bluuebunny/crossref_metadata_2025 huggingface dataset:
Elimination Kinetics of the Tobacco-Specific Biomarker and Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol
Authors: Goniewicz Maciej L. , Havel Christopher M. , Peng Margaret Wilson , Jacob Peyton , Dempsey Delia , Yu Lisa , Zielinska-Danch Wioleta , Koszowski Bartosz , Czogala Jan , Sobczak Andrzej , Benowitz Neal L.
Published: December 2009

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is tobacco specific and has a longer half-life than other tobacco biomarkers studied thus far. An accurate measurement of the NNAL half-life is important for optimal use to assess exposure to tobacco smoke. We determined the half-life of NNAL in urine in eight daily smokers on a clinical research ward and in five occasional smokers in a real-life environment. Total NNAL in urine was monitored for 14 days in daily smokers after stopping smoking and for up to 60 days in occasional smokers. The average half-life for the terminal phase in the daily smoker group using a two-compartmental body model was 10.3 days (beta phase), and using a noncompartmental model, it was 9.1 days. In the occasional group, these values were 17.6 and 16.0 days, respectively. The alpha-phase half-lives were 14.3 and 27.8 hours for the two groups, respectively. The inter-subject coefficient of variation of the NNAL terminal half-life ranged from 14% to 30%, and the intra-subject coefficient of variation ranged from 3% to 18%. There was very good agreement between the plasma and urinary half-lives in two subjects with plasma analyses: 7.4 versus 7.9 days and 9.2 versus 10.7 days. Mean renal clearance of NNAL was 13 ± 2.3 mL/min. The terminal half-life of NNAL of 10 to 18 days indicates that this biomarker can be used to detect tobacco smoke exposure for 6 to 12 weeks after cessation of exposure and requires a similar time to assess the steady levels of NNAL after switching from one tobacco product to another. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3421–5)
Does Film Smoking Promote Youth Smoking in Middle-Income Countries?: A Longitudinal Study among Mexican Adolescents
Authors: Thrasher James F. , Sargent James D. , Huang Liling , Arillo-Santillán Edna , Dorantes-Alonso Ana , Pérez-Hernández Rosaura
Published: December 2009

Objective: To determine whether exposure to smoking imagery in films predicts smoking onset among never-smoking Mexican adolescents.

Methods: The analytic sample was comprised of 11- to 14-year-old secondary school students who reported never having tried smoking at baseline, 83% (1,741/2,093) of whom were successfully followed-up after 1 year. Exposure to 42 popular films that contained smoking was assessed at baseline, whereas smoking behavior and risk factors were assessed at baseline and at follow-up. Logistic regression was used to estimate bivariate and adjusted relative risks (ARR) of trying smoking and current smoking at follow-up.

Results: At follow-up, 36% reported having tried smoking and 8% reported having smoked in the previous month. Students who were successfully followed-up were exposed to an average of 43.8 minutes of smoking in the films they reported viewing at baseline. ARRs indicated that students in the two highest levels of exposure to film smoking were more than twice as likely to have smoked in the previous 30 days at follow-up [ARR3v1 = 2.44; 95% confidence interval (CI), 1.31-4.55; ARR4v1 = 2.23; 95% CI, 1.19-4.17]. The ARR of having tried smoking by the time of follow-up reached statistical significance only when comparing the third highest to the lowest exposure group (ARR3v1 = 1.54; 95% CI, 1.01-2.64). Having a parent or best friend who smoked at baseline were the only other variables that independently predicted both outcomes.

Conclusions: Exposure to movie smoking is a risk factor for smoking onset among Mexican youth, although this risk appears weaker than in countries with stronger tobacco marketing regulations.(Cancer Epidemiol Biomarkers Prev 2009;18(12):3444–50)
Smoking Behavior 1 Year after Computed Tomography Screening for Lung Cancer: Effect of Physician Referral for Abnormal CT Findings
Authors: Styn Mindi A. , Land Stephanie R. , Perkins Kenneth A. , Wilson David O. , Romkes Marjorie , Weissfeld Joel L.
Published: December 2009

Background: Computed tomography (CT) lung cancer screening offers a unique clinical setting in which to promote smoking cessation. Focusing on outcomes related to the reporting of CT abnormality, we examined the natural history of smoking in the Pittsburgh Lung Screening Study.

Methods: Pittsburgh Lung Screening Study recruited 50- to 79-year-old current and former cigarette smokers living in the Pittsburgh area. We examined self-reported smoking outcomes 1 year after study entry in a subgroup that contained 2,094 active cigarette smokers without interval lung cancer diagnosis (50.7% women; median age, 57 years; 40-year median duration of cigarette smoking; and 65.2% ≥20 cigarettes/d). Analyses compared efforts to quit in relation to physician referral for abnormal CT.

Results: Since study entry, 58.5% [95% confidence interval (95% CI), 56.3-60.6%] reported any quit attempt and 27.2% (95% CI, 25.3-29.1%) reported any quit interval >30 days. One year after study entry, 15.5% (95% CI, 14.0-17.1%) reported not smoking for >30 days. Comparing persons referred because of CT abnormalities creating moderate or high lung cancer suspicion (n = 156; 7.4%) to persons not referred for any reason (n = 1145; 54.7%), propensity score-adjusted fractions with any quit attempt and with any quit interval >30 days increased 18.8% (95% CI, 11.1-26.5%) and 17.7% (95% CI, 9.4-26.0%), respectively. The fraction quit >30 days at 1 year increased 12.2% (95% CI, 4.9-19.5%).

Conclusions: Persons who experienced referral because of abnormal CT reported more smoking cessation. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3484–9)
Cigarette Filter–based Assays as Proxies for Toxicant Exposure and Smoking Behavior—A Literature Review
Authors: Pauly John L. , O'Connor Richard J. , Paszkiewicz Geraldine M. , Cummings K. Michael , Djordjevic Mirjana V. , Shields Peter G.
Published: December 2009

Background: Cigarettes are being marketed with filters that differ in composition and design. The filters have different toxicant trapping efficiencies, and smoking stains reflect variations in smoking behavior. Presented herein are the results of a structured literature review that was done to identify cigarette filter–based assays that may serve as proxies for mouth-level exposure and assessing smoking methods.

Methods: A search of the published scientific literature and internal tobacco company documents from 1954 to 2009 was carried out.

Results: The literature search identified diverse schemes for assessing cigarette filters, including visual inspection and digital imaging of smoked-stained spent filters, and quantitative determinations for total particulate matter (TPM), nicotine, and solanesol. The results also showed that: (a) there are sufficient data to link filter-based chemical measures to standardized smoking machine–measured yields of tar and nicotine; (b) TPM eluted from filters or in chemical digest of filters can be used to estimate the efficiency of the filter for trapping smoke solids; (c) visual and digital inspection of spent filters is useful in finding indicators of variations in smoking behaviors; and (d) there is a correlation between solanesol and nicotine measured in filters and exposure biomarkers in smokers.

Conclusions: The cigarette filter may prove useful in estimating smoking behaviors such as filter vent blocking and puffing intensity, and may have utility as proxy measures of mouth-level smoke exposure in clinical trials. Additional investigations are needed to compare the different proposed assay schemes and the assay results with measurements of human biomarker assays of smoke exposure. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3321–3333)
Alcohol and Tobacco Use Prediagnosis and Postdiagnosis, and Survival in a Cohort of Patients with Early Stage Cancers of the Oral Cavity, Pharynx, and Larynx
Authors: Mayne Susan T. , Cartmel Brenda , Kirsh Victoria , Goodwin W. Jarrard
Published: December 2009

As more people begin to survive first cancers, there is an increased need for science-based recommendations to improve survivorship. For survivors of head and neck cancer, use of tobacco and alcohol before diagnosis predicts poorer survival; however, the role of continuing these behaviors after diagnosis on mortality is less clear, especially for more moderate alcohol consumption. Patients (n = 264) who were recent survivors of early stage head and neck cancer were asked to retrospectively report their tobacco and alcohol histories (before diagnosis), with information prospectively updated annually thereafter. Patients were followed for an average of 4.2 years, with 62 deaths observed. Smoking history before diagnosis dose-dependently increased the risk of dying; risks reached 5.4 [95% confidence interval (95% CI), 0.7-40.1] among those with >60 pack-years of smoking. Likewise, alcohol history before diagnosis dose-dependently increased mortality risk; risks reached 4.9 (95% CI, 1.5-16.3) for persons who drank >5 drinks/d, an effect explained by beer and liquor consumption. After adjusting for prediagnosis exposures, continued drinking (average of 2.3 drinks/d) postdiagnosis significantly increased risk (relative risk for continued drinking versus no drinking, 2.7; 95% CI, 1.2-6.1), whereas continued smoking was associated with nonsignificantly higher risk (relative risk for continued smoking versus no smoking, 1.8; 95% CI, 0.9-3.9). Continued drinking of alcoholic beverages after an initial diagnosis of head and neck cancer adversely affects survival; cessation efforts should be incorporated into survivorship care of these patients. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3368–74)
Assessing Consumer Responses to Potential Reduced-Exposure Tobacco Products: A Review of Tobacco Industry and Independent Research Methods
Authors: Rees Vaughan W. , Kreslake Jennifer M. , Cummings K. Michael , O'Connor Richard J. , Hatsukami Dorothy K. , Parascandola Mark , Shields Peter G. , Connolly Gregory N.
Published: December 2009

Background: Internal tobacco industry documents and the mainstream literature are reviewed to identify methods and measures for evaluating tobacco consumer response. The review aims to outline areas in which established methods exist, identify gaps in current methods for assessing consumer response, and consider how these methods might be applied to evaluate potentially reduced exposure tobacco products and new products.

Methods: Internal industry research reviewed included published articles, manuscript drafts, presentations, protocols, and instruments relating to consumer response measures were identified and analyzed. Peer-reviewed research was identified using PubMed and Scopus.

Results: Industry research on consumer response focuses on product development and marketing. To develop and refine new products, the tobacco industry has developed notable strategies for assessing consumers' sensory and subjective responses to product design characteristics. Independent research is often conducted to gauge the likelihood of future product adoption by measuring consumers' risk perceptions, responses to product, and product acceptability.

Conclusions: A model that conceptualizes consumer response as comprising the separate, but interacting, domains of product perceptions and response to product is outlined. Industry and independent research supports the dual domain model and provides a wide range of methods for assessment of the construct components of consumer response. Further research is needed to validate consumer response constructs, determine the relationship between consumer response and tobacco user behavior, and improve reliability of consumer response measures. Scientifically rigorous consumer response assessment methods will provide a needed empirical basis for future regulation of potentially reduced-exposure tobacco products and new products, to counteract tobacco industry influence on consumers, and enhance the public health. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3225–40)
Abuse Liability Assessment of Tobacco Products Including Potential Reduced Exposure Products
Authors: Carter Lawrence P. , Stitzer Maxine L. , Henningfield Jack E. , O'Connor Rich J. , Cummings K. Michael , Hatsukami Dorothy K.
Published: December 2009

The harm produced by tobacco products is a result of frequent use of a highly toxic product. Reducing the adverse public health impact of tobacco products might be most effectively achieved by reducing the likelihood of their use and the toxicity of the products. Products that retain some characteristics of cigarettes but have been altered with the intention of reducing toxicity have been referred to as modified risk tobacco products or potential reduced exposure products (MRTP/PREP). Evaluation of their content, emission, and toxicity is discussed in other articles in this special issue. Here, we discuss the methodology that has been used to examine the likelihood of abuse or addiction. Abuse liability assessment (ALA) methodology has been used by the Food and Drug Administration (FDA) and other drug regulatory agencies world-wide for decades to assess the risks posed by a wide variety of pharmacologically active substances. ALA is routinely required among other evaluations of safety during the pre-market assessment of new drugs, and is continually adapted to meet the challenges posed by new drug classes and drug formulations. In the 2009 law giving FDA regulation over tobacco products, FDA is now required to evaluate new tobacco products including MRTP/PREPs to determine their risk for abuse and toxicity at the population level. This article describes the traditional tools and methods of ALA that can be used to evaluate new tobacco and nicotine products including MRTP/PREPs. Such ALA data could contribute to the scientific foundation on which future public policy decisions are based. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3241–62]
Effectiveness of a Nurse-Managed, Lay-Led Tobacco Cessation Intervention Among Ohio Appalachian Women
Authors: Wewers Mary Ellen , Ferketich Amy K. , Harness Judith , Paskett Electra D.
Published: December 2009

Objectives: The purpose of this study was to evaluate a nurse-managed, lay-led tobacco cessation intervention delivered to adult women in Ohio Appalachia.

Methods: A randomized controlled experimental design included intervention participants (n = 147) enrolled in a nurse-managed, lay-led protocol that incorporated nicotine replacement and behavioral counseling. Control participants (n = 155) received a personalized letter from their clinic physician, who advised them to quit smoking and requested they schedule a clinic appointment to discuss cessation.

Results: Self-reported and cotinine-validated quit rates were significantly higher among intervention group participants compared with control group participants at 3-and 6-month follow-up (P < 0.02). At 12 months, self-reported abstinence was 19.1% (intervention group) and 9.0% (control group), with cotinine-validated rates of 12.2% and 7.1%, respectively (P = 0.13). Prolonged abstinence rates were significantly different between groups at 3, 6, and 12 months (P < 0.02). Logistic regression analyses indicated adjusted odds of cotinine-validated quitting was associated with cigarette consumption per day (odds ratio, 0.94; 95% confidence interval, 0.89-0.99) and Center for Epidemiologic Studies Depression Scale score ≥ 16 (odds ratio, 0.39; 95% confidence interval, 0.17-0.90).

Conclusions: A lay-led approach that is managed by a nurse may serve as an effective cessation strategy among this high-risk population. Additional efforts are needed to sustain long-term abstinence, even after intensive intervention. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3451–8)
Assessing Tumor Mutations to Gain Insight into Base Excision Repair Sequence Polymorphisms and Smoking in Colon Cancer
Authors: Curtin Karen , Samowitz Wade S. , Wolff Roger K. , Ulrich Cornelia M. , Caan Bette J. , Potter John D. , Slattery Martha L.
Published: December 2009

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3384–8)
Nicotine Withdrawal Sensitivity, Linkage to chr6q26, and Association ofOPRM1SNPs in the SMOking in FAMilies (SMOFAM) Sample
Authors: Hardin Jill , He Yungang , Javitz Harold S. , Wessel Jennifer , Krasnow Ruth E. , Tildesley Elizabeth , Hops Hyman , Swan Gary E. , Bergen Andrew W.
Published: December 2009

Background: Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms.

Methods: The objectives of these analyses were to (a) assess the influence of nicotine withdrawal sensitivity on relapse, (b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and (c) explore family-based association of single nucleotide polymorphism (SNP) at the mu opioid receptor candidate gene (OPRM1) with nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores.

Results: An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, 1.25; 95% confidence interval, 1.10-1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family-based association test with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P values <0.05 and false discovery rate Q values <0.06.

Conclusion: An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs were found with Rasch-modeled nicotine withdrawal sensitivity scores in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.(Cancer Epidemiol Biomarkers Prev 2009;18(12):3399–406)
Evaluation of In vitro Assays for Assessing the Toxicity of Cigarette Smoke and Smokeless Tobacco
Authors: Johnson Michael D. , Schilz Jodi , Djordjevic Mirjana V. , Rice Jerry R. , Shields Peter G.
Published: December 2009

Background: In vitro toxicology studies of tobacco and tobacco smoke have been used to understand why tobacco use causes cancer and to assess the toxicologic impact of tobacco product design changes. The need for toxicology studies has been heightened given the Food and Drug Administration's newly granted authority over tobacco products for mandating tobacco product performance standards and evaluate manufacturers' health claims about modified tobacco products. The goal of this review is to critically evaluate in vitro toxicology methods related to cancer for assessing tobacco products and to identify related research gaps.

Methods: PubMed database searches were used to identify tobacco-related in vitro toxicology studies published since 1980. Articles published before 1980 with high relevance also were identified. The data were compiled to examine (a) the goals of the study, (b) the methods for collecting test substances, (c) experimental designs, (d) toxicologic end points, and (e) relevance to cancer risk.

Results: A variety of in vitro assays are available to assess tobacco smoke that address different modes of action, mostly using non–human cell models. However, smokeless tobacco products perform poorly in these assays. Although reliable as a screening tool for qualitative assessments, the available in vitro assays have been poorly validated for quantitative comparisons of different tobacco products. Assay batteries have not been developed, although they exist for nontobacco assessments. Extrapolating data from in vitro studies to human risks remains hypothetical.

Conclusions: In vitro toxicology methods are useful for screening toxicity, but better methods are needed for today's context of regulation and evaluation of health claims. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3263–304)
Measures for Assessing Subjective Effects of Potential Reduced-Exposure Products
Authors: Hanson Karen , O'Connor Richard , Hatsukami Dorothy
Published: December 2009

Potential reduced-exposure products (PREP) may reduce toxicant exposure and thereby may possibly reduce health risks associated with conventional tobacco use. However, lessened health risk to the individual or harm to the population through the use of PREPs is unknown. Research is being conducted to evaluate the possible health effects associated with PREP use. As part of this evaluation, it is critical to provide sound measures of subjective responses to PREPs to determine the use and the abuse potential of a product, that is, the likelihood that the product will lead to addiction. The goal of this paper is to conduct a systematic review of scales that have been used to measure the subjective responses to PREPs and examine their characteristics. In this article, scales are identified and the items on the scales are described. Scales are also examined to determine whether they are sensitive in testing PREPs. Furthermore, scales to assess PREPs are recommended to investigators. Where no scales exist, items that may be critical for the development and validation of new scales are identified. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3209–24)
Reconciling Human Smoking Behavior and Machine Smoking Patterns: Implications for Understanding Smoking Behavior and the Impact on Laboratory Studies
Authors: Marian Catalin , O'Connor Richard J. , Djordjevic Mirjana V. , Rees Vaughan W. , Hatsukami Dorothy K. , Shields Peter G.
Published: December 2009

Background: Recent Food and Drug Administration legislation enables the mandating of product performance standards for cigarette smoke and the evaluation of manufacturers' health claims for modified tobacco products. Laboratory studies used for these evaluations and also for understanding tobacco smoke toxicology use machines to generate smoke. The goal of this review is to critically evaluate methods to assess human smoking behavior and replicate this in the laboratory.

Methods: Smoking behavior and smoking machine studies were identified using PubMed and publicly available databases for internal tobacco company documents.

Results: The smoking machine was developed to generate smoke to allow for comparing cigarette tar and nicotine yields. The intent was to infer relative human disease risk, but this concept was flawed because humans tailor their smoking to the product, and chemical yields and toxicologic effects change with different smoking profiles. Although smoking machines also allow for mechanistic assessments of smoking-related diseases, the interpretations also are limited. However, available methods to assess how humans puff could be used to provide better laboratory assessments, but these need to be validated. Separately, the contribution of smoke mouth-holding and inhalation to dose need to be assessed, because these parts of smoking are not captured by the smoking machine. Better comparisons of cigarettes might be done by tailoring human puff profiles to the product based on human studies and comparing results across regimens.

Conclusions: There are major research gaps that limit the use of smoking machine studies for informing tobacco control regulation and mechanistic studies. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3305–20)
Raf Kinase Inhibitor Protein Enhances Neuronal Differentiation in Human SH-SY5Y Cells
Authors: Hellmann Julian , Rommelspacher Hans , Mühlbauer Eckhard , Wernicke Catrin
Published: December 2009

Neuronal differentiation has evolved as an essential process even in the adult brain, once disturbed being associated with the pathogenesis of several psychiatric disorders. To study the effects of Raf kinase inhibitor protein (RKIP) on neuronal differentiation, we generated neuroblastoma cell lines overexpressing RKIP (RKIP+) and expressing RKIP-directed short hairpin RNA for downregulation of RKIP (RKIP–). During a 4-week time course of continuous differentiation by retinoic acid (RA), expression of neuronal and glial markers, intracellular cyclic adenosine monophosphate (cAMP) levels, protein kinase C (PKC) signal transduction to extracellular signal-regulated kinase 1/2 (ERK-1/2) and cellular morphology were investigated in relation to RKIP levels. RKIP+ cells showed accelerated neurite outgrowth, formation of elaborated neuronal networks and increased neuronal marker expression both in RA-induced differentiation and to some extent even in non-RA-treated cells. RKIP– cells showed glial-like cell bodies and increased glial fibrillary acidic protein, suggesting a shift from neuronal to glial phenotype. With respect to differentiation-inducing signal pathways, PKC-mediated ERK-1/2 activation significantly correlated with RKIP levels. Furthermore, basal and forskolin-stimulated intracellular cAMP was potently increased in RKIP+ cells versus controls. In conclusion, the conserved signal transduction modulator RKIP was shown to enhance several aspects of neuronal differentiation via enhanced crosstalk from PKC to ERK-1/2 and enhancement of G-protein-coupled receptor signaling.
8-OHdG in Cerebrospinal Fluid as a Marker of Oxidative Stress in Various Neurodegenerative Diseases
Authors: Gmitterová K. , Heinemann U. , Gawinecka J. , Varges D. , Ciesielczyk B. , Valkovic P. , Benetin J. , Zerr I.
Published: December 2009

Background: The 8-hydroxy-2 deoxyguanosine (8-OHdG) is a product of nucleoside oxidation of DNA and a reliable marker of oxidative stress markers. Increased levels of oxidative stress have been reported in the cerebrospinal fluid (CSF) of patients with various neurodegenerative disorders. Objective: In search of a biochemical indicator of Parkinson’s disease (PD), we analyzed the levels 8-OHdG in the CSF of 99 patients, using ELISA to assess the differences between various neurodegenerative disorders. Results: Statistically significant higher CSF levels (p = 0.022) of 8-OHdG in non-demented PD patients as compared to the control group were observed. No differences between CSF 8-OHdG levels and age at the time of lumbar puncture, presence or severity of dementia, or gender were found. Conclusions: 8-OHdG levels could be potentially useful in the neurochemically supported diagnosis of PD.
Missense Variants in Plakophilin-2 in Arrhythmogenic Right Ventricular Cardiomyopathy Patients – Disease-Causing or Innocent Bystanders?
Authors: Christensen Alex Hørby , Benn Marianne , Tybjærg-Hansen Anne , Haunso Stig , Svendsen Jesper Hastrup
Published: December 2009

Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic. Methods: We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Results: Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146–2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations. Conclusions: Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2, functional characterization and large-scale sequencing to clarify normal variation in the gene.
Clevudine Demonstrates Potent Antiviral Activity in Naïve Chronic Hepatitis B Patients
Authors: Lee June Sung , Park Eun Taek , Kang Seung Sik , Gu Eun Sil , Kim Jong Sun , Jang Dong Seob , Lee Kyoung Seog , Lee Jae-Su , Park Nung Hwa , Bae Chang Hwang , Baik Soon Koo , Yu Byeong Jeon , Lee Soon Hyung , Lee Eun Jong , Park Sung Il , Bae Myoung , Shin Jung Woo , Choi Jae Hong , Gu Chul , Moon Sin Kil , Chun Gab Jin , Kim Ju Hyun , Kim Hong Soo , Choi Sung-Kyu
Published: December 2009

Objectives: Clevudine has demonstrated antiviral potency in the treatment of naïve chronic hepatitis B patients in pivotal studies. The objectives of this study were to evaluate the safety and efficacy of a 1-year treatment with clevudine in chronic hepatitis B patients. Methods: This is a post-marketing surveillance using case report forms which were submitted to the health authorities. Results: Analysis of individual data showed that hepatitis B virus (HBV) DNA after a 1-year treatment was <141,500 copies/ml in 96% of hepatitis B e antigen (HBeAg)-positive and 100% of HBeAg-negative patients. The proportion of patients with HBV DNA <2,000 copies/ml after a 1-year treatment was 74%: 71% of HBeAg-positive and 93% of HBeAg-negative patients. Most of the patients with HBV DNA below the detection limit with each assay at week 24 showed sustained viral suppression up to week 48. The proportion of patients who showed normal alanine aminotransferase at week 48 was 86% in HBeAg-positive patients and 87% in HBeAg-negative patients. The rates of HBeAg-loss were 21%. Two patients showed viral breakthrough during treatment. Conclusion: Clevudine monotherapy demonstrates potent antiviral activity as well as biochemical and serological response with a 0.7% rate of viral breakthrough in naïve chronic hepatitis B patients.
Impact of Serial Hepatitis B Virus DNA on Hepatocellular Carcinoma Development in Patients with Liver Cirrhosis
Authors: Kwon Jung Hyun , Choi Jong Young , Jang Jeong Won , Bae Si Hyun , Yoon Seung Kew , Yang Jin Mo , Han Nam Ik , Lee Chang Don , Lee Young Seok , Chung Kyu Won
Published: December 2009

Objectives: We investigated the pattern of serial HBV DNA levels in known cirrhosis patients and its impact on the development of hepatocellular carcinoma (HCC). Methods: We analyzed a retrospective case/control study based on 352 HCC patients associated with HBV between 2005 and 2007. Prior to HCC development, 49 cirrhosis patients were tested for HBV DNA levels more than once a year (median 4 times) during the follow-up period. Ninety-eight consecutive cirrhosis patients without HCC, matched for age, sex and HBe Ag status were included as controls. Eighty-three patients in both groups had undergone antiviral therapy. Results: In cirrhosis, the most common HBV DNA pattern was fluctuating (33.3%), followed by persistently high (≧104 copies/ml, 23.8%). Compared to a persistently low pattern (<104 copies/ml), the relative risks of HCC in patients with persistently high and fluctuating patterns were 2.650 and 1.475. At multivariate analysis, a persistently high pattern was an independent risk factor for HCC (hazard ratio 3.135). Patients with sustained HBV DNA suppression during antiviral therapy were less likely to develop HCC than those with viral breakthrough/nonresponse. Conclusions: This study showed that persistent suppression of HBV DNA is also important to prevent the development of HCC in known cirrhosis patients.
Therapeutic Effects of Maternal Melatonin Administration on Ischemia/Reperfusion-Induced Oxidative Cerebral Damage in Neonatal Rats
Authors: Hamada Fumiaki , Watanabe Kazushi , Wakatsuki Akihiko , Nagai Ryuhei , Shinohara Koichi , Hayashi Yoshihiro , Imamura Rina , Fukaya Takao
Published: December 2009

Background: We have previously demonstrated that prophylactic administration of melatonin to pregnant rats can protect against ischemia/reperfusion (I/R)-induced oxidative cerebral damage in fetal rats. However, the effects of maternal administration of melatonin after an ischemic episode on the brains of neonatal rats exposed to oxidative stress in utero have not been evaluated. Objectives: The purpose of the present study was to investigate whether maternal administration of melatonin after an ischemic episode can prevent oxidative cerebral damage in neonatal rats. Methods: The utero-ovarian arteries were occluded bilaterally for 30 min in female Wistar rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (10 mg/kg) or vehicle was injected intraperitoneally at 0, 1, 3, 6, and 12 h after reperfusion. After surgery, melatonin solution (20 µg/ml) or vehicle was administered freely via drinking water up to vaginal delivery. Control rats underwent a sham operation. We collected brain tissue from neonatal rats that were delivered naturally and measured the respiratory control index (RCI) as indicators of mitochondrial respiratory activity. Histological evaluation was performed on the cornu ammonis (CA1) and CA3 regions of the hippocampus. Results: I/R significantly reduced the RCI, but melatonin administration at postreperfusion hour 0 or 1 reversed I/R-induced reductions in the RCI. In contrast, melatonin administration at postreperfusion hours 3–12 had no protective effect. Histological analysis revealed a decrease in the ratio of normal to whole pyramidal cell number in the CA1 and CA3 regions in the I/R group. While melatonin administration within 3 h protected against degeneration, administration 6 h after reperfusion failed to protect. Conclusions: These results suggest that maternal administration of melatonin within 1 h after an ischemic/oxidative episode can prevent I/R-induced oxidative cerebral damage in neonatal rats.
An Oral Sorbent, AST-120, Increases Klotho Expression and Inhibits Cell Senescence in the Kidney of Uremic Rats
Authors: Adijiang Ayinuer , Niwa Toshimitsu
Published: December 2009

Background/Aim: Klotho, an anti-aging gene, is primarily expressed in the kidney, and its renal expression is decreased in chronic renal failure (CRF). We determined if administration of an oral sorbent, AST-120, increases the expression of Klotho, and inhibits cell senescence in the kidney of CRF rats. Methods: CRF rats were produced by 4/5-nephrectomy. AST-120 was administered to the CRF rats at a dose of 4 g/kg with powder chow for 16 weeks, whereas powder chow alone was administered to control CRF rats. The expression of Klotho and cell senescence (senescence-associated β-galactosidase: SA-β-gal) was detected by immunohistochemistry. Results: The expression of Klotho was significantly decreased in the kidney of CRF rats as compared with normal rats. AST-120-treated CRF rats showed significantly increased renal expression of Klotho as compared with CRF rats. The expression of SA-β-gal was significantly increased in the kidney of CRF rats as compared with normal rats. AST-120-treated CRF rats showed significantly decreased expression of SA-β-gal in the kidney as compared with CRF rats. AST-120 significantly decreased serum and urine levels of indoxyl sulfate. Conclusions: AST-120 increased Klotho expression, and inhibited cell senescence in the kidney of CRF rats, probably by alleviating indoxyl sulfate overload on the kidney.
Effects of γ-Secretase Inhibition on the Amyloid β Isoform Pattern in a Mouse Model of Alzheimer’s Disease
Authors: Portelius Erik , Zhang Bin , Gustavsson Mikael K. , Brinkmalm Gunnar , Westman-Brinkmalm Ann , Zetterberg Henrik , Lee Virginia M.-Y. , Trojanowski John Q. , Blennow Kaj
Published: December 2009

Background:Accumulation of amyloid β (Aβ) in the brain is believed to represent one of the earliest events in the Alzheimer disease process. Aβ is generated from amyloid precursor protein after sequential cleavage by β- and γ-secretase. Alternatively, α-secretase cleaves within the Aβ sequence, thus, precluding the formation of Aβ. A lot of research has focused on Aβ production, while less is known about the non-amyloidogenic pathway. We have previously shown that Aβ is present in human cerebrospinal fluid (CSF) as several shorter C-terminal truncated isoforms (e.g. Aβ1–15 and Aβ1–16), and that the levels of these shorter isoforms are elevated in media from cells that have been treated with γ-secretase inhibitors. Objective:To explore the effect of N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase-inhibitor, treatment on the Aβ isoform pattern in brain tissue and CSF from Tg2576 mice. Methods: Immunoprecipitation using the anti-Aβ antibodies 6E10 and 4G8 was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry. Results: All fragments longer than and including Aβ1–17 displayed a tendency towards decreased levels upon γ-secretase inhibition, whereas Aβ1–15 and Aβ1–16 indicated slightly elevated levels during treatment. Conclusion: These data suggest that Aβ1–15 and Aβ1–16 may be generated through a third metabolic pathway independent of γ-secretase, and that these Aβ isoforms may serve as biomarkers for secretase inhibitor treatment.
Sleep and Biomarkers of Atherosclerosis in Elderly Alzheimer Caregivers and Controls
Authors: von Känel Roland , Ancoli-Israel Sonia , Dimsdale Joel E. , Mills Paul J. , Mausbach Brent T. , Ziegler Michael G. , Patterson Thomas L. , Grant Igor
Published: December 2009

Background: Perturbed sleep might contribute to cardiovascular disease by accelerating atherosclerosis. Sleep is poor in Alzheimer caregivers who are also a group at increased cardiovascular risk. Objective: To test the hypothesis that impaired sleep relates to elevated levels of biomarkers of atherosclerosis in community-dwelling elderly and that this association would possibly be stronger in caregivers than in non-caregiving controls. Methods: We studied 97 Alzheimer caregivers and 48 non-caregiving controls (mean age 71 ± 8 years, 72% women) who underwent wrist actigraphy at their homes. Measures of objective sleep were averaged across 3 consecutive nights. The Pittsburgh Sleep Quality Index was administered by an interviewer to rate subjective sleep quality. Morning fasting blood samples were collected to determine measures of inflammation, coagulation and endothelial dysfunction. Results: There were independent associations between decreased subjective sleep quality and increased levels of fibrin D-dimer (p = 0.022, ΔR2 = 0.029) and von Willebrand factor antigen (p = 0.029, ΔR2 = 0.034) in all participants. Percent sleep (p = 0.025) and subjective sleep quality (p = 0.017) were lower in caregivers than in controls. In caregivers, the correlation between decreased percent sleep and elevated levels of interleukin-6 (p = 0.042, ΔR2 = 0.039) and C-reactive protein (p < 0.10, ΔR2 = 0.027) was significantly stronger than in controls. Conclusion: Perceived impairment in sleep related to increased coagulation activity and endothelial dysfunction in all participants, whereas objectively impaired sleep related to inflammation activity in caregivers. The findings provide one explanation for the increased cardiovascular risk in elderly poor sleepers and dementia caregivers in particular.
Foot and Ankle Strength Assessment Using Hand-Held Dynamometry: Reliability and Age-Related Differences
Authors: Spink Martin J. , Fotoohabadi Mohammad R. , Menz Hylton B.
Published: December 2009

Background: Age-related reduction in lower limb muscle strength has been shown to be related to disability, falls and loss of independence. While there have been a number of studies on age-related changes in muscle strength, they have concentrated on more proximal muscle groups with little research into how ageing affects the muscles of the foot and ankle. Objective: To evaluate the intra- and interrater reliability of hand-held dynamometry for the assessment of foot and ankle strength, and to compare the values obtained between young and older people. Methods:The muscle groups which perform ankle dorsiflexion, plantar flexion, inversion, eversion and plantar flexion of the hallux and lesser digits were recorded for 36 young participants (17 males, 19 females, mean age 23.2 ± 4.3 years) and 36 older people (17 males, 19 females, mean age 77.1 ± 5.7 years) using a Citec hand-held dynamometer. Differences in muscle strength between the groups as well as intrarater and interrater reliability of two assessors were determined. Results: The reliability of the hand-held dynamometry procedure was excellent for both intrarater (ICC3,1 = 0.78–0.94) and interrater (ICC3,1 = 0.77–0.88) comparisons. There were significant differences between the muscle strength of the young and older participants for all muscle groups tested (p < 0.001) with older participants being weaker than the young participants by a magnitude of between 24 and 37%. Conclusions:Hand-held dynamometry is a reliable instrument to measure the foot and ankle strength of young and older adults. Ageing is associated with a reduction in strength of between 24 and 37% for the muscles responsible for movement of the foot and ankle.
Sleep Breathing Flow Characteristics as a Sign for the Detection of Wakefulness in Patients with Sleep Apnea
Authors: Guerrero Arnoldo , Embid Cristina , Farre Ramon , Navajas Daniel , Masa Juan F. , Duran Joaquín , Montserrat J.M.
Published: December 2009

Background: To improve the performance of simplified sleep studies, it is essential to properly estimate the sleep time. Objectives: Our aim is to estimate sleep efficiency on the basis of flow breathing signal characteristics. Methods: Twenty subjects with sleep apnea-hypopnea syndrome diagnosed by polysomnography were studied. A characteristic pattern of flow signal defined our criteria for wakefulness and sleep. Sleep was analyzed in 2 different runs: (1) in the usual manner (neurological and respiratory variables), and (2) only the nasal cannula flow signal was displayed on the computer screen and the sleep and wakefulness periods were scored according to our criteria. At the end of the scoring process, all the signals were displayed on the screen to analyze the concordance. Results: Three thousand and sixty-nine screens were analyzed. The polysomnography sleep efficiency measured was 80.8%. The estimated sleep efficiency measured by nasal prongs was 78.9%. The detection and concordance of wakefulness had a sensitivity of 58.7%, a specificity of 96.4%, a positive predictive value of 81.3% and a negative predictive value of 89.6%. Conclusions: Our criteria for sleep and wakefulness based on airflow waveform morphology are a helpful parameter for estimating sleep efficiency in a simplified sleep study.
Catheter Ablation of Multiple Unstable Macroreentrant Tachycardia Within the Right Atrium Free Wall in Patients Without Previous Cardiac Surgery
Authors: Satomi Kazuhiro , Chun K.R. Julian , Tilz Roland , Bänsch Dietmar , Ernst Sabine , Antz Matthias , Schmidt Boris , Kuck Karl-Heinz , Ouyang Feifan
Published: December 2009

Background—

Macroreentrant atrial tachycardia (AT) involving the right atrial free wall (RAFW) has been reported in patients without atriotomy. Catheter ablation of these ATs remains challenging due to the multiple morphologies of ATs with unstable reentrant circuits in some patients. The purpose of this study was to clarify the electrophysiological characteristics of these ATs and attempt the novel approach for catheter ablation.

Methods and Results—

Electrophysiological study and catheter ablation were performed in 17 patients (14 men; 71 [quartile 1, 67; quartile 3, 76] years) with reentrant ATs originating from the RAFW using 3D mapping. All patients had no history of cardiac surgery. Clinical ATs with stable cycle length and atrial activation were identified in 11 patients (group A). All ATs were successfully ablated. In the remaining 6 patients, clinical tachycardia continuously changed, with a different cycle length and P-wave morphology and atrial activation sequence during mapping or entrainment study (group B). A complete isolation of the RAFW was attempted in group B. After complete isolation was achieved in 5 of 6 patients, ATs were not induced in these 6 patients. The number of previous failed catheter ablations and induced ATs were higher in group B than in group A. During 31 (19; 37) months of follow-up, AT recurrence developed in 27% patients from group A and 33% from group B.

Conclusions—

Multiple and unstable macroreentrant ATs from the RAFW can occur in patients without a history of cardiac surgery. The RAFW isolation has the potential to abolish all ATs.
The Works of Abū Mansūr al-Tha'ālibī (350-429/961-1039)
Authors: Orfali Bilal
Published: December 2009

This article deals with the oeuvre of Abū Mansūr al-Tha'ālibī, a prominent literary figure of the Eastern part of the Islamic world in the 4th/10th century. It deals with some of the literary and social issues that led to the numerous problems of false attribution and duplication in his bibliography, such as patronage and the periodical reworking of his books. This is followed by an up-to-date bibliography for al-Tha'ālibī, based on archives, primary sources and secondary literature. Works in print and manuscript form are assessed as to their authenticity and content, including bibliographical information on published works and locations of manuscripts. A further list reunites lost works and those surviving in quotations with references to the extant passages.