bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron Overload Is Associated with Hepatic Oxidative Damage to DNA in Nonalcoholic Steatohepatitis
Authors: Fujita Naoki , Miyachi Hirohide , Tanaka Hideaki , Takeo Masaki , Nakagawa Naoki , Kobayashi Yoshinao , Iwasa Motoh , Watanabe Shozo , Takei Yoshiyuki
Published: February 2009

Several lines of evidence have suggested that oxidative stress plays an important role for the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, by using immunohistochemical staining of liver biopsy samples, we measured hepatic 7,8-dihydro-8-oxo-2′ deoxyguanosine (8-oxodG), a DNA base-modified product generated by hydroxyl radicals, of 38 NASH patients and compared with 24 simple steatosis and 10 healthy subjects. Relation of hepatic 8-oxodG with clinical, biochemical, and histologic variables and changes after iron reduction therapy (phlebotomy plus iron–restricted diet) were also examined. Hepatic 8-oxodG levels were significantly higher in NASH compared with simple steatosis (17.5 versus 2.0 8-oxodG–positive cells/105 μm2; P < 0.0001). 8-oxodG was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients. Logistic regression analysis also showed that hepatic iron deposit and insulin resistance were independent variables associated with elevated hepatic 8-oxodG. After the iron reduction therapy, hepatic 8-oxodG levels were significantly decreased (from 20.7 to 13.8 positive cells/105 μm2; P < 0.01) with concomitant reductions of serum transaminase levels in NASH patients. In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH. (Cancer Epidemiol Biomarkers Prev 2009;18(2):424–32)
Dietary Intake of ω-6 and ω-3 Fatty Acids and Risk of Colorectal Cancer in a Prospective Cohort of U.S. Men and Women
Authors: Daniel Carrie R. , McCullough Marjorie L. , Patel Roshni C. , Jacobs Eric J. , Flanders William D. , Thun Michael J. , Calle Eugenia E.
Published: February 2009

Background: ω-6 and ω-3 polyunsaturated fatty acids intakes may play opposing roles in inflammation-driven colorectal carcinogenesis. We examined the relationship of these polyunsaturated fatty acids and the ratio of their intake with colorectal cancer risk in a large U.S. prospective cohort.

Design: Participants in the Cancer Prevention Study-II Nutrition Cohort completed a detailed questionnaire on diet, medical history, and lifestyle in 1999. Between 1999 and 2005, 869 incident colorectal cancer cases (452 men and 417 women) were identified among 99,080 participants (43,108 men and 55,972 women). Multivariate-adjusted rate ratios were calculated using Cox proportional hazards models.

Results: The ratio of total ω-6 to total ω-3 intake was not associated with colorectal cancer risk in either sex. Contrary to our initial hypothesis, total ω-6 intake was inversely related to colorectal cancer risk in men [multivariate relative risk (95% confidence interval) for highest to lowest quartile, 0.81 (0.61-1.07); Ptrend = 0.07], and α-linolenic acid, the primary contributor to total ω-3 intake, was associated with increased risk in women for quartiles 2 through 4 versus the lowest quartile [relative risk (95% confidence interval), 1.50 (1.12-2.01), 1.40 (1.04-1.87), and 1.38 (1.02-1.85), respectively; Ptrend = 0.13]. In women, total ω-6 and marine ω-3 intake appeared to be associated with higher and lower risk, respectively, but associations were attenuated with adjustment for other risk factors.

Conclusions: The ratio of ω-6 to ω-3 intake was not related to colorectal cancer risk in this cohort, which may be due to unexpected findings for the individual components. Differential associations by sex warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(2):516–25)
Health Risk Appraisal Models for Mass Screening for Esophageal and Pharyngeal Cancer: An Endoscopic Follow-up Study of Cancer-Free Japanese Men
Authors: Yokoyama Akira , Kumagai Yoshiya , Yokoyama Tetsuji , Omori Tai , Kato Hoichi , Igaki Hiroyasu , Tsujinaka Toshimasa , Muto Manabu , Yokoyama Masako , Watanabe Hiroshi
Published: February 2009

Purpose: To assess the performance of our health risk appraisal (HRA) models for screening individuals at high risk of esophageal/pharyngeal squamous cell carcinoma (EPSCC).

Methods: Based on the results of our previous case-control study, we invented HRA models that enable screening for EPSCC cases in Japanese men with high sensitivity and specificity based on either their aldehyde dehydrogenase-2 genotype (HRA-G model) or alcohol flushing (HRA-F model) and drinking, smoking, and dietary habits. Follow-up endoscopy combined with esophageal iodine staining (median follow-up period: 5.0 years) was done on 404 Japanese men (50-78 years) who were registered as cancer-free controls in the previous study.

Results: The follow-up endoscopy resulted in a diagnosis of 6 esophageal SCC (Tis in 5 and T1 in 1), 1 hypopharyngeal SCC (T2), and 1 oropharyngeal SCC (T2). Seven and 6 of the 8 EPSCC cases were in the top 10% risk group at baseline according to the HRA-G and HRA-F models, respectively. The EPSCC detection rates per 100 person-years in the top 10% risk groups by the HRA-G and HRA-F models were 4.38 (95% confidence interval, 1.76-9.01) and 3.48 (95% confidence interval, 1.28-7.58), respectively. Their age-adjusted relative risk was 95.1- and 26.3-fold, respectively (P < 0.0001), higher than in the bottom 90% risk groups.

Conclusions: The high detection rates for EPSCC in the top 10% risk group of this preliminary follow-up study were in good agreement with those predicted by the HRA models and thus encouraged the screening based on our HRA models in larger populations of Japanese men. (Cancer Epidemiol Biomarkers Prev 2009;18(2):651–5)
Antacid Drug Use and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County
Authors: Duan Lei , Wu Anna H. , Sullivan-Halley Jane , Bernstein Leslie
Published: February 2009

Objectives: Concern has been expressed that antacid drugs increase the risk of esophageal and gastric adenocarcinomas.

Methods: This population-based case-control study recruited patients with incident esophageal adenocarcinoma (n = 220), gastric cardiac adenocarcinoma (n = 277), or distal gastric adenocarcinoma (n = 441) diagnosed between 1992 and 1997, and 1,356 control participants in Los Angeles County. Unconditional polychotomous multivariable logistic regression analyses were done to evaluate the association between antacid drug use and these cancers.

Results: Among participants who took nonprescription acid neutralizing agents for >3 years, the odds ratio for esophageal adenocarcinoma was 6.32 compared with never users (95% confidence interval, 3.14-12.69; Ptrend < 0.01). Analyses stratified by history of physician diagnosed upper gastrointestinal (UGI) disorders revealed a greater increase in esophageal adenocarcinoma risk associated with nonprescription antacid use among persons with no UGI disorder than among those with an UGI disorder (homogeneity of trends P = 0.07). Regular use of nonprescription acid neutralizing agents was not associated with risk of adenocarcinomas of the gastric cardia or distal stomach. Regular use of prescription acid suppressive drugs was not associated with risk for any of these cancers.

Conclusion: We found risk of esophageal adenocarcinoma was greater among long-term nonprescription acid neutralizing drugs in participants without physician-diagnosed UGI conditions than among those with these conditions; this may represent self medication for undiagnosed precursor conditions or it may be that nonprescription acid neutralizing drugs, taken without limitation on amount used when symptoms are most intense, may permit alkaline bile reflux into the lower esophagus, thereby increasing esophageal adenocarcinoma risk. (Cancer Epidemiol Biomarkers Prev 2009;18(2):526–33)
Aberrant Cytoplasmic Expression of p63 and Prostate Cancer Mortality
Authors: Dhillon Preet K. , Barry Marc , Stampfer Meir J. , Perner Sven , Fiorentino Michelangelo , Fornari Alessandro , Ma Jing , Fleet Julia , Kurth Tobias , Rubin Mark A. , Mucci Lorelei A.
Published: February 2009

Protein expression of p63 is used to differentiate prostate cancer from benign mimickers. Recent studies suggest that it may also distinguish aggressive prostate cancer with down-regulated expression occurring in men with more advanced disease. We conducted a prospective study among 298 men ages 51 to 84 years who were diagnosed with prostate cancer in the Physicians' Health Study in 1983 to 2004 and whose tissue was available for immunohistochemical staining. We used Cox proportional hazards regression to evaluate the association of p63 protein expression with fatal prostate cancer. We correlated p63 expression with tumor cell proliferation (Ki-67) and apoptosis (TUNEL staining). The predominant location of tumor p63 staining occurred in the cytoplasm, an uncommon departure from the strong nuclear staining usually observed in nonneoplastic basal cells. Increasing expression of cytoplasmic p63 (tertiles) was associated with prostate cancer mortality (n = 19 deaths); the hazard ratios (95% confidence intervals) were 1.0 (reference), 4.0 (0.9-18.9), and 5.9 (1.3-27.5; Ptrend = 0.03). The positive trend remained significant (P = 0.047) after multivariable adjustment for age, year of diagnosis, and Gleason score. Higher tertiles of cytoplasmic p63 were also associated with reduced levels of apoptosis (Ptrend = 0.0408) and increased cellular proliferation (Ptrend = 0.0026). We found aberrant expression of p63 in the cytoplasm to be associated with increased prostate cancer-specific mortality up to 20 years after diagnosis. The mislocalized expression was associated with reduced apoptosis and higher proliferative activity and may suggest an oncogenic role in prostate cancer progression and survival. (Cancer Epidemiol Biomarkers Prev 2009;18(2):595–600)
Association of Thymidylate Synthase Gene with Endometrial Cancer Risk in a Chinese Population
Authors: Xu Wang-Hong , Long Ji-Rong , Zheng Wei , Ruan Zhi-Xian , Cai Qiuyin , Cheng Jia-Rong , Zhao Gen-Ming , Xiang Yong-Bing , Shu Xiao-Ou
Published: February 2009

We comprehensively evaluated genetic variants in the thymidylate synthase (TYMS) gene in association with endometrial cancer risk in a population-based case-control study of 1,199 incident endometrial cancer cases and 1,212 age frequency-matched population controls. Exposure information was obtained via in-person interview, and DNA samples (blood or buccal cell) were collected. Genotyping of 11 haplotype-tagging single nucleotide polymorphisms (SNP) for the TYMS gene plus the 5-kb flanking regions was done for 1,028 cases and 1,003 controls by using the Affymetrix MegAllele Targeted Genotyping System. Of 11 haplotype-tagging SNPs identified, 7 that are located in flanking regions of the TYMS gene are also in the ENOSF1 (rTS) gene. The SNP rs3819102, located in the 3′-flanking region of the TYMS gene and in an intron of the ENOSF1 gene, was associated with risk of endometrial cancer. The odds ratio (95% confidence interval) for the CC genotype was 1.5 (1.0-2.2) compared with the TT genotype. Haplotype TTG in block 2 of the TYMS gene, which includes SNPs rs10502289, rs2298583, and rs2298581 (located in introns of the ENOSF1 gene), was associated with a marginally significant decrease in risk of endometrial cancer under the dominant model (odds ratio, 0.8; 95% confidence interval, 0.6-1.0). This study suggests that genetic polymorphisms in the TYMS or ENOSF1 genes may play a role in the development of endometrial cancer among Chinese women. (Cancer Epidemiol Biomarkers Prev 2009;18(2):579–84)
Staphylococcus aureusand Squamous Cell Carcinoma of the Skin
Authors: Kullander Johanna , Forslund Ola , Dillner Joakim
Published: February 2009

Squamous cell carcinoma (SCC) of the skin is a tumor with greatly increased incidence among immunosuppressed patients; therefore, an infectious cause of SCC has long been sought. We performed a hospital-based case-control study of Staphylococcus aureus and biopsies of SCC (n = 82), basal cell carcinoma (n = 142), actinic keratosis (n = 57), and seborrhoeic keratosis (n = 72) in comparison with biopsies from healthy skin of these 353 immunocompetent patients. In a S. aureus-specific PCR, targeting the nuc gene, presence of S. aureus DNA was strongly associated with SCC (29.3% positive specimens; adjusted odds ratio, 6.23; 95% confidence interval, 3.10-12.53) compared with healthy skin (5.7% positive specimens). There was also a tendency for association of S. aureus with actinic keratosis, but no association was found for basal cell carcinoma or seborrhoeic keratosis. Analysis using cotton swab samples taken on top of the lesions and from healthy skin gave similar results (adjusted odds ratio for SCC compared with healthy skin, 2.67; 95% confidence interval, 1.47-4.83). In conclusion, there is a strong association between SCC and presence of S. aureus. The study design used cannot determine whether the association implies that presence of S. aureus might influence carcinogenesis or whether it may imply that SCC has an increased susceptibility to S. aureus colonization. (Cancer Epidemiol Biomarkers Prev 2009;18(2):472–8)
Bladder Cancer–Associated Gene Expression Signatures Identified by Profiling of Exfoliated Urothelia
Authors: Rosser Charles J. , Liu Li , Sun Yijun , Villicana Patrick , McCullers Molly , Porvasnik Stacy , Young Paul R. , Parker Alexander S. , Goodison Steve
Published: February 2009

Bladder cancer is the fifth most commonly diagnosed malignancy in the United States and one of the most prevalent worldwide. It harbors a probability of recurrence of >50%; thus, rigorous, long-term surveillance of patients is advocated. Flexible cystoscopy coupled with voided urine cytology is the primary diagnostic approach, but cystoscopy is an uncomfortable, invasive procedure and the sensitivity of voided urine cytology is poor in all but high-grade tumors. Thus, improvements in noninvasive urinalysis assessment strategies would benefit patients. We applied gene expression microarray analysis to exfoliated urothelia recovered from bladder washes obtained prospectively from 46 patients with subsequently confirmed presence or absence of bladder cancer. Data from microarrays containing 56,000 targets was subjected to a panel of statistical analyses to identify bladder cancer-associated gene signatures. Hierarchical clustering and supervised learning algorithms were used to classify samples on the basis of tumor burden. A differentially expressed geneset of 319 gene probes was associated with the presence of bladder cancer (P < 0.01), and visualization of protein interaction networks revealed vascular endothelial growth factor and angiotensinogen as pivotal factors in tumor cells. Supervised machine learning and a cross-validation approach were used to build a 14-gene molecular classifier that was able to classify patients with and without bladder cancer with an overall accuracy of 76%. Our results show that it is possible to achieve the detection of bladder cancer using molecular signatures present in exfoliated tumor urothelia. Further investigation and validation of the cancer-associated profiles may reveal important biomarkers for the noninvasive detection and surveillance of bladder cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):444–53)
Neuroimmunoendocrine Modulation in the Host by Helminth Parasites: A Novel Form of Host-Parasite Coevolution?
Authors: Escobedo Galileo , López-Griego Lorena , Morales-Montor Jorge
Published: February 2009

Helminth parasites have evolved diverse molecular mechanisms that facilitate their establishment, growth and reproduction inside an immunologically hostile environment. Thus, the physiological interactions during the course of the immune response to helminths are complex. Infection induces antigen-specific recognition by the immune system, which is consequently charged with the responsibility of marshalling the appropriate effector responses necessary to destroy the parasite, or at the very least inhibit its progression. Obviously, the immune system should accomplish this task while minimizing collateral damage to the host. As our understanding of the neuroendocrine system grows, it has become increasingly clear that this complex network of neurotransmitters, hormones, and cytokines plays an important role in mediating immunity. Helminths present an especially complex relationship between pathogen and these physiological systems, with hormonally dependent host factors such as sex and age correlated with parasite success. On top of the effect that this particular type of parasites may have on the invaded host, recent experimental evidence suggests that helminth parasites not only actively evade immune response, but are also able to exploit the hormonal microenvironment within their host to favor their establishment, growth and reproduction. This complex strategy of host-parasite relationship is much better exemplified by two helminth parasites: the trematode Schistosoma mansoni andthe cestode Taenia crassiceps that respond to adrenal steroids and sexual steroids, respectively. Understanding how the host endocrine system can under certain circumstances favor the establishment of a parasitic infection opens interesting perspectives into the host-parasite relationship field.
Predictive Models in Colorectal Liver Metastases – Can We Personalize Treatment and Outcome?
Authors: Welsh Fenella K.S. , Tekkis Paris P. , John Timothy G. , Rees Myrddin
Published: February 2009

Background/Aims: Hepatic resection for colorectal liver metastases offers patients the best chance of long-term survival. Survival rates after resection range from 25 to 60%. Predictive models may risk-stratify patients and allow improved selection for surgery or other therapies. This review aims to achieve consensus regarding the predictors of survival after hepatic resection for colorectal metastases and evaluate current predictive models of outcome. Methods: A comprehensive literature review of published studies with more than 500 patients describing models for predicting long-term survival in patients undergoing hepatic resection for colorectal metastases. Results: Five large predictive models have been published to date. The three predictive models developed from the largest series agree over the key independent predictors of poor long-term outcome for patients undergoing liver resection for colorectal metastases. All five models have individual shortcomings, and whilst three have been internally validated, two have been externally validated with conflicting results. The Basingstoke Predictive Index appears to be accurate and internally validated. Conclusions: There is need within the international surgical oncology community for consensus regarding a predictive model to be universally adopted for risk-stratifying patients who may benefit from intensive surveillance and selection for adjuvant therapy and clinical trials.
Resection of Colorectal Liver Metastases with Extrahepatic Disease
Authors: de Haas Robbert J. , Wicherts Dennis A. , Adam René
Published: February 2009

Extrahepatic disease in combination with colorectal liver metastases has long been considered an absolute contraindication for surgery. However, in many reported series, long-term survival is achieved in selected patients with concomitant extrahepatic disease as long as the resection of all metastatic sites is complete. Owing to these results, an increasing number of patients with advanced metastatic colorectal disease are now being referred for surgery. For patients with concomitant liver and lung metastases, sequential resection of both disease sites has proven to be safe, offering a 5-year survival rate of more than 30%. On the contrary, hepatectomy combined with resection of regional lymph node metastases can only provide long-term survival in case of pedicular lymph node involvement. Furthermore, control of the disease by preoperative chemotherapy appears to be crucial. For peritoneal carcinomatosis, aggressive treatment combining cytoreductive surgery and intraperitoneal chemotherapy can offer a chance of prolonged long-term survival to selected patients with limited peritoneal extension. In conclusion, resection of both intra- and extrahepatic colorectal metastases should be considered if resection of all metastatic sites can be complete and the disease is controlled by chemotherapy. Long-term survival in these patients with advanced disease could be achieved if they are managed by experienced multidisciplinary teams.
Resection of Primary Pancreatic Cancer and Liver Metastasis: A Systematic Review
Authors: Michalski Christoph W. , Erkan Mert , Hüser Norbert , Müller Michael W. , Hartel Mark , Friess Helmut , Kleeff Jörg
Published: February 2009

Resection of liver metastases for locally resectable pancreatic cancer has rarely been performed. Recently, promising results regarding morbidity and mortality as well as long-term survival have been shown. Thus, we conducted a systematic review of the literature on pancreatic cancer resection with associated liver metastasis resection. There are 3 case reports and 18 studies including less than 10 patients. Only three studies are larger series with 10 or more patients in whom pancreatic resections and hepatic metastasectomies were performed. Here, morbidity and mortality ranged from 24.1 to 26% and from 0 to 4.3%, respectively. Median survival was reported to be between 5.8 and 11.4 months. In total, all identified studies included 103 patients in whom a metastasis resection was performed. Liver metastasis resection for locally resectable pancreatic cancer can be performed in selected cases with low morbidity and mortality. Overall survival in cases with one or few liver metastases which are concomitantly resected seems to be comparable to cases without evidence of metastasis. Therefore, randomized controlled clinical trials will have to be initiated to determine the value of such resections and to identify factors which will allow for selection of patients in whom the extension of the resectability criteria might confer a survival benefit.
Pharmacogenetics in Europe: Barriers and Opportunities
Authors: Gurwitz D. , Zika E. , Hopkins M.M. , Gaisser S. , Ibarreta D.
Published: February 2009

This paper reviews the current situation in the field of pharmacogenetics/pharmacogenomics (PGx) in Europe. High expectations surrounding the clinical application of PGx remain largely unmet, as only a limited number of such applications have actually reached the market and clinical practice. Thus, the potential impact of PGx-based diagnostics on healthcare and its socio-economic implications are still unclear. With the aim of shedding some light on these uncertainties, the Institute for Prospective Technological Studies (IPTS) of the European Commission’s Joint Research Centre (JRC) has conducted a review of the ‘state of the art’ and a further analysis on the use of pharmacogenetics diagnostics for preventing toxic drug reactions and improving drug efficacy in Europe. The paper presents highlights from the JRC-IPTS studies and discusses possibilities for improving translation of PGx research in Europe by comparing some experiences in the USA. We also illustrate the related barriers for the clinical uptake of PGx in Europe with specific case-studies. Most of the barriers identified extend beyond the European context. This reflects the global problems of scarcity of data demonstrating proven clinical validity or utility and favorable cost-effectiveness studies to support the clinical application of PGx diagnostic tests in the clinical setting. Another key barrier is the lack of incentives for the private sector to invest in the development and licensing of PGx diagnostic tests for improving the safety and efficacy of out-of-patent drugs. It therefore seems that one key aspect where policy can affect the clinical uptake of PGx is via sustaining large-scale industry-academia collaborations for developing and proving the utility of PGx diagnostics.
Pharmacogenomics, Evidence, and the Role of Payers
Authors: Deverka P.A.
Published: February 2009

Initial enthusiasm for the potential of pharmacogenomics (PGx) to transform medical practice has been tempered by the reality that the process of biomarker discovery, validation, and clinical qualification has been disappointingly slow, with a limited number of PGx tests entering the marketplace since the initial publication of the human genome sequence. Reasons for the delays include the complexity of the underlying science as well as clinical, economic, and organizational barriers to the effective delivery of personalized health care. Nevertheless, payers are interested in using PGx services to ensure that drug use is safer and more effective, particularly in the settings of medications that are widely used, have significant risks of serious adverse events, have poor or highly variable drug response, or are very expensive. However, public and private payers have specific evidence requirements for new health care technologies that must be met prior to obtaining favorable coverage and reimbursement status. These evaluation criteria are frequently more rigorous than the current level of evidence required for regulatory approval of new PGx tests or PGx-related drug labeling. To support payer decision-making, researchers will need to measure the impact of PGx testing on clinical and economic outcomes and demonstrate the net benefit of PGx testing as compared to usual care. By linking payer information needs with the current PGx research agenda, there is the opportunity to develop the data required for informed decision-making. This strategy will increase the likelihood that PGx services will be both reimbursed and used appropriately in clinical practice.
The Disruptive Nature of Personalized Medicine Technologies: Implications for the Health Care System
Authors: Carlson R.J.
Published: February 2009

Genomics technologies, notwithstanding rising complexity and low productivity to date, once translated to clinical care, promise significantly improved outcomes through cost-effective interventions and prevention. But, along the way, every business model and every stakeholder group will be challenged to adapt to the disruptions that will arise as our health care system seeks to embrace those technologies. This paper identifies many of the key issues and stakeholders to be directly effected, including payers, providers, and suppliers. An even greater challenge faces public policy makers if these technologies are to be optimized. Many of these issues are raised as well. Finally, the point is made that the greatest barriers are not necessarily raised by stakeholders but rather arise from the deepening complexity of the science itself, requiring a long-term, large, and consistent research commitment from both the public and private sectors – a commitment made harder by the indisputable need to reform the current health care system.
Promoter Polymorphism in the MS4A2 Gene and Asthma in the Indian Population
Authors: Sharma Shilpy , Ghosh Balaram
Published: February 2009

Background: A previous study from our laboratory identified 3-locus risk and protective haplotypes of the MS4A2 gene, a prime candidate for asthma and atopy, that were associated with differential histamine release profiles from basophils and FcεRIβ transcript levels in the Indian population. Methods: To explore the role of promoter polymorphisms in the observed association, 4 additional promoter polymorphisms (–752C/T, –654C/T, –426T/C and –109T/C) were investigated in 240 nuclear families with atopic asthma, 237 atopic asthmatics and 221 unrelated controls, all of whom were clinically well characterized. The β-subunit transcript levels were measured for 15 individuals and were correlated with the associated promoter polymorphisms. Results: We observed a significant association of the –752C/T and –109T/C polymorphisms with asthma, in addition to the already reported association for the INT2 G/A, intron 5 (CA)n and 3′-UTR C/T polymorphisms. Additionally, the allele T of the –109T/C polymorphism was associated with a reduced risk of asthma and lower percent peripheral blood eosinophils, thereby pointing towards a protective role for this allele in asthma. Further, the 7-locus haplotypes C_C_T_C_A_16_C and T_C_T_T_G_18_T were identified as the major risk/susceptibility and protective haplotypes, respectively (p < 0.05). Three-locus sliding-window haplotype analysis also identified the –426T/C, –109T/C and INT2 G/A polymorphisms to be in regions of high priority (p < 0.00001). Indeed, the –109T allele was found to be associated with reduced expression levels for FcεRIβ. Conclusions: A promoter-dependent mechanism with altered transcriptional regulation of FcεRIβ may be involved for its association with asthma. These results, therefore, could be useful in predicting the genetic susceptibility of individuals for developing asthma.
Re-Treatment with Omalizumab at One Year Interval for Japanese Cedar Pollen-Induced Seasonal Allergic Rhinitis Is Effective and Well Tolerated
Authors: Ogino Satoshi , Nagakura Toshikazu , Okubo Kimihiro , Sato Norio , Takahashi Masao , Ishikawa Takeru
Published: February 2009

Background: Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollens is a serious problem in Japan. Omalizumab, a humanized monoclonal anti-IgE antibody, improves symptoms associated with SAR, but a study comprehensively investigating the clinical efficacy, safety and pharmacological effects of omalizumab re-treatment has not yet been conducted. Methods: The open-label, 12-week study was carried out in 34 patients who had been treated with omalizumab in the core study conducted in the previous Japanese cedar pollen season. The study plan including study period, efficacy and safety endpoints, as well as dose regimen, was designed to be the same as in the core study. Omalizumab was administered subcutaneously every 2 or 4 weeks based on the serum IgE level and body weight of each patient. Results: Time course changes in daily nasal symptom medication scores as well as in daily ocular symptom medication scores throughout the pollen period were comparable with those in the omalizumab group in the core study. Serum free IgE levels decreased to below the target level in all patients and were equal to those in the omalizumab group in the core study. The adverse reaction profiles were similar to those in the core study. In addition, the overall incidence of drug-related adverse events and injection site reactions in the re-treatment study did not increase compared with those in the omalizumab group in the core study. There were no serious adverse events, and no anti-omalizumab antibodies were detected. Conclusion: Omalizumab was effective and safe when consecutively readministered in the second Japanese cedar pollen season.
Allergic Airway Inflammation Initiates Long-Term Vascular Remodeling of the Pulmonary Circulation
Authors: Rydell-Törmänen Kristina , Uller Lena , Erjefält Jonas S.
Published: February 2009

Background: Asthma and allergic airway inflammation are associated with persistent structural alterations in the bronchi, i.e. airway remodeling. Previous studies have shown that during allergic airway inflammation, similar structural alterations may also be evoked in the pulmonary circulation. However, it remained unknown whether remodeling of the pulmonary circulation is as persistent as airway remodeling. The aim of this study is to investigate the reversibility and resolution of vascular remodeling, induced by allergic airway inflammation. Methods: A validated mouse model of allergic airway inflammation, utilizing ovalbumin as allergen, was employed. Animals were sacrificed 1 day, 1 week or 1 month after the last allergen exposure, and different parameters of remodeling (smooth muscle mass, proliferation of smooth muscle cells and endothelial cells as well as number of myofibroblasts and procollagen-I-producing cells) were investigated and quantified histologically. Results: Allergen exposure resulted in allergic airway inflammation characterized by a transient leukocyte infiltration and in structural alterations in both airway and vascular compartments. The increase in vascular smooth muscle mass and endothelial proliferation persisted at 1 month after the last allergen exposure. The other parameters and cellular inflammatory response returned to baseline within 1 month after the last allergen challenge. Conclusions: Based on the findings in this study, we conclude that acute allergic airway inflammation, although being initiated from the airways, is able to evoke similar long-term structural alterations in pulmonary vessels as described for bronchi.
Efficacy of Intravenous Gammaglobulin for Immunoglobulin G Subclass and/or Antibody Deficiency in Adults
Authors: Abdou Nabih I. , Greenwell Cindy A. , Mehta Reena , Narra Madhu , Hester Jeffery D. , Halsey John F.
Published: February 2009

Background: The clinical significance and efficacy of treating patients who have immunoglobulin (Ig) G subclass deficiency and/or antibody deficiency with Ig-replacement therapy has been debated. There are no clear guidelines to recommend intravenous gammaglobulin (IgIV) in these patients as there are few published studies documenting its efficacy. Methods: We studied in an open-label protocol 10 adult patients with recurrent respiratory infections and IgG subclass and/or antibody deficiency. All patients received monthly IgIV for 12 months and then were observed for 3 months without IgIV infusions. We studied quality of life, incidence of infections, need for antibiotics, frequency of hospitalizations due to infections, IgG subclass and antibody (tetanus and pneumococcal) levels. Innate immunity was evaluated by studying the status of Toll-like receptors and polymorphisms, mannan-binding lectin levels and genotypes. Correction of the immune defects during IgIV therapy was evaluated. Results: Monthly IgIV significantly improved quality of life, decreased the number of infections and the need for antibiotics, and improved IgG subclass and antibody serum levels. No consistent finding of innate immunity could be detected. Conclusions: IgIV could be beneficial in patients with IgG subclass or antibody deficiency.
Cysteinyl Leukotrienes Induce Monocyte Chemoattractant Protein-1 in Human Monocyte/Macrophages via Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways
Authors: Hashimoto Kunio , Ichiyama Takashi , Hasegawa Masanari , Hasegawa Shunji , Matsubara Tomoyo , Furukawa Susumu
Published: February 2009

Background: We have previously demonstrated that cysteinyl leukotriene (CysLT) induced monocyte chemoattractant protein-1 (MCP-1) production in monocytes/macrophages. The intracellular signal transduction pathway of MCP-1 production induced by CysLT in human monocytes/macrophages is unclear. Methods: The activation of mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK by phosphorylation, and nuclear factor-κB (NF-κB) by leukotriene (LT) D4 and LTC4 was determined in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood CD14+ monocytes/macrophages. We examined the inhibitory effects of inhibitors of ERK1/2, JNK, p38 MAPK and NF-κB and pranlukast as a CysLT1 receptor antagonist on induction of MCP-1 production by LTD4 and LTC4. Results: LTD4 and LTC4 induced significant phosphorylations of ERK1/2 and JNK, but not p38 MAPK, in THP-1 cells and peripheral blood CD14+ monocytes/macrophages. Pretreatment with the ERK1/2 inhibitor PD98059 and JNK inhibitor SP600125 attenuated MCP-1 production by CysLTs. NF-κB activation was induced by addition of LTD4 and LTC4. Pretreatment with the NF-κB inhibitors caffeic acid phenylethyl ester and MG-132 inhibited MCP-1 production by CysLTs. Pranlukast inhibited phosphorylation of ERK1/2 and JNK, NF-κB activation, and the MCP-1 production induced by CysLTs. Conclusion: CysLTs induce MCP-1 and this induction is mediated by ERK1/2 and JNK in MAPK, and NF-κB pathways via the CysLT1 receptor, for the most part, in human monocytes/macrophages.
Inhibition of Nitric Oxide Synthases Abrogates Pregnancy-Induced Uterine Vascular Expansive Remodeling
Authors: Osol George , Barron Carolyn , Gokina Natalia , Mandala Maurizio
Published: February 2009

Background/Aims: It was the aim of this study to test the hypothesis that hypertension and/or inhibition of nitric oxide (NO) synthases alters uterine vascular remodeling during pregnancy. Methods: Using a model of hypertension (NO synthase inhibition with L-NAME) in nonpregnant and pregnant rats, comparisons were made with age-matched controls, as well as with animals receiving hydralazine along with L-NAME to maintain normotension in the presence of NO synthase inhibition. Circumferential and axial remodeling of large (main uterine, MUA) and small (premyometrial radial) arteries were quantified and compared. Results:L-NAME treatment prevented expansive circumferential remodeling of the MUA; cotreatment with hydralazine was without effect. Circumferential remodeling of smaller premyometrial radial arteries was also significantly attenuated in hypertensive pregnant animals, while premyometrial radial arteries from rats receiving hydralazine with L-NAME were of intermediate diameter. Neither hypertension nor NO synthase inhibition had any effect on the substantial (200–300%) axial growth of MUA or premyometrial radial arteries. Conclusion: NO plays a major role in facilitating pregnancy-induced expansive remodeling in the uterine circulation, particularly in larger arteries. Some beneficial effects of hydralazine on expansive circumferential remodeling were noted in smaller radial vessels, and these may be linked to its prevention of systemic hypertension and/or to local effects on the arterial wall. Neither NO synthase inhibition nor hypertension had any effect on arterial longitudinal growth.
Isolation and Characterization of Human Coronary Artery-Derived Endothelial Cells in vivo from Patients Undergoing Percutaneous Coronary Interventions
Authors: Yu Shi-Yong , Song Yao-Ming , Li Ai-Min , Yu Xue-Jun , Zhao Gang , Song Ming-Bao , Lin Chun-Mei , Tao Chun-Rong , Huang Lan
Published: February 2009

Background/Aims: Human coronary artery-derived endothelial cells (ECs) seem to be the most appropriate cells for the pathogenesis study of coronary artery disease. But limited availability of endothelial tissue is a major constraint. In this study, we developed a method to isolate human coronary artery ECs in vivo from patients. Methods: Coronary guidewires were used to obtain EC samples from coronary arteries in 76 patients. Cells were eluted from wire tips and purified by immunomagnetic beads. Von Willebrand factor and CD31 were used as immunocytochemical markers to identify cells as endothelium. Cell viability was evaluated in terms of cell membrane integrity, energy-dependent uptake of DiI-labeled acetylated low-density lipoprotein, and apoptosis. Nitric oxide synthase (eNOS) expression and nitric oxide (NO) production of cells were detected to evaluate cell function. Results: About 96 coronary artery ECs were obtained per guidewire. Cells manifested endothelial morphology and immunoreactivity for von Willebrand factor and CD31 with good viability. But eNOS expression and NO production of cells were decreased. Conclusions: Viable coronary endothelium could be obtained during routine percutaneous coronary interventions combined with immunomagnetic beads. These cells may be used for advanced cellular functional analyses such as immunocytochemistry and molecular biology. Such information could aid in understanding mechanisms of coronary artery diseases.
Prognostic Significance of Ankle-Brachial Index, Brachial-Ankle Pulse Wave Velocity, Flow-Mediated Dilation, and Nitroglycerin-Mediated Dilation in End-Stage Renal Disease
Authors: Morimoto Satoshi , Yurugi Takatomi , Aota Yasuko , Sakuma Takao , Jo Fusakazu , Nishikawa Mitsushige , Iwasaka Toshiji , Maki Kei
Published: February 2009

Background: Identifying patients at high risk of cardiovascular disease is important in managing patients undergoing hemodialysis. Methods: We evaluated a series of prognostic values: flow-mediated dilation (FMD) and nitrogen-mediated dilation (NMD), an index of endothelium-dependent and endothelium-independent function, respectively, ankle-brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV) in patients undergoing chronic hemodialysis. Results: A cohort of 199 patients was studied. At entry, these values were examined and the prognostic significances were investigated. In estimating the significance of baPWV, patients with ABI <0.9 were excluded. During the follow-up period, 24 deaths occurred including 14 cardiovascular and 10 noncardiovascular fatal events. Overall, the survival rates were significantly lower in the low ABI than in the high ABI group, but the survival rates were not significantly different between the high and low FMD, NMD, or baPWV groups. Cardiovascular survival rates were significantly lower in the low ABI than in the high ABI group, and in the high baPWV than in the low baPWV group. The survival rates were not significantly different between the high and low FMD or NMD groups. Conclusions: Screening hemodialysis patients by means of ABI and baPWV but not FMD or NMD provides complementary information in identifying a high-risk population in these patients.
Fruit and Vegetable Intake and Risk of Amyotrophic Lateral Sclerosis in Japan
Authors: Okamoto K. , Kihira T. , Kobashi G. , Washio M. , Sasaki S. , Yokoyama T. , Miyake Y. , Sakamoto N. , Inaba Y. , Nagai M.
Published: February 2009

Background: There has been little interest in the role of nutrition in the prevention of amyotrophic lateral sclerosis (ALS). We investigated the relationship between dietary intake of vegetables, fruit, and antioxidants and the risk of ALS in Japan. Methods: Between 2000 and 2004, we recruited 153 ALS patients aged 18–81 years with disease duration of 3 years within the study period in accordance with El Escorial World Federation of Neurology criteria. Three hundred and six gender- and age-matched controls were randomly selected from the general population. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Results: A higher consumption of all fruits and vegetables and fruit alone in the highest quartiles was associated with a statistically significantly reduced risk of ALS. Although not statistically significant, a beneficial association between intake of all vegetables, green and yellow vegetables and other vegetables and ALS was found. No statistically significant dose-response relationship was observed between intake of β-carotene, vitamin C and vitamin E and the risk of ALS. Conclusion: Our findings suggest that higher intake of food rich in antioxidants such as fruit and vegetables confer protection against the development of ALS.
Changes in Prevalence and Incidence of Parkinson’s Disease in Japan during a Quarter of a Century
Authors: Yamawaki Mika , Kusumi Masayoshi , Kowa Hisanori , Nakashima Kenji
Published: February 2009

Background/Aim: To determine the prevalence and incidence of Parkinson’s disease (PD) and compare them with results from our previous studies. Methods: We examined epidemiological characteristics of PD patients using a service-based study in Yonago City, and a door-to-door study in Daisen Town. The prevalence days were April 1, 2004 in Yonago, and April 1, 2003 in Daisen. Results: In Yonago, we identified 254 PD patients. The crude prevalence was 180.3 (95% CI, 158.1–202.4) per 100,000 population. The adjusted prevalence was 145.8 (95% CI, 145.2–146.5) in 1980, 147.0 (95% CI, 146.3–147.6) in 1992, and 166.8 (95% CI, 166.1–167.5) in 2004, when calculated using the Japanese population in 2004. The crude incidence was 18.4 (95% CI, 11.3–25.5) per 100,000 population per year. The crude incidence in 1980 was 10.2 (95% CI, 4.6–15.8), and the adjusted incidence was 9.8 (95% CI, 4.3–15.3) in 1992, and 10.3 (95% CI, 4.7–15.9) in 2004, when calculated using the population in Yonago in 1980. In Daisen, there were 21 PD patients. The crude prevalence was 306.6 (95% CI, 175.7–437.6) and the adjusted prevalence was 192.6 (95% CI, 191.9–193.8). Conclusions: The prevalence of PD had increased, primarily because the population had aged. Differences in prevalence between these adjacent areas may have resulted from differences in the methods of investigation.
Cross-Cultural Application of the Korean Version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module
Authors: Shin Dong Wook , Ahn Eunmi , Kim Yong-Man , Kang Sokbom , Kim Byoung-Gie , Seong Seok Ju , Cha Soon Do , Park Chan-Yong , Yun Young Ho
Published: February 2009

Objectives: This study was conducted to evaluate the psychometric properties of the Korean version of the Quality of Life questionnaire cervical cancer module (QLQ-CX24), developed by the European Organization for Research and Treatment of Cancer (EORTC). Methods: The EORTC QLQ-CX24 and the core questionnaire (the EORTC QLQ-C30) were administered to 860 Korean disease-free survivors of cervical cancer and 494 female control subjects from the general Korean population. The construct reliability and validity of the EORTC QLQ-CX24 questionnaire were assessed via factor analysis, multitrait scaling analyses and known group comparisons. Results: Factor structure of the Korean version of the EORTC QLQ-CX24 questionnaire agreed with the originally hypothesized scale structure. Scale reliability was confirmed by Cronbach’s α coefficients for internal consistency, which ranged from 0.78 to 0.87. Convergent and discriminant validity was confirmed by multitrait scaling analysis, which revealed scaling errors of 0.9. The clinical validity of the Korean version of the EORTC QLQ-CX24 was demonstrated by the ability to discriminate among controls and patient subgroups of different stages, treatments and overall health status. Conclusions: The Korean version of the EORTC QLQ-CX24 was found to be a reliable and a valid measure of quality of life among survivors of cervical cancer when administered in a large survey setting.
Biomechanical Perspective on the Remineralization of Dentin
Authors: Bertassoni L.E. , Habelitz S. , Kinney J.H. , Marshall S.J. , Marshall Jr. G.W.
Published: February 2009

The objective of this article is to critically evaluate the methods that are used to assess outcomes of remineralization of dentin. Currently, the most used assessment methods fall either into quantitative analysis of the mineral content of the remineralized structures or dry measurements of their mechanical properties. Properties obtained from the dehydrated organic dentin matrix may not reflect the true mechanical behavior of the remineralized tissue under physiological and hydrated conditions. Here we seek to clarify the biomechanical aspects of remineralization of dentin, pointing out the effects of hydration and dehydration on the mechanical properties of treated tissues. We also emphasize that a more appropriate endpoint to evaluate the effectiveness of remineralization in dentin should be associated with the recovery of the mechanical properties of the hydrated tissue, which is presumed to correlate well with its overall functionality.