Suppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the high-affinity antibody response in C57BL/6 mice.

In the humoral immune response to an invasion of foreign antigens, B cells differentiate into low-affinity antibody-forming cells (AFCs) that mainly secrete IgM or, through germinal center (GC) formation, into high-affinity AFCs that secrete IgG-class antibodies with a higher affinity for the antigen. Previous studies have established the suppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on low-affinity antibody responses to antigens. However, whether and how TCDD affects the high-affinity antibody response to antigens has not yet been clarified. In this paper we investigate the effects of TCDD on GC formation, high-affinity AFC generation, and high-affinity antibody production in the primary humoral immune response. C57BL/6 mice were orally administered 0 or 20 microg/kg of TCDD and subsequently immunized with alum-precipitated ovalbumin (OVA) on day 0. Then the GC formation in the spleen and OVA-specific antibodies in the plasma, was evaluated until day 14 postimmunization. TCDD exposure reduced the production of OVA-specific IgG1 on days 10 and 14. GC formation in the spleen was also suppressed by TCDD exposure, and the suppression persisted from day 7 until day 14. In TCDD-administered mice, on day 7, cellular proliferation in the GCs was significantly suppressed, although apoptosis was not markedly affected. In order to measure high-affinity antibody and high-affinity AFCs, the mice were administered TCDD followed by immunization with alum-precipitated (4-hydroxy-3-nitrophenyl) acetyl linked to chicken gamma-globulin (NP-CG). The frequency of high-affinity NP-specific AFCs that bind to low-haptenated antigen was clearly shown to be reduced in the spleen on days 10 and 14. Furthermore, the high-affinity anti-NP IgG1 levels on days 10 and 14 postimmunization were significantly reduced by TCDD exposure. Taken together, the results of this paper demonstrate that TCDD exposure inhibits the generation of high-affinity AFCs and high-affinity antibody production during the primary humoral immune response and suggest that these alterations were caused by the suppression of antigen-responding B-cell proliferation induced by TCDD during GC formation.     

Calcaneus Bone Mineral Density is Lower Among Men and Women with Lower Physical Performance

Fracture risk is influenced by both bone strength and by falls. Measures of physical function and performance are predictors of falls. However, the interrelationships among bone mineral density (BMD), regular physical activity, and measures of physical performance are not well known. We studied 447 community-dwelling Japanese people aged 40 years and over (96 men and 351 women) to examine the association of calcaneus BMD with measures of physical performance (grip strength, walking speed, chair stand, and functional reach) and regular physical activity. Calcaneus BMD decreased with age by approximately 25% in men and 42% in women. Measures of physical performance decreased with age by approximately 30% in both genders, however, performance on the chair stand test declined by approximately 60%. There were only minimal differences in performance measures and calcaneus BMD between people with and those without regular physical activity in both genders, and most differences were not significant. However, there were significant BMD increases of 3–6% per standard deviation (SD) increase in all performance measures for women and a 7% increase in BMD per SD increase in grip strength for men, after adjusting for age. These associations remained after additional adjustment for body mass index and regular physical activity. These findings suggest that bone density and physical function decline markedly in both men and women with age, and that low BMD and poor function tend to occur together, which would increase fracture risk more than either risk factor alone. Received: 9 August 1999 / Accepted: 4 February 2000     

Domino liver transplantation from a living related donor

BACKGROUND: Although domino liver transplantations (OLT) from cadaveric donors have been performed in about 50 cases since 1995, only one case in the Japanese literature has been reported on a domino OLT from a living related donor. The difficulties of the later surgery lie in the small size of the graft volume and the short length of the vascular cuffs in the graft. METHODS: The left lobe graft was procured from a 43-year-old younger brother of a familial amyloidotic polyneuropathy (FAP) patient. Next, the left lobe graft (510 g, 44% of the estimated standard liver volume of the FAP patient) was implanted into the 48-year-old female FAP patient. At surgery for the FAP patient, a sufficient length of the vascular cuffs was secured by an extended left lobe resection, although the right lobe graft was able to maintain sufficient vascular cuffs. The right lobe graft (720 g, 54% of the recipient's estimated standard liver volume) was then implanted in the 43-year-old male patient with liver cirrhosis and hepatocellular carcinoma (stage IV-A). RESULTS: The two recipients were discharged from the hospital 1 month after OLT. At 7 months after OLT, they are both doing well and the domino recipient is free of any tumor recurrence. CONCLUSION: A domino OLT from the living related donor can therefore be done safely when careful attention is paid to the graft volume and the length of the vascular cuffs for anastomosis.     

Effects of transfusion on gastrointestinal anastomotic wound healing and leukocyte function in rats

BACKGROUND: This study was done to investigate the effects of blood transfusion on gastrointestinal anastomotic wound healing and leukocyte function. METHODS: Closed-colony male Wistar rats were divided into five groups in a group-mixed fashion and underwent laparotomy (the CONT and WB groups) or gastrectomy and gastroduodenostomy (the GAST, GAST/WB and GAST/LDRWB groups). Immediately, they received 3 ml of saline (the CONT and GAST groups) or blood from Wistar donors (the WB and GAST/WB groups, whole blood; the GAST/LDRWB group, a transfusion of irradiated and leukocyte-depleted whole blood). The animals were killed 7 days after surgery. RESULTS: The GAST/WB group had a higher incidence of anastomotic abscess, a lower level of factor XIII and a lower maximum breaking strength than the GAST group. Gastrectomy decreased L-DCL (luminol-dependent chemiluminescence) more than whole-blood transfusion. In the GAST/WB group, L-DCL was severely reduced, while in the GAST/LDRWB group it was roughly equivalent to the level in the GAST group. CONCLUSIONS: Whole-blood transfusion increased the incidence of anastomotic abscess and impaired anastomotic wound healing, and these might relate to the reduction of L-DCL. Irradiated and leukocyte-depleted transfusion can improve these effects.     

Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-alpha to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-alpha treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.     

TH1/TH2 and regulatory cytokines in adults with otitis media with effusion.

OBJECTIVE: Otitis media with effusion is one of the most common and intractable ear diseases. However, the role of Th1, Th2, and immunoregulatory cytokines on the pathogenesis of the disease in adult patients remains to be determined. The aim of this study is to disclose the cytokine expression in middle ear effusions (MEEs) in adults and to compare the profile on the basis of the presence of allergic rhinitis and the type of effusions. STUDY DESIGN: A prospective controlled clinical study. PATIENTS: MEEs were collected from 80 adult subjects. The concentration of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, and interferon (IFN)-gamma in MEEs were determined by using enzyme-linked immunosorbent assay. RESULTS: IL-2, IL-4, IL-5, IL-10, IL-12, and IFN-gamma in MEEs were detected in 60 (75.0%), 33 (41.3%), 42 (52.5%), 14 (17.5%), 80 (100%), and 66 (82.5%) samples, respectively. Among these cytokines, only the concentration of IL-4 in the allergic rhinitis-positive group was significantly higher than that in the allergic rhinitis-negative group. On the other hand, IL-2, IL-12, and IFN-gamma were detected, regardless of the presence of allergic rhinitis, and the concentration of these cytokines correlated with each other. The correlation between the concentration of IL-4 and IL-5 was also detected. In addition, both the incidence rate and the concentration of IL-10 in MEEs were significantly higher in the mucoid type compared with those in the serous type effusions. CONCLUSION: Regardless of allergic status, IL-12 may play a critical role in the pathogenesis of otitis media with effusion by affecting the production of IL-2 and IFN-gamma. In addition, IL-4 may have some impact on the immunologic condition in adults with allergic rhinitis. IL-10 potentially affects the viscosity of MEEs.     

Property of thimerosal-induced decrease in cellular content of glutathione in rat thymocytes: a flow cytometric study with 5-chloromethylfluorescein diacetate.

There is a concern on the part of public health community that adverse health consequences by thimerosal, a preservative in vaccines for infants, may occur among infants during immunization schedule. Therefore, the effect of thimerosal on cellular content of glutathione was examined on thymocytes obtained from 4-week-old rats using a flow cytometer and 5-chloromethylfluorescein diacetate. Thimerosal at concentrations ranging from 1 to 10 microM reduced the cellular content of glutathione in a concentration-dependent manner, and the complete depletion of cellular glutathione was observed when the cells were treated with 30 microM thimerosal. L-Cysteine significantly attenuated the actions of thimerosal to reduce the glutathione content and to increase the intracellular Ca2+ concentration. Prolonged incubation (24 h) with 1-3 microM thimerosal induced the apoptosis. The cytotoxic action of thimerosal was greatly augmented when the cells suffered oxidative stress induced by H2O2. It may be unlikely that thimerosal exerts potent cytotoxic action under the in vivo condition because the blood concentration of thimerosal after receiving vaccines does not seem to reach micromolar range and nonprotein thiols at micromolar concentrations are present in the blood.     

Atypical Shone's Complex Diagnosed at 70 Years Old: Presenting with Double-orifice Mitral Valve,Bicuspid Aortic Valve,and Aortic Coarctation

Atypical Shone''s complex is a rare congenital anomaly involving a left-sided obstructive lesion of two or three cardiovascular levels. A 70-year-old man with dyspnea on exertion was diagnosed with severe aortic stenosis (AS) with a bicuspid valve, complicated by severe aortic coarctation (CoA) and a double-orifice mitral valve. He underwent surgery for AS and CoA in one session. It is important to search for complicated malformations, even in cases of bicuspid aortic valve found in old age.     

Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation

Aims: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. Methods: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using¹⁸fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day,n=16) for 12weeks.¹⁸F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function. Results: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%).¹⁸F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of¹⁸F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery. Conclusions: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.