bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Diversity of the Antimicrobial Domain of Beta-Defensin 3 and Homologous Peptides
Authors: Nava Gerardo M. , Escorcia Magdalena , Castañeda M. Pilar
Published: November 2009

Human -defensin 3 has received great interest for possible pharmaceutical applications. To characterize the biology of this antimicrobial peptide, the mouse -defensin 14 has been selected as a prototypical model. This report provides definite evidence of true orthology between these defensins and reveals molecular diversity of a mammalian specific domain responsible for their antimicrobial activity. Specifically, this analysis demonstrates that eleven amino acid residues of the antimicrobial domain have been mutated by positive selection to confer protein niche specialization. These data support the notion that natural selection acts as evolutionary force driving the proliferation and diversification of defensins and introduce a novel strategy for the design of more effective antibiotics.
In Vitro Synergy of Levofloxacin Plus Piperacillin/Tazobactam againstPseudomonas aeruginosa
Authors: Chachanidze Vladimir , Curbelo-Irizarry Aixa , Ashcraft Deborah , Pankey George
Published: November 2009

In vitro synergy testing using levofloxacin (LVX) plus piperacillin/tazobactam (TZP) was performed by Etest and time-kill assay (TKA) for 31 unique fluoroquinolone-resistantPseudomonas aeruginosaisolates. The Etest method showed synergy for 9/31 (29%) of isolates, while TKA showed synergy with 14/31 (45%) of isolates. When comparing the Etest method and TKA, concordant results for synergy, antagonism, and indifference were obtained for 24/31 (77%) of the isolates tested.
Diagnosis of Charcot‐Marie‐Tooth Disease
Authors: Banchs Isabel , Casasnovas Carlos , Albertí Antonia , De Jorge Laura , Povedano Mónica , Montero Jordi , Martínez-Matos Juan Antonio , Volpini Victor
Published: November 2009

Charcot‐Marie‐Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked), according to electrophysiological findings (demyelinating or axonal), or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data.
Circulating Tumor Cells in Gastrointestinal Malignancies: Current Techniques and Clinical Implications
Authors: Lurje Georg , Schiesser Marc , Claudius Hoffmann Andreas , Schneider Paul Magnus
Published: November 2009

Since their introduction more than 50 years by Engell, circulating tumor cells (CTCs) have been evaluated in cancer patients and their detection has been correlated with clinical outcome, in esophageal, gastric, and colorectal cancer. With the availability of refined technologies, the identification of CTCs from peripheral blood is emerging as a useful tool for the detection of malignancy, monitoring disease progression, and measuring response to therapy. However, increasing evidence suggests a variety of factors to be responsible for disease progression. The analysis of a single CTC marker is therefore unlikely to accurately predict progression of disease with sufficient resolution and reproducibility. Here we discuss the current concept of CTCs, summarize the available techniques for their detection and characterization, and aim to provide a comprehensive update on the clinical implications of CTCs in gastrointestinal (GI) malignancies.
Some Applications of Fractional Calculus in Engineering
Authors: Tenreiro Machado J. A. , Silva Manuel F. , Barbosa Ramiro S. , Jesus Isabel S. , Reis Cecília M. , Marcos Maria G. , Galhano Alexandra F.
Published: November 2009

Fractional Calculus (FC) goes back to the beginning of the theory of differential calculus. Nevertheless, the application of FC just emerged in the last two decades, due to the progress in the area of chaos that revealed subtle relationships with the FC concepts. In the field of dynamical systems theory some work has been carried out but the proposed models and algorithms are still in a preliminary stage of establishment. Having these ideas in mind, the paper discusses FC in the study of system dynamics and control. In this perspective, this paper investigates the use of FC in the fields of controller tuning, legged robots, redundant robots, heat diffusion, and digital circuit synthesis.
Prediagnostic Total and High-Density Lipoprotein Cholesterol and Risk of Cancer
Authors: Ahn Jiyoung , Lim Unhee , Weinstein Stephanie J. , Schatzkin Arthur , Hayes Richard B. , Virtamo Jarmo , Albanes Demetrius
Published: November 2009

Background: Circulating total cholesterol has been inversely associated with cancer risk; however, the role of reverse causation and the associations for high-density lipoprotein (HDL) cholesterol have not been fully characterized. We examined the relationship between serum total and HDL cholesterol and risk of overall and site-specific cancers among 29,093 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort.

Methods: Fasting serum total and HDL cholesterol were assayed at baseline, and 7,545 incident cancers were identified during up to 18 years of follow-up. Multivariable proportional hazards models were conducted to estimate relative risks (RR).

Results: Higher serum total cholesterol concentration was associated with decreased risk of cancer overall (RR for comparing high versus low quintile, 0.85; 95% confidence interval, 0.79-0.91; P trend <0.001; >276.7 versus <203.9 mg/dL), and the inverse association was particularly evident for cancers of the lung and liver. These associations were no longer significant, however, when cases diagnosed during the first 9 years of follow-up were excluded. Greater HDL cholesterol was also associated with decreased risk of cancer (RR for high versus low quintile, 0.89; 95% confidence interval, 0.83-0.97; P trend = 0.01; >55.3 versus <36.2 mg/dL). The inverse association of HDL cholesterol was evident for cancers of lung, prostate, liver, and the hematopoietic system, and the associations of HDL cholesterol with liver and lung cancers remained after excluding cases diagnosed within 12 years of study entry.

Conclusion: Our findings suggest that prior observations regarding serum total cholesterol and cancer are largely explained by reverse causation. Although chance and reverse causation may explain some of the inverse HDL associations, we cannot rule out some etiologic role for this lipid fraction. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2814–21)
Effects of Vitamin D and Calcium on Proliferation and Differentiation In Normal Colon Mucosa: a Randomized Clinical Trial
Authors: Fedirko Veronika , Bostick Roberd M. , Flanders W. Dana , Long Qi , Sidelnikov Eduard , Shaukat Aasma , Daniel Carrie R. , Rutherford Robin E. , Woodard Jill Joelle
Published: November 2009

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop “treatable” phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D3 versus placebo over 6 months. Overall expression and distributions of p21waf1/cip1 (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may “normalize” the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2933–41)
Efficacy of Skin Self-Examination Practices for Early Melanoma Detection
Authors: Pollitt Ricardo A. , Geller Alan C. , Brooks Daniel R. , Johnson Timothy M. , Park Elyse R. , Swetter Susan M.
Published: November 2009

Although skin self-examination (SSE) may increase rates of early melanoma detection, the efficacy of different SSE practices has not been thoroughly studied. We examined associations between SSE practices and tumor thickness in patients with recently diagnosed melanoma.

Methods: 321 melanoma patients at three hospitals completed questionnaires on demographics and SSE practices. Patient-reported SSE was measured by routine examination of 13 specific body areas, frequency of mole examination, and use of a melanoma picture aid to assist with SSE. Histologic diagnoses and Breslow depth were confirmed by dermatopathologists. Regression analyses were used to calculate ratios of geometric mean tumor thickness and odds ratios for having thicker versus thinner tumors for different SSE behaviors.

Results: Rates of SSE varied considerably by SSE item. Patients routinely examining at least some of their skin had thinner melanomas [adjusted geometric mean tumor ratio, 0.73; 95% confidence interval (95% CI), 0.50-0.94]. Frequency of mole examination did not predict tumor thickness. Using a melanoma picture as a SSE aid was strongly associated with reduced tumor thickness (adjusted ratio, 0.75; 95% CI, 0.66-0.85 for ever versus never use). A composite measure of thoroughness of SSE was the best predictor of thickness (adjusted ratio, 0.58; 95% CI, 0.36-0.75) for high versus low thoroughness.

Conclusions: SSE was associated with decreased tumor thickness by most measures. However, the diverse rates of SSE practices and the distinct associations between these practices and melanoma thickness suggest a complexity in SSE that should be addressed in future studies. SSE should be evaluated by more than one measure. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3018–23)
Evaluation of an ELISA for p16INK4a as a Screening Test for Cervical Cancer
Authors: Balasubramanian Akhila , Hughes James , Mao Constance , Ridder Ruediger , Herkert Matthias , Kiviat Nancy B. , Koutsky Laura A.
Published: November 2009

Background: The low sensitivity of cytology and low specificity of human papillomavirus testing prompts searching for more accurate cervical cancer screening strategies. Our goal was to evaluate an ELISA-based test for p16INK4a.

Methods: 1,781 women undergoing routine screening provided cervical specimens for p16INK4a ELISA (original and enhanced versions of a prototype), liquid-based cytology, and Hybrid Capture II (hc2) testing. All women with a positive result and a random sample of those with negative results on all tests were referred for histologic diagnosis. Cervical intraepithelial neoplasia grade ≥3 (≥CIN3) was the main outcome. The original analysis included all ≥CIN3 outcomes (n = 28). The a posteriori analysis was used to represent clinically relevant results with ≥CIN3 as outcomes only when detected after a positive screening test (n = 27).

Results: Participants had a median age of 23 years. The prevalence of high-risk human papillomavirus DNA was 30.6%. In a posteriori analyses, the sensitivity and specificity for p16INK4a ELISA (≥8 pg/mL cut-point), cytology, and hc2 were 50.9%, 58.1%, and 100.0%, respectively, and 90.4%, 89.3%, and 69.2%, respectively. Referral to colposcopy of women with positive results for hc2 and p16INK4a (enhanced ELISA, ≥6 pg/mL cut-point) had a sensitivity of 91.8% (95% confidence interval, 79.1-100.0%) and specificity of 86.0% (95% confidence interval, 82.0-89.0%). Results of the original analyses had similar specificity but substantially lower sensitivity due to the strong influence of the single CIN3 case with completely negative screening results.

Conclusions: An enhanced version of this prototypic p16INK4a ELISA showed promise in screening, particularly when combined with hc2. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3008–17)
Incidence of Cancer in Finnish Families with Clinically Aggressive and Nonaggressive Prostate Cancer
Authors: Pakkanen Sanna , Pukkala Eero , Kainulainen Heidi , Matikainen Mika P. , Koivisto Pasi A. , Tammela Teuvo L.J. , Schleutker Johanna
Published: November 2009

Background: Clinical features of familial prostate cancer (PCa) and other malignancies associated with PCa are poorly described. Using a large family-based data registry of histologically confirmed cancers with a 40-year follow-up, we sought to determine incidence of cancer in Finnish PCa families, separately for clinically aggressive and clinically nonaggressive PCa.

Methods: We calculated standardized incidence ratios (SIR) for 5,523 members of 202 families by dividing the number of observed cancers (altogether 497 cases) by the number of expected cancers. The number of expected cancers is based on the national cancer incidence rates.

Results: SIR for overall cancer risk, excluding PCa, for male relatives in clinically nonaggressive families was 0.7 [95% confidence interval (95% CI), 0.6-0.8] and in clinically aggressive families 0.8 (95% CI, 0.6-1.0). The respective SIRs for women were 1.0 (95% CI, 0.8-1.1) and 1.1 (95% CI, 0.8-1.3). The incidence of lung cancer among men was significantly lower than in the general population. The SIR for gastric cancer among women was 1.9 in both clinically nonaggressive and clinically aggressive families. In clinically aggressive families, there was borderline significant excess of cancer of the gallbladder in men and liver cancer in women.

Conclusions: The incidence of non-PCa cancers is not increased in clinically aggressive or clinically nonaggressive PCa families except for stomach cancer among women. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3049–56)
Methylation Markers for CCNA1 and C13ORF18 Are Strongly Associated with High-Grade Cervical Intraepithelial Neoplasia and Cervical Cancer in Cervical Scrapings
Authors: Yang Nan , Eijsink Jasper J.H. , Lendvai Ágnes , Volders Haukeline H. , Klip Harry , Buikema Henk J. , van Hemel Bettien M. , Schuuring Ed , van der Zee Ate G.J. , Wisman G. Bea A.
Published: November 2009

Purpose: Recently, we reported 13 possible cervical cancer–specific methylated biomarkers identified by pharmacologic unmasking microarray in combination with large-genome computational screening. The aim of the present study was to perform an in-depth analysis of the methylation patterns of these 13 candidate genes in cervical neoplasia and to determine their diagnostic relevance.

Experimental Design and Results: Five of the 13 gene promoters (C13ORF18, CCNA1, TFPI2, C1ORF166, and NPTX1) were found to be more frequently methylated in frozen cervical cancer compared with normal cervix specimens. Quantitative methylation analysis for these five markers revealed that both CCNA1 and C13ORF18 were methylated in 68 of 97 cervical scrapings from cervical cancer patients and in only 5 and 3 scrapings, respectively, from 103 healthy controls (P < 0.0005). In cervical scrapings from patients referred with an abnormal Pap smear, CCNA1 and C13ORF18 were methylated in 2 of 43 and 0 of 43 CIN 0 (no cervical intraepithelial neoplasia) and in 1 of 41 and 0 of 41 CIN I, respectively. Furthermore, 8 of 43 CIN II, 22 of 43 CIN III, and 3 of 3 microinvasive cancer patients were positive for both markers. Although sensitivity for CIN II or higher (for both markers 37%) was low, specificity (96% and 100%, respectively) and positive predictive value (92% and 100%, respectively) were high.

Conclusion: Methylation of CCNA1 and C13ORF18 in cervical scrapings is strongly associated with CIN II or higher-grade lesions. Therefore, these markers might be used for direct referral to gynecologists for patients with a methylation-positive scraping. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3000–7)
An Admixture Scan in 1,484 African American Women with Breast Cancer
Authors: Fejerman Laura , Haiman Christopher A. , Reich David , Tandon Arti , Deo Rahul C. , John Esther M. , Ingles Sue A. , Ambrosone Christine B. , Bovbjerg Dana Howard , Jandorf Lina H. , Davis Warren , Ciupak Gregory , Whittemore Alice S. , Press Michael F. , Ursin Giske , Bernstein Leslie , Huntsman Scott , Henderson Brian E. , Ziv Elad , Freedman Matthew L.
Published: November 2009

African American women with breast cancer present more commonly with aggressive tumors that do not express the estrogen receptor (ER) and progesterone receptor (PR) compared with European American women. Whether this disparity is the result of inherited factors has not been established. We did an admixture-based genome-wide scan to search for risk alleles for breast cancer that are highly differentiated in frequency between African American and European American women, and may contribute to specific breast cancer phenotypes, such as ER-negative (ER−) disease. African American women with invasive breast cancer (n = 1,484) were pooled from six population-based studies and typed at ∼1,500 ancestry-informative markers. We investigated global genetic ancestry and did a whole genome admixture scan searching for breast cancer–predisposing loci in association with disease phenotypes. We found a significant difference in ancestry between ER+PR+ and ER−PR− women, with higher European ancestry among ER+PR+ individuals, after controlling for possible confounders (odds ratios for a 0 to 1 change in European ancestry proportion, 2.84; 95% confidence interval, 1.13-7.14; P = 0.026). Women with localized tumors had higher European ancestry than women with non–localized tumors (odds ratios, 2.65; 95% confidence interval, 1.11-6.35; P = 0.029). No genome-wide statistically significant associations were observed between European or African ancestry at any specific locus and breast cancer, or in analyses stratified by ER/PR status, stage, or grade. In summary, in African American women, genetic ancestry is associated with ER/PR status and disease stage. However, we found little evidence that genetic ancestry at any one region contributes significantly to breast cancer risk or hormone receptor status. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3110–7)
Colorectal Mucosal Expression of MSH2 as a Potential Biomarker of Risk for Colorectal Neoplasms
Authors: Sidelnikov Eduard , Bostick Roberd M. , Flanders W. Dana , Long Qi , Seabrook March E.
Published: November 2009

To characterize the expression of the mismatch repair gene MSH2 in normal colorectal crypts in humans and assess parameters of its expression as a potential modifiable biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MSH2 protein, and analyzed using custom quantitative image analysis procedures. MSH2 expression in adenoma cases was lower than in controls by 49% (P = 0.01) and 23% (P = 0.06) in the ascending colon and rectum, respectively, but not in the sigmoid colon. MSH2 expression in the rectum was 39% (P = 0.04) higher in subjects who regularly took a nonsteroidal anti-inflammatory drug than in those who did not, and it tended to be lower in those with adenomas in the right colon and those who had an adenoma with more advanced characteristics. These preliminary data suggest that lower MSH2 expression in the normal colonic mucosa, at least in the ascending colon and rectum, may be associated with increased risk of incident, sporadic colorectal adenoma as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MSH2 expression as a potential modifiable biomarker of risk for colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2965–73)
Selenium Supplementation Reduced Oxidative DNA Damage in Adnexectomized BRCA1 Mutations Carriers
Authors: Dziaman Tomasz , Huzarski Tomasz , Gackowski Daniel , Rozalski Rafal , Siomek Agnieszka , Szpila Anna , Guz Jolanta , Lubinski Jan , Wasowicz Wojciech , Roszkowski Krzysztof , Olinski Ryszard
Published: November 2009

Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2923–8)
Long-Term and Recent Recreational Physical Activity and Survival After Breast Cancer: The California Teachers Study
Authors: West-Wright Carmen Nicole , Henderson Katherine DeLellis , Sullivan-Halley Jane , Ursin Giske , Deapen Dennis , Neuhausen Susan , Reynolds Peggy , Chang Ellen , Ma Huiyan , Bernstein Leslie
Published: November 2009

Introduction: Long-term physical activity is associated with lower breast cancer risk. Little information exists on its association with subsequent survival.

Methods: California Teachers Study cohort members provided information in 1995-1996 on long-term (high school through age 54 years) and recent (past 3 years) participation in moderate and strenuous recreational physical activities. The 3,539 women diagnosed with invasive breast cancer after cohort entry and through December 31, 2004, were followed through December 31, 2005. Of these, 460 women died, 221 from breast cancer. Moderate and strenuous physical activities were combined into low (≤0.50 h/wk/y of any activity), intermediate (0.51-3.0 h/wk/y of moderate or strenuous activity but no activity >3.0 h/wk/y), or high activity (>3.0 h/wk/y of either activity type). Multivariable relative risks (RR) and 95% confidence intervals (95% CI) for mortality were estimated using Cox proportional hazards methods, adjusting for race/ethnicity, estrogen receptor status, disease stage, and baseline information on comorbidities, body mass index, and caloric intake.

Results: Women with high or intermediate levels of long-term physical activity had lower risk of breast cancer death (RR, 0.53; 95% CI, 0.35-0.80; and RR, 0.65; 95% CI, 0.45-0.93, respectively) than women with low activity levels. These associations were consistent across estrogen receptor status and disease stage, but were confined to overweight women. Deaths due to causes other than breast cancer were related only to recent activity.

Conclusions: Consistent long-term participation in physical activity before breast cancer diagnosis may lower risk of breast cancer death, providing further justification for public health strategies to increase physical activity throughout the lifespan. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2851–9)
CYP1A2, GSTM1, andGSTT1Polymorphisms and Diet Effects on CYP1A2 Activity in a Crossover Feeding Trial
Authors: Peterson Sabrina , Schwarz Yvonne , Li Shuying S. , Li Lin , King Irena B. , Chen Chu , Eaton David L. , Potter John D. , Lampe Johanna W.
Published: November 2009

Cytochrome P-450 1A2 (CYP1A2) is a biotransformation enzyme that activates several procarcinogens. CYP1A2 is induced by cruciferous and inhibited by apiaceous vegetable intake. Using a randomized, crossover feeding trial in humans, we investigated the dose effects of cruciferous vegetables and the effects of any interaction between cruciferous and apiaceous vegetables on CYP1A2 activity. We also investigated whether response varied by CYP1A2*1F, GSTM1, and GSTT1 genotypes (glutathione S-transferases that metabolize crucifer constituents) and whether CYP1A2 activity rebounds after apiaceous vegetables are removed from the diet. Participants (N = 73), recruited based on genotypes, consumed four diets for two weeks each: low-phytochemical diet (basal), basal plus single dose of cruciferous (1C), basal plus double dose of cruciferous (2C), and basal plus single dose of cruciferous and apiaceous vegetables (1C+A). CYP1A2 activity was determined by urine caffeine tests administered at baseline and the end of each feeding period. Compared with basal diet, the 1C diet increased CYP1A2 activity (P < 0.0001) and the 2C diet resulted in further increases (P < 0.0001), with men experiencing greater dose-response than women. The 1C+A diet decreased CYP1A2 activity compared with the 1C and 2C diets (P < 0.0001 for both). Although there was no overall effect of CYP1A2*1F or GSTM1-null/GSTT1-null genotypes or genotype-by-diet interactions, there were significant diet response differences within each genotype. Additionally, CYP1A2 activity recovered modestly one day after the removal of apiaceous vegetables. These results suggest complex interactions among dietary patterns, genetic variation, and modulation of biotransformation that may not be apparent in observational studies. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3118–25)
Colorectal Cancer Incidence and Postmenopausal Hormone Use by Type, Recency, and Duration in Cancer Prevention Study II
Authors: Hildebrand Janet S. , Jacobs Eric J. , Campbell Peter T. , McCullough Marjorie L. , Teras Lauren R. , Thun Michael J. , Gapstur Susan M.
Published: November 2009

The Women's Health Initiative randomized trials showed a reduction in colorectal cancer risk with the use of estrogen plus progesterone (E + P), but not with estrogen alone (E-only), after intervention periods <7 years. Using data from the Cancer Prevention Study II Nutrition Cohort, we examined associations of colorectal cancer risk with E-only and E + P, including analyses by recency and duration of hormone use. During 13.2 years of follow-up, 776 cases of invasive colorectal cancer occurred among 67,412 postmenopausal women participants. Cox proportional hazards models were used to estimate multivariate-adjusted relative risks (RR) and 95% confidence intervals (95% CI) of colorectal cancer for current and former hormone users according to hormone type and duration of use. Relative to women who never used postmenopausal hormones, current, but not former, use of E-only was associated with a reduced risk of colorectal cancer (RR 0.76; 95% CI, 0.59-0.97). Among current E-only users, duration of use was inversely and linearly associated with risk (Ptrend = 0.01). Use of E-only for <5 years was not associated with reduced risk, whereas use for ≥20 years was associated with a 45% reduction in risk (RR, 0.55; 95% CI, 0.36-0.86). There were no statistically significant associations between E + P and colorectal cancer risk. Our results suggest a strong inverse association of long-term use of E-only with colorectal cancer risk, underscoring the importance of collecting data on duration of hormone use in epidemiologic studies of postmenopausal hormones and risk of disease. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2835–41)
Breast Cancer Recurrence in Older Women Five to Ten Years after Diagnosis
Authors: Bosco Jaclyn L.F. , Lash Timothy L. , Prout Marianne N. , Buist Diana S.M. , Geiger Ann M. , Haque Reina , Wei Feifei , Silliman Rebecca A. ,   for the BOW Investigators
Published: November 2009

Little is known about the risk of recurrence >5 years after diagnosis among older breast cancer survivors. A community-based population of women ≥65 years diagnosed with early-stage breast cancer who survived disease free for 5 years was followed for 5 additional years or until a diagnosis of breast cancer recurrence, second primary, death, or loss to follow-up. These 5-year disease-free survivors (N = 1,277) had primary breast cancers that were node negative (77%) and estrogen receptor positive or unknown (86%). Five percent (n = 61) developed a recurrence between 5 and 10 years after diagnosis: 25% local, 9.8% regional, and 66% distant. Women who were node positive [hazard ratio (HR), 3.9; 95% confidence interval (95% CI), 1.5-10], had poorly differentiated tumors (HR, 2.5; 95% CI, 0.9-6.6), or who received breast conserving surgery without radiation therapy (HR, 2.4; 95% CI, 1.0-5.8) had higher recurrence rates compared with node negative, well differentiated, and receipt of mastectomy, respectively. Not receiving adjuvant tamoxifen, compared with receiving adjuvant tamoxifen, was also positively associated with late recurrence among women with estrogen receptor–positive/unknown tumors. Although relatively few women experience a late recurrence, most recurrences present as advanced disease, which is difficult to treat in older women. This study of late recurrence emphasizes that the risk, although small, is not negligible even in this group at high risk of death due to competing causes. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2979–83)
Asbestos Exposure and Gestational Trophoblastic Disease: A Hypothesis
Authors: Reid Alison , Heyworth Jane , de Klerk Nick , Musk A.W.
Published: November 2009

Among 2,968 women and girls exposed to crocidolite (blue asbestos) at Wittenoom, three cases of choriocarcinoma and three cases of hydatidiform mole have been identified (crude incidence rate of 9.9 per 1000 women and 1.7 per 1000 deliveries for choriocarcinoma and hydatidiform mole, respectively). The women with choriocarcinoma were resident at Wittenoom at the time of disease development, whereas hydatidiform mole occurred much later in women who had first been exposed to asbestos as young girls. Four of the six cases were known to have lived with asbestos company workers who brought their dusty work-clothes home for washing. Asbestos fibers have been reported in the lung, the pleural and peritoneal mesothelium, and the human ovary. They have also been detected in placental digests of live and stillborn infants. This cluster of gestational trophoblastic diseases has some biological plausibility for asbestos causation. Taking an occupational and residential history and examining pathologic specimens for asbestos fibers or bodies may prove useful in patients with gestational trophoblastic disease. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2895–8)
Therapeutic Options to Modulate Barrier Defects in Inflammatory Bowel Disease
Authors: Hering Nina A. , Schulzke Jörg-Dieter
Published: November 2009

In inflammatory bowel disease (IBD), epithelial barrier function is impaired contributing to diarrhea by a leak flux mechanism and perpetuating inflammation by an increased luminal antigen uptake. This barrier of the intestinal epithelium is composed of the apical enterocyte membrane and the epithelial tight junction (TJ) and can be affected by TJ alterations, induction of epithelial apoptoses and appearance of gross lesions like erosions or ulcers as well as by accelerated transcytotic antigen uptake. TJ strands are reduced in Crohn’s disease (CD) and strand breaks appear. Several of the 24 claudins are concerned in CD as e.g. claudin-2, -5 and -8. The epithelial apoptotic rate has also been shown to be elevated causing focal lesions. As far as regulation is concerned, Th1 cytokines like TNF-α and interferon-γ are important for CD, while Th2 responses are dominated by interleukin (IL)-13 and TNF-α in ulcerative colitis (UC). IL-13 does stimulate epithelial apoptosis as well as upregulates claudin-2 in UC. Together with an IL-13-dependent restitution arrest, this may explain why ulcer lesions are seen already early in UC but only in advanced stages of CD. Luminal antigen uptake occurs via TJ discontinuities, epithelial gross lesions and endocytotically. Therapeutically, anti-inflammatory remedies as e.g. TNF-α antibodies are most effective in improving active IBD and in parallel repairing barrier function. Again, this is assumed to be due to reduced cytokine release in active IBD, as a result of immune cell apoptosis. However, other agents can also directly affect barrier function. Glutamine is discussed as a candidate for barrier therapy but has never been shown to have a direct barrier influence in CD, although it is an important metabolic fuel for enterocytes and has been shown to preserve barrier functions in laboratory models. Also, probiotics and TGF-β and have beneficial effects in models, but no data exist on barrier repair in IBD. In contrast, zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown. Finally, food components can strengthen the epithelial barrier as for example the flavonoid quercetin which has been shown to upregulate claudin-4 within the epithelial TJ.
Inflammation in the Intestinal Tract: Pathogenesis and Treatment
Authors: Blumberg Richard S.
Published: November 2009

Over the past decade a major hypothesis has emerged for the etiopathogenesis of inflammatory bowel disease (IBD). This hypothesis proposes that IBD represents a dysregulated mucosal immune response to antigens derived from the commensal microbiota in a genetically susceptible host that initially derives from innate immune abnormalities leading to an excessive proinflammatory cytokine derived from CD4+ T cells (T-helper 1, T-helper 2, and T-helper 17 cytokines) over and above the response that is normally associated with tolerance and immunoregulation derived from T-regulatory cells. Given that the genetic predisposition has increasingly been recognized to affect the regulation of innate and adaptive immunity, intestinal epithelial cell physiologic barrier function and the potential inappropriate access of antigens to the mucosal immune system through this dysfunctional barrier function, a key point in understanding IBD pathophysiology is to understand the immunoregulatory pathways associated with the intestinal immune system as they apply to IBD. Therefore, immunogenetic pathways associated with innate and adaptive immunity, the cytokines secreted by innate and adaptive immune cells, the epithelial factors and leukocyte factors that are associated with inflammation and structures on the endothelium that regulate the recruitment of leukocytes define potential pathways that may be amenable to therapeutic manipulation in IBD.
The Role of Hepcidin in Iron Metabolism
Authors: Nemeth Elizabeta , Ganz Tomas
Published: November 2009

Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler played a significant role in advancing our understanding of the function of hepcidin. This review is dedicated to his memory.
Iron Deficiency, Helicobacter Infection and Gastritis
Authors: Hershko Chaim , Ronson Aharon
Published: November 2009

Despite elegant regulatory mechanisms, iron deficiency anemia (IDA) remains one of the most common nutritional deficiencies of mankind. Iron deficiency is the result of an interplay between increased host requirements, limited external supply, and increased blood loss. When related to increased physiologic needs associated with normal development, iron deficiency is designated physiologic or nutritional. By contrast, pathological iron deficiency, with the exception of gross menorrhagia, is most often the result of gastrointestinal disease associated with abnormal blood loss or malabsorption. If gastroenterologic evaluation fails to disclose a likely cause of IDA, or in patients refractory to oral iron treatment, screening for celiac disease (anti-tissue transglutaminase antibodies), autoimmune gastritis (gastrin, anti-parietal or anti-intrinsic factor antibodies), and Helicobacter pylori (IgG antibodies and urease breath test) is recommended. Recent studies indicate that 20–27% of patients with unexplained IDA have autoimmune gastritis, about 50% have evidence of active H. pylori infection, and 4–6% have celiac disease. The implications for abnormal iron absorption of celiac disease or autoimmune gastritis are obvious. In patients with unexplained IDA and H. pylori infection, cure of refractory IDA by H. pylori eradication offers strong evidence for a cause-and-effect relation between H. pylori infection and unexplained IDA. Stratification by age cohorts in autoimmune gastritis implies a disease presenting as IDA many years before the establishment of clinical cobalamin deficiency. It is likely caused by an autoimmune process triggered by antigenic mimicry between H. pylori epitopes and major autoantigens of the gastric mucosa. Recognition of the respective roles of H. pylori and autoimmune gastritis in the pathogenesis of iron deficiency may have a strong impact on the diagnostic workup and management of unexplained, or refractory IDA.
Mitochondrial Iron Metabolism and Sideroblastic Anemia
Authors: Sheftel Alex D. , Richardson Des R. , Prchal Josef , Ponka Prem
Published: November 2009

Sideroblastic anemias are a heterogeneous group of disorders, characterized by mitochondrial iron overload in developing red blood cells. The unifying characteristic of all sideroblastic anemias is the ring sideroblast, which is a pathological erythroid precursor containing excessive deposits of non-heme iron in mitochondria with perinuclear distribution creating a ring appearance. Sideroblastic anemias may be hereditary or acquired. Hereditary sideroblastic anemias are caused by defects in genes present on the X chromosome (mutations in the ALAS2, ABCB7, or GRLX5 gene), genes on autosomal chromosomes, or mitochondrial genes. Acquired sideroblastic anemias are either primary (refractory anemia with ring sideroblasts, RARS, representing one subtype of the myelodysplastic syndrome) or secondary due to some drugs, toxins, copper deficiency, or chronic neoplastic disease. The pathogenesis of mitochondrial iron loading in developing erythroblasts is diverse. Ring sideroblasts can develop as a result of a heme synthesis defect in erythroblasts (ALAS2 mutations), a defect in iron-sulfur cluster assembly, iron-sulfur protein precursor release from mitochondria (ABCB7 mutations), or by a defect in intracellular iron metabolism in erythroid cells (e.g. RARS).
Rare Types of Genetic Hemochromatosis
Authors: Camaschella Clara , Poggiali Erika
Published: November 2009

Most types of genetic hemochromatosis are due to mutations in the HFE gene, although similar iron overload and organ damage can also result from mutations in genes other than HFE in rare types of hemochromatosis. Non-HFE hemochromatoses have been divided into two subgroups with distinctive features. The first includes juvenile and TFR2-related hemochromatoses that, similar to HFE hemochromatosis, show recessive inheritance, increased transferrin saturation, iron storage in hepatocytes and responsiveness to phlebotomy. Disorders in this subgroup, although differing regarding the severity of iron overload and/or the age at presentation, are all either due to hepcidin deficiency or to the inability to increase hepcidin levels according to iron stores. The second subgroup of hemochromatosis is caused by autosomal dominant mutations in the SLC40A1 gene encoding the iron exporter ferroportin with distinctive features. Iron loading of Kupffer cells and normal transferrin saturation characterize the so-called ‘ferroportin disease’. In contrast, few mutations in SLC40A1 that cause hepcidin resistance lead to a hemochromatosis-like phenotype with dominant inheritance. The precise diagnosis of the genetic type of hemochromatosis is relevant for the follow-up, treatment, and for family counseling.
Iron Metabolism and Iron Chelation in Sickle Cell Disease
Authors: Walter Patrick B. , Harmatz Paul , Vichinsky Elliott
Published: November 2009

This review highlights recent advances in iron metabolism that are relevant to sickle cell disease (SCD). SCD is a common hemoglobinopathy that results in chronic inflammation. Improved understanding of how iron metabolism is controlled by proteins such as hepcidin, ferroportin, hypoxia-inducible factor 1, and growth differentiation factor 15 have revealed how they are involved in the organ toxicity of SCD. SCD patients have lower levels of non-transferrin-bound iron (NTBI) relative to other hemoglobinopathies, such as thalassemia. Care for SCD now commonly uses transfusion that results in iron overload and necessitates the need for chelation. New oral chelation therapy using deferasirox (Exjade/ICL670) appears to be safe and may even lower the amount of toxic free NTBI and enhance patient compliance. Finally, we suggest that iron metabolism and trafficking is different in SCD compared to other hemoglobinopathies. The high levels of inflammatory cytokines in SCD may enhance macrophage/reticuloendothelial cell iron and/or renal cell iron retention. This makes the tissues that retain iron different in SCD, and thus the organs that fail in SCD are different from those of other hemoglobinopathies, such as the cardiomyopathy or endocrinopathies of thalassemia.
Development of Subepidermal Bullae in the Split-Skin Graft Donor Site of a Psoriatic
Authors: Barker D.J. , Cotterill J.A.
Published: November 2009

A case of blistering eruption developing at the donor site of a split skin graft in a 48-year-old woman is described. Conventional histology revealed a subepidermal bulla. Direct immunofluorescence was negative. The significance of these findings is discussed.
Intravenous Zinc Sulfate Therapy in Zinc-Depleted Patients
Authors: Weismann Kaare
Published: November 2009

Zinc sulfate was administered intravenously in 3 patients with severe conditional zinc deficiency. The dosage ranged from 10 to 20 mg ionic zinc daily, and the duration of the treatment did not exceed 2 weeks. The rise in serum zinc and urinary zinc per 24 h, as well as in serum alkaline phosphatase, occurred at a faster rate than observed in a patient who was given 135 mg zinc daily by mouth. No subjective or biochemical side effects of the intravenous zinc therapy was observed.
Evaluation of the Local Antihistaminic Activity of Dimetindene Maleate by a Quantitative Method
Authors: Rampini Enrico , Oberhauser Vittorio , Nunzi Enrico
Published: November 2009

The topical application of a 0.1% dimetindene maleate gel on the forearms of 11 subjects reduces the areas of both erythema and wheal produced by the intradermal injection of 0.025 mg of histamine hydrochloride to a statistically greater degree than 1% d-chlorpheniramine maleate cream (p < 0.005 and p < 0.0005, respectively). The quantitative method employed in this study has proved to be an excellent means for the evaluation of the antihistaminic activity of topical preparations.
Summertime Actinic Lichenoid Eruption
Authors: Bedi Tilak R.
Published: November 2009

A distinct summertime skin disorder seen in 25 Indian patients is described under a tentative designation of summertime actinic lichenoid eruption (SALE). The eruption predominantly affects females in their 2nd to 4th decade. The initial lesions are in the form of closely aggregated pruritic lichenoid papules starting during summer months on the exposed parts of the body. The lesions respond favourably to sun protection and corticosteroid cream but the recurrences are common during the subsequent summers when the lesions tend to become more persistent, pruritic and lichenified. Histopathologic features include early basal cell degeneration, spongiotic vesiculation with or without focal parakeratosis and an intense lymphocytic infiltrate in the dermis. In spite of strong clinical evidence of relation to sunlight, the lesions are not easily reproducible by artificial light.
Warts in a Pediatric Renal Transplant Population
Authors: Ingelfinger Julie R. , Grupe Warren E. , Topor Michele , Levey Raphael H.
Published: November 2009

18 of 49 pediatric renal transplant recipients, all of whom were on continual steroid and immunosuppressive treatment, were found to have warts. Although all 18 patients received treatment for this problem, only 5 had the warts successfully eradicated. The frequency of warts among transplant patients is three times that of the general childhood population and twice that of a group of nephrotic pediatric patients who received immunosuppressive therapy. We propose that drug-induced suppression of cell-mediated, and to a lesser extent, humoral immunity, may predispose people to develop warts.
Dermatofibrosarcoma of the Face
Authors: Jacyk W.K. , Pasnikowski T.
Published: November 2009

Two Nigerian patients with dermatofibrosarcoma protuberans of the face are described. Both patients developed histologically typical tumours of unusual size. The condition is discussed in relation to previous reports of this unusual location and the frequency of dermatofibrosarcoma protuberans in Africa.
Condylomata Acuminata Associated with Morbus Bowen (Carcinoma in situ)
Authors: Grussendorf Elke-Ingrid , Bär Thomas
Published: November 2009

Description of a case of M. Bowen developing from condylomata acuminata. The ultrastructural alterations of the wart cells and the possible influence of papova-virus on carcinogenesis are discussed.
Balsam of Peru as Screening Agent for Essential Oils Sensitivity
Authors: Rudzki Edward , Grzywa Zdisława
Published: November 2009

The standard series and 35 essential oils were tested on 450 patients with dermatitis. It was found that those simultaneously sensitive to essential oils are more frequently negative than positive to balsam of Peru. The remaining 3 balsams, however (colophony, turpentine and wood tars), are also screening agents for essential oils. All four balsams reveal sensitivity to essential oils in most of the subjects tested. In patients negative to all 4 balsams of the standard series, attempts to find an essential oil with which tests would be simultaneously frequently positive with those for other essential oils failed.