Search

The pemphigoid family of bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are autoimmune disorders that are characterized by subepidermal blistering and the development of oral lesions. We herein describe the clinical and pathological features of 11 cases of pemphigoid encountered in our department. Eight cases were diagnosed with BP and three with MMP. One case of BP was diagnosed as dipeptidyl peptidase-4 inhibitor-induced BP. Oral lesions were located in the gingiva in seven cases, the buccal mucosa in five, the lip in two, and the soft palate and tongue in one in the first visit. Seven cases of BP (7/8) had skin lesions, and one case of MMP (1/3) had a mucous lesion in the conjunctiva in the first visit. Oral lesions were detected at an average of 2.8 sites. Enzyme-linked immunosorbent assays showed that 8 (8/11) cases were positive for the anti-BP180-NC16a antibody. All cases with oral lesions received oral care, a topical treatment with dexamethasone valerate, and mouth rinse with sodium gualenate hydrate. This study might suggest that pemphigus could be suspected, diagnosed, and treated through oral lesions.

Perioperative oral management (POM) reduces the risk of postoperative pneumonia. Povidone iodine (PVP-I) is used in the self-care aspect of POM in Japan; however, its bactericidal capability may be reduced by dilution or saliva. Thus, we conducted a randomized parallel controlled feasibility study to evaluate the effects of 0.05% cetylpyridinium chloride (CPC) mouthwash compared to PVP-I gargle on the oral flora as perioperative self-care, in addition to brushing.

Purpose: We propose methods to estimate a suitable number of patients for implementing selective safety data collection (SSDC) in clinical investigations based on a confidence interval of the incidence rate or risk difference using Monte Carlo simulation. Methods: The incidence rates and risk differences of adverse events (AEs) were based on the safety outcome measures. A suitable number of patients for implementing SSDC was estimated based on the probability that the half-width of the two-sided 95% confidence interval of incidence rate or risk difference was equal to or less than a pre-specified cut-off value (0.5–3.0%). Monte Carlo simulation was used to estimate the suitable number of patients at probabilities of 70%, 80%, and 90%. The applicability of our proposed method for estimating a suitable number of patients for SSDC implementation was confirmed based on the incidence rates or risk differences from actual clinical trial data for panitumumab. Results: We demonstrated the performance of our proposed method in estimating a suitable number of patients to implement SSDC in several situations. Furthermore, according to the safety datasets of three phase III clinical trials, the number of suitable patients for implementing SSDC using incidence rates or risk differences of common AEs with panitumumab could confirm the applicability of our proposed method. Conclusion: A suitable number of patients estimated based on our proposed method may be one of the foundations for implementing SSDC, as additional data accrual may not impact the precision of the estimates of the frequency of common AEs.

Background: The selective safety data collection (SSDC) proposed in The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E19 guideline is a more selective approach to collect safety data of medicinal products with well-characterized safety profiles. There has been no systematic survey of the implementation status of SSDCs. Methods: A literature search was conducted on clinical trials using SSDC published in The New England Journal of Medicine from February 1, 2016, to December 31, 2019. By reviewing the retrieved texts, protocols, and statistical analysis plans, we identified the method of safety data collection and evaluated whether each trial adopted SSDC. Results: Of the 459 trials of medicinal products searched, 44 clinical trials adopted SSDC. The common objectives of these studies were “to study additional endpoints” (31 trials, 70.5%) and “new indications of approved drugs” (8 trials, 18.2%). Participant number was more than 1000 in 33 trials (75.0%). Most trials adopted SSDC for the entire study population throughout the trial period. Death and serious adverse events (SAEs) were recorded in all trials. Twenty-nine (66.6%) recorded death, SAE, and AE leading to drug discontinuation, which were specified in the E19 draft guideline as the data that should be collected under all circumstances. Conclusion: There have already been cases where SSDC was used in clinical trials for regulatory application. It is desirable that the E19 guideline will harmonize the method for implementation of SSDC, making SSDC more common as an option for clinical trial design.

The purpose of the present study was to identify histological biomarkers that could be used to predict adipose tissue invasion by oral squamous cell carcinoma (OSCC). The medical records and preoperative computed tomography scans of patients with primary OSCC with suspected buccal fat pad invasion were retrospectively reviewed, and an immunohistochemical study of candidate predictive biomarkers of adipose tissue invasion (α-SMA, E-cadherin, N-cadherin, FABP4, Col VI, and MMP-11) was carried out. Thirty OSCC patients whose tumors were suspected to be in contact with the buccal fat pad based on preoperative imaging were included in this study. Of these, infiltrative adipose tissue invasion was histopathologically confirmed in 6 patients (20.0 %). The significant higher immunoreactivity of candidate predictive biomarkers was detected in the tumor-buccal fat pad contact area compared to in the tumor surface area.(Pearson’s correlation coefficient test: α-SMA: 0.422, p < 0.05; N-cadherin: 0.476, p < 0.01; FABP4: 0.467, p < 0.01;). In the tumor-buccal fat pad contact area, Col VI immunoreactivity was significantly higher in the OSCC with buccal fat pad invasion than without buccal fat pad invasion (median test, p < 0.01). Furthermore, high α-SMA expression exhibited a tendency towards an association with OSCC with buccal fat pad invasion, as did high FABP4 expression (median test, α-SMA: p = 0.06, FABP4: p = 0.07). These results suggest that the expression levels of α-SMA and FABP4 may be useful biomarkers for predicting aggressive adipose tissue invasion in OSCC.

The changes in dose distribution caused by backscatter radiation from a common commercial dental alloy (Au-Ag-Pd dental alloy; DA) were investigated to identify the optimal material and thicknesses of a dental device (DD) for effective prevention of mucositis. To this end, 1 cm3of DA was irradiated with a 6-MV X-ray beam (100 MU) in a field size of 10 × 10 cm2using a Novalis TX linear accelerator. Ethylene vinyl acetate copolymer, polyolefin elastomer, and polyethylene terephthalate (PET) were selected as DD materials. The depth dose along the central axis was determined with respect to the presence/absence of DA and DDs at thicknesses of 1-10 mm using a parallel-plate ionization chamber. The dose in the absence of DDs showed the lowest value at a distance of 5 mm from the DA surface and gradually increased with distance between the measurement point and the DA surface for distances of ≥5 mm. Except for PET, no significant difference between the DA dose curves for the presence and absence of DDs was observed. In the dose curve, PET showed a slightly higher dose for DA with DD than for DA without DD for thicknesses of ≥4 mm. The findings herein suggest that the optimal DD material for preventing local dose enhancement of the mucosa caused by DA backscatter radiation should have a relatively low atomic number and physical density and that optimal DD thickness should be chosen considering backscatter radiation and percentage depth dose.

29Si-NMR Study of antiferromagnet CeRh2Si2with a tetragonal ThCr2Si2-type structure has been performed using single crystals. The Knight shifts along the aand the caxes have been measured as a function of temperatures in the paramagnetic state. At ambient pressure, the Knight shifts show the Ising-type anisotropy along the caxis, which is similar to the magnetic susceptibility. The hyperfine coupling constants for 29Si along the aand the caxes have been determined from Knight shift versus static susceptibility plots.

The magnetic excitation of a narrow gap semiconductor β-US2was studied by means of neutron scattering. At low temperatures, clear crystalline electric-field (CEF) excitations were observed, indicating the localized character of 5felectrons. The pseudo-doublet state at an excitation energy of ∼7 meV is consistent with the level scheme based on the 5f2configuration of U4+ions, which reproduces the magnetic susceptibility, magnetization, and specific heat. At elevated temperatures, the conductivity recovers, with the excitation of 5fcarriers being beyond the conduction gap of 90 K. Simultaneously, the CEF excitation becomes weak and broad, and is replaced by a quasi-elastic response of magnetic origin, indicating a crossover of the 5fcharacter from localized to itinerant.

The aim of this study is refinement of proton(s) hopping rate by applying new model for Molecular Dynamics (MD) calculation with Empirical Valence Bond (EVB) method. The overview about this new model is an acceptor selection method based on energy prediction instead of the one based on distance. The effect of water molecules outside the Eigen cation was mainly considered in this new model. Then, microenvironment interaction to the formation of the cluster and proton hopping were reasonably expressed as an actual condition. This procedure was applied for proton hopping. The total number of cluster formation and cancel were also analyzed.

Single crystals of uranium- and thorium-copper oxyphosphide, UCuPO and ThCuPO, have been grown by an iode-transport method. The crystallographic parameters for UCuPO and ThCuPO are determined at room temperature by single crystal X-ray diffraction. These materials crystallize in a tetragonal ZrCuSiAs-type structure. UCuPO is confirmed to be a semimetallic antiferromagnet with a Néel temperature of $T_{\text{N}}= 220$ K, while ThCuPO shows non-magnetic metallic behavior. The specific heat measurements at temperatures much lower than $T_{\text{N}}$ indicate that the density of states (DOS) for both compounds is quite low, and that the 5fcomponent of DOS is fully gapped due to antiferromagnetic ordering in UCuPO. The magnetic susceptibility for a single crystal of UCuPO shows a large uniaxial anisotropy along the $c$ axis in the paramagnetic state. The resistivity measurements for UCuPO under high pressures up to 2.45 GPa indicate a slight increase of the Néel temperature. When compared with the data for the reference material ThCuPO, the semimetallic conductivity may come mainly from Cu 4s--P 3pbands with low DOS, while the ordered and paramagnetic moments seem to be carried only by localized 5felectrons.

Pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy is now a popular treatment for patients with chronic hepatitis C; however, the reported sustained virologic response (SVR) rate remains at nearly 50 in genotype 1b infected patients. Therefore, it is of clinical benefit to be able to predict the effect of combination therapy on individual patients earlier in the treatment. We estimated the predictive serum HCV core antigen levels for SVR in the early therapeutic stage of combination therapy.

Recent investigations indicate that telomerase activity regulates the life span of cells by compensating for telomere shortening during DNA replication. In addition, as differentiation progresses, telomerase activity is reduced in several different cell lineages. These findings lend support to the theory that more immature cells have greater remaining proliferative capacity and longer life span. However, it has not been directly demonstrated that the differentiation along a hepatocytic or a bile ductal lineage is accompanied by reduction of telomerase activity. In this study, we present direct evidence that telomerase activity is reduced during hepatocytic and biliary epithelial differentiation by using our unique cell lines including a stem-like cell line, ETK-1. When hepatocytic differentiation was induced in ETK-1 by 5-azacytidine, telomerase activity decreased significantly. Similarly, when we compared the telomerase activity on SSP-25 and RBE cell lines from the same origin but representing different maturation stages of cholangiocarcinoma, more mature cells were found to possess significantly lower activity. These results indicate that the generally accepted relationship between telomerase activity and differentiation stage also applies in the hepatocytic and biliary epithelial lineages. Copyright © 2001 John Wiley & Sons, Ltd.

Recent investigations indicate that telomerase activity regulates the life span of cells by compensating for telomere shortening during DNA replication. In addition, as differentiation progresses, telomerase activity is reduced in several different cell lineages. These findings lend support to the theory that more immature cells have greater remaining proliferative capacity and longer life span. However, it has not been directly demonstrated that the differentiation along a hepatocytic or a bile ductal lineage is accompanied by reduction of telomerase activity. In this study, we present direct evidence that telomerase activity is reduced during hepatocytic and biliary epithelial differentiation by using our unique cell lines including a stem‐like cell line, ETK‐1. When hepatocytic differentiation was induced in ETK‐1 by 5‐azacytidine, telomerase activity decreased significantly. Similarly, when we compared the telomerase activity on SSP‐25 and RBE cell lines from the same origin but representing different maturation stages of cholangiocarcinoma, more mature cells were found to possess significantly lower activity. These results indicate that the generally accepted relationship between telomerase activity and differentiation stage also applies in the hepatocytic and biliary epithelial lineages. Copyright © 2001 John Wiley & Sons, Ltd.

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global pandemic. Patients with hematological disorders are known to be at high risk of morbidity and mortality from COVID-19, and vaccines against SARS-CoV-2 have been rapidly developed. Although mRNA vaccines against SARS-CoV-2 are reported to be effective, efficacy in patients with hematological malignancies who have received anti-CD20 antibody treatment remains unclear. Here, we prospectively evaluated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody.

Yakushijin: Chugai pharmaceutical Co. Ltd.: Research Funding; Jazz pharmaceuticals: Research Funding; Nippon Shinyaku: Honoraria. Kiyota: Bristol-Myers Squibb: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astra-Zeneca: Honoraria, Research Funding; Roche Phamaceuticals: Research Funding; Merck Biopharma: Honoraria; Merck Sharp & Dohme: Honoraria; Eisai: Honoraria; Bayer: Honoraria. Matsuoka: Takeda Pharmaceutical Company: Research Funding; Sysmex: Research Funding. Minami: Behring: Research Funding; CSL: Research Funding; Yakult Honsha: Research Funding; Nippon Shinyaku: Research Funding; Astellas Pharma: Research Funding; Asahi-Kasei Pharma: Research Funding; Eli Lilly: Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Merck Serono: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; DaiichiSankyo: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer Yakuhin: Honoraria, Research Funding; Nippon Kayaku: Research Funding; Celgene: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Shire Japan: Honoraria; Genomic Health: Honoraria; Abbvie: Honoraria.

To identify virological parameters (serostatus of hepatitis B surface antigen [HBsAg] and antibodies to hepatitis C virus [anti‐HCV], HCV genotypes and HCV‐RNA titer) and other clinico‐biological and lifestyle variables that may influence or predict the development of hepatocellular carcinoma (HCC) in cirrhosis, we followed 100 cirrhotic patients without HCC, who visited Kyushu University Hospital between 1985 and 1987, until the end of 1995 (follow‐up rate: 98%; average follow‐up period: 5.3 years). After elimination of 4 patients who developed HCC or were censored within the initial 6 months, 37 (39%) out of 96 patients developed HCC during follow‐up. As compared with HBsAg(+) patients, anti‐HCV(+) HBsAg(–) patients demonstrated significantly elevated HCC risk (adjusted hazard ratio [HR]=5.85, 95% confidence interval [CI] 1.65–20.67). Genotype 1 HCV infection was not associated with increased risk compared with genotype 2 (HR = 0.64, 95% CI 0.21–1.99). For genotype 1 HCV infection, patients with HCV‐RNA levels <1 Meq/ml tended to present lower risk than patients with ≥1 Meq/ml (P= 0.03). Male sex, advanced Child's class, lower serum albumin, and higher serum aminotransferase and α‐fetoprotein were also found to be strong predictors. Overall, drinking and smoking habits were not associated with significantly elevated risk. Among virological parameters, anti‐HCV positivity and, possibly high HCV‐RNA titer, were predictive of HCC occurrence in cirrhosis in our clinical setting.

To investigate the profiles of adverse events (AEs) in randomized controlled trials of antihypertensive agents therapy with the technique of meta-analysis. A total of 620 articles were selected from MEDLINE, EMBASE, JAPIC-DOC, JMEDICINE and manual searching. Two independent reviewers examined the 620 selected articles according to the following criteria: (1) the methods of randomization, (2) making for allocating treatments, (3) therapeutic class of drugs, (4) sample sizes, (5) duration of the treatment, (6) primary endpoint, (7) reporting method for all adverse events, (8) method of monitoring AEs, and (9) incidence rates of all reported AEs. To combine the risk difference and risk ratios of incidence between CCBs and beta blockers or diuretics, the method of DerSimonian and Laird based on random effect model was applied. A total of 3073 patients were included in this meta-analysis of serious adverse events (SAEs). There was no significant difference in the total incidence of SAEs between CCBs and diuretics or between CCBs and beta blockers. We found that patients treated with CCBS had 0.14% fewer SAEs compared with the patients treated with diuretics. Contrarily, the patients treated with CCBs had 0.29% more SAEs compared with the patients treated with beta blockers. There was a significant difference between the patients treated with CCBs and those treated with diuretics in the symptoms with headache and oedema. With respect to the comparison between CCBs and beta blockers, flushing occurred 8.75% more frequently in the CCBs group than in the beta blockers group. A meta-analysis can be applied to safety analyses of data obtained in clinical trials if all of the RCT articles used include a complete description of adverse experiences. Copyright © 1999 John Wiley & Sons, Ltd.

Hepatic stellate cells play a central role inthe pathogenesis of liver fibrosis, both via productionof extracellular matrix proteins and through secretionof matrix metalloproteinases. In this study, effects of soluble cell adhesion peptides oncollagen type I accumulation and on expression of matrixmetalloproteinases were analyzed. First, we revealed theexpression of α5-integrin on hepaticstellate cells by immunostaining. Treatment with 100μg/ml of soluble Arg-Gly-Asp (RGD) peptides was foundto reduce accumulation of type I collagen without anyeffects on its transcriptional level in rat hepatic stellate cells, whereas a control peptideGly-Arg-Gly-Glu-Ser (GRGES) had no such effect. SolubleRGD peptides also increased the secretion of collagenaseby stellate cells. These data suggested that reduced accumulation of type I collagen caused by theRGD peptide ligation to integrins on hepatic stellatecells was partly due to stimulated expression ofcollagenase by stellate cells.

We measured plasma levels of endothelin-1, a potent vasoconstrictor peptide, in 6 healthy controls and 20 patients with cirrhosis and correlated them with various clinical and laboratory parameters and other vasoactive substances. There was a trend toward increased endothelin-1 levels in patients with cirrhosis compared with controls (6.0 ± 2.5 vs. 4.4 ± 1.5 pg/ml, NS). The presence of ascites did not influence plasma endothelin-1 levels, and plasma endothelin-1 levels were not significantly correlated with serum albumin, serum bilirubin, or prothrombin time. Plasma endothelin-1 levels were significantly elevated in cirrhotic patients with esophageal varices compared with those without varices (7.5 ± 2.5 vs. 4.5 ± 1.6, p < 0.05). The elevation of endothelin-1 levels in patients with varices may represent a physiological compensation for the systemic vasodilation present in patients with liver cirrhosis and portal hypertension.

To evaluate the effect of percutaneous ethanol injection given alone, we studied disease recurrence and prognosis in 37 patients with solitary hepatocellular carcinoma up to 2 cm. The patients were classified as Child's class A, 22; B, 11; and C, 4. During follow-up for periods ranging from 10 to 44 (mean, 26) months, 15 of the 37 patients (40.5) had disease recurrence. The 1-, 2-, and 3-year recurrence rates were 37, 49, and 53, respectively (Kaplan-Meier method). Significant risk factors for recurrence included the hypervascularity and the histological differentiation of the tumor (p < 0.01). Of those 15 patients, two had local recurrence, eight had nodular recurrence (fewer than two nodules), and five had widespread multinodular recurrence. The patients with local or nodular recurrence then received repeated injections of ethanol, while those with multinodular recurrence received transarterial embolization or chemolipiodolization therapy as possible. Seven of the 37 patients died during follow-up. The 1-, 2-, and 3-year survival rates were 95, 81, and 70, respectively (Kaplan–Meier method). No factor was significant in prognosis. We observed a significant relationship between recurrence pattern and prognosis. Patients with a widespread multinodular recurrence had a significantly shorter survival (p < 0.01). In summary, ethanol injections given alone appeared to be effective in treating small and solitary hepatocellular carcinomas. Repeated injection of ethanol of the site of recurrence was useful in prolonging survival.

A patient with reactive lymphoid hyperplasia of the liver was symptom free and had no underlying disease except for diabetes mellitus. The hepatic tumor was found by ultrasound examination at routine checkup. The preoperative diagnosis of the tumor was unsuccessful despite various radiological examinations. Histological examination of the resected tumor showed that it was composed of benign-appearing lymphocytic proliferations forming lymphoid follicles that included numerous germinal centers. The germinal center was mainly composed of B-cell marker, L26-positive lymphocytes, but a few T cells were also found. Lymphocytes surrounding germinal centers were mainly T-cell marker, UCHL1-positive T-cells, and a small number of B cells. The B cells in the lymphoid follicles were stained for both and light chains at equal frequency, indicating polyclonal and benign nature. A diagnosis of reactive lymphoid hyperplasia of the liver seems justified.

The capacity for intercellular communication (IC) via gap junctions is found in normal pancreatic acinar cells. The major role of IC is considered to be the maintenance of tissue homeostasis and the regulation of signal transmissions. Up to now, the participation of IC via gap junctions in acute pancreatitis has not been reported. We investigated the role of IC in cerulein (Cn)-induced acute pancreatitis in rats using irsogladine, an enhancer of IC via gap junction. Acute edematous pancreatitis was induced in rats by two intraperitoneal injections of 40 μg/kg Cn. Rats received various doses (25, 50, or 100 mg/kg body weight) of irsogladine orally, 15 and 2 h before the first Cn injection. The normal control group received only vehicle. The severity of pancreatitis was evaluated enzymatically and histologically 5 h after the first Cn injection. In Cn-induced acute pancreatitis, irsogladine significantly lowered the serum amylase level, the pancreatic wet weight, and the pancreatic amylase and DNA contents, in a dose-dependent manner. Particularly, the amylase content improved to the level of the normal controls. Histologically, the severity of pancreatitis was reduced significantly by treatment with irsogladine and no discernible vacuolization was seen in the group with 100 mg/kg irsogladine treatment. By immunofluorostaining pancreata with anti-connexin 32 (Cx32; a gap junction protein) antibody, we found that pancreatic acini were diffusely positive for Cx32 in the control group, but the number of Cx32-positive grains decreased markedly, to 19, in the pancreatitis group. With 100 mg/kg irsogladine treatment, the number of Cx32 grains recovered to 70 of the normal control value. These findings indicate that IC via gap junction is disturbed in Cn-induced pancreatitis, which may result in the breakdown of tissue homeostasis and the progression of acute pancreatitis.

Kupffer cells play important roles in the development of liver injury by producing cytokines and free radicals. In consequence inhibition of these inflammatory mediators will be one of the targets for treating liver diseases. Retinoids modulate a wide variety of functions of monocytes/macrophages. Cellular effects of retinoids are mediated by two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We examined the effects of several kinds of natural and synthetic retinoids on the production of tumour necrosis factor‐α (TNF‐α) and nitric oxide (NO) by LPS‐stimulated rat Kupffer cells in vitro. Of the various retinoids tested, 9‐cis‐retinoic acid (9‐cis‐RA) and Ro 13‐6307, which are agonists of both RARs and RXRs, suppressed the production of TNF‐α and NO in a concentration‐dependent fashion, whereas three types of RAR‐selective agonists, Ro 13‐7410, Ro 40‐6055 and Ro 19‐0645 did not show any effect. Furthermore, the RARα antagonist, Ro 41‐5253, did not prevent the effects induced by 9‐cis‐RA. The results suggest that these effects of 9‐cis RA and Ro 13‐6307 were induced by the RXRs‐dependent signalling pathway. © 1997 John Wiley & Sons, Ltd.

A case of surgically confirmed primary malignant fibrous histiocytoma of the liver is presented. A 35-year-old man was admitted to hospital with an epigastric mass. No abnormal laboratory findings, including tumor markers, were detected. Ultrasound and computed tomography showed the main tumor in the left lateral segment and a daughter nodule in the posterior segment of the liver. Arteriography demonstrated a slightly hypervascuIar mass in the left lateral segment. Histological examination of the resected tumor showed bundles of spindle cells with a focal storiform pattern, which were intermingled with bizarre giant cells, therefore a diagnosis of malignant fibrous histocytoma was made.

Kupffer cells play important roles in the development of liver injury by producing cytokines and free radicals. In consequence inhibition of these inflammatory mediators will be one of the targets for treating liver diseases. Retinoids modulate a wide variety of functions of monocytes/macrophages. Cellular effects of retinoids are mediated by two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We examined the effects of several kinds of natural and synthetic retinoids on the production of tumour necrosis factor-α (TNF-α) and nitric oxide (NO) by LPS-stimulated rat Kupffer cells in vitro. Of the various retinoids tested, 9-cis-retinoic acid (9-cis-RA) and Ro 13-6307, which are agonists of both RARs and RXRs, suppressed the production of TNF-α and NO in a concentration-dependent fashion, whereas three types of RAR-selective agonists, Ro 13-7410, Ro 40-6055 and Ro 19-0645 did not show any effect. Furthermore, the RARα antagonist, Ro 41-5253, did not prevent the effects induced by 9-cis-RA. The results suggest that these effects of 9-cis RA and Ro 13-6307 were induced by the RXRs-dependent signalling pathway. © 1997 John Wiley & Sons, Ltd.

It has been shown that the circulating antibodies, which bind to rat hepatic microsomal proteins obtained after in vivo exposure to halothane, are detectable by immunoblotting in patients with “halothane hepatitis (HH),” and that rabbit immunized anti-sera against trifluoroacetylated rabbit serum albumin (TFA-RSA) recognizes rat microsomal distorted polypeptides in almost the same way as do sera from patients with HH. In this paper, we report first the development of a novel method of synthesizing TFA-RSA using p-nitrophenyl TFA, and second the results of tests for circulating anti-TFA antibodies in the serum of 86 patients who had received halothane anaesthesia and developed no (67 patients) or mild (19 patients, the maximum activity of serum alanine aminotransaminase 519 IU · L−1) liver damage. Serum was selected from stored sera of post-transfusion patients. The new method of synthesizing TFA-RSA was convenient and was able to be done at neutral pH. Rabbit sera obtained after immunization with the newly synthesized TFA-RSA recognized the same polypeptides (109 kDa, 92 kDa, 80 kDa, 76 kDa, 64 kDa and 59 kDa) as the established anti-sera against TFA-RSA, and these reactions were inhibited in the presence of TFA-lysine. Circulating antibodies were not detected in our patients who had developed no or mild liver damage. The present finding supports the hypothesis that the appearance of circulating antibodies against microsomal distorted proteins are specific to patients with HH. Furthermore, we have shown here that the halothane-induced mild increase in ALT activity is not associated with the appearance of those circulating antibodies, supporting the pathophysiological difference between HH and halothane-induced mild hepatic damage.

A bioassay using dispersed pancreatic acini was used to measure fasting plasma cholecystokinin (CCK) concentrations in 105 patients with various kinds of gastrointestinal diseases, 17 patients with diabetes mellitus, and 6 healthy voluntters. High plasma CCK bioactivities were observed in patients with obstructive jaundice, choledocolithiasis, and primary biliary cirrhosis. Twenty-three samples with high CCK bioactivities were assayed by the same bioassay after the addition of a specific CCK antagonist and by a CCK radioimmunoassay in order to determine whether the high CCK-like bioactivity was due to circulating CCK or other factors. High CCK bioactivities were partially inhibited by the specific CCK antagonist, CR-1409, but the activities were not totally abolished. The residual bioactivities (not inhibited by CR-1409) correlated with plasma bile acid concentrations. The inhibitable CCK bioactivities correlated with plasma CCK levels obtained by radioimmunoassay. Although the bioassay using dispersed pancreatic acini has several advantages for measuring plasma CCK, this method overestimates CCK bioactivities in patients with high plasma bile acid concentrations.

Using a scintigraphic technique, we investigated gastric emptying of a semisolid meal in 20 patients with liver cirrhosis and in 10 control subjects and correlated gastric emptying with gastrointestinal symptoms and with autonomic nervous function as determined by R-R interval variation on the electrocardiogram. All subjects lacked endoscopic abnormalities that might explain their gastrointestinal symptoms. None had alcoholic liver disease, diabetes, or other diseases known to affect gastric emptying. The half-time for gastric emptying was significantly prolonged in the cirrhotic patients (51.3±16.6 minutes) as compared with control subjects (29.9±8.4) (P<0.01). There was a significant correlation between the gastrointestinal symptom score and the half-time for gastric emptying (r=0.46,P<0.05) in the cirrhotic patients. However, the decreases in R-R interval variation and gastric emptying were not significantly correlated. These observations indicate that delayed gastric emptying is frequently present in patients with liver cirrhosis and may produce their gastrointestinal symptoms.

All‐transretinoic acid (ATRA) has been reported to exert major effects on the immune system, including monocytes/macrophages. The present study was designed to determine whether ATRA would modulate macrophage‐associated liver injury induced by Propionibacterium acnesand lipopolysaccharide (LPS) in rats. All‐transretinoic acid administration alleviated the liver injury and reduced the incidence of death following hepatic failure. Serum alanine aminotransferase (ALT) levels 5 h after, and survival rates within 12 h after the administration of LPS were significantly lower in the ATRA‐treated group (134 ± 119 IU/L and 72.7%) compared with the control group (713 ± 411 IU/L and 18.2%; P< 0.05). Histological findings supported these results. These effects may be due to suppression of tumour necrosis factor‐α (TNF‐α) and superoxide anions produced by activated macrophages. Serum levels of TNF‐α 1 h after LPS administration were significantly lower in the ATRA‐treated group (60.5 ± 7.0 ng/mL) as compared with the control group (105.2 ± 39.3 ng/mL; P< 0.05). Formazan deposition that was generated by the perfusion of the liver with nitroblue tetrazolium, also suggested suppression of the release of superoxide anions from hepatic macrophages. These results suggest that ATRA acts as an immunomodulator in liver injury by suppressing the activation of liver macrophages.

The most common forms of chronic pancreatitisare related to alcohol ingestion, whereas the entity ofnon-alcohol-associated (idiopathic) pancreatitis ispoorly understood. Autoimmunity has been suggested as a possible etiologic factor of idiopathicchronic pancreatitis. A total of 362 Japanese patientsunderwent endoscopic retrograde pancreatography (ERP)for suspected pancreatic disease, and 161 were diagnosed with chronic pancreatitis. Among them, we foundthree cases (1.86% incidence) of unique chronicpancreatitis, in which ERP revealed diffuse narrowing ofthe main pancreatic duct with an irregular wall. We diagnosed these three patients as havingpancreatitis associated with an autoimmune mechanismmorphologically and biochemically and started them onsteroid therapy. The characteristics of the these three patients were as follows:hypergammaglobulinemia, eosinophilia, ultrasonographyshowing hypoehoic diffuse swelling in the pancreas(sausage-like appearance), ERP showing diffuse narrowingof the main pancreatic duct with irregular like thumbprintlike marks,reversible exocrine insufficiency, and positiveanti-carbonic anhydrase II antibody. After one month ofthe treatment with steroids, pancreatitis dramatically improved morphologically and enzymatically.Here we describe these cases of the suspected autoimmunechronic pancreatitis. We must recognize the concept andthe features of autoimmune pancreatitis in order to avoid unnecessary surgery as pancreaticcancer.