bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Admixture among Hispanics and Candidate Gene Polymorphisms: Potential for Confounding in a Breast Cancer Study?
Authors: Sweeney Carol , Wolff Roger K. , Byers Tim , Baumgartner Kathy B. , Giuliano Anna R. , Herrick Jennifer S. , Murtaugh Maureen A. , Samowitz Wade S. , Slattery Martha L.
Published: January 2007

Hispanics in the U.S. Southwest have genetic ancestry from Europeans and from American Indians, two groups with markedly different breast cancer incidence rates. Genetic admixture may therefore bias estimates of associations between candidate cancer susceptibility genes and breast cancer in Hispanics. We estimated genetic admixture using 15 ancestry-informative markers for 1,239 Hispanics and 2,505 non-Hispanic Whites in a breast cancer case-control study in the Southwest, the Four Corners Study. Confounding risk ratios (CRR) were calculated to quantify potential bias due to admixture. Genetic admixture was strongly related to self-reported race and ethnic background (P < 0.0001). Among Hispanic controls, admixture was significantly associated with allele frequency for 5 of 11 candidate gene single nucleotide polymorphisms (SNP) examined. Hispanics in the highest versus the lowest quintile of American Indian admixture had higher mean body mass index at age 30 years (25.4 versus 23.6 kg/m2; P = 0.003), shorter mean height (1.56 versus 1.58 m; P = 0.01), higher prevalence of diabetes (14.8% versus 7.2%; P = 0.04), and a larger proportion with less than a high school education (38.5% versus 23.2%; P = 0.001). Admixture was not associated with breast cancer risk among Hispanics (P = 0.65). CRRs for potential bias to candidate SNP-breast cancer risk ratios ranged from 0.99 to 1.01. Thus, although genetic admixture in Hispanics was associated with exposures, confounding by admixture was negligible due to the null association between admixture and breast cancer. CRRs from simulated scenarios indicated that appreciable confounding by admixture would occur only when within-group candidate SNP allele frequency differences are much larger than any that we observed. (Cancer Epidemiol Biomarkers Prev 2007;16(1):142–50)
High-Order Interactions among Genetic Variants in DNA Base Excision Repair Pathway Genes and Smoking in Bladder Cancer Susceptibility
Authors: Huang Maosheng , Dinney Colin P. , Lin Xin , Lin Jie , Grossman H. Barton , Wu Xifeng
Published: January 2007

Cancer is a common multifactor human disease resulting from complex interactions between many genetic and environmental factors. In this study, we used a multifaceted analytic approach to explore the relationship between eight single nucleotide polymorphisms in base excision repair (BER) pathway genes, smoking, and bladder cancer susceptibility in a hospital-based case-control study. Overall, we did not find an association between any single BER gene single nucleotide polymorphism and bladder cancer risk. However, in stratified analysis, the OGG1 S326C variant genotypes in ever smokers (odds ratio, 0.74; 95% confidence interval, 0.56-0.99) and ADP-ribosyltransferase (ADPRT) V762A variant genotypes in never smokers (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) conferred a significantly reduced risk. Using logistic regression, we observed that there was a two-way interaction between ADPRT V762A and smoking status. We next used classification and regression tree analysis to explore high-order gene-gene and gene-environment interactions. We found that smoking is the most important influential factor for bladder cancer risk. Consistent with the above findings, we found that the ADPRT V762A was only significantly involved in bladder cancer risk in never smokers and the OGG1 S326C was only significantly involved in ever smokers. We also observed gene-gene interactions among OGG1 S326C, XRCC1 R194W, and MUTYH H335Q in ever smokers. Using multifactor dimensionality reduction approach, the four-factor model, including smoking status, OGG1 S326C (rs1052133), APEX1 D148E (rs3136820), and ADPRT762 (rs1136410), had the best ability to predict bladder cancer risk with the highest cross-validation consistency (100%) and the lowest prediction error (37.02%; P < 0.001). These results support the hypothesis that genetic variants in BER genes contribute to bladder cancer risk through gene-gene and gene-environmental interactions. (Cancer Epidemiol Biomarkers Prev 2007;16(1):84–91)
Mammographic Breast Density as a General Marker of Breast Cancer Risk
Authors: Vachon Celine M. , Brandt Kathleen R. , Ghosh Karthik , Scott Christopher G. , Maloney Shaun D. , Carston Michael J. , Pankratz V. Shane , Sellers Thomas A.
Published: January 2007

Mammographic breast density is a strong risk factor for breast cancer but whether breast density is a general marker of susceptibility or is specific to the location of the eventual cancer is unknown. A study of 372 incident breast cancer cases and 713 matched controls was conducted within the Mayo Clinic mammography screening practice. Mammograms on average 7 years before breast cancer were digitized, and quantitative measures of percentage density and dense area from each side and view were estimated. A regional density estimate accounting for overall percentage density was calculated from both mammogram views. Location of breast cancer and potential confounders were abstracted from medical records. Conditional logistic regression was used to estimate associations, and C-statistics were used to evaluate the strength of risk prediction. There were increasing trends in breast cancer risk with increasing quartiles of percentage density and dense area, irrespective of the side of the breast with cancer (Ptrends < 0.001). Percentage density from the ipsilateral side [craniocaudal (CC): odds ratios (ORs), 1.0 (ref), 1.7, 3.1, and 3.1; mediolateral oblique (MLO): ORs, 1.0 (ref), 1.5, 2.2, and 2.8] and the contralateral side [CC: ORs, 1.0 (ref), 1.8, 2.2, and 3.7; MLO: ORs, 1.0 (ref), 1.6, 1.9, and 2.5] similarly predicted case-control status (C-statistics, 0.64-65). Accounting for overall percentage density, density in the region where the cancer subsequently developed was not a significant risk factor [CC: 1.0 (ref), 1.3, 1.0, and 1.2; MLO: 1.0 (ref), 1.1, 1.0, and 1.1 for increasing quartiles]. Results did not change when examining mammograms 3 years on average before the cancer. Overall mammographic density seems to represent a general marker of breast cancer risk that is not specific to breast side or location of the eventual cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(1):43–9)
Endogenous Androgens and Risk of Epithelial Ovarian Cancer: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC)
Authors: Rinaldi Sabina , Dossus Laure , Lukanova Annekatrin , Peeters Petra H.M. , Allen Naomi E. , Key Timothy , Bingham Sheila , Khaw Kay-Tee , Trichopoulos Dimitrios , Trichopoulou Antonia , Oikonomou Eleni , Pera Guillem , Larrañaga Nerea , Martinez-Garcia Carmen , Ardanaz Eva , Quirós J. Ramón , Tormo María-José , Tjønneland Anne , Olsen Anja , Overvad Kim , Chang-Claude Jenny , Linseisen Jakob , Schulz Mandy , Boeing Heiner , van Gils Carla H. , Bueno-de-Mesquita Bas H. , Pala Valeria , Palli Domenico , Panico Salvatore , Tumino Rosario , Vineis Paolo , Clavel-Chapelon Françoise , Mesrine Sylvie , Boutron-Ruault Marie-Christine , Lundin Eva , Ågren Åsa , Berglund Göran , Manjer Jonas , Kumle Merethe , Lund Eiliv , Slimani Nadia , Saracci Rodolfo , Riboli Elio , Kaaks Rudolf
Published: January 2007

Few epidemiologic studies have examined the hypothesis that circulating androgens are involved in the development of ovarian cancer. We investigated the association between prediagnostic serum levels of androgens and sex hormone–binding globulin (SHBG) and ovarian cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort. One hundred and ninety-two ovarian cancer cases and 346 matched controls not using exogenous hormones at baseline blood donation were eligible for the study. Serum levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, and SHBG were measured by direct immunoassays. Free testosterone (fT) was calculated according to mass action laws. Multivariate conditional logistic regression was used to estimate odds ratios adjusted for possible confounders. Overall, there was no association between serum concentrations of androgens or SHBG and ovarian cancer risk. In postmenopausal women, fT concentrations were inversely related to risk [highest versus lowest tertile odds ratio 0.45 (0.24-0.86); Ptrend = 0.01]. Among women diagnosed before the age of 55 years, there was a negative association with SHBG and a positive association with fT and ovarian cancer risk, although these associations were not statistically significant. The present study suggests that circulating androgens and SHBG levels are not strongly associated with ovarian cancer risk, although levels of fT may be associated with an increased risk among women diagnosed at relatively young age. The heterogeneity of results on the associations of fT with ovarian cancer risk in postmenopausal women deserves further investigation. (Cancer Epidemiol Biomarkers Prev 2007;16(1):23–9)
Flavonoids and the Risk of Renal Cell Carcinoma
Authors: Bosetti Cristina , Rossi Marta , McLaughlin Joseph K. , Negri Eva , Talamini Renato , Lagiou Pagona , Montella Maurizio , Ramazzotti Valerio , Franceschi Silvia , LaVecchia Carlo
Published: January 2007

Intake of flavonoids has been inversely related to the risk of various common neoplasms, but limited data exist on renal cell carcinoma (RCC). We used data from a case-control study conducted between 1994 and 2002 in four Italian areas to study the relation between major flavonoid classes and RCC. The study included 767 cases with incident, histologically confirmed RCC and 1,534 hospital controls admitted for acute, nonneoplastic conditions and matched with cases by study center, sex, and quinquennia of age. We applied published data on food and beverage content of six major classes of flavonoids to dietary information collected through a validated food frequency questionnaire. After adjustment for major recognized confounding factors and total energy intake, the odds ratios for subjects in the highest versus the lowest quintile of intake were 0.80 [95% confidence interval (95% CI), 0.58-1.11] for total flavonoids, 0.76 (95% CI, 0.56-1.03) for isoflavones, 0.94 (95% CI, 0.60-1.47) for anthocyanidins, 0.77 (95% CI, 0.56-1.06) for flavan-3-ols, 0.90 (95% CI, 0.67-1.21) for flavanones, 0.68 (95% CI, 0.50-0.93) for flavones, and 0.69 (95% CI, 0.50-0.95) for flavonols. Allowance for vegetable and fruit consumption only partly explained these inverse relations. Thus, flavonoids, and particularly flavones and flavonols, may account, at least in part, for the favorable role of plant foods on RCC. (Cancer Epidemiol Biomarkers Prev 2007;16(1):98–101)
Adenovirus type 5 E1A gene therapy for ovarian clear cell carcinoma: a potential treatment strategy
Authors: Itamochi Hiroaki , Kigawa Junzo , Kanamori Yasunobu , Oishi Tetsuro , Bartholomeusz Chandra , Nahta Rita , Esteva Francisco J. , Sneige Nour , Terakawa Naoki , Ueno Naoto T.
Published: January 2007

Resistance of ovarian clear cell carcinoma (CCC) to platinum-based chemotherapy is associated with poor prognosis, and an effective treatment for advanced disease is urgently needed. HER2/neu is up-regulated more often in CCC than in other histologic types of epithelial ovarian cancer. The purpose of this study was to assess possible treatment for ovarian CCC with the anti-HER2 antibody trastuzumab or human adenovirus type 5 E1A. We treated 10 CCC cell lines with trastuzumab or E1A and assessed cell viability, proliferation, and colony formation and the expression of HER2 and wild-type p53 proteins and molecules downstream of those signaling pathways. HER2 protein was detected at various levels in all 10 cell lines by Western blotting and in 5 CCC cell lines by immunohistochemical staining; HER2 gene amplification was detected (by fluorescence in situ hybridization) in only one cell line (RMG-I). Trastuzumab did not inhibit proliferation in any of the four CCC cell lines tested (RMG-I, SKOV-2, OVTOKO, and OVSAYO). However, transfection with E1A (as compared with control vectors) reduced colony formation in all 10 CCC cell lines regardless of HER2 expression level. Infection of RMG-I and SMOV-2 cells with an adenoviral vector encoding E1A led to significant (P < 0.05) suppression of proliferation and enhancement of cell death; this effect required stabilization of p53 (but not p73) protein and was associated with the up-regulation of Bax and the cleavage of caspase-9. Other mechanisms, such as p53-independent apoptosis, may also be involved in E1A-mediated cell death in CCC. Finally, treatment with E1A prolonged survival in a CCC xenograft model (P < 0.001). E1A gene therapy, because of its ability to stabilize wild-type p53, is worth exploring as a treatment modality for women with ovarian CCC, which typically expresses wild-type p53. [Mol Cancer Ther 2007;6(1):227–35]
Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells
Authors: Kamada Masayuki , So Alan , Muramaki Mototsugu , Rocchi Palma , Beraldi Eliana , Gleave Martin
Published: January 2007

Heat shock protein 27 (Hsp27) is a cytoprotective chaperone that is phosphoactivated during cell stress that prevents aggregation and/or regulate activity and degradation of certain client proteins. Recent evidence suggests that Hsp27 may be involved in tumor progression and the development of treatment resistance in various tumors, including bladder cancer. The purpose of this study was to examine, both in vitro and in vivo, the effects of overexpression of Hsp27 and, correspondingly, the down-regulation of Hsp27 using small interfering (si) RNA and OGX-427, a second-generation antisense oligonucleotide targeting Hsp27. Hsp27 overexpression increased UMUC-3 cell growth and resistance to paclitaxel. Both OGX-427 and Hsp27 siRNA decreased Hsp27 protein and mRNA levels by >90% in a dose- and sequence-specific manner in human bladder cancer UMUC-3 cells. OGX-427 or Hsp27 siRNA treatment induced apoptosis and enhanced sensitivity to paclitaxel in UMUC-3 cells. In vivo, OGX-427 significantly inhibited tumor growth in mice, enhanced sensitivity to paclitaxel, and induced significantly higher levels of apoptosis compared with xenografts treated with control oligonucleotides. Collectively, these findings suggest that Hsp27 knockdown with OGX-427 and combined therapy with paclitaxel could be a novel strategy to inhibit the progression of bladder cancer. [Mol Cancer Ther 2007;6(1):299–308]
Diet Regulates the Development of Gut-Associated Lymphoid Tissue in Neonatal Piglets
Authors: Helm Ricki M. , Golden Chris , McMahon Meredith , Thampi Prajitha , Badger Thomas M. , Nagarajan Shanmugam
Published: January 2007

Background: Controversy exists concerning diet-induced changes to gut epithelia and immunocytes that occur during weaning. Furthermore, studies on dietary effects on the development of the neonatal immune system, especially gut-associated lymphoid tissue (GALT), are lacking. Objective: The purpose of this study was to investigate growth and development, intestinal morphology, and GALT immune maturation in sow-reared littermates in comparison with early-weaned piglets fed a casein-based liquid diet. Method: Piglets were breast fed by the sow or were weaned at 48 h to a casein-based diet (formula) that provided the amount of nutrient requirements recommended by the National Research Council. Results: Gross physical appearance and visual inspection of the gastrointestinal tract and other organs at necropsy revealed normal organogenesis in both cohorts. On postnatal day 21, body weight, liver and kidney weight relative to body weight, small intestine length, and weight-to-length ratio were greater in formula-fed piglets as compared with sow-reared piglets (p < 0.05). The CD21+ B lymphocyte component of GALT and spleen was reduced in the formula-fed piglets. This was associated with lower circulating IgG and IgM levels in the formula-fed as compared with the breast-fed neonatal piglets (p < 0.001). Conclusions: Feeding a casein-based formula to newborn piglets may compromise the development of GALT and systemic immune system. Further, the neonatal piglet model may be used to identify the effects of dietary factors on the development of the neonatal immune system.
Gamma-Knife-Based Stereotactic Radiosurgery for Uveal Melanoma
Authors: Fakiris Achilles J. , Lo Simon S. , Henderson Mark A. , Witt Thomas C. , Worth Robert M. , Danis Ronald P. , Des Rosiers Paul M. , Timmerman Robert D.
Published: January 2007

Nineteen patients with uveal melanoma were treated with Gamma-Knife-based stereotactic radiosurgery (SRS). The radiation dose was 40 Gy prescribed to the 50% isodose line for all patients. The median follow-up was 40 months. The 3- and 5-year overall survival rates were 86 and 55%, respectively. The 3- and 5-year tumor control rates were both 94%. Six of the 19 treated patients (32%) developed distant metastasis 31–75 months after SRS. Out of the 19 patients treated with SRS, 2 had improved, 4 had stable and 13 had worse vision in the treated eye. Gamma-Knife-based SRS appears to provide excellent local control of uveal melanoma. The risk of distant metastasis is significant. Effective systemic therapy is to be explored to improve the treatment outcome of uveal melanoma.
Bilateral Stereotactic Amygdalotomy for Self-Mutilation Disorder
Authors: Fountas Kostas N. , Smith Joseph R. , Lee Gregory P.
Published: January 2007

Bilateral stereotactic amygdalotomy for the management of patients with severe aggressive behavior disturbances was first introduced by Hideki Narabayashi in 1961. Since then, more than 500 cases have been reported in scientific literature, with a variety of cited behavior improvement rates. The advances of psychopharmacology along with the existent skepticism of the medical community in regards to psychosurgery have resulted in a dramatic decrease in the number of amygdalotomies performed worldwide. In our current communication, we report a case of bilateral stereotactic amygdalotomy for a medically refractory self-mutilation disorder. We also review the pertinent literature with an emphasis on the selection of the most appropriate anatomical targets, the procedure-related complications and the outcomes of this occasionally helpful procedure.
Longitudinal Study of the Simultaneous Secretion of Melatonin and Leptin during Normal Puberty
Authors: Molina-Carballo A. , Fernández-Tardáguila E. , Uberos-Fernández J. , Seiquer I. , Contreras-Chova F. , Muñoz-Hoyos A.
Published: January 2007

Background/Aims: Pubertal changes are a consequence of the activation of the hypothalamic-pituitary-gonadal axis due to an increase in the frequency and magnitude of pulses of gonadotropin-releasing hormone (GnRH), which may depend on the intrinsic properties of the neurons of the hypothalamic arcuatus nucleus, or on the influence of neurotransmitters and/or neuromodulators. We evaluated the serum concentrations of melatonin and leptin in healthy prepubertal and adolescent subjects of both sexes, to define their participation at the initial stages and during the progression of pubertal development. Methods: 80 pediatric subjects (47 females and 33 males), aged 6–18 years, were divided into 2 groups, prepubertal (n = 25) and adolescent (n = 55), according to the absence or presence, respectively, of physical signs of pubertal development. The subjects were assessed on two occasions: at the time of their inclusion in the study, and 12–18 months later when the subject had advanced one pubertal stage according to the Tanner classification. Blood was obtained in fasting for clinical purposes and for the hormonal study. Melatonin and leptin were measured by radioimmunoanalysis. Results: As described previously, melatonin decreases at the onset of puberty and during pubertal development. Both the absolute melatonin value and the decrease between evaluations tended to be greater in females; the variations were correlated with neither an increase in body weight nor with the degree of pubertal development. The concentration of leptin increased in both sexes with the progression of puberty, this value being 40% greater in women, and correlated with the indicators of an increase in body volume and fat accumulation. Although its concentration remained stable between evaluations for both sexes, among the males the association between leptin and pubertal development took place at the start of the process, while for the females we observed a significant overall association between pubertal stage and leptin concentration, this association being stronger at more advanced Tanner stages. Neither at the onset of puberty nor during its course did we observe any significant relation between melatonin concentration and any of the Tanner stages, whether for males or for females. Neither was there any correlation between the absolute values or rates of modification of melatonin and leptin. Conclusion: According to the evolutionary dynamics of their respective concentrations, both initially and during pubertal progress, melatonin and leptin do not interact in the initiation or progression of human pubertal development, and do not seem to play a key role in this process.
Preserved Bone Health in Adolescent Elite Rhythmic Gymnasts despite Hypoleptinemia
Authors: Courteix D. , Rieth N. , Thomas T. , Van Praagh E. , Benhamou C.L. , Collomp K. , Lespessailles E. , Jaffré C.
Published: January 2007

Background/ Aims: Leptin is linked to hormonal disturbances occurring in anorexia and positively linked with bone mineral density. The aim of this study was to determine whether hypoleptinemia occurring in rhythmic gymnasts may affect bone health. Method: Leptin, insulin, cortisol, IGF1 levels and bone markers were determined in 36 rhythmic gymnasts (EG) and 20 controls (C). Body composition, BMD at the whole body (WBBMD), lumbar spine (LSBMD) and bone ultrasound properties (SOS, BUA) were measured. Results: The rhythmic gymnasts had lower fat mass and leptin level than the controls. There was no difference for IGF1, cortisol and insulin levels. Bone turnover rate was higher in elite gymnasts. The uncoupling index showed that remodeling favored the bone formation. LSBMD, WBBMD, SOS and BUA were higher in elite gymnasts after adjustment for fat mass. Leptin correlated positively with fat mass and negatively with physical activity. Conclusion: High impact training is able to counterbalance bone effects usually encountered in hormonally disturbed subjects. Our results suggest that hypoleptinaemia might be related to direct osteogenic effects and indirect hormonal mechanisms including preservation of IGF and cortisol levels.
Steroid-Dependent ACTH-Produced Thymic Carcinoid: Regulation of POMC Gene Expression by Cortisol via Methylation of Its Promoter Region
Authors: Mizoguchi Yoko , Kajiume Teruyuki , Miyagawa Shin-ichiro , Okada Satoshi , Nishi Yoshikazu , Kobayashi Masao
Published: January 2007

Aims: Metyrapone causes a decrease in the serum cortisol level without affecting ACTH production in ectopic tumors. We report a case who presented with Cushing’s syndrome due to an ectopic ACTH-producing thymic carcinoid. In the present case, it was demonstrated that metyrapone administration resulted in a significant decrease in the plasma ACTH and serum cortisol levels. We hypothesized that the steroid hormone may promote proopiomelanocortin (POMC) gene expression in the carcinoid cells. Methods: An 11-year-old boy presented with Cushing’s syndrome. Prior to the detection of a thymic tumor, metyrapone was administered to ameliorate the symptoms of Cushing’s syndrome. Interestingly, plasma ACTH as well as serum cortisol levels immediately decreased after metyrapone administration. The levels of cortisol and ACTH were observed to be normal after complete surgical resection of the tumor. Biological characterization of the tumor cells was by in vitro analysis. Results: Thein vitro culture of the tumor cells showed an increased expression of POMC in the presence of cortisol. A CpG methylation assay showed that the demethylation of the POMC promoter was induced by a steroid hormone. Conclusion: These findings suggest that the ectopic ACTH-producing tumor may partly be regulated by the elevated levels of cortisol.
Association between Haptoglobin Gene Variants and Diabetic Nephropathy: Haptoglobin Polymorphism in Nephropathy Susceptibility
Authors: Conway Bryan R. , Savage David A. , Brady Hugh R. , Maxwell Alexander P.
Published: January 2007

Background/Aims: The Hp1/Hp2 DNA polymorphism has previously been implicated in susceptibility to diabetic nephropathy in some but not all studies. In an attempt to clarify these conflicting findings, we conducted a case-control association study in a Caucasian population. Methods: We recruited 224 and 285 type 1 diabetic patients with (cases) and without (controls) nephropathy, respectively, from 2 centres based in Northern Ireland and the Republic of Ireland. Hp1/Hp2 genotyping was performed using a combination of long-range and multiplex PCR. Allele and genotype frequencies in cases and controls were compared using the χ2 test. Results: There was a statistically significant increase in the frequency of the Hp2 allele in cases compared to controls (65.6 vs. 58.6%, OR = 1.35, 95% CI: 1.04–1.76, p = 0.03). The distributions of genotypes were in Hardy-Weinberg equilibrium for both cases and controls, and the overall frequency of the Hp1 allele was 38.3%, which is similar to that found in other Western European populations. Conclusions: The results suggest that the Hp2 allele may confer susceptibility to nephropathy in patients with type 1 diabetes.
Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE−/−Mice
Authors: Davis Harry R. , Hoos Lizbeth M. , Tetzloff Glen , Maguire Maureen , Zhu Li-ji , Graziano Michael P. , Altmann Scott W.
Published: January 2007

Objective—The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 (Npc1l1) prevents atherosclerosis in apoE null mice.

Methods and Results—Npc1l1−/−/apoE null−/−mice were generated and found to have a significant reduction in cholesterol absorption (−77%) compared with wild-type or apoE−/−mice. Npc1l1/apoE−/−mice were fed a chow or Western diet for 24 weeks, then lipoprotein, hepatic, and biliary cholesterol, and atherosclerosis development was compared with apoE−/−, Npc1l1−/−, wild-type, and ezetimibe-treated apoE−/−mice. Chylomicron remnant/ VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet-fed Npc1l1/apoE−/−mice relative to apoE−/−mice. Male Npc1l1−/−and Npc1l1/apoE−/−mice were completely resistant to diet induced hypercholesterolemia, and both male and female mice were completely resistant to increases in hepatic and biliary cholesterol levels. Atherosclerosis was reduced 99% in aortic lesion surface area, 94% to 97% in innominate artery intimal lesion area, and >90% in aortic root lesion area in both male and female Npc1l1/apoE−/−mice relative to apoE−/−mice.

Conclusions—Lack of Npc1l1, the molecular target of the cholesterol absorption inhibitor ezetimibe, in apoE−/−mice results in a significant reduction in cholesterol absorption and plasma cholesterol levels, and causes a nearly complete protection from the development of atherosclerosis, under both cholesterol-fed and non-cholesterol-fed conditions.
Fluid Shear Stress and NO Decrease the Activity of the Hydroxy-Methylglutaryl Coenzyme A Reductase in Endothelial Cells via the AMP-Activated Protein Kinase and FoxO1
Authors: Fisslthaler Beate , Fleming Ingrid , Keserü Benjamin , Walsh Kenneth , Busse Rudi
Published: January 2007

The rate-limiting enzyme for cholesterol synthesis, the hydroxy-methylglutaryl coenzyme A reductase (HCR), is phosphorylated by the AMP-activated protein kinase (AMPK). As shear stress activates the AMPK in endothelial cells, we determined whether it affects HCR activity and subsequent HCR-dependent signaling. Shear stress (12 dynes cm
−2
) rapidly increased the phosphorylation and activity (6.5- and 4-fold, respectively) of the AMPK in cultured endothelial cells and the activated AMPK phosphorylated the HCR in vitro. Moreover, shear stress and the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated endothelial HCR activity by 37% and 33%, respectively. Inhibition of NO production attenuated the acute shear stress–induced phosphorylation of the AMPK and the decrease in HCR activity. Prolonged shear stress (18 hours) led to a significant (50%) decrease in HCR mRNA expression that was dependent on NO, AMPK, and the subsequent phosphorylation and degradation of FoxO1a. Correspondingly, the downregulation of FoxO (small interfering RNA) decreased HCR expression. Prolonged shear stress also attenuated the bradykinin-induced activation of Ras and extracellular signal-regulated kinase 1/2, a phenomenon that was comparable to the effects of cerivastatin and that was reversed by mevalonate and thus attributed to HCR inhibition. A decrease (35%) in HCR expression was also detected in femoral arteries from mice following voluntary exercise, and the bradykinin-induced vasodilatation of the mouse hindlimb was attenuated by both exercise and the HCR inhibitor cerivastatin. These data indicate that fluid shear stress regulates the activity and expression of the HCR in endothelial cells and determines responsiveness to stimuli, such as bradykinin via a mechanism involving NO, AMPK, FoxO1a, and p21Ras.
Noninvasive Evaluation of Dynamic Cerebrovascular Autoregulation Using Finapres Plethysmograph and Transcranial Doppler
Authors: Lavinio Andrea , Schmidt Eric Albert , Haubrich Christina , Smielewski Piotr , Pickard John D. , Czosnyka Marek
Published: January 2007

Background and Purpose—

Mx is an index of cerebrovascular autoregulation. It is calculated as the correlation coefficient between slow spontaneous fluctuations of cerebral perfusion pressure (cerebral perfusion pressure=arterial blood pressure−intracranial pressure) and cerebral blood flow velocity. Mx can be estimated noninvasively (nMxa) with the use of a finger plethysmograph arterial blood pressure measurement instead of an invasive cerebral perfusion pressure measurement. We investigated the agreement between nMxa and the previously validated index Mx.

Methods—

The study included 10 head-injured adults. Intracranial pressure was monitored with a parenchymal probe. Arterial blood pressure was monitored simultaneously with an arterial catheter and with the Finapres plethysmograph. Flow velocity in the middle cerebral artery was measured bilaterally with transcranial Doppler. Mx and nMxa were computed in both hemispheres, and asymmetry of autoregulation was calculated.

Results—

Ninety-six measures of Mx and nMxa were obtained (48 for each side) in 10 patients. Mx correlated with nMxa (
R
=0.755,
P
<0.001; 95% agreement=±0.36; bias=0.01). Asymmetry in autoregulation assessed with Mx correlated significantly with asymmetry estimated with nMxa (
R
=0.857,
P
<0.0001; 95% agreement=±0.26; bias=−0.03).

Conclusions—

The noninvasive index of autoregulation nMxa correlates with Mx and is sensitive enough to detect autoregulation asymmetry. nMxa is proposed as a practical tool to assess cerebral autoregulation in patients who do not require invasive monitoring.
Qualitative Methodology and Comparative Politics
Authors: Mahoney James
Published: January 2007

Leading methods for pursuing qualitative research in the field of comparative politics are discussed. On one hand, qualitative researchers in this field use a variety of methods of theory development: procedures for generating new hypotheses, tools for pursuing conceptual innovation, and techniques for identifying populations of homogeneous cases. On the other hand, they employ both within-case and cross-case methods of theory testing. Within-case methods include techniques for identifying intervening mechanisms and testing multiple observable implications of theories. Cross-case methods include a host of approaches for assessing hypotheses about necessary and sufficient causes. The article discusses the distinctive leverage offered by qualitative research for addressing questions in comparative politics.
The Costs of Marginalization
Authors: Pierson Paul
Published: January 2007

In the past few decades research relying primarily on qualitative methods has been almost completely marginalized within the subfield of American politics. After outlining the unusual organizational contours of the subfield, the author demonstrates that even as it has been marginalized, qualitative work continues to make very important contributions to scholars’ understanding of American politics. Much of the strength of this work comes from its focus on the substance of politics, its configurative approach to explanation, and its attentiveness to the temporal dimensions of social processes. Despite the high quality of much quantitative work in American politics, the marginalization of qualitative approaches has come at a substantial cost, introducing a range of biases and shortcomings in the subfield’s main research programs.
Qualitative Methods and Cross-Method Dialogue in Political Science
Authors: Levy Jack S.
Published: January 2007

The author accepts the basic argument that recent advances in qualitative methods have had an uneven impact on the three major empirical fields in political science. He emphasizes that scholars in all three fields have made significant contributions to qualitative methodology, but these contributions have a more profound impact on the practice of qualitative work in comparative and international politics than in American politics. The author argues that the differences between qualitative and quantitative or formal research are less pronounced than some would believe. In particular, the author argues that scholars have overstated the argument that qualitative researchers are significantly more skeptical of universal generalizations, more inclined to incorporate scope conditions into their theories, and more complex in their views of social reality than are quantitative and formal researchers.
Soft Tissue Tendon Graft Fixation in Serially Dilated or Extraction-Drilled Tibial Tunnels
Authors: Dunkin Brad S. , Nyland John , Duffee Andrew R. , Brunelli Jeffrey A. , Burden Robert , Caborn David
Published: January 2007

Background

Tibial tunnel preparation may contribute to improved soft tissue graft fixation.

Hypothesis

Step dilation produces greater tunnel wall bone volume than does extraction drilling and increases fixation strength. Bioabsorbable interference screw divergence decreases fixation strength, regardless of tunnel preparation method.

Study Design

Controlled laboratory study.

Methods

Twenty porcine tibias were divided into 2 groups of 10 with matching mean apparent bone mineral density. One group received 9-mm-diameter extraction-drilled tunnels, and the other group received 7-mm-diameter extraction-drilled tunnels followed by step dilation to 9 mm. High-resolution quantitative computerized tomography scans and voxel analysis techniques determined tunnel wall bone volume fraction. Screws secured 8.5-mm-diameter porcine grafts in the tunnels. Repeat scans were used to determine screw divergence. Cyclic loading was performed in a servohydraulic device before load to failure testing.

Results

The step dilation group had greater tunnel wall bone volume/total volume than did the extraction drilled group; however, a significant increase in fixation strength was not detected. Specimens with screw divergence angles less than 15° had superior fixation and insertion torques compared with specimens with angles 15° or more. Screw divergence correlated more strongly with fixation strength than did mean apparent bone mineral density or screw insertion torque.

Conclusion

Step dilation increased tunnel wall bone volume/total volume, but fixation strength did not improve. Screw divergence ≥15° decreases graft-bone tunnel fixation whether or not step dilation is performed.

Clinical Relevance

Screw alignment plays a greater role in anterior cruciate ligament graft fixation than does extraction drilling or step dilation tunnel preparation methods in healthy bone.
Ankle Sprain Injuries and Risk Factors in Amateur Soccer Players during a 2-Year Period
Authors: Kofotolis Nikolaos D. , Kellis Eleftherios , Vlachopoulos Symeon P.
Published: January 2007

Background

Although ankle sprains are common in soccer, the role of various risk factors in amateur soccer players is unclear.

Purpose

To identify the incidence of ankle sprain injuries, associated time loss of participation, and risk factors during two consecutive seasons in amateur players.

Study Design

Descriptive epidemiology study.

Methods

Of 336 athletes enrolled in the study, 312 male amateur soccer players were observed during a 2-year period. Ankle sprain injury incidents, participation time loss, injury mechanisms, ankle region injured, and other risk factors were recorded in games and practice sessions using questionnaires.

Results

During the study 208 ankle injuries were recorded, of which 139 were ankle sprains. These led to 975 sessions lost (on average, 7 lost sessions per injury). Most incidents (80.6%) were contact injuries, occurring mostly in defenders. Injury rates were equal between games and practice, while 61.1% of injuries were observed toward the end of each half of the game (P < .05). The injury incidence rate was higher during the first 2 months of the season as opposed to the last month (P < .05). Multinomial logistic regression showed that previous ankle sprain (P < .05) is a significant predictor of ankle sprain injury.

Conclusion

Ankle sprain injuries in amateur soccer players are primarily contact injuries, occurring mainly in defenders and during both games and practice. It appears that more injuries occur in players with previous ankle injury. Injury rates are higher toward the end of a game and chiefly occur during the first 2 months of the season.
Ethics in Sports Medicine
Authors: Dunn Warren R. , George Michael S. , Churchill Larry , Spindler Kurt P.
Published: January 2007

Physicians have struggled with the medical ramifications of athletic competition since ancient Greece, where rational medicine and organized athletics originated. Historically, the relationship between sport and medicine was adversarial because of conflicts between health and sport. However, modern sports medicine has emerged with the goal of improving performance and preventing injury, and the concept of the “team physician” has become an integral part of athletic culture. With this distinction come unique ethical challenges because the customary ethical norms for most forms of clinical practice, such as confidentiality and patient autonomy, cannot be translated easily into sports medicine. The particular areas of medical ethics that present unique challenges in sports medicine are informed consent, third parties, advertising, confidentiality, drug use, and innovative technology. Unfortunately, there is no widely accepted code of sports medicine ethics that adequately addresses these issues.
Forefoot Loading during 3 Athletic Tasks
Authors: Queen Robin M. , Haynes Benjamin B. , Hardaker W. Mack , Garrett William E.
Published: January 2007

Background

Due to the popularity of soccer and the high incidence of injury among soccer players, it is valuable to know the effects of tasks like side cuts, crossover cuts, and forward acceleration on the foot.

Purpose

To determine the differences in forefoot loading during three different athletic tasks.

Study Design

Descriptive laboratory study.

Methods

Thirty-six subjects (17 women and 19 men) were tested. Subjects ran a slalom-style agility course 5 times while plantar pressure data was collected at 100 Hz. Plantar pressure was recorded under both feet; however, a right-foot contact was used in the analysis of the side-cut task, a left-foot plant was used in the analysis of the crossover cut, and an average of the 3 steps of acceleration were used in the analysis. The peak pressure, contact area, and contact time for the entire foot were compared between the 3 tasks. The force and the force-time integral were obtained during 5 trials for each of the 3 tasks. The foot was divided into 8 masked regions, which were used to determine the loading patterns specifically in the forefoot. Each variable was analyzed using a 1 × 3 analysis of variance to determine differences between the three movement tasks in the forefoot region (a = .05).

Results

Significant differences in peak pressure, contact area, and contact time existed between the movement tasks when examining the entire foot. In addition, significant differences in the force-time integral and peak pressure in the forefoot existed between the movement tasks. The force-time integral was highest during the side cut in the medial forefoot, hallux, and the lesser toes, while the force-time integral was highest during the crossover cut in the middle forefoot and the lateral forefoot. Similarly, the peak pressure was highest during the side cut in the medial forefoot, hallux, and the lesser toes, while peak pressure was highest in the middle forefoot during the acceleration task and highest in the lateral forefoot during the crossover-cutting task.

Conclusions

The results of this study demonstrated that the crossover cut places an increased load on the lateral portion of the forefoot, while the side-cut task places an increased load on the medial portion of the forefoot and the acceleration task places increased load on the middle forefoot.

Clinical Relevance

The differences in loading patterns based on athletic task are important for understanding potential injury mechanisms. In addition, this information could be important for defining a return to play protocol for athletes who have had specific injuries.
Bone Morphogenetic Proteins-Signaling Plays a Role in Tendon-to-Bone Healing
Authors: Ma C. Benjamin , Kawamura Sumito , Deng Xiang-Hua , Ying Ling , Schneidkraut Jason , Hays Peyton , Rodeo Scott A.
Published: January 2007

Background

Successful anterior cruciate ligament reconstruction requires secure healing between tendon and bone.

Hypothesis

Bone morphogenetic protein-signaling plays an important role in tendon-to-bone healing. rhBMP-2, a powerful osteoinductive agent, can improve tendon-bone interdigitation.

Study Design

Controlled laboratory study.

Methods

The study was designed in 2 phases: Phase I consisted of a dose-response study where 21 New Zealand White rabbits underwent bilateral anterior cruciate ligament reconstructions. Rabbits received either rhBMP-2 (11.5, 50, or 115 µg) or noggin (10, 15, 30, or 100 ng) (a potent bone morphogenetic proteins inhibitor) delivered in an injectable calcium phosphate matrix. Animals were sacrificed at 2 weeks and histomorphometric analyses were performed. In phase II, 60 rabbits underwent bilateral anterior cruciate ligament reconstructions and were assigned to 3 groups rhBMP-2 (115 µg), noggin (30 ng) in a calcium phosphate carrier, and calcium phosphate carrier alone. Animals were sacrificed at 2, 4, and 8 weeks and histomorphometric and biomechanical analyses were performed.

Results

rhBMP-2 treatment led to a significant increase in the width of new bone formation at the tendon-bone interface in a dose-dependent fashion (0.24-0.35 mm vs 0.13-0.16 mm in controls). All dosages of noggin inhibited new bone formation (0.06-0.1 mm vs 0.15-0.16 mm in controls); however, there was no dose-dependent effect in the concentrations studied. In the phase II study, rhBMP-2 resulted in a significant increase in new bone formation (81%, 89%, and 113%) at increasing time periods compared with controls. Tunnel diameters in the rhBMP-2 group were significantly smaller (15%-45%) than in the carrier group. The negative effect of noggin was not sustained, as new bone formation increased with time. The rhBMP-2 group demonstrated significantly increased stiffness at 8 weeks, while there was no significant difference in ultimate tensile load when compared with the other 2 groups.

Conclusion

rhBMP-2 demonstrated a strong, positive dose-dependent effect on osteointegration at the tendon-bone junction. In contrast, noggin decreased osteointegration. No tunnel widening was detected with rhBMP-2 using the calcium phosphate carrier.

Clinical Relevance

Further studies are needed to investigate the potential clinical application of enhancing healing and decreasing recovery time using bone morphogenetic proteins in soft tissue ligament reconstruction.
Stained Glass Makes the Ceiling Visible
Authors: Adams Jimi
Published: January 2007

While women represent the vast majority of participants in religious organizations in the United States, their participation in top leadership positions within Christian congregations remains remarkably low. In this article, the author uses the National Congregations Study to examine the situations that lead to this “stained glass ceiling” effect, prohibiting women from attaining top congregational leadership positions. The author also investigates similar barriers that exist at other levels of congregational leadership. The results suggest that while a queue-like process appears, the specifically religious nature of these organizations produces barriers that are quite different from the traditional glass ceiling conceptualization.
Adolescents' Perceptions of Inpatient Postpartum Nursing Care
Authors: Peterson Wendy E. , Sword Wendy , Charles Cathy , DiCenso Alba
Published: January 2007

The authors used a transcendental phenomenological approach to describe adolescent mothers' satisfactory and unsatisfactory inpatient postpartum nursing care experiences. They analyzed data from 14 in-depth interviews and found that adolescent mothers' satisfaction is dependent on their perceptions of the nurse's ability to place them “at ease.” Nursing care qualities that contributed to satisfactory experiences included nurses' sharing information about themselves, being calm, demonstrating confidence in mothers, speaking to adolescent and adult mothers in the same way, and anticipating unstated needs. Nursing care was perceived to be unsatisfactory when it was too serious, limited to the job required, or different from care to adult mothers, or when nurses failed to recognize individual needs. In extreme cases, unsatisfactory experiences hindered development of an effective nurse-client relationship. These findings illustrate the value of qualitative inquiry for understanding patients' satisfaction with care, can be used for self-reflection, and have implications for nursing education programs.
Experiences of Living With Non-Cancer-Related Lymphedema: Implications for Clinical Practice
Authors: Bogan Lisa K. , Powell Janet M. , Dudgeon Brian J.
Published: January 2007

Lymphedema is a chronic medical condition caused by lymphatic insufficiency that can lead to extreme swelling and susceptibility to infection. Physical and psychosocial effects of the condition can have a significant impact on an individual's life and level of participation. Research about experiences of individuals living with lymphedema has focused primarily on women with breast cancer, yet individuals with non-cancer-related lymphedema are a distinct group. In this study, the authors used qualitative description to explore the experience of 7 individuals living with advanced and complicated cases of lymphedema who had been treated in an inpatient setting. Findings reveal the extensive impact lymphedema has on those who live with it. Participants spoke of difficulty finding a correct diagnosis and effective treatment, the importance of their inpatient experiences, and the challenges of daily self-management. The authors make recommendations to increase lymphedema awareness, promote inpatient treatment programs, and create effective self-management techniques.