Effects of glycyrrhizin on immune-mediated cytotoxicity

Intravenous administration of glycyrrhizin is known to decrease elevated plasma transaminase levels in patients with chronic viral hepatitis, in which immune-mediated cytotoxicity by cytotoxic T lymphocytes and tumour necrosis factor (TNF)-α is considered to play an important pathogenic role. However, the immunological interpretation of the transaminase-lowering action of glycyrrhizin is not known. Studies were performed to elucidate this action immunologically by assessing the effects of glycyrrhizin on immune-mediated cytotoxicity using an antigen-specific murine CD4⁺ T hybridoma line, which exhibits cytotoxicity against antigen-presenting cells after stimulation with specific antigen, and a murine TNF-α-sensitive fibroblast line. Glycyrrhizin inhibited the cytotoxic activity of the T cells against antigen-presenting cells and also suppressed TNF-α-induced cytotoxicity in the TNF-α-sensitive cell line in vitro. These results suggest that the decrease of elevated transaminase levels by glycyrrhizin in patients with chronic viral hepatitis is mediated in part by inhibition of immune-mediated cytotoxicity against hepatocytes.     

Intraspinal Metastasis of Neuroblastoma -- Report of a Case Detected at Autopsy --

Metastasis to the brain or spinal cord parenchyma is extremelyrare in cases of neuroblastoma. We present a 3-year-7-month-old boy with neuroblastoma, stageIV, with intraspinal metastasis. He had no neurologic manifestationexcept incontinentia urinae and ataxia at the terminal stage.His cranial computed tomography scan showed high density areasin both cerebellar hemispheres which seemed to be distant metastaticmasses. At autopsy, the metastases in the cerebellum were foundto be due to dural infiltration but in the spinal cord parenchymaof the lumbar spine metastases were detected macroscopically.There were multiple distant metastatic areas near the roots,anterior and posterior. The neuroblastoma seemed to have spreadalong the roots by direct invasion from the meninges. In the future, the number of patients with metastasis into thebrain or spinal cord parenchyma will increase because patientswith progressive disease could live for a long time as a resultof intensive chemotherapy. Observation of these cases will behelpful to clarify the routes of metastasis to these areas.     

Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients

Hasegawa T, Okamoto A, Kamimura T, Tatsuno I, Hashikawa S‐N, Yabutani M, Matsumoto M, Yamada K, Isaka M, Minami M, Ohta M. Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients. APMIS 2010; 118: 167–78. Streptococcal toxic shock syndrome (STSS) is a re‐emerging infectious disease in Japan and many other developed countries. Epidemiological studies have revealed that the M1 serotype of Streptococcus pyogenes is the most dominant causative isolate of STSS. Recent characterization of M1 isolates revealed that the mutation of covS, one of the two‐component regulatory systems, plays an important role in STSS by altering protein expression. We analyzed the M1 S. pyogenes clinical isolates before or after 1990 in Japan, using two‐dimensional gel electrophoresis (2‐DE) and pulsed‐field gel electrophoresis (PFGE). PFGE profiles were different between the isolates before and after 1990. Markedly different profiles among isolates after 1990 from STSS and pharyngitis patients were detected. Sequence analysis of two‐component regulatory systems showed that covS mutations were detected not only in STSS but also in three pharyngitis isolates, in which proteins from the culture supernatant displayed the invasive type. The mutated CovS detected in the pharyngitis isolates had impaired function on the production of streptococcal pyrogenic exotoxin B (SpeB) analyzed by 2‐DE. These results suggest that several covS mutations that lead to the malfunction of the CovS protein occurred even in pharyngeal infection.     

A Biodegradable Poly-l-lactic Acid Coronary Stent in the Porcine Coronary Artery

Although biocompatibility of biodegradable stents is controversial, stents made of high molecular weight poly- l -lactic acid (PLLA) are thought to be the most promising. We investigated the biocompatibility of PLLA stents histologically and angiographically in porcine coronary arteries. The Igaki-Tamai stent is made of PLLA monofilaments (molecular mass 183 kD) with a zigzag helical coil design. Fourteen PLLA stents in 6 pigs and 9 Palmaz-Schatz half stents in 9 pigs were implanted in 15 normocholesterolemic pigs. Stents were mounted on a delivery catheter, and were implanted percutaneously into coronary arteries. Coronary angiography was performed before and immediately after stenting, at 2 and 6 weeks in five PLLA pigs and nine Palmaz-Schatz pigs. Histological studies were performed in PLLA pigs: 2 pigs at 2 weeks, 3 pigs at 6 weeks, and 1 pig at 16 weeks with hematoxylin-eosin and elastica van Giesons stains. All PLLA stents were successfully delivered. No stent thrombosis was detected in either group. There were no significant differences in minimal lumen diameter (MLD) or percent diameter stenosis between the PLLA and Palmaz-Schatz stent groups immediately after implantation, or at 2 or 6 weeks after implantation. Histological studies at 2, 6, and 16 weeks revealed no inflammation and minimal neointimal coverage on the PLLA stent struts. The PLLA stent maintained its structure for up to 16 weeks. These results suggest sufficient biocompatibility and strength of PLLA biodegradable stents in porcine coronary arteries. Clinical trial is now underway to validate the safety and usefulness of PLLA stents in humans.     

Influence of piecemeal necrosis on the compensatory increase of mitochondrial respiratory enzymes of the tumour-bearing liver: Clinical study of 53 surgical cases

The relationships between histological findings, adaptively increased cytochrome a(+a3) levels in chronic liver disease and complications after hepatectomy were studied in order to clarify the mechanism of mitochondrial derangement. The liver specimens of 53 hepatectomized patients were randomly evaluated by three independent hepatopathologists and were compared with cytochrome a(+a3) levels in the biopsied liver, the extent of operation and postoperative complications. The cytochrome a(+a3) concentrations did not show any significant difference between cases of chronic hepatitis and liver cirrhosis nor groups classified by regeneration. Severity of piecemeal necrosis was categorized into three groups: group A--minimal (n = 20); group B--moderate (n = 19); and group C--severe (n = 14). There were significant differences (P less than 0.01) in cytochrome a(+a3) concentrations between the groups (A: 99 +/- 9; B: 135 +/- 6; C: 155 +/- 10 pmol/mg of mitochondrial protein). Extensive hepatectomy, involving segmentectomy or more, was frequently complicated (four of nine, 44.4%) in group C, whereas there were few complications (two of 16, 12.5%) in group A cases in which extensive hepatectomy was performed. Evidence will be presented which will show that deranged liver function, as indicated by cytochrome a(+a3) levels, is closely correlated with piecemeal necrosis. This may be attributed to the damage of periportal hepatocytes which are the main sites of oxidative phosphorylation.     

Alternating Non-Cross Resistant Chemotherapy for Small Cell Lung Cancer

After stratification for the extent of disease, previously untreatedpatients .with small cell lung cancer randomized to receivetherapy with the four-drug combination of cyclophosphamide,oncovin, nimustine hydrochloride (ACNU), and procarbazine (CONP)every four weeks (continuous regimen) or to receive CONP alternatingwith the three-drug combination of etoposide (VP-16), adriamycinand cisplatin (VAD) at four-week intervals (alternating regimen).Sixty-nine patients were entered in the study. Of 34 evaluablepatients receiving the continuous regimen, six (17.6%) achievedcomplete response (CR) and 16 (47.1%) achieved partial response(PR). Of 31 evaluable patients receiving the alternating regimen,10 (32.3%) achieved CR, and 16 (51.6%) achieved PR. There wasa tendency in favor of the alternating regimen in CR and overall response rates (0.05 < p < 0.1). There were no significantdifferences be tween the regimens in response duration or survival.The projected median survival times were 9.2 months and 9.4months for the continuous and alternating regimens, respectively.One patient receiving the continuous regimen and three receivingthe alternating regimen have been living for more than two years.The major toxicity was myelosuppression in both regimens. Onepatient died of hemorrhage due to thrombocytopenia during inductionwith CONP, and one patient died of cisplatin-induced renal failure.We conclude that alternating non-cross resistant chemotherapyleads to improved CR and response rates, but does not improvesurvival.     

Randomized Trial Comparing Chemotherapy Alone and Chemotherapy Plus Chest Irradiation in Limited Stage Small Cell Lung Cancer: A Preliminary Report

In order to assess the effectiveness of chest irradiation inaddition to intensive chemotherapy in limited stage small celllung cancer, 50 patients were randomized to receive either chemotherapyalone or chemotherapy plus chest irradiation, between April1981 and October 1985. The chemotherapy regimen consisted ofa four-drug combination of cyclophosphamide, vincristine, methotrexate,and procarbazine, and a three-drug combination of etoposide,adriamycin, and nimustine, given alternately every 8 weeks.One group of 26 patients received the chemotherapy alone, andanother group of 24 patients received chest irradiation with40 Gy between cycles 1 and 2 of the chemotherapy. Complete responserates were quite similar in the two groups; 50% for those receivingchemotherapy alone, and 59% for those receiving chemotherapyplus chest irradiation. There were no significant differencesin median survival (15 months versus 12 months) and in long-termsurvival rates between the two groups with a median follow-upperiod of 26 months. The combined modality treat ment was moretoxic than chemotherapy aIone two patients receiving such treatmentdied of radiation pneumonitis. It is concluded that chest irradiationcombined with chemotherapy does not affect the response rate,survival, or pattern of recurrence in patients with limitedstage small cell lung cancer.     

‘Atypical adenomatous hyperplasia’ in liver cirrhosis: low-grade hepatocellular carcinoma or borderline lesion?

Adenomatous hyperplasia, defined as a sizable parenchymal nodule in cirrhosis, was examined morphologically. Ninety-seven nodules of adenomatous hyperplasia were obtained from 47 cirrhotic livers and were divided into 'ordinary' (44 nodules) and 'atypical' (53 nodules) types. The former consisted of hepatocytes similar to those of the surrounding liver, and showed regularly distributed portal tracts. The latter type was composed of hepatocytes showing nuclear atypia, relative to the surrounding liver, and showed irregular or sparse portal tracts. Atypical nodules were histologically heterogeneous, possessing areas of normo-trabecular, compact, pseudoglandular and/or scirrhous patterns. Several cytological changes, such as clear cell change, small or large cell change and fatty change, were intermingled variably within a given nodule. Atypical nodules showed expansive and/or replacing growth into the surrounding liver. Atypical hepatocytes also infiltrated into the fibrous septa and portal tracts. Foci of overt hepatocellular carcinoma were found in 11 of the 53 atypical nodules. These findings suggest that ordinary adenomatous hyperplasia may be a large-sized regenerative nodule, while atypical adenomatous hyperplasia may be a hepatocellular neoplasm, a peculiar form of low-grade hepatocellular carcinoma or borderline lesion, in which overt hepatocellular carcinoma is likely to evolve through multiple steps.     

Stage–specific antigens of Hymenolepis microstoma recognized in BALB/c mice

Antigenicity of eggs (oncospheres), cysticercoids and adults (with immature segments only) of the bile duct tapeworm Hymenolepsis microstoma was analysed using immunoblotting techniques and indirect immunofluorescent antibody (IFA) techniques with immune sera of BALB/c mice (i) infected with different doses of cysticercoids, (ii) during patent or prepatent infection with the lumen phase of the parasite or (iii) sensitized with live or dead eggs. Antibody responses detected by IFA test and immunoblotting showed that antigenicity of eggs (oncospheres) differed from that of cysticercoids and adults. Single worm infections were sufficient to stimulate antibody responses. Mice which had patent infection showed strong antibody responses to all three (egg (oncosphere), cysticercoid, adult) antigens, while mice given two prepatent infections showed some antibody responses to cysticercoid and adult antigens only. Although the normal intermediate hosts of this parasite are arthropods, antibodies to some major egg (oncosphere) antigens were produced in mice given eggs of this parasite orally, either through inoculation of eggs or ingestion of faeces contaminated with eggs. Antibodies were not produced in mice dosed with non-viable eggs. The results are consistent with the hypothesis that cestode parasites express phase- (or stage-) specific antigens.     

Fast-Slow Type of Atrioventricular Nodal Reentrant Tachycardia: Horizontal Dissociation of the AV Node During Tachycardia

Two patients with recurrent supraventricular tachycardia are presented. The tachycardia was initiated and terminated by atrial extrastimulation beyond the atrial relative refractory period and the atrial activation sequence during the tachycardia was low to high. The induction of tachycardia was dependent on a critical AH interval. In patient 1 who had ventriculoatrial conduction, the tachycardia was initiated by the premature ventricular stimulation followed by double atrial response. In patient 2 the ventriculoatrial conduction was not observed. In both patients, the unchanged atrial cycle length during the tachycardia with antegrade Wenckebach AH block was observed. When AH block occurred during tachycardia the first AH interval was shorter than the subsequent HA interval. In patient 2 verapamil (5 mg) prolonged the atrial cycle length during tachycardia and rapid intravenous injection of adenosine triphosphate (10 mg) terminated the tachycardia. Oral diltiazem (280 mg/day) suppressed the tachycardia in patient 1. These findings suggest that the mechanism of tachycardia may be fast-slow type of AV nodal reentry in the upper portion of the AV node and this type of arrhythmia has tendency to show incessant form.