bluuebunny/crossref_metadata_2025 huggingface dataset:
Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney
Authors: An Won Suk , Kim Hyun Ju , Cho Kyu-Hyang , Vaziri Nosratola D.
Published: August 2009

Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g·kg−1·day−1by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-β, Smad2, α-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-κB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91phox, p47phox, p22phox), PAI-1, TGF-β, connective tissue growth factor, α-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-κB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression
Authors: Alexandre Cristianne da Silva , de Bragança Ana Carolina , Shimizu Maria Heloísa Massola , Sanches Talita Rojas , Fortes Maria Angela Zanella , Giorgi Ricardo Rodrigues , Andrade Lúcia , Seguro Antonio Carlos
Published: August 2009

Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg2+channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.
Early postnatal overfeeding induces early chronic renal dysfunction in adult male rats
Authors: Boubred Farid , Daniel Laurent , Buffat Christophe , Feuerstein Jean-Marc , Tsimaratos Michel , Oliver Charles , Dignat-George Françoise , Lelièvre-Pégorier Martine , Simeoni Umberto
Published: August 2009

Low birth weight is associated with an increased risk of hypertension and renal dysfunction at adulthood. Such an association has been shown to involve a reduction of nephron endowment and to be enhanced by accelerated postnatal growth in humans. However, while low-birth-weight infants often undergo catch-up growth, little is known about the long-term vascular and renal effects of accelerated postnatal growth. We surimposed early postnatal overfeeding (OF; reduction of litter size during the suckling period) to appropriate-birth-weight (NBW+OF) and intrauterine growth restriction (IUGR; IUGR+OF) pups, obtained after a maternal gestational low-protein diet. Blood pressure (systolic blood pressure; SBP) and renal function (glomerular filtration rate; GFR) were measured in young and aging offspring. Glomerulosclerosis and nephron number were determined in aging offspring (22 mo). Nephron number was reduced in both IUGR and IUGR+OF male offspring (by 24 and 26%). GFR was reduced by 40% in 12-mo-old IUGR+OF male offspring, and both NBW+OF and IUGR+OF aging male offspring had sustained hypertension (+25 mmHg) and glomerulosclerosis, while SBP and renal function were unaffected in IUGR aging offspring. Female offspring were unaffected. In conclusion, in this experimental model, early postnatal OF in the neonatal period has major long-lasting effects. Such effects are gender dependent. Reduced nephron number alone, associated with IUGR, may not be sufficient to induce long-lasting physiological alterations, and early postnatal OF acts as a “second hit.” Early postnatal OF is a suitable model with which to study the long-term effects of postnatal growth in the pathogenesis of vascular disorders and renal disease.
Quantification of lung microstructure with hyperpolarized 3He diffusion MRI
Authors: Yablonskiy Dmitriy A. , Sukstanskii Alexander L. , Woods Jason C. , Gierada David S. , Quirk James D. , Hogg James C. , Cooper Joel D. , Conradi Mark S.
Published: August 2009

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized 3He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii—parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials.
Excitatory Roles of Protein Kinase C in Striatal Cholinergic Interneurons
Authors: Deng Ping , Pang Zhi-Ping , Lei Zhigang , Xu Zao C.
Published: August 2009

Protein kinase C (PKC) plays critical roles in neuronal activity and is widely expressed in striatal neurons. However, it is not clear how PKC activation regulates the excitability of striatal cholinergic interneurons. In the present study, we found that PKC activation significantly inhibited A-type potassium current ( IA), but had no effect on delayed rectifier potassium currents. Consistently, application of PKC activator caused an increase of firing in response to depolarizing currents in cholinergic interneurons, which was persistent in the presence of both excitatory and inhibitory neurotransmission blockers. These excitatory effects of PKC could be partially mimicked and occluded by blockade of IA with potassium channel blocker 4-aminopyridine. In addition, immunostaining demonstrated that PKCα, but not PKCγ and PKCε, was expressed in cholinergic interneurons. Furthermore, activation of group I metabotropic glutamate receptors (mGluRs) led to an inhibition of IA through a PKC-dependent pathway. These data indicate that activation of PKC, most likely PKCα, increases the neuronal excitability of striatal cholinergic interneurons by down-regulating IA. Group I mGluR-mediated IA inhibition might be important for the glutamatergic regulation of cholinergic tone in the neostriatum.
Phrenic Motoneuron Discharge Patterns During Hypoxia-Induced Short-Term Potentiation in Rats
Authors: Lee Kun-Ze , Reier Paul J. , Fuller David D.
Published: August 2009

Hypoxia-induced short-term potentiation (STP) of respiratory motor output is manifested by a progressive increase in activity after the acute hypoxic response and a gradual decrease in activity on termination of hypoxia. We hypothesized that STP would be differentially expressed between physiologically defined phrenic motoneurons (PhrMNs). Phrenic nerve “single fiber” recordings were used to characterize PhrMN discharge in anesthetized, vagotomized and ventilated rats. PhrMNs were classified as early (Early-I) or late inspiratory (Late-I) according to burst onset relative to the contralateral phrenic neurogram during normocapnic baseline conditions. During hypoxia (FIO2 = 0.12–0.14, 3 min), both Early-I and Late-I PhrMNs abruptly increased discharge frequency. Both cell types also showed a progressive increase in frequency over the remainder of hypoxia. However, Early-I PhrMNs showed reduced overall discharge duration and total spikes/breath during hypoxia, whereas Late-I PhrMNs maintained constant discharge duration and therefore increased the number of spikes/breath. A population of previously inactive (i.e., silent) PhrMNs was recruited 48 ± 8 s after hypoxia onset. These PhrMNs had a Late-I onset, and the majority (8/9) ceased bursting promptly on termination of hypoxia. In contrast, both Early-I and Late-I PhrMNs showed post-hypoxia STP as reflected by greater discharge frequencies and spikes/breath during the post-hypoxic period ( P < 0.01 vs. baseline). We conclude that the expression of phrenic STP during hypoxia reflects increased activity in previously active Early-I and Late-I PhrMNs and recruitment of silent PhrMNs. post-hypoxia STP primarily reflects persistent increases in the discharge of PhrMNs, which were active before hypoxia.
Visual Cues Signaling Object Grasp Reduce Interference in Motor Learning
Authors: Cothros Nicholas , Wong Jeremy , Gribble Paul L.
Published: August 2009

Recent motor learning studies show that human subjects and nonhuman primates form neural representations of novel mechanical environments and associated forces. Whereas proficient adaptation is seen for a single force field, when faced with multiple novel force environments, movement performance and in particular the ability to switch between different force environments declines. It is difficult to reconcile these findings with the notion that primates can proficiently switch between multiple motor skills. Conceivably, particular kinds of sensory, cognitive, or perceptual contextual cues are required. This study examined the effect of visual feedback on motor learning, in particular, cues that simulated interaction with a virtual object. A robot arm was used to deliver novel patterns of forces (force fields) to the limb during reaching movements. We tested the possibility that subjects transition more easily between novel forces and their sudden absence when they are accompanied by visual cues that relate to object grasp. We used a virtual display system to present subjects with different kinds of visual feedback during reaching, including illusory feedback, indicating grasp of a virtual object during reaching in the force field, and object release in the absence of forces. Throughout the experiment, subjects in fact maintained grasp of the robot. We found that, indeed, the most effective visual cues were those associating the force field with grasp of the virtual object and the absence of the force field with release of the object. Our findings show more broadly that specific visual cues can protect motor skills from interference.
Temporal Development of Anticipatory Reflex Modulation to Dynamical Interactions During Arm Movement
Authors: Kimura Toshitaka , Gomi Hiroaki
Published: August 2009

It is known that somatosensory reflex during voluntary arm movement is modulated anticipatorily according to given tasks or environments. However, when and how reflex amplitude is set remains controversial. Is the reflex modulation completed preparatorily before movement execution or does it vary with the movement? Is the reflex amplitude coded in a temporal manner or in a spatial (or state-dependent) manner? Here we studied these issues while subjects performed planar reaching movements with upcoming opposite (rightward/leftward) directions of force fields. Somatosensory reflex responses of shoulder muscles induced by a small force perturbation were evaluated at several points before the arm encountered predictable force fields after movement start. We found that the shoulder flexor reflex responses were generally higher for the rightward than for the leftward upcoming force fields, whereas the extensor reflex responses were higher for the leftward force field. This reflex amplitude depending on the upcoming force field direction became prominent as the reflex was evoked closer to the force fields, indicating continuous changes in reflex modulation during movement. An additional experiment further showed that the reflex modulation developed as a function of the temporal distance to the force fields rather than the spatial distance. Taken together, the results suggest that, in the force field interaction task, somatosensory reflex amplitude during the course of movement is set anticipatorily on the basis of an estimate of the time-to-contact rather than the state-to-contact, to upcoming dynamical interaction during voluntary movement.
Dietary Supplement Use and Prostate Cancer Risk in the Carotene and Retinol Efficacy Trial
Authors: Neuhouser Marian L. , Barnett Matt J. , Kristal Alan R. , Ambrosone Christine B. , King Irena B. , Thornquist Mark , Goodman Gary G.
Published: August 2009

We investigated dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, double-blinded, placebo-controlled trial testing a daily dose of 30 mg β-carotene + 25,000 IU retinyl palmitate for lung cancer prevention (1985-1996; active follow-up occurred through 2005). Secondary outcomes, including prostate cancer, were also assessed. Participants were queried about dietary supplements, health history, family history of cancer, smoking, and lifestyle habits. Cox proportional hazards regression estimated multivariate-adjusted relative risk [and 95% confidence intervals (95% CI)] of prostate cancer for dietary supplement users and nonusers with or without the high-dose CARET vitamins during the intervention and postintervention phases. After an average of 11 years of follow-up, 890 prostate cancer cases were reported. Neither the CARET nor other supplements were associated with total prostate cancer risk. For aggressive prostate cancer, men in the CARET intervention arm who used additional supplements had a relative risk for aggressive prostate cancer (Gleason ≥7 or stage III/IV) of 1.52 (95% CI, 1.03-2.24; P < 0.05), relative to all others. These associations disappeared in the postintervention period (0.75; 95% CI, 0.51-1.09). Conversely, there was no association of CARET + other supplements with nonaggressive disease, relative to all others. There was no effect modification by smoking or time on CARET intervention in any analyses. CARET only included smokers, so findings reported here may not apply to nonsmokers. Our results are consistent with other studies suggesting that dietary supplements may influence prostate cancer risk.(Cancer Epidemiol Biomarkers Prev 2009;18(8):2202–6)
GSTP1-1 in Ovarian Cyst Fluid and Disease Outcome of Patients With Ovarian Cancer
Authors: Kolwijck Eva , Zusterzeel Petra L.M. , Roelofs Hennie M.J. , Hendriks Jan C. , Peters Wilbert H.M. , Massuger Leon F.A.G.
Published: August 2009

Detoxification enzymes, especially glutathione S-transferase P1-1 (GSTP1-1), have been implicated in resistance to platinum-based chemotherapy. We studied GSTP1-1 levels in ovarian cyst fluid (oCF), obtained during surgery before chemotherapy, of patients with epithelial ovarian cancer and clinical outcomes were correlated. GSTP1-1 was determined by ELISA in oCF of 56 patients with epithelial ovarian cancer and 109 noncancer controls (21 borderline and 88 benign ovarian tumors). Differences in median GSTP1-1 between clinicopathologic subgroups were studied using Mann-Whitney U and Kruskal Wallis tests. Differences in disease-free (DFS) and overall survival (OS) between groups were analyzed by applying Kaplan-Meyer estimates and log-rank tests. Univariate and multivariate analysis were done using Cox proportional hazard model. Significantly higher levels of GSTP1-1 were found in the oCF of malignant (median, 383; range, 10-32,695 ng/mL) compared with benign (median, 20; range, 0-1,128 ng/mL) ovarian tumors (P < 0.01). Significantly higher GSTP1-1 levels were found in patients with advanced International Federation of Gynaecologists and Obstetricians stage (P = 0.01), high-grade tumors (P = 0.44), and/or high levels of preoperative CA 125 (P = 0.01). Of patients who received chemotherapy (stage, ≥Ic; n = 30), high GSTP1-1 levels were significantly associated with a poor DFS and OS (log-rank P = 0.047 and P = 0.033, respectively). International Federation of Gynaecologists and Obstetricians stage was the only independent predictor for DFS. GSTP1-1 was the only independent predictor for OS. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2176–81)
Human Papillomavirus Vaccine Recommendations and Agreement with Mandated Human Papillomavirus Vaccination for 11-to-12-Year-Old Girls: a Statewide Survey of Texas Physicians
Authors: Kahn Jessica A. , Cooper H. Paul , Vadaparampil Susan T. , Pence Barbara C. , Weinberg Armin D. , LoCoco Salvatore J. , Rosenthal Susan L.
Published: August 2009

Background: The purpose of this study was to examine Texas physicians' recommendations for the quadrivalent human papillomavirus (HPV) vaccine in 11-to-12-year-old girls, intention to recommend HPV vaccines to 11-to-12-year-old boys, and attitudes about mandated HPV vaccination for 11-to-12-year-old girls.

Materials and Methods: We conducted a cross-sectional, web-based survey of Texas physicians who provide direct patient care in family medicine, pediatrics, obstetrics/gynecology, and internal medicine in September 2008. The three outcome variables were: HPV vaccine recommendations to 11-to-12-year-old girls, likelihood of recommending the vaccine to 11-to-12-year-old boys, and agreement with mandated vaccination of 11-to-12-year-old girls. Univariate and logistic regression analyses were used to determine practice-related and attitudinal factors associated with each outcome.

Results: Of the 1,122 respondents, 48.5% stated they always recommended HPV vaccines to girls, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. In multivariate logistic regression models, variables independently associated with recommendation to 11-to-12-year-old girls included: percentage of patients with Medicaid [odds ratio (OR), 1.02; 95% confidence interval (95% CI), 1.01-1.03], academic versus nonacademic practice (OR, 2.11; 95% CI, 1.05-4.23), office procedures to maximize vaccination (OR, 1.25; 95% CI, 1.01-1.56), HPV knowledge (OR, 1.25; 95% CI, 1.04-1.49), valuing HPV vaccine information from both professional organizations (OR, 1.90; 95% CI, 1.15-3.16) and professional conferences (OR, 1.68; 95% CI, 1.10-2.57), belief in mandated HPV vaccination (OR, 5.38; 95% CI, 3.28-8.83), and barriers to vaccination (OR, 1.08; 95% CI, 1.00-1.16).

Discussion: Half of the physicians in this study did not follow current recommendations for universal HPV vaccination of 11-to-12-year-old girls. Factors linked to vaccine recommendations may be targeted in educational or policy interventions. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2325–32)
The Association of Lifestyle and Dietary Factors with the Risk for Serrated Polyps of the Colorectum
Authors: Wallace Kristin , Grau Maria V. , Ahnen Dennis , Snover Dale C. , Robertson Douglas J. , Mahnke Daus , Gui Jiang , Barry Elizabeth L. , Summers Robert W. , McKeown-Eyssen Gail , Haile Robert W. , Baron John A.
Published: August 2009

Some serrated polyps of the colorectum are likely preinvasive lesions, evolving through a newly recognized serrated pathway to colorectal cancer. To assess possible risk and protective factors for serrated polyps and particularly to explore differences in risk factors between polyps in the right and left colorectum, we pooled data from three large multicenter chemoprevention trials. A serrated polyp was defined broadly as any serrated lesion (hyperplastic, sessile serrated adenoma, “traditional” serrated adenoma, mixed adenoma) diagnosed during each trial's main treatment period of ∼3 to 4 years. Using generalized linear regression, we computed risk ratios and 95% confidence intervals as measures of the association between risk for serrated polyps and demographic, lifestyle, and dietary variables. Of the 2,830 subjects that completed at least one follow-up exam after randomization, 675 (23.9%) had at least one left-sided serrated polyp and 261 (9.2%) had at least one right-sided lesion. In the left colorectum, obesity, cigarette smoking, dietary fat, total energy intake, and red meat intake were associated with an increased risk for serrated polyps. In the right colon, aspirin treatment was associated with a reduced risk and family history of polyps and folate treatment were associated with an increased risk for serrated polyps. Our results suggest that several common lifestyle and dietary variables are associated with risk for serrated polyps, and some of these may differ for the right and left colorectum. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2310–7)
Race/Ethnicity Has No Effect on Outcome for Breast Cancer Patients Treated at an Academic Center with a Public Hospital
Authors: Chu Quyen D. , Smith Mark H. , Williams Mallory , Panu Lori , Johnson Lester W. , Shi Runhua , Li Benjamin D.L. , Glass Jonathan
Published: August 2009

Background: African American women have a higher breast cancer mortality rate than Caucasian women. To understand this difference, socioeconomic status (SES) needs to be controlled, which can be achieved by evaluating outcome within a population that is underinsured or low SES. We elected to examine the effect of race/ethnicity on outcome of patients with operable breast cancer by evaluating outcome in a population with low SES and similar access to care.

Methods: From a prospective breast cancer database created in 1998, we examined outcome for 786 patients with stage 0 to III breast cancer treated up to September 2008. Patients were treated at Louisiana State University Health Sciences Center in Shreveport and E.A. Conway Hospital and the majority received standard definitive surgery as well as appropriate adjuvant treatment. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, Cox proportional hazards model, independent-samples t test, and χ2 test. P ≤ 0.05 was considered statistically significant.

Results: Sixty percent of patients were African American and over two thirds of patients were classified as either free care or Medicaid. The 5-year overall survival (OS) for African American and Caucasian patients was similar (81% and 84%, respectively; P = 0.23). On multivariate analysis, race/ethnicity was not an independent predictor of OS (P = 0.5); OS for the entire cohort was comparable with what was reported in the National Cancer Data Base.

Conclusion: In a predominantly indigent population, race/ethnicity had no effect on breast cancer outcome. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2157–61)
Cutaneous Melanoma Is Related to Immune Suppression in Kidney Transplant Recipients
Authors: Vajdic Claire M. , van Leeuwen Marina T. , Webster Angela C. , McCredie Margaret R.E. , Stewart John H. , Chapman Jeremy R. , Amin Janaki , McDonald Stephen P. , Grulich Andrew E.
Published: August 2009

Melanoma incidence is increased after organ transplantation, but there is uncertainty as to why this occurs. Diagnoses of invasive melanoma were ascertained in 8,152 kidney transplant recipients (1982-2003) by linking national Australian population-based registers, the Australia and New Zealand Dialysis and Transplant Registry, and the Australian National Cancer Statistics Clearing House. Incidence rate ratios (IRR) and standardized incidence ratios were used to compare melanoma risk during periods of transplant function and failure. Standardized incidence ratios were also computed by time since transplantation. Risk factors were examined using multivariate Poisson regression. Linkage identified 82 melanomas (134/100,000 person-years). Incidence was lower after resumption of dialysis and reduction of immune suppression than during transplant function [IRR, 0.09; 95% confidence interval (95% CI), 0.01-0.66]. During first transplant function, melanoma (n = 74) relative risk peaked in the second year and declined linearly thereafter (P trend = 0.03). During first transplant function, risk was positively associated with increasing year of age (IRR, 1.05; 95% CI, 1.03-1.07) and receipt of lymphocyte-depleting antibody (IRR, 1.73; 95% CI, 1.05-2.84). Female sex (IRR, 0.57; 95% CI, 0.35-0.94), non-Caucasian race (IRR, 0.15; 95% CI, 0.02-1.05), and increasing time since transplantation (P trend = 0.06) were inversely associated with risk. The incidence pattern and risk factor profile for melanoma after transplantation strongly suggest that the current receipt, intensity, and possibly the recency of iatrogenic immunosuppression increase melanoma risk. Melanoma risk was also associated with proxy indicators of high personal sun exposure and sensitivity. These findings show the marked influence of immunologic control over melanoma incidence. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2297–303)
Pregnancy Outcomes among Adult Survivors of Childhood Cancer in the British Childhood Cancer Survivor Study
Authors: Reulen Raoul C. , Zeegers Maurice P. , Wallace W. Hamish B. , Frobisher Clare , Taylor Aliki J. , Lancashire Emma R. , Winter Dave L. , Hawkins Mike M. ,   on behalf of the British Childhood Cancer Survivor Study
Published: August 2009

Purpose: We used data from the first large-scale overwhelmingly population-based study (a) to quantify the risk of adverse pregnancy outcomes in survivors of childhood cancer in relation to cancer type and treatment and (b) to assess live birth rates relative to the general population.

Methods: A questionnaire, including questions inquiring about pregnancy outcomes, was completed by 10,483 survivors. A total of 7,300 pregnancies were reported. Odds ratios (OR) for live birth, miscarriage, termination, stillbirth, premature birth, and low birth weight were calculated for different types of childhood cancer and by whether initial treatment involved chemotherapy and abdominal or brain irradiation. For females, the observed number of live births was compared with that expected based on the general population of England and Wales.

Results: Female survivors exposed to abdominal irradiation had a significantly increased OR of delivering preterm [OR, 3.2; 95% confidence interval (95% CI), 2.1-4.7] and producing offspring with a low birth weight (OR, 1.9; 95% CI, 1.1-3.2). An increased OR of miscarriage was also associated with abdominal radiotherapy (OR, 1.4; 95% CI, 1.0-1.9). The number of live births observed from all female survivors was two thirds of that expected (O/E, 0.64; 95% CI, 0.62-0.66) and lowest among survivors treated with brain (O/E, 0.52; 95% CI, 0.48-0.56) and abdominal radiotherapy (O/E, 0.55; 95% CI, 0.50-0.61).

Conclusion: Female survivors of childhood cancer treated with abdominal radiotherapy are at 3-fold increased risk of delivering preterm, 2-fold increased risk of low birth weight, and a small increased risk of miscarriage. Overall, female survivors produce considerably fewer offspring than expected, particularly those treated with abdominal or brain radiotherapy. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2239–47)
Transferrin Dipstick as a Potential Novel Test for Colon Cancer Screening: A Comparative Study With Immuno Fecal Occult Blood Test
Authors: Sheng Jian-qiu , Li Shi-rong , Wu Zi-tao , Xia Chang-hong , Wu Xia , Chen Jigui , Rao Jianyu
Published: August 2009

Recent proteomic studies identified Transferrin (Tf) as a potential biomarker for cancer. We examined the efficacy of the newly developed Tf dipstick for detecting colorectal cancer and premalignant lesions, and compared that to Immuno Fecal Occult Blood test (IFOBT). Fecal samples from 110 patients including 40 colorectal cancer, 36 premalignant subjects (including 16 with high-risk adenomas and 20 with ulcerative colitis), and 34 low-risk subjects were collected before colonoscopic examination. Compared with IFOBT, Tf had a significantly higher positive rate in patients with colorectal cancer and premalignant lesions (76% for Tf versus 61% for IFOBT, respectively; χ2 = 4.38; P < 0.05). The difference of positivity was mainly observed in patients with premalignant lesions (72% for Tf versus 44% for IFOBT; χ2 = 5.71; P < 0.05), whereas the positive rates in cancer group and in low-risk group were similar (both P > 0.05). Combining Tf with IFOBT together (either/or) had 90% positive rate in cancer patients, 78% in premalignant patients, and 29% in low-risk subjects. The overall accuracy of IFOBT and Tf tests for detecting colorectal cancer and premalignant lesion was 69.0% and 76.4%, respectively. Tf dipstick test seems to be a highly sensitive test for detecting not only cancer, but also premalignant lesions, and provides an additional tool for colorectal cancer screening. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2182–5)
Cancer Incidence in First Generation U.S. Hispanics: Cubans, Mexicans, Puerto Ricans, and New Latinos
Authors: Pinheiro Paulo S. , Sherman Recinda L. , Trapido Edward J. , Fleming Lora E. , Huang Youjie , Gomez-Marin Orlando , Lee David
Published: August 2009

Background:The diversity among Hispanics/Latinos, defined by geographic origin (e.g., Mexico, Puerto Rico, Cuba), has been neglected when assessing cancer morbidity. For the first time in the United States, we estimated cancer rates for Cubans, Mexicans, Puerto Ricans, and other Latinos, and analyzed changes in cancer risk between Hispanics in their countries of origin, U.S. Hispanics in Florida, and non-Hispanic Whites in Florida.

Methods: Florida cancer registry (1999-2001) and the 2000 U.S. Census population data were used. The Hispanic Origin Identification Algorithm was applied to establish Hispanic ethnicity and subpopulation.

Results: The cancer rate of 537/100,000 person-years (95% confidence interval, 522.5-552.5) for Hispanic males in Florida was lower than Whites (601; 595.4-606.9). Among women, these rates were 376 (365.6-387.1) and 460 (455.6-465.4), respectively. Among Florida Hispanics, Puerto Ricans had the highest rates, followed by Cubans. Mexicans had the lowest rates. Rates for Hispanics in Florida were at least 40% higher than Hispanics in their countries of origin, as reported by the IARC.

Conclusion: Substantial variability in cancer rates occurs among Hispanic subpopulations. Cubans, unlike other Hispanics, were comparable with Whites, especially for low rates of cervical and stomach cancers. Despite being overwhelmingly first generation in the U.S. mainland, Puerto Ricans and Cubans in Florida showed rates of colorectal, endometrial, and prostate cancers similar to Whites in Florida. Because rates are markedly lower in their countries of origin, the increased risk for cancer among Cubans, Mexicans, and Puerto Ricans who move to the United States should be further studied. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2162–9)
Internal Validation of Procedure Codes on Medicare Claims for Digital Mammograms and Computer-Aided Detection
Authors: Fenton Joshua J. , Green Pamela , Baldwin Laura-Mae
Published: August 2009

Background: Billing data, such as Medicare claims, are a potential data source for evaluative studies of new digital mammography technologies, such as digital mammography and computer-aided detection (CAD).

Objective: To assess the internal validity of procedure codes on Medicare claims for screening mammography interpreted with either digital mammography or CAD.

Study Design: We assessed agreement of procedure coding for digital versus film mammography and CAD use versus nonuse for mammograms with claims appearing in two independent Medicare claims files (the Carrier Claims and Outpatient files).

Subjects and Setting: Women enrolled in fee-for-service Medicare who received screening mammography in 2001 to 2003 within Surveillance, Epidemiology, and End Results regions, representing 25% of the U.S. population (n = 35,642 women who received 57,632 total mammograms).

Measures: Coding agreement beyond chance (κ), overall, and by year.

Results: Overall coding agreement was excellent for both digital versus film mammography [κ = 0.81 (95% confidence interval, 0.80-0.83)] and for CAD use versus nonuse [κ = 0.82 (95% confidence interval, 0.81-0.83)]. However, in 2001, agreement was only moderate (κ = 0.51 for digital versus film and κ = 0.50 for CAD use versus nonuse) but increased to higher levels in 2002 and 2003 (κ > 0.80 for both technologies).

Conclusions: High internal agreement in procedure codes for digital mammography technologies is consistent with accurate coding on Medicare claims after 2001, although external validation remains desirable. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2186–9)
Artificial Sweeteners and the Risk of Gastric, Pancreatic, and Endometrial Cancers in Italy
Authors: Bosetti Cristina , Gallus Silvano , Talamini Renato , Montella Maurizio , Franceschi Silvia , Negri Eva , La Vecchia Carlo
Published: August 2009

Background: The role of sweeteners on cancer risk has been widely debated over the last few decades. To provide additional information on saccharin and other artificial or low-calorie sweeteners (mainly aspartame), we updated the analysis of an integrated network of case-control studies conducted in Italy between 1991 and 2004 including data on cancers of the stomach, pancreas, and endometrium.

Patients and Methods: Cases were 230 patients with incident, histologically confirmed cancers of the stomach and 547 corresponding controls, 326 of the pancreas and 652 controls, and 454 of the endometrium and 908 controls. All controls were patients admitted to the same hospitals as cases for acute, non-neoplastic disorders. Odds ratios (OR) and corresponding confidence intervals (CI) were derived by unconditional logistic regression models.

Results: After allowance for various confounding factors, ORs for ever users of sweeteners versus nonusers were 0.80 (95% CI, 0.45-1.43) for gastric cancer, 0.62 (95% CI, 0.37-1.04) for pancreatic cancer, and 0.96 (95% CI, 0.67-1.40) for endometrial cancer. Corresponding ORs for saccharin were 0.65, 0.19, and 0.71, and for other sweeteners were 0.86, 1.16, and 1.07, respectively, for the three cancer sites.

Conclusions: The present study adds further evidence on the absence of an adverse effect of low-calorie sweetener (including aspartame) consumption on the risk of common neoplams in the Italian population. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2235–8)
Changes in Anterior Chamber Depth due to Contusion
Authors: Kashiwagi Kenji , Tateno Yasushi , Kashiwagi Fumiko , Tsukahara Shigeo
Published: August 2009

Purpose: We aimed to investigate changes in anterior chamber depth (ACD) prospectively in patients with recent unilateral contusion but no signs of angle recession, using a scanning peripheral anterior chamber depth analyzer (SPAC). Methods: Among patients whose chief complaint was recent unilateral contusion and who showed no signs of angle recession by gonioscopy in 2006 and 2007, those who satisfied the following criteria were subjected to SPAC evaluation of ACD from the central to the peripheral region: no history of ocular diseases or ocular surgery including laser treatment, and similar refractory error in both eyes before trauma. Results: Thirty-seven patients satisfied the criteria (29 males, 8 females; age: 28.6 ± 23.5 years). Fourteen patients presented with commotio retinae. Fifteen showed no ocular manifestations related to the contusion. The mean SPAC-determined ACD grades of contused and noncontused eyes were 10.7 ± 1.6 and 9.8 ± 2.1, respectively, demonstrating that the contused eyes had significantly larger ACD values than the noncontused ones (p = 0.0005). The contused eyes had larger ACD values in both the central and the peripheral regions. The difference in ACD between the contused and noncontused eyes tended to increase with greater distance from the center. The equivalent refractive errors were –2.3 ± 2.2 and –1.7 ± 2.1 dpt, respectively (p = 0.004). There were no significant differences in best-corrected visual acuity and intraocular pressure between the contused and the noncontused eyes. Conclusion: Contusion may increase ACD particularly in the peripheral region even in patients who have no apparent manifestations in the anterior ocular segment.
Structural Insights into the Recognition Properties of Human Ficolins
Authors: Garlatti Virginie , Martin Lydie , Lacroix Monique , Gout Evelyne , Arlaud Gérard J. , Thielens Nicole M. , Gaboriaud Christine
Published: August 2009

Innate immunity relies upon the ability of a variety of recognition molecules to sense pathogens through conserved molecular signatures that are often carbohydrates. Ficolins are oligomeric proteins assembled from collagen-like stalks and fibrinogen-like domains that have the ability to sense these molecular patterns on both pathogens and apoptotic cell surfaces. Three ficolins, termed L, H and M, have been identified in humans. They differ in their localization and concentration in extracellular fluids, their mode of secretion and their recognition properties. From a structural point of view, ficolins are assembled from basal trimeric subunits comprising a collagen-like triple helix and a globular domain composed of 3 fibrinogen-like domains. The globular domains are responsible for sensing danger signals whereas the collagen-like stalks provide a link with immune effectors. This review mainly focuses on the structure and recognition properties of the 3 human ficolins, as revealed by recent crystallographic analysis of their recognition domains. The ligand binding sites have been identified in the 3 ficolins and their recognition mechanisms have been characterized at the atomic level. In the case of M-ficolin, a structural transition at acidic pH disables the binding pocket, and thus likely participates in the functional cycle of this protein.
Role of Cytokines and Platelet-Activating Factor in Microvascular Immune Injury
Authors: Braquet Pierre , Hosford David , Braquet Monique , Bourgain Rene , Bussolino Federico
Published: August 2009

Inflammation is usually a tightly controlled process which confines tissue damage, prevents infection, and assists in cellular regeneration. However, if the inflammatory response becomes unregulated, this normally beneficial local event may escalate into a wider malignant activity, characterized by endothelial injury, excessive cell infiltration, and vascular leakage. Due to the ability of platelet-activating factor and tumor necrosis factor to elicit the release of each other, ‘prime’ cell responses, and influence the activity of other cytokines, we propose that these two mediators play a pivotal role in the formation of deleterious feedback cycles leading to the above endothelial damage which may underlie pathologies such as shock, sepsis, ischemia, and asthma. Platelet-activating factor antagonists such as BN 52021 inhibit the priming and other effects induced by platelet-activating factor and thus may be of therapeutic value in such conditions.
Possible Role of IL-6 in Pathogenesis of Immune Complex-Mediated Glomerulonephritis in NZB/W F1 Mice: Induction of IgG Class Anti-DNA Autoantibody Production
Authors: Mihara Masahiko , Ohsugi Yoshiyuki
Published: August 2009

This study demonstrates that interleukin-6 (IL-6) increases the autoantibody production by B cells from NZB/W F1 mice. Splenic B cells were cultured for 5 days in the presence or absence of human IL-6, and then the anti-DNA antibody and immunoglobulin contents in the culture supernatants were measured by ELISA. Adding IL-6 increased IgG anti-DNA antibody production by B cells from old mice (30 weeks), but not from young ones (17 weeks). B cells obtained from both young and old mice produced IgM anti-DNA antibody, which increased when IL-6 was added. The increased anti-DNA antibody production was suppressed by anti-recombinant human IL-6 antibody to the background level, i.e. antibody contents in the absence of IL-6. In contrast, murine IL-5 did not increase IgG anti-DNA antibody production, although it promoted the production of IgM anti-DNA antibody. Furthermore, when IL-5 was added in combination with IL-6, there was an additive increase in IgM, but not in IgG anti-DNA antibody production. Similar results were obtained in the measurement of the immunoglobulin contents. These results suggest the possible role of IL-6 in the pathogenesis of autoimmune disease in NZB/W Fl mice.
Protein S as Cofactor for TFPI
Authors: Hackeng Tilman M. , Rosing Jan
Published: August 2009

In the last decades evidence was obtained that protein S not only acts as cofactor of activated protein C (APC) in the downregulation of coagulation, but also expresses anticoagulant activity in the absence of APC. The search for the mechanism(s) underlying the APC-independent anticoagulant activity of protein S was hampered by the fact that protein S exhibited 2 seemingly identical anticoagulant activities in model systems and in plasma. Later it was shown that the anticoagulant activity of purified protein S in model systems was dependent on the concentration of phospholipid vesicles and was explained by low amounts of protein S multimers generated during purification that effectively inhibited phospholipid-dependent coagulation reactions via competition for phospholipid binding sites. Plasma does not contain multimers, and the anticoagulant activity of protein S in plasma was not affected by the phospholipid concentration but was dependent on the amount of tissue factor (TF) used for initiation of thrombin generation. This led to the discovery that protein S acts as cofactor of tissue factor pathway inhibitor (TFPI) which stimulates the inhibition of factor Xa by TFPI ≈10-fold. The current review describes the background of the TFPI-cofactor activity of protein S as well as the rationale for the observation that the TFPI/protein S system particularly inhibits the TF pathway at low procoagulant stimuli.
Identification and Functional Analyses of Molecular Haplotypes of the Human Osteoprotegerin Gene Promoter
Authors: Hagedorn Claudia , Telgmann Ralph , Dördelmann Corinna , Schmitz Boris , Hasenkamp Sandra , Cambien François , Paul Martin , Brand Eva , Brand-Herrmann Stefan-Martin
Published: August 2009

Objective—

Osteoprotegerin (OPG) has been reported to be involved in the development of atherosclerotic disease, and
OPG
gene variation has been associated with plasma OPG levels and different cardiovascular disease phenotypes. However, the genetic architecture of the
OPG
promoter and its transcriptional regulation are poorly characterized.

Methods and Results—

We identified 1008 bp of the
OPG
5′-flanking region to be sufficiently transcriptionally active in osteosarcoma cell lines and generated serial promoter deletion constructs. Individual subcloning revealed the existence of 3 molecular haplotypes (MolHaps): [T
−960
-A
−946
-G
−900
-T
−864
; MolHap1, wild type], [T
−960
-G
−946
-G
−900
-T
−864
; MolHap2], [C
−960
-G
−946
-A
−900
-G
−864
; MolHap4]. Compared to MolHap1, transcriptional activities of MolHaps 2 and 4 were significantly reduced (
P
=0.0018). Whereas introduction of the −159C allele reduced transcriptional activities of the full-length constructs (
P
=0.0014), it significantly increased activities of the deletion constructs (
P
=0.0005). Electrophoretic mobility shift, competition, and chromatin immunoprecipitation assays revealed specific DNA:protein interactions for the MolHaps with Sp1 and NF-1, and identified Egr1 interacting exclusively with the −159T allele.

Conclusions—

We propose new structural and transcriptional features within the
OPG
promoter region and identified MolHaps being differentially transcriptionally active and allele-dependently interacting with a proximal polymorphic site.
Saturated Fatty Acids Do Not Directly Stimulate Toll-Like Receptor Signaling
Authors: Erridge Clett , Samani Nilesh J.
Published: August 2009

Objective—

Toll-like receptors (TLRs) initiate inflammatory signaling in response to conserved microbial molecules. It has been proposed that dietary saturated fatty acids (SFAs) may also serve as endogenous ligands of TLR2 or TLR4, thereby promoting diseases associated with inflammation and dyslipidemia, including atherosclerosis and insulin resistance.

Methods and Results—

We investigated the effects of SFAs on TLR-dependent signaling using a broad range of cell types and readouts. In HEK-293 cells transfected with TLR2, TLR4, or TLR5, SFAs complexed with fatty-acid-free bovine serum albumin (BSA)-stimulated TLR-dependent signaling. However, SFAs alone did not elicit a similar response. Further analysis showed that the effect seen with the complexed SFAs was attributable to LPS and lipopeptide contamination of fatty-acid-free BSA. Additional studies in macrophages, endothelial cells, smooth muscle cells, adipocytes, skeletal muscle cells, and human peripheral blood mononuclear cells confirmed the lack of stimulation of TLR-dependent signaling pathways or expression of TLR-target genes by SFAs.

Conclusions—

SFAs do not directly stimulate TLR-dependent signaling, suggesting that alternative mechanisms link dietary fat intake with TLR-associated pathologies. LPS and lipopeptide contamination of the widely used reagent fatty-acid-free BSA explains the previously reported stimulation of TLR2 and TLR4 by SFAs.