm³ in one patient. In three of the four patients with an initial eosinophil count of 500/mm³, an increase to 500/mm³ occurred 7–12 days after the onset. The remaining patient did not develop peripheral eosinophilia. In conclusion, in the early stage of eosinophilic myocarditis, peripheral hypereosinophilia is not present initially in some patients, and may not develop during the course of the illness in a subset of these patients.