bluuebunny/crossref_metadata_2025 huggingface dataset:
Iatrogenic Migration of an Impacted Pharyngeal Foreign Body of the Hypopharynx to the Prevertebral Space
Authors: Hajiioannou Jiannis , Kousoulis Panagiotis , Florou Vassiliki , Stavrianou Eleni
Published: December 2011

Impaction of foreign bodies in the upper aerodigestive tract is commonly encountered in ENT practice. The present paper describes an iatrogenic complication with migration of an impacted foreign body (chicken bone) of the hypopharynx into the prevertebral space, after unsuccessful attempt of endoscopic removal. The foreign body was visualized with cervical CT scan lying extraluminally between the major vessels of the neck. An open surgical procedure with neck exploration was necessary for the definite treatment.
Early Postoperative Outcomes and Medication Cost Savings after Laparoscopic Sleeve Gastrectomy in Morbidly Obese Patients with Type 2 Diabetes
Authors: Slater Bethany J. , Bellatorre Nina , Eisenberg Dan
Published: December 2011

Background. We investigated the effect of laparoscopic sleeve gastrectomy (LSG) on morbidly obese diabetics and examined the short-term impact of LSG on diabetic medication cost.Methods. A prospective database of consecutive bariatric patients was reviewed. Morbidly obese patients with type 2 diabetes who underwent LSG were included in the study. Age, gender, body mass index (BMI), diabetic medication use, glucose, insulin, and HbA1c levels were documented preoperatively, and at 2 weeks, 2 months, 6 months, and 12 months postoperatively. Insulin resistance was estimated using the homeostatic model assessment (HOMA). Use and cost of diabetic medications were followed.Results. Of 178 patients, 22 were diabetics who underwent LSG. Diabetes remission was observed in 62% of patients within 2 months and in 75% of patients within 12 months. HOMA-IR improved after only two weeks following surgery (16.5 versus 6.6, ). Average number of diabetic medications decreased from 2.2 to <1, within 2 weeks after surgery; corresponding to a diabetes medication cost savings of 80%, 91%, 99%, and 99.7% after 2 weeks, 2 months, 6 months, and 12 months, respectively.Conclusion. Morbidly obese patients with diabetes who undergo LSG have high rates of diabetes remission early after surgery. This translates to a significant medication cost savings.
Periodic Solutions for Autonomous (q, p)‐Laplacian System with Impulsive Effects
Authors: Yang Xiaoxia , Chen Haibo
Published: December 2011

By using the variational method, some existence theorems
are obtained for periodic solutions of autonomous (q, p)‐Laplacian system with impulsive effects.
The Simultaneous Effects of Spatial and Social Networks on Cholera Transmission
Authors: Giebultowicz Sophia , Ali Mohammad , Yunus Mohammad , Emch Michael
Published: December 2011

This study uses social network and spatial analytical methods simultaneously to understand cholera transmission in rural Bangladesh. Both have been used separately to incorporate context into health studies, but using them together is a new and recent approach. Data include a spatially referenced longitudinal demographic database consisting of approximately 200,000 people and a database of all laboratory-confirmed cholera cases from 1983 to 2003. A complete kinship-based network linking households is created, and distance matrices are also constructed to model spatial relationships. A spatial error-social effects model tested for cholera clustering in socially linked households while accounting for spatial factors. Results show that there was social clustering in five out of twenty-one years while accounting for both known and unknown environmental variables. This suggests that environmental cholera transmission is significant and social networks also influence transmission, but not as consistently. Simultaneous spatial and social network analysis may improve understanding of disease transmission.
Effect of High- versus Low-Fat Meal on Serum 25-Hydroxyvitamin D Levels after a Single Oral Dose of Vitamin D: A Single-Blind, Parallel, Randomized Trial
Authors: Raimundo Fabiana Viegas , Faulhaber Gustavo Adolpho Moreira , Menegatti Paula Kalinka , Marques Leonardo da Silva , Furlanetto Tania Weber
Published: December 2011

Background/Aims. Vitamin D3is liposoluble, so dietary fat could increase its oral absorption. Our aim was to compare serum 25-hydroxyvitamin D [25(OH)D] after the oral intake of cholecalciferol with a high- or low-fat meal.Methods. In a single-blind, parallel clinical trial, 32 healthy physicians were divided into two groups. In the same day, they ingested 50,000 IU (1.25 mg) of vitamin D3with food: group 1 (G1): lipids: 25.6 g and group 2 (G2) lipids: 1.7 g. Serum 25(OH)D (0, 7, and 14 days), and parathyroid hormone (PTH), and calcium (0 and 14 days) were measured.Results. Baseline mean serum 25(OH)D levels were42.7±19.0 nmol/L in G1 and36.4±19.0 nmol/L in G2 (P=0.38). After cholecalciferol, mean serum 25(OH)D was higher in G1 (P<0.001): 7 days: G1 = 46.2 (38.4–53.9) nmol/L and G2 = 33.7 (25.4–40.1) nmol/L; 14 days: G1 = 53.7 (45.2–62.1) nmol/L and G2 = 33.7 (25.2–42.2) nmol/L. Serum PTH and 25(OH)D were negatively correlated before and after the intake of vitamin D3, respectively,r=-0.42(P=0.02) andr=-0.52(P=0.003).Conclusions. A high-fat meal increased the absorption of vitamin D3, as measured by serum 25(OH)D.
Optimal Hedging and Pricing of Equity‐Linked Life Insurance Contracts in a Discrete‐Time Incomplete Market
Authors: Josephy Norman , Kimball Lucia , Steblovskaya Victoria
Published: December 2011

We present a method of optimal hedging and pricing of equity‐linked life insurance products in an incomplete discrete‐time financial market. A pure endowment life insurance contract with guarantee is used as an example. The financial market incompleteness is caused by the assumption that the underlying risky asset price ratios are distributed in a compact interval, generalizing the assumptions of multinomial incomplete market models. For a range of initial hedging capitals for the embedded financial option, we numerically solve an optimal hedging problem and determine a risk‐return profile of each optimal non‐self‐financing hedging strategy. The fair price of the insurance contract is determined according to the insurer′s risk‐return preferences. Illustrative numerical results of testing our algorithm on hypothetical insurance contracts are documented. A discussion and a test of a hedging strategy recalibration technique for long‐term contracts are presented.
Dysregulation of Ezrin Phosphorylation Prevents Metastasis and Alters Cellular Metabolism in Osteosarcoma
Authors: Ren Ling , Hong Sung-Hyeok , Chen Qing-Rong , Briggs Joseph , Cassavaugh Jessica , Srinivasan Satish , Lizardo Michael M. , Mendoza Arnulfo , Xia Ashley Y. , Avadhani Narayan , Khan Javed , Khanna Chand
Published: December 2011

Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers; however, the precise mechanistic basis for its role remains unknown. Here, we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphomimetic T567D) or closed (phosphodeficient T567A) and compared their biologic characteristics to full-length wild-type Ezrin in osteosarcoma cells. Unexpectedly, cells expressing open, active Ezrin could form neither primary orthotopic tumors nor lung metastases. In contrast, cells expressing closed, inactive Ezrin were also deficient in metastasis but were unaffected in their capacity for primary tumor growth. By imaging single metastatic cells in the lung, we found that cells expressing either open or closed Ezrin displayed increased levels of apoptosis early after their arrival in the lung. Gene expression analysis suggested dysregulation of genes that are functionally linked to carbohydrate and amino acid metabolism. In particular, cells expressing closed, inactive Ezrin exhibited reduced lactate production and basal or ATP-dependent oxygen consumption. Collectively, our results suggest that dynamic regulation of Ezrin phosphorylation at amino acid T567 that controls structural transitions of this protein plays a pivotal role in tumor progression and metastasis, possibly in part by altering cellular metabolism. Cancer Res; 72(4); 1001–12. ©2011 AACR.
Identification of Molecular Vulnerabilities in Human Multiple Myeloma Cells by RNA Interference Lethality Screening of the Druggable Genome
Authors: Tiedemann Rodger E. , Zhu Yuan Xao , Schmidt Jessica , Shi Chang Xin , Sereduk Chris , Yin Hongwei , Mousses Spyro , Stewart A. Keith
Published: December 2011

Despite recent advances in targeted treatments for multiple myeloma, optimal molecular therapeutic targets have yet to be identified. To functionally identify critical molecular targets, we conducted a genome-scale lethality study in multiple myeloma cells using siRNAs. We validated the top 160 lethal hits with four siRNAs per gene in three multiple myeloma cell lines and two non-myeloma cell lines, cataloging a total of 57 potent multiple myeloma survival genes. We identified the Bcl2 family member MCL1 and several 26S proteasome subunits among the most important and selective multiple myeloma survival genes. These results provided biologic validation of our screening strategy. Other essential targets included genes involved in RNA splicing, ubiquitination, transcription, translation, and mitosis. Several of the multiple myeloma survival genes, especially MCL1, TNK2, CDK11, and WBSCR22, exhibited differential expression in primary plasma cells compared with other human primary somatic tissues. Overall, the most striking differential functional vulnerabilities between multiple myeloma and non–multiple myeloma cells were found to occur within the 20S proteasome subunits, MCL1, RRM1, USP8, and CKAP5. We propose that these genes should be investigated further as potential therapeutic targets in multiple myeloma. Cancer Res; 72(3); 757–68. ©2011 AACR.
Measured Body Mass Index in Adolescence and the Incidence of Colorectal Cancer in a Cohort of 1.1 Million Males
Authors: Levi Zohar , Kark Jeremy D. , Barchana Micha , Liphshitz Irena , Zavdy Ofir , Tzur Dorit , Derazne Estela , Furman Moshe , Niv Yaron , Gordon Barak , Afek Arnon , Shamiss Ari
Published: December 2011

Background and Aims: The increasing prevalence of adolescent obesity affects adult health. We investigated the association of adolescent overweight with colorectal cancer incidence in a large cohort of males.

Methods: Body mass index (BMI) was measured in 1.1 million Jewish Israeli males who underwent a general health examination at ages 16 to 19 between 1967 and 2005. Overweight was defined as BMI ≥ 85th percentile of the standard U.S. distribution in adolescence. Colorectal cancer was identified by linkage with the Israel National Cancer Registry up to 2006. The mean follow-up period was 17.6 ± 10.9 years, reflecting 19.5 million person-years. Cox proportional hazards modeling was used.

Results: The prevalence of adolescent overweight increased from 9.9% to 16.8% in the first 10 and last 10 annual examination cohorts. Colon (n = 445) and rectal cancer (n = 193) cases were detected. Overweight predicted an increased risk of colon cancer [HR = 1.53; 95% confidence interval (CI), 1.17–2.02, P = 0.002] but not of rectal cancer (HR = 1.09; 95% CI, 0.38–1.73, P = 0.72). The risk was greatest for nonmucinous adenocarcinoma of the colon (HR = 1.68, 95% CI, 1.26–2.23, P = 0.001). The association of BMI ≥ 85th percentile with colon cancer was even more pronounced in analyses that were restricted to men followed until at least 40 years of age [N = 367,478; HR = 1.75 (95% CI, 1.33–2.3, P < 0.001)].

Conclusions: Adolescent overweight is substantially associated with colon cancer incidence in young to middle-aged adults.

Impact: These long-term sequelae add to the urgency to seriously address increasing childhood and adolescent obesity with its attendant increasing population impact. Cancer Epidemiol Biomarkers Prev; 20(12); 2524–31. ©2011 AACR.
Cancer Risk Associated with Long-term Use of Acetaminophen in the Prospective VITamins and Lifestyle (VITAL) Study
Authors: Walter Roland B. , Brasky Theodore M. , White Emily
Published: December 2011

Background: Acetaminophen (paracetamol) is a widely used over-the-counter drug, but concerns of genotoxic effects have been raised. After we recently found an almost two-fold increased risk of hematologic malignancies associated with high use of acetaminophen in the prospective VITamins And Lifestyle (VITAL) study, we herein further examined the association between acetaminophen use and cancer risk in the VITAL cohort.

Methods: A total of 62,841 men and women aged 50 to 76 years were recruited from 2000 to 2002, and incident malignancies other than nonmelanoma skin cancer (n = 5,750) were identified through December 2008 via linkage to the Surveillance, Epidemiology, and End Results cancer registry. HRs associated with acetaminophen use for incidence of total cancers and nonhematologic cancer subcategories were estimated with Cox proportional hazards models that were adjusted for age, demographics, cancer risk factors, and medical conditions that may be indications for acetaminophen use.

Results: Use of acetaminophen was not associated with total cancer risk. We also observed no associations for most major nonhematologic cancer sites, including cancers of the gastrointestinal system, lung, urinary tract, skin, prostate, or female organs.

Conclusion: This study failed to provide evidence of an association between acetaminophen use and total cancer risk or incidence of nonhematologic malignancies.

Impact: Together with our previous findings, the analyses from the VITAL study suggest a particular sensitivity of the hematopoietic system to the mutagenic effects of acetaminophen. Cancer Epidemiol Biomarkers Prev; 20(12); 2637–41. ©2011 AACR.
Endogenous Sex Steroids and Risk of Cervical Carcinoma: Results from the EPIC Study
Authors: Rinaldi Sabina , Plummer Martyn , Biessy Carine , Castellsagué Xavier , Overvad Kim , Krüger Kjær Susanne , Tjønneland Anne , Clavel-Chapelon Françoise , Chabbert-Buffet Nathalie , Mesrine Sylvie , Lukanova Annekatrin , Kaaks Rudolf , Weikert Cornelia , Boeing Heiner , Trichopoulou Antonia , Lagiou Pagona , Trichopoulos Dimitrios , Palli Domenico , Agnoli Claudia , Tumino Rosario , Vineis Paolo , Panico Salvatore , Bueno-de-Mesquita Bas , van Kranen Henk J. , Peeters Petra HM. , Bakken Kjersti , Lund Eiliv , Gram Inger Torhild , Rodríguez Laudina , Bosch F Xavier , Sánchez Maria-José , Dorronsoro Miren , Navarro Carmen , Gurrea Aurelio Barricarte , Kjellberg Lennart , Dillner Joakim , Manjer Jonas , Butt Salma , Khaw Kay-Tee , Wareham Nicholas , Allen Naomi E. , Travis Ruth , Romieu Isabelle , Ferrari Pietro , Riboli Elio , Franceschi Silvia
Published: December 2011

Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC).

Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection–related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E2); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone–binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E2 were calculated from absolute concentrations of T, E2, and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression.

Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile = 5.16, 95% CI, 1.50–20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E2, fE2, and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR = 3.14; 95% CI, 1.21–9.37), whereas E2 and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women.

Conclusions: Our findings suggest for the first time that T and possibly E2 may be involved in the etiology of ICC.

Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring. Cancer Epidemiol Biomarkers Prev; 20(12); 2532–40. ©2011 AACR.
HIV Infection, Immunodeficiency, Viral Replication, and the Risk of Cancer
Authors: Silverberg Michael J. , Chao Chun , Leyden Wendy A. , Xu Lanfang , Horberg Michael A. , Klein Daniel , Towner William J. , Dubrow Robert , Quesenberry Charles P. , Neugebauer Romain S. , Abrams Donald I.
Published: December 2011

Background: Few studies have compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.

Methods: We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996 to 2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity.

Results: We observed elevated RRs for Kaposi sarcoma (KS; RR = 199; P < 0.001), non-Hodgkin lymphoma (NHL; RR = 15; P < 0.001), anal cancer (RR = 55; P < 0.001), Hodgkin lymphoma (HL; RR = 19; P < 0.001), melanoma (RR = 1.8; P = 0.001), and liver cancer (RR = 1.8; P = 0.013), a reduced RR for prostate cancer (RR = 0.8; P = 0.012), and no increased risk for oral cavity/pharynx (RR = 1.4; P = 0.14), lung (RR = 1.2; P = 0.15), or colorectal (RR = 0.9; P = 0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P < 0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 < 200 cells/μL and for melanoma and liver cancer with CD4 < 500 cells/μL. Only KS and NHL were associated with HIV RNA.

Conclusion: Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors.

Impact: Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population. Cancer Epidemiol Biomarkers Prev; 20(12); 2551–9. ©2011 AACR.
Early-Life Factors and Breast Cancer Risk in Hispanic Women: the Role of Adolescent Body Size
Authors: Sangaramoorthy Meera , Phipps Amanda I. , Horn-Ross Pamela L. , Koo Jocelyn , John Esther M.
Published: December 2011

Background: Adult body size has long been known to influence breast cancer risk, and there is now increasing evidence that childhood and adolescent body size may also play a role.

Methods: We assessed the association with body size at ages 10, 15, and 20 years in 475 premenopausal and 775 postmenopausal Hispanic women who participated in a population-based case–control study of breast cancer conducted from 1995 to 2004 in the San Francisco Bay Area. We used unconditional logistic regression to estimate ORs and 95% CIs for the associations with self-reported relative weight compared with peers and body build at ages 10, 15, and 20 years.

Results: In premenopausal women, we found inverse associations with relative weight compared with peers, with ORs of 0.63 (Ptrend = 0.05), 0.31 (Ptrend < 0.01), and 0.44 (Ptrend = 0.02) for heavier versus lighter weight at ages 10, 15, and 20 years, respectively. These inverse associations were stronger in currently overweight women and U.S.-born women and did not differ significantly for case groups defined by estrogen receptor status. In postmenopausal women, not currently using hormone therapy, inverse associations with relative weight were limited to U.S.-born Hispanics.

Conclusions: Large body size at a young age may have a long-lasting influence on breast cancer risk in premenopausal, and possibly postmenopausal, Hispanic women that is independent of current body mass index.

Impact: These findings need to be weighed against adverse health effects associated with early-life obesity. Cancer Epidemiol Biomarkers Prev; 20(12); 2572–82. ©2011 AACR.
Opposing Effects of Runx2 and Estradiol on Breast Cancer Cell Proliferation: In Vitro Identification of Reciprocally Regulated Gene Signature Related to Clinical Letrozole Responsiveness
Authors: Chimge Nyam-Osor , Baniwal Sanjeev K. , Luo Jingqin , Coetzee Simon , Khalid Omar , Berman Benjamin P. , Tripathy Debu , Ellis Matthew J. , Frenkel Baruch
Published: December 2011

Purpose: To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro.

Experimental Design: MCF7/Rx2dox breast cancer cells were treated with estradiol and/or doxycycline to induce Runx2, and global gene expression was profiled to define genes regulated by estradiol, Runx2, or both. Anchorage-independent growth was assessed by soft-agar colony formation assays. Expression of gene sets defined using the MCF7/Rx2dox system was analyzed in pre- and on-treatment biopsies from hormone receptor–positive patients undergoing neoadjuvant letrozole treatment in two independent studies, and short-term changes in gene expression were correlated with tumor size reduction or Ki67 index at surgery.

Results: Reflecting its oncogenic property, estradiol strongly promoted soft-agar colony formation, whereas Runx2 blocked this process suggesting tumor suppressor property. Transcriptome analysis of MCF7/Rx2dox cells treated with estradiol and/or doxycycline showed reciprocal attenuation of Runx2 and estrogen signaling. Correspondingly in breast cancer tumors, expression of estradiol- and Runx2-regulated genes was inversely correlated, and letrozole increased expression of Runx2-stimulated genes, as defined in the MCF7/Rx2dox model. Of particular interest was a gene set upregulated by estradiol and downregulated by Runx2 in vitro; its short-term response to letrozole treatment associated with tumor size reduction and Ki67 index at surgery better than other estradiol-regulated gene sets.

Conclusion: This work provides clinical evidence for the importance of antagonism between Runx2 and E2 signaling in breast cancer. Likely sensing the tension between them, letrozole responsiveness of a genomic node, positively regulated by estradiol and negatively regulated by Runx2 in vitro, best correlated with the clinical efficacy of letrozole treatment. Clin Cancer Res; 18(3); 901–11. ©2011 AACR.
Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9
Authors: Petrul Heike M. , Schatz Christoph A. , Kopitz Charlotte C. , Adnane Lila , McCabe Timothy J. , Trail Pamela , Ha Sha , Chang Yong S. , Voznesensky Andrei , Ranges Gerald , Tamburini Paul P.
Published: December 2011

Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody–drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors. Mol Cancer Ther; 11(2); 340–9. ©2011 AACR.
Identifying Earlier Alzheimer’s Disease: Insights from the Preclinical and Prodromal Phases
Authors: Molinuevo Jose Luis , Sánchez-Valle Raquel , Lladó Albert , Fortea Juan , Bartrés-Faz David , Rami Lorena
Published: December 2011

Alzheimer’s disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. The objective of this paper is to present recent data that show how cerebrospinal fluid (CSF) biomarkers behave in preclinical AD. These studies have been performed in presymptomatic subjects (PreS) and asymptomatic subjects at risk for the disease (AsymR). In brief, the results show in PreS subjects that CSF biomarkers present a positive correlation with time to disease onset to reach floor levels at symptom onset. In addition, memory performance presents distinct associations in the AD continuum, being related to Aβ1–42 levels in AsymR subjects and to t-tau and p-tau in prodromal AD. Furthermore, an increase in cortical thickness of typical AD areas was observed when mean Aβ1–42 levels were still within the normal range in PreS subjects, or they presented transitional values in AsymR subjects. Overall, these findings suggest that the preclinical stage is biologically active and that there may be structural changes when amyloid is starting its deposition.
Linking Amyloid-β and Tau: Amyloid-β Induced Synaptic Dysfunction via Local Wreckage of the Neuronal Cytoskeleton
Authors: Zempel Hans , Mandelkow Eva-Maria
Published: December 2011

Background: In Alzheimer’s disease (AD), amyloid-β (Aβ) is the major component of extracellular plaques, whereas the microtubule-associated protein tau forms the main component of intracellular tangles. In contrast to frontotemporal dementias and other neurodegenerative diseases, both proteins form pathological aggregates and are considered key players for the development of AD. However, the connection between Aβ and tau and the functional loss of neurons and synapses, which ultimately lead to cognitive impairments, is still not well understood. Objectives: Making use of primary neurons exposed to Aβ oligomers, we sought to determine how tau mediates the Aβ-induced neuronal dysfunction. Additionally, we asked how the microtubule cytoskeleton is involved in the combined Aβ and tau toxicity. Methods: We exposed mature primary rat neurons with developed synapses to Aβ oligomers and used immunofluorescence and electron microscopy to investigate tau, actin, neurofilament and microtuble cytoskeleton changes. Results: Aβ oligomers preferentially associate with synapses, notably dendritic spines, throughout the neuronal cell culture. As a consequence, endogenous tau gets missorted from the axonal into the somatodendritic compartment in a subset of cells. These missorted cells also display missorting of neurofilaments, and a dramatic loss of microtubules, which can be prevented by the microtubule stabilizer taxol. Conclusions: Aβ causes tau missorting, loss of neuronal cell polarity and loss of dendritic microtubules. This in turn leads to impaired organelle/mitochondria transport, whereby synapses cannot be maintained properly and eventually decay. The data support the view that the microtubule cytoskeleton is a valid therapeutic target in AD.
Spontaneous Eyeblink Rate in Focal Cerebrovascular Lesions
Authors: Anagnostou Evangelos , Kouzi Ioanna , Vassilopoulou Sofia , Paraskevas Georgios P. , Spengos Konstantinos
Published: December 2011

Background: The involvement of different brain areas in spontaneous eyeblink rate control is largely unknown. Methods: Spontaneous eyeblink rate was assessed in 211 consecutive acute stroke patients within two days after symptom onset and was correlated with infarction location as well as with other parameters such as the presence of hemineglect or significant small vessel disease in MRI or CT scans. Blink rates were measured in two conditions: (1) during a trivial conversation requiring no cognitive effort and (2) during mental arithmetic. Results: Patients and healthy controls displayed similar average blink rates at rest (19.1 and 17.3 blinks/min, respectively) and during mental arithmetic (22.6 and 20.2 blinks/min, respectively). The latter condition reliably increased blinking frequency in both patients and control subjects. The subgroups of patients with frontal, frontoparietal and frontotemporal infarctions exhibited a significantly higher blink rate modulation, expressed as an increased relative difference of blinking at rest compared with blinking during mental arithmetic. Conclusion: As a whole, patients with acute cerebrovascular disease do not show changes in blink rate. Subjects with frontal infarcts, however, systematically increase their blink rates during cognitive effort, most probably due to a lack of frontal inhibitory control on blinking modulation.
Tissue Transglutaminase: A Novel Therapeutic Target in Cerebral Amyloid Angiopathy
Authors: Wilhelmus Micha M.M. , de Jager Mieke , Drukarch Benjamin
Published: December 2011

Accumulation of amyloid-β (Aβ) in brain vessel walls, known as cerebral amyloid angiopathy (CAA), plays a key role in Alzheimer’s disease pathogenesis. CAA might result from impaired transport of Aβ out of the brain. Although the mechanisms underlying reduced Aβ transport are largely unknown, thickening of basement membrane extracellular matrix (ECM) is likely involved. Tissue transglutaminase (tTG) is an enzyme capable of modulating the ECM by covalently cross-linking ECM proteins. Recently, our group found that tTG and its cross-linking activity are associated with CAA pathology, suggesting a role for tTG in ECM modulation in CAA. Therefore, inhibition of tTG activity might be a promising novel therapeutic target to counteract CAA.
Growth Kinetics in Von Hippel-Lindau-Associated Renal Cell Carcinoma
Authors: Jilg C.A. , Neumann H.P. , Gläsker S. , Schäfer O. , Ardelt P.U. , Schwardt M. , Schultze-Seemann W.
Published: December 2011

Objective: To evaluate the growth kinetics of renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease in a large trial by CT/MRI scan. VHL disease is a multisystemic disorder predisposing to renal cysts and cancer. There is a general assumption that VHL-associated RCC presents slower growth rates than sporadic RCC. Patients and Methods: We describe growth kinetics of 96 renal tumours in 64 VHL patients with analysed germline mutation (54/64 treated, 10/64 active surveillance) over a mean follow-up of 54.9 months. We calculated tumour volume, growth rate, multiplication of tumour volume per year and overall, as well as tumour volume doubling time. Results: The mean growth rate of 96 tumours was 4.4 mm/year (SD 3.2, median 4.1 mm/year), mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). We saw a median 1.4-fold increase in tumour volume per year. At treatment time point, VHL kidneys comprised 39% tumour and 15.7% cyst volume fraction. We saw no correlation between tumour size and growth parameters. Conclusion: VHL-associated RCC show large variances in tumour growth behaviour. Compared to the literature, in our study the growth rates (mm/year) of RCC in VHL disease did not differ from those of sporadic RCC. Fast tumour growth increases the risk for metastases.
Long-Term Structural and Functional Outcomes of Therapy in Juvenile-Onset Primary Open-Angle Glaucoma : A Five-Year Follow-Up
Authors: Gupta Viney , Ov Mary , Rao Aparna , Sharma Ajay , Sihota Ramanjit
Published: December 2011

Objective: To evaluate long-term structural and functional changes of the optic nerve head in medically and surgically treated juvenile-onset primary open-angle glaucoma (JOAG). Methods: Forty-two eyes of 42 consecutive primary JOAG patients presenting between January 2000 and January 2003. Results were analysed for long-term intra-ocular pressure (IOP) control, IOP fluctuation, disc characteristics on a Heidelberg Retinal Tomograph II and for visual field changes over a 5-year period. The parameters were compared between medically and surgically treated eyes. Results: The average age of the patients was 26.8 ± 6.1 years. The average baseline IOP was 35.3 ± 14.9 mm Hg. An IOP control <18 mm Hg was achieved in 84% of eyes that underwent filtering surgery (n = 17), compared to 63% on medical therapy alone (n = 25) at the end of 5 years; log rank test p = 0.38. Over 5 years, 4 eyes showed progression (9.5%) of which 3 had been medically treated and 1 had failed surgery (p = 0.45). Conclusion: A tenth of JOAG eyes showed progression over 5 years, and this was more common in those treated medically. Aggressive IOP lowering may thus be needed in eyes with JOAG.
Preventive Effects of Exenatide on Endothelial Dysfunction Induced by Ischemia-Reperfusion Injury via K
ATP
Channels
Authors: Ha Sang Jin , Kim Weon , Woo Jong Shin , Kim Jin Bae , Kim Soo Joong , Kim Woo-Shik , Kim Myeong Kon , Cheng Xian Wu , Kim Kwon Sam
Published: December 2011

Objective—

The purpose of this study was to evaluate whether exenatide administration can prevent impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) injury and whether this effect is mediated by K
ATP
channel opening.

Methods and Results—

In a double-blind, placebo-controlled, crossover design, 20 volunteers were randomly assigned to 2 groups: subcutaneous exenatide (10 μg) or placebo administration. At 30 minutes after the study drug administration, endothelium-dependent flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion) injury. Seven days later, both groups were crossed over and received the other treatment (ie, placebo or exenatide) and underwent the same protocol. Pre-IR radial artery diameter, FMD, and baseline radial artery diameter after IR injury were similar between 2 groups (
P
=no significant difference). After placebo administration, IR significantly blunted FMD (before IR: 12.0±6.23%; after IR: 4.6±3.57%,
P
=0.02). Exenatide prevented this impairment (FMD before IR: 15.0±7.14%; FMD after IR: 15.0±5.96%,
P
=no significant difference;
P
<0.001 compared with placebo). In a separate protocol, this protective effect was completely abolished by pretreatment with glibenclamide (glyburide, 5 mg), a blocker of K
ATP
channels (n=7; FMD before IR: 12.0±2.2%; after IR: 3.2±2.1%,
P
<0.001).

Conclusion—

The present study demonstrates that subcutaneous exenatide protects IR-induced endothelial dysfunction through opening of K
ATP
channels in human IR injury model.
Genetic Variation in
ABCG1
and Risk of Myocardial Infarction and Ischemic Heart Disease
Authors: Schou Jesper , Frikke-Schmidt Ruth , Kardassis Dimitris , Thymiakou Efstathia , Nordestgaard Børge G. , Jensen Gorm , Grande Peer , Tybjærg-Hansen Anne
Published: December 2011

Objective—

ATP binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux from macrophages to mature high-density lipoprotein particles. Whether genetic variation in
ABCG1
affects risk of atherosclerosis in humans remains to be determined.

Methods and Results—

We resequenced the core promoter and coding regions of
ABCG1
in 380 individuals from the general population. Next, we genotyped 10 237 individuals from the Copenhagen City Heart Study for the identified variants and determined the effect on lipid and lipoprotein levels and on risk of myocardial infarction (MI) and ischemic heart disease (IHD). g.−376C>T, g.-311T>A, and Ser630Leu predicted risk of MI in the Copenhagen City Heart Study, with hazard ratios of 2.2 (95% confidence interval: 1.2–4.3), 1.7 (1.0–2.9), and 7.5 (1.9–30), respectively. These results were confirmed for g.−376C>T in a case-control study comprising 4983 independently ascertained IHD cases and 7489 controls. Expression levels of
ABCG1
mRNA were decreased by approximately 40% in g.−376C>T heterozygotes versus noncarriers (probability values: 0.005–0.009). Finally, in vitro specificity protein 1 (Sp1) bound specifically to a putative Sp1 binding site at position −382 to −373 in the
ABCG1
promoter, and the presence of the −376 T allele reduced binding and transactivation of the promoter by Sp1.

Conclusion—

This is the first report of a functional variant in
ABCG1
that associates with increased risk of MI and IHD in the general population.
Apolipoprotein B Secretion Is Regulated by Hepatic Triglyceride, and Not Insulin, in a Model of Increased Hepatic Insulin Signaling
Authors: Moon Byoung C. , Hernandez-Ono Antonio , Stiles Bangyan , Wu Hong , Ginsberg Henry N.
Published: December 2011

Objective—

States of insulin resistance, hyperinsulinemia, and hepatic steatosis are associated with increased secretion of triglycerides (TG) and apolipoprotein B (apoB), even though insulin targets apoB for degradation. We used hepatic-specific “phosphatase and tensin homologue deleted on chromosome 10” (
Pten
) knockout (h
Pten
-ko) mice, with increased hepatic insulin signaling, to determine the relative roles of insulin signaling and hepatic TG in regulating apoB secretion.

Methods and Results—

TG and apoB secretion was elevated in h
Pten
-ko mice. When hepatic TG was reduced by inhibition of diacylglycerol acyltransferase 1/diacylglycerol acyltransferase 2 or sterol regulatory element-binding protein-1c, both TG secretion and apoB secretion fell without changes in hepatic insulin signaling. Acute reconstitution of h
Pten
reduced hepatic TG content, and both TG and apoB secretion fell within 4 days despite decreased hepatic insulin signaling. Acute depletion of hepatic
Pten
by adenoviral introduction of Cre into
Pten
floxed mice caused steatosis within 4 days, and secretion of both TG and apoB increased despite increased hepatic insulin signaling. Even when steatosis after acute Pten depletion was prevented by pretreatment with SREBP-1c antisense oligonucleotides, apoB secretion was not reduced after 4 days. Ex vivo results were in primary hepatocytes were similar.

Conclusion—

Either hepatic TG is the dominant regulator of apoB secretion or any inhibitory effects of hepatic insulin signaling on apoB secretion is very short-lived.
Investigating the Role of the Coronary Vasculature in the Mechanisms of Defibrillation
Authors: Bishop Martin J. , Plank Gernot , Vigmond Edward
Published: December 2011

Background—

The direct role of coronary vessels in defibrillation, although hypothesized to be important, remains to be elucidated. We investigated how vessel-induced virtual electrode polarizations assist reentry termination.

Methods and Results—

A highly anatomically detailed rabbit ventricular slice bidomain computer model was constructed from 25-μm magnetic resonance data, faithfully representing both structural and electric properties of blood vessels. For comparison, an equivalent simplified model with intramural cavities filled in was also built. Following fibrillation induction, 6 initial states were selected, and biphasic shocks (5–70 V) were applied using a realistic implanted cardioverter-defibrillator electrode configuration. A fundamental mechanism of biphasic defibrillation was uncovered in both models, involving successive break excitations (after each shock phase) emanating from opposing myocardial surfaces (in septum and left ventricle), which rapidly closed down excitable gaps. The presence of vessels accelerated this process, achieving more-rapid and successful defibrillation. Defibrillation failed in 5 cases (all because of initiation of new activity) compared with 8 with the simplified model (5/8 failures because of surviving activity). At stronger shocks, virtual electrodes formed around vessels, rapidly activating intramural tissue because of break excitations, assisting the main defibrillation mechanism, and eliminating all activity <15 ms of shock end in 60% of successful shocks (36% in simplified model). Subsequent analysis identified that only vessels >200 μm in diameter participated through this mechanism. Consequently, wavefronts could survive intramurally in the simplified model, leading to reentry and shock failure.

Conclusions—

We provide new insight into defibrillation mechanisms by showing how intramural blood vessels facilitate more-effective elimination of existing wavefronts, rapid closing down of excitable gaps, and successful defibrillation and give guidance toward the required resolution of cardiac imaging and model generation endeavors for mechanistic defibrillation analysis.
Estimating and Reporting on the Quality of Inpatient Stroke Care by Veterans Health Administration Medical Centers
Authors: Arling Greg , Reeves Mathew , Ross Joseph , Williams Linda S. , Keyhani Salomeh , Chumbler Neale , Phipps Michael S. , Roumie Christianne , Myers Laura J. , Salanitro Amanda H. , Ordin Diana L. , Myers Jennifer , Bravata Dawn M.
Published: December 2011

Background—

Reporting of quality indicators (QIs) in Veterans Health Administration Medical Centers is complicated by estimation error caused by small numbers of eligible patients per facility. We applied multilevel modeling and empirical Bayes (EB) estimation in addressing this issue in performance reporting of stroke care quality in the Medical Centers.

Methods and Results—

We studied a retrospective cohort of 3812 veterans admitted to 106 Medical Centers with ischemic stroke during fiscal year 2007. The median number of study patients per facility was 34 (range, 12–105). Inpatient stroke care quality was measured with 13 evidence-based QIs. Eligible patients could either pass or fail each indicator. Multilevel modeling of a patient's pass/fail on individual QIs was used to produce facility-level EB-estimated QI pass rates and confidence intervals. The EB estimation reduced interfacility variation in QI rates. Small facilities and those with exceptionally high or low rates were most affected. We recommended 8 of the 13 QIs for performance reporting: dysphagia screening, National Institutes of Health Stroke Scale documentation, early ambulation, fall risk assessment, pressure ulcer risk assessment, Functional Independence Measure documentation, lipid management, and deep vein thrombosis prophylaxis. These QIs displayed sufficient variation across facilities, had room for improvement, and identified sites with performance that was significantly above or below the population average. The remaining 5 QIs were not recommended because of too few eligible patients or high pass rates with little variation.

Conclusions—

Considerations of statistical uncertainty should inform the choice of QIs and their application to performance reporting.
Clopidogrel Use and Early Outcomes Among Older Patients Receiving a Drug-Eluting Coronary Artery Stent
Authors: Roth Gregory A. , Morden Nancy E. , Zhou Weiping , Malenka David J. , Skinner Jonathan
Published: December 2011

Background—

Clopidogrel use after drug-eluting stent (DES) coronary artery implantation is essential for the prevention of early in-stent thrombosis, but clopidogrel use among older DES recipients has not been widely studied. We sought to identify characteristics associated with failure to fill a clopidogrel prescription and to examine the relationship between a clopidogrel prescription fill and hospitalization for acute myocardial infarction (AMI) or death.

Methods and Results—

This study was a retrospective analysis of administrative data (20% sample) of 15 996 Medicare Part D enrollees who received a DES in 2006 to 2007. We modeled the adjusted probability and odds of clopidogrel prescription fill within 7 and 90 days of discharge and its association with AMI hospitalization or death. Of the study sample, 19.7% did not fill a clopidogrel prescription within 7 days of discharge, falling to 13.3% by day 90. The adjusted probability of filling a clopidogrel prescription within 7 or 90 days of discharge was lower for patients with dementia (20.2% less likely; 95% CI, 10.4%–30.1%), depression (10.7% less likely; 95% CI, 6.9%–14.5%), age >84 years compared to age 65 to 69 years (10.6% less likely; 95% CI, 8.6%–12.7%), black race (6.6% less likely; 95% CI, 4.2%–9.0%), intermediate levels of medication cost share (5.2% less likely; 95% CI, 2.9%–7.6%), and female sex (3.3% less likely; 95% CI, 2.1%–4.5%). It was higher for patients initially hospitalized for an AMI (12.5% more likely; 95% CI, 11.3%–13.6%). Failure to fill a clopidogrel prescription within 7 days of discharge was associated with a higher adjusted odds ratio of death during days 8 to 90 (2.44; 95% CI, 1.76–3.38) but was not associated with an increased risk of hospitalization for AMI.

Conclusions—

One in 5 patients failed to fill a prescription for clopidogrel at 7 days after DES placement, and 1 in 7 failed to do so by 3 months. Individual characteristics available at the time of hospital discharge were associated with a clopidogrel prescription fill. Those characteristics most strongly associated with nonadherence, including age >84 years, not having an AMI, depression, and dementia, may guide clinicians and health systems seeking to target this high-risk population and improve health outcomes after percutaneous coronary intervention.