Cigarette smoking, CYP1A1 MspI and GSTM1 genotypes, and colorectal adenomas

Cigarette smoking has been related to increased risk of colorectal adenomas, but the underlying mechanisms are unknown. Genetic polymorphisms are known for enzymes involved in the activation of polycyclic aromatic hydrocarbons and other tobacco-related carcinogens. Polycyclic aromatic hydrocarbons are activated by cytochrome P4501A1 (CYP1A1) and detoxified by glutathione S-transferases. We investigated the relation of CYP1A1 MspI and GSTM1 genotypes to the risk of colorectal adenomas with special reference to interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in a male Japanese population. Cigarette smoking was strongly associated with increased risk of colorectal adenomas. Overall, neither the CYP1A1 MspI genotype nor the GSTM1 genotype was related to colorectal adenomas. A significant trend for increased risk of colorectal adenomas associated with smoking was observed for each of the CYP1A1 MspI genotypes, and the increasing trends did not differ by MspI genotype. The positive association between smoking and colorectal adenomas did not vary much with GSTM1 genotypes. Among former and current smokers, adenoma risk did not differ according to the combination of CYP1A1 MspI and GSTM1 genotypes. CYP1A1 MspI and GSTM1 genotypes do not seem to modify the risk of colorectal adenomas associated with cigarette smoking.     

Three-dimensional reconstruction of computed tomographic images of anomalous origin of the left main coronary artery from the pulmonary trunk in an adult

We present a 49-year-old female case of anomalous origin of the left main coronary artery from the pulmonary trunk. Multidetector computed tomography was performed, and 3-dimensional reconstruction of computed tomographic images found that the left main coronary artery originated from left sinus of the pulmonary trunk and the right coronary artery from the right coronary cusp of the aorta. We speculate that this patient's long life may be due to the dominant right coronary artery and rich collateral from the right coronary artery to the left coronary artery.     

Indications of total ankle arthroplasty for rheumatoid arthritis: evaluation at 5 years or more after the operation

 The postoperative results of total ankle arthroplasty (TAA) were surveyed, and the indications of TAA for rheumatoid arthritis (RA) were examined. We have performed TAA in properly selected patients with indication of ankle joint destruction due to RA. The subjects were 18 RA patients (20 joints) who underwent TAA between April 1988 and April 1996. Type-ND or type-TNK Bioceram was used without cement for possible revision of TAA. No destruction of large joints was found in 8 patients, and TAA was used as part of multiple arthroplasty in 10 patients. After the operation, decrease in or disappearance of joint pain was obtained, and range of motion and improved ability to walk were secured. The clinical results were superior to those obtained for 17 joints of 17 patients who underwent ankle arthrodesis during the same period. However, a radiolucent zone was observed an X-ray examination in every case, after 8 years on average (range 5–12 years) after operation. Under present conditions, ankle arthrodesis should be used for younger patients. When no destruction of the hip or knee joint is found and the patient is 65 years of age or older, we believe TAA is indicated. In cases of multiple arthroplasty or with bilateral ankle joint destruction, TAA appears to be useful if patients are young, considering their better life expectancy and quality of life. Received: April 30, 2002 / Accepted: August 26, 2002     

Cytokeratin 19 fragment in patients with nonmalignant respiratory diseases

STUDY OBJECTIVE: Cytokeratin 19 fragment (CYFRA) is a specific tumor marker in patients with lung cancer; however, it has been reported that serum CYFRA levels are elevated in some patients with nonmalignant respiratory diseases such as interstitial pulmonary fibrosis (IPF) and collagen disease-associated pulmonary fibrosis (CDPF). To investigate the serum CYFRA levels in nonmalignant respiratory diseases in detail, we studied 413 patients with respiratory diseases. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Four hundred thirteen patients with nonmalignant respiratory diseases and lung cancer. Measurements and results: Serum CYFRA levels were measured with a commercially available enzyme immunoassay kit. Immunohistochemical study was performed using monoclonal antibody Ks 19.1 (Rosch Diagnosica; Bern, Switzerland) on surgically resected or autopsied lung specimens. Gel electrophoresis and immunoblotting was performed with serum samples. In 149 patients with nonmalignant diseases except IPF and CDPF, the ratio of patients with > 3.5 ng/mL of serum CYFRA was 13.4%. In 13 of 30 patients (43.3%) with IPF and CDPF, the serum CYFRA levels were abnormally elevated. The 95th percentile serum CYFRA level of the patients with nonmalignant respiratory diseases was 6.2 ng/mL, and none of them had CYFRA levels > 20.3 ng/mL. Survival in patients with IPF and CDPF with elevated serum CYFRA levels were significantly lower than in those with normal range (p = 0.0335). Western blotting using serum from nonmalignant lung diseases and patients with lung cancer showed no apparent difference between them. An immunohistochemical study indicated CYFRA was selectively expressed in the pulmonary epithelial cells that covered the remodeling alveolar septi in nonmalignant respiratory disease. CONCLUSION: Serum CYFRA was elevated in some nonmalignant respiratory diseases, especially in IPF and CDPF. The value of serum CYFRA would reflect the severity of lung injury in nonmalignant respiratory diseases and might be related to the prognosis in patients with IPF and CDPF.     

A microRNA regulatory mechanism of osteoblast differentiation

Growing evidence shows that microRNAs (miRNAs) regulate various developmental and homeostatic events in vertebrates and invertebrates. Osteoblast differentiation is a key step in proper skeletal development and acquisition of bone mass; however, the physiological role of non-coding small RNAs, especially miRNAs, in osteoblast differentiation remains elusive. Here, through comprehensive analysis of miRNAs expression during osteoblast differentiation, we show that miR-206, previously viewed as a muscle-specific miRNA, is a key regulator of this process. miR-206 was expressed in osteoblasts, and its expression decreased over the course of osteoblast differentiation. Overexpression of miR-206 in osteoblasts inhibited their differentiation, and conversely, knockdown of miR-206 expression promoted osteoblast differentiation. In silico analysis and molecular experiments revealed connexin 43 (Cx43), a major gap junction protein in osteoblasts, as a target of miR-206, and restoration of Cx43 expression in miR-206-expressing osteoblasts rescued them from the inhibitory effect of miR-206 on osteoblast differentiation. Finally, transgenic mice expressing miR-206 in osteoblasts developed a low bone mass phenotype due to impaired osteoblast differentiation. Our data show that miRNA is a regulator of osteoblast differentiation.     

Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone

Osteoclastic bone resorption requires a number of complex steps that are under the control of local regulatory molecules. Osteopontin is expressed in osteoclasts and is also present in bone matrix; however, its biological function has not been fully understood. To elucidate the role of osteopontin in the process of osteoclastic bone resorption, we conducted ectopic bone implantation experiments using wild-type and osteopontin knockout mouse. In the wild-type group, bone discs from calvariae implanted ectopically in muscle were resorbed, and their mass was reduced by 25% within 4 weeks. In contrast, the mass of the bone discs from calvariae of osteopontin knockout mice was reduced by only 5% when implanted in osteopontin knockout mice. Histological analyses indicated that the number of osteoclasts associated with the implanted bones was reduced in the osteopontin knockout mice. As osteopontin deficiency does not suppress osteoclastogenesis per se, we further examined vascularization immunohistologically and found that the number of vessels containing CD31-positive endothelial cells around the bone discs implanted in muscle was reduced in the osteopontin knockout mice. Furthermore, sc implantation assays indicated that the length and branching points of the newly formed vasculatures associated with the bone discs were also reduced in the absence of osteopontin. In this assay, tartrate-resistant acid phosphatase-positive area of the bone discs was also reduced in the osteopontin knockout mice, indicating further the link between the osteopontin-dependent vascularization and osteoclast accumulation. The bone resorption defect could be rescued by topical administration of recombinant osteopontin to the bones implanted in muscle. These observations indicate that osteopontin is required for efficient vascularization by the hemangiogenic endothelial cells and subsequent osteoclastic resorption of bones.     

Short-Term and Long-Term Effects of Low-Density Lipoprotein (LDL) Apheresis on Restenosis after Percutaneous Transluminal Coronary Angioplasty (PTCA): Is Lowering Lp(a) by LDL Apheresis Effective on Restenosis after PTCA?

Abstract: It has been reported that serum lipoprotein(a) (Lp[a]) levels in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA) were significantly higher than in patients without restenosis. In this study, we evaluated the preventive effect of LDL apheresis on restenosis after PTCA in patients with hypercholesterolemia. For 10 patients who had shown a serum cholesterol level of more than 220 mg/dl despite treatment with antihypercholesterolemic drugs, LDL apheresis was conducted every 2 weeks after a successful PTCA until restenosis could be checked. In 4 patients, LDL apheresis was conducted for 2 years. LDL apheresis significantly reduced serum cholesterol from 248 ± 22 mg/dl to 135 ± 26 mg/dl and Lp(a) from 42 ± 34 mg/dl to 21 ± 16 mg/dl. The average degree of stenosis in the 11 lesions undergoing PTCA was 92 ± 6% before PTCA, 35 ± 10% immediately after PTCA, and 38 ± 19% at 3 to 4 months after PTCA. Restenosis was observed in only 1 lesion. In 4 patients who received LDL apheresis for 2 years, restenosis did not occur in any of the 4 lesions treated. We concluded that LDL apheresis was an efficacious therapy to prevent restenosis after PTCA in patients with hypercholesterolemia.     

Kampo Medicines for Mite Antigen-Induced Allergic Dermatitis in NC/Nga Mice

We have established an allergic dermatitis model in NC/Nga miceby repeated local exposure of mite antigen for analyzing atopicdermatitis. We examined how four Kampo medicines, Juzen-taiho-to,Hochu-ekki-to, Shofu-san and Oren-gedoku-to, on the dermatitismodel to obtain basic information on their usefulness for treatingatopic dermatitis. Mite antigen (Dermatophagoides farinae crudeextract) solution at a concentration of 10 mg/ml was paintedon the ear of NC/Nga mice after tape stripping. The procedurewas repeated five times, at 7 day intervals. An apparent biphasicear swelling was caused after the fourth and fifth antigen exposureswith elevated serum IgE levels and accumulation of inflammatorycells. In the cervical lymph nodes and ear lobes, the five proceduresof antigen exposure induced interleukin-4 mRNA expression butreduced interferon- mRNA expression. Oral administration ofall four Kampo medicines inhibited the formation of ear swellingand inflammatory cell accumulation. Juzen-taiho-to and Hochu-ekki-toapparently prevented the elevation of serum IgE level. Furthermore,the four Kampo medicines showed a tendency to prevent not onlythe increase in interleukin-4 mRNA expression but also the decreasein interferon- mRNA expression. The present results indicatethat Juzen-taiho-to, Hochu-ekki-to, Shofu-san and Oren-gedoku-tomay correct the Th1/Th2 balance skewed to Th2, and this activityhelps inhibit dermatitis in NC/Nga mice. The ability of theKampo medicines to correct the Th1/Th2 balance seems to underlietheir effectiveness in treating of atopic dermatitis.     

Monoclonal anti-human IgG antibodies for quantitation of allergen-specific IgG in human sera

Eight monoclonal anti-human IgG antibodies were fully characterized and evaluated as possible reagents in solid phase radioimmunoassay for quantitating allergen-specific IgG antibody. Four monoclonal antibodies (HG24D, HG2-14, HG2-18, and HG2-25) recognize CH2 domain of human IgG and bind to human IgG fixed to microtiter plate with high affinities. These monoclonal antibodies were more suitable than polyclonal rabbit anti-human IgG antibody in Phadebas RAST for honey bee venom-specific IgG antibody. Nonspecific binding was much lower, and the slopes of standard curves were much steeper. In contrast to polyclonal antibody, the standard curve was hardly influenced by human serum IgG in sample diluent. These advantages of monoclonal antibodies that recognize CH2 domain of human IgG made it possible to quantitate egg white- and Dermatophagoides pteronyssinus-specific IgG antibodies with use of allergen disks prepared for IgE RAST. This property allows a single system to be used for measurement of IgG and IgE antibodies against clinically relevant allergens.     

Effects of pravastatin on progression of glucose intolerance and cardiovascular remodeling in a type II diabetes model

OBJECTIVES: We examined the effects of early treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on the progression of glucose intolerance and cardiovascular remodeling in a model of spontaneously developing type II diabetes mellitus (DM), the Otsuka Long-Evans Tokushima Fatty (OLETF) rats. BACKGROUND: Clinical trials showed that pravastatin prevented new-onset DM in hypercholesterolemic patients, and that it was effective in prevention of cardiovascular events in diabetics. METHODS: The OLETF rats were treated with pravastatin (100 mg/kg/day) from 5 weeks of age and compared with age-matched untreated OLETF rats and normal Long-Evans Tokushima Otsuka (LETO) rats on serial oral glucose tolerance tests (OGTT) and Doppler echocardiography and on histopathological/biochemical analyses of the heart at 30 weeks. RESULTS: The OGTT revealed that 40% and 89% of untreated OLETF rats were diabetic at 20 and 30 weeks, respectively, but 0% and only 30%, respectively, were diabetic in the treated OLETF. Left ventricular diastolic function was found impaired from 20 weeks in untreated OLETF but remained normal in the treated-OLETF. The wall-to-lumen ratio and perivascular fibrosis of coronary arteries were increased in untreated-OLETF but were limited in the treated-OLETF at 30 weeks. Moreover, cardiac expressions of a fibrogenic growth factor, transforming growth factor-beta1 (TGF-beta1), and a proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), were increased in untreated-OLETF. However, in the treated-OLETF, overexpressions of TGF-beta1 and MCP-1 were attenuated, which was associated with overexpression of endothelial nitric oxide synthase (eNOS) (2.5-fold of control LETO). CONCLUSIONS: Early pravastatin treatment prevented cardiovascular remodeling in the spontaneous DM model by retarding the progression of glucose intolerance, overexpressing cardiac eNOS, and inhibiting overexpressions of fibrogenic/proinflammatory cytokines.