bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Risk of Bladder Cancer Using Clinical and Demographic Information from Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Participants
Authors: Mir Maria C. , Stephenson Andrew J. , Grubb Robert L. , Black Amanda , Kibel Adam S. , Izmirlian Grant
Published: October 2013

Background: Effective screening and prevention strategies for bladder cancer require accurate risk stratification models. We developed models to predict the risk of bladder cancer based on clinical and sociodemographic data on participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial.

Methods: Baseline clinical and sociodemographic data were obtained from 149,542 PLCO participants, ages 55 to 74 years, without a prior history of bladder cancer. Cox proportional hazards models were used to predict the risk of all bladder cancers (ABC) and of high-grade bladder cancers (HGBC) from baseline information. We used the HGBC risk model to design a hypothetical bladder cancer mortality prevention trial.

Results: Over a median follow-up of 12 years, 1,124 men and 259 women developed bladder cancer (including 392 and 72 with HGBC, respectively). The incidence in men and in women was 133.6 and 29.6 cases per 100,000 person-years, respectively. Nomograms constructed for predicting the risk of ABC and HGBC had c-indices of 0.746 and 0.759, respectively. Age, race, education, smoking (intensity and duration), comorbidity, prostatitis, syphilis, and hormone replacement therapy use were statistically significant predictors in the models. We show that our risk model can be used to design a bladder cancer mortality prevention trial half the size of a trial designed without risk stratification.

Conclusion: Models to predict the risk of ABC and HGBC have been developed and validated.

Impact: Using the upper 40th percentile from the HGBC model, a suitable cohort for a screening or chemoprevention trial could be identified, although the size and follow-up of such a trial would be costly. Cancer Epidemiol Biomarkers Prev; 22(12); 2241–9. ©2013 AACR.
Seropositivity to Helicobacter pylori and Risk of Pancreatic Cancer
Authors: Yu Guoqin , Murphy Gwen , Michel Angelika , Weinstein Stephanie J. , Männistö Satu , Albanes Demetrius , Pawlita Michael , Stolzenberg-Solomon Rachael Z.
Published: October 2013

Helicobacter pylori (H. pylori) seropositivity has been inconsistently associated with pancreatic cancer. We, therefore, investigated the association between H. pylori seropositivity and pancreatic cancer in a case–control study nested within Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) cohort of Finnish male smokers. Pancreatic cancer cases (n = 353) and control subjects (n = 353) were matched on date of baseline serum collection, age at randomization, and follow-up time (up to 23.9 years). We used a multiplex serology assay to determine the sero-status of antibodies against 15 H. pylori–specific antigens in fasting serum samples. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Neither targeted H. pylori antigens in serum nor the combination of all was associated with development of pancreatic cancer (combination of all: OR, 0.85; 95% CI, 0.49–1.49). Our results suggest that H. pylori is not a risk factor for pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 22(12); 2416–9. ©2013 AACR.
Quantification of Excision Repair Cross-Complementing Group 1 and Survival in p16-Negative Squamous Cell Head and Neck Cancers
Authors: Mehra Ranee , Zhu Fang , Yang Dong-Hua , Cai Kathy Q. , Weaver JoEllen , Singh Mahendra K. , Nikonova Anna S. , Golemis Erica A. , Flieder Douglas B. , Cooper Harry S. , Lango Miriam , Ridge John A. , Burtness Barbara
Published: October 2013

Purpose: Multimodality treatment of squamous cell carcinoma of the head and neck (SCCHN) often involves radiotherapy and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined excision repair cross-complementing group 1 (ERCC1) expression in human papillomavirus (HPV)-negative SCCHN treated with surgery [±adjuvant radiotherapy/chemoradiation (CRT)].

Experimental Design: We assessed ERCC1 protein expression in archival tumors using immunofluorescence staining and automatic quantitative analysis (AQUA) with three antibodies to ERCC1 (8F1, FL297, and HPA029773). Analysis with Classification and Regression Tree (CART) methods ascertained the cutoff points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T, and N stage. Kaplan–Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed.

Results: ERCC1 low/high groups were defined on the basis of AQUA analysis with 8F1/2009, FL297, and HPA029773. Among patients treated with surgery plus adjuvant radiotherapy/CRT, longer median survival was observed in ERCC1-low versus ERCC1-high tumors (64 vs. 29 months; P = 0.02; HPA029773). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody.

Conclusions: Using AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low-ERCC1 tumors from patients treated with surgery and adjuvant radiotherapy. Clin Cancer Res; 19(23); 6633–43. ©2013 AACR.
Activity of the Hypoxia-Activated Prodrug, TH-302, in Preclinical Human Acute Myeloid Leukemia Models
Authors: Portwood Scott , Lal Deepika , Hsu Yung-Chun , Vargas Rodrigo , Johnson Megan K. , Wetzler Meir , Hart Charles P. , Wang Eunice S.
Published: October 2013

Purpose: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth.

Experimental Design: We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models.

Results: We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models.

Conclusions: Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. Clin Cancer Res; 19(23); 6506–19. ©2013 AACR.
A Phase II and Biomarker Study of Ramucirumab, a Human Monoclonal Antibody Targeting the VEGF Receptor-2, as First-Line Monotherapy in Patients with Advanced Hepatocellular Cancer
Authors: Zhu Andrew X. , Finn Richard S. , Mulcahy Mary , Gurtler Jayne , Sun Weijing , Schwartz Jonathan D. , Dalal Rita P. , Joshi Adarsh , Hozak Rebecca R. , Xu Yihuan , Ancukiewicz Marek , Jain Rakesh K. , Nugent Francis W. , Duda Dan G. , Stuart Keith
Published: October 2013

Purpose: To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers.

Experimental Design: Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients.

Results: Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6–5.7], ORR was 9.5% (95% CI, 2.7–22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1–19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5–9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1–23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2.

Conclusion: Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents. Clin Cancer Res; 19(23); 6614–23. ©2013 AACR.
Systematic Screen Identifies miRNAs That Target RAD51 and RAD51D to Enhance Chemosensitivity
Authors: Huang Jen-Wei , Wang Yemin , Dhillon Kiranjit K. , Calses Philamer , Villegas Emily , Mitchell Patrick S. , Tewari Muneesh , Kemp Christopher J. , Taniguchi Toshiyasu
Published: October 2013

Homologous recombination mediates error-free repair of DNA double-strand breaks (DSB). RAD51 is an essential protein for catalyzing homologous recombination and its recruitment to DSBs is mediated by many factors including RAD51, its paralogs, and breast/ovarian cancer susceptibility gene products BRCA1/2. Deregulation of these factors leads to impaired DNA repair, genomic instability, and cellular sensitivity to chemotherapeutics such as cisplatin and PARP inhibitors. microRNAs (miRNA) are short, noncoding RNAs that posttranscriptionally regulate gene expression; however, the contribution of miRNAs in the regulation of homologous recombination is not well understood. To address this, a library of human miRNA mimics was systematically screened to pinpoint several miRNAs that significantly reduce RAD51 foci formation in response to ionizing radiation in human osteosarcoma cells. Subsequent study focused on two of the strongest candidates, miR-103 and miR-107, as they are frequently deregulated in cancer. Consistent with the inhibition of RAD51 foci formation, miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA-damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107–mediated chemosensitization. Furthermore, endogenous regulation of RAD51D by miR-103/107 was observed in several tumor subtypes. Taken together, these data show that miR-103 and miR-107 overexpression promotes genomic instability and may be used therapeutically to chemosensitize tumors.

Implications: These findings demonstrate a role for miR-103 and -107 in regulating DNA damage repair, thereby identifying new players in the progression of cancer and response to chemotherapy. Mol Cancer Res; 11(12); 1564–73. ©2013 AACR.
Activation of the Wnt Pathway through AR79, a GSK3β Inhibitor, Promotes Prostate Cancer Growth in Soft Tissue and Bone
Authors: Jiang Yuan , Dai Jinlu , Zhang Honglai , Sottnik Joe L. , Keller Jill M. , Escott Katherine J. , Sanganee Hitesh J. , Yao Zhi , McCauley Laurie K. , Keller Evan T.
Published: October 2013

Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3β) inhibits Wnt signaling by inducing β-catenin degradation, and a GSK3β inhibitor, AR79, is being evaluated as an osteoanabolic agent. However, Wnt activation has the potential to promote tumor growth; therefore, the goal of this study was to determine if AR79 has an impact on the progression of prostate cancer. Prostate cancer tumors were established in subcutaneous and bone sites of mice followed by AR79 administration, and tumor growth, β-catenin activation, proliferation, and apoptosis were assessed. Additionally, prostate cancer and osteoblast cell lines were treated with AR79, and β-catenin status, proliferation (with β-catenin knockdown in some cases), and proportion of ALDH+CD133+ stem-like cells were determined. AR79 promoted prostate cancer tumor growth, decreased phospho-β-catenin, increased total and nuclear β-catenin, and increased tumor-induced bone remodeling. Additionally, AR79 treatment decreased caspase-3 and increased Ki67 expression in tumors and increased bone formation in normal mouse tibiae. Similarly, AR79 inhibited β-catenin phosphorylation, increased nuclear β-catenin accumulation in prostate cancer and osteoblast cell lines, and increased proliferation of prostate cancer cells in vitro through β-catenin. Furthermore, AR79 increased the ALDH+CD133+ cancer stem cell–like proportion of the prostate cancer cell lines. In conclusion, AR79, while being bone anabolic, promotes prostate cancer cell growth through Wnt pathway activation.

Implications: These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth. Mol Cancer Res; 11(12); 1597–610. ©2013 AACR.
Aberrant DNA Methylation at Genes Associated with a Stem Cell-like Phenotype in Cholangiocarcinoma Tumors
Authors: Sriraksa Ruethairat , Zeller Constanze , Dai Wei , Siddiq Afshan , Walley Andrew J. , Limpaiboon Temduang , Brown Robert
Published: October 2013

Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium's HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly and epigenetically regulated in this tumor type. Using a linear model for microarray data, we identified 1610 differentially methylated autosomal CpG sites, with 809 hypermethylated (representing 603 genes) and 801 hypomethylated (representing 712 genes) in cholangiocarcinoma versus adjacent normal tissues (false-discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12, and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Cancer Prev Res; 6(12); 1348–55. ©2013 AACR.
A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process
Authors: Yuan Huiling , Qin Fujun , Movassagh Mercedeh , Park Hong , Golden Wendy , Xie Zhongqiu , Zhang Peng , Sklar Jeffrey , Li Hui
Published: October 2013

Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3–FOXO1, identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3–FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG—two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specific chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage.

Significance: A chimeric fusion RNA, PAX3–FOXO1, associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3–FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis. Cancer Discov; 3(12); 1394–1403. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1317
Molecular Neuropsychology: Creation of Test-Specific Blood Biomarker Algorithms
Authors: O'Bryant Sid E. , Xiao Guanghua , Barber Robert , Cullum C. Munro , Weiner Myron , Hall James , Edwards Melissa , Grammas Paula , Wilhelmsen Kirk , Doody Rachelle , Diaz-Arrastia Ramon ,   Texas Alzheimer’s Research and Care Consortium
Published: October 2013

Background: Prior work on the link between blood-based biomarkers and cognitive status has largely been based on dichotomous classifications rather than detailed neuropsychological functioning. The current project was designed to create serum-based biomarker algorithms that predict neuropsychological test performance. Methods: A battery of neuropsychological measures was administered. Random forest analyses were utilized to create neuropsychological test-specific biomarker risk scores in a training set that were entered into linear regression models predicting the respective test scores in the test set. Serum multiplex biomarker data were analyzed on 108 proteins from 395 participants (197 Alzheimer patients and 198 controls) from the Texas Alzheimer's Research and Care Consortium. Results: The biomarker risk scores were significant predictors (p < 0.05) of scores on all neuropsychological tests. With the exception of premorbid intellectual status (6.6%), the biomarker risk scores alone accounted for a minimum of 12.9% of the variance in neuropsychological scores. Biomarker algorithms (biomarker risk scores and demographics) accounted for substantially more variance in scores. Review of the variable importance plots indicated differential patterns of biomarker significance for each test, suggesting the possibility of domain-specific biomarker algorithms. Conclusions: Our findings provide proof of concept for a novel area of scientific discovery, which we term ‘molecular neuropsychology'.
Cognitive Assessment in Elderly Residents of Long-Stay Institutions
Authors: Medeiros de A. Nunes Vilani , Alchieri João Carlos , Azevedo Lívia Maria , Varela de Oliveira Karla Maryjara , Pereira Danilo Assis
Published: October 2013

Objective: To evaluate the cognitive performance of institutionalized elderly in the city of Natal, state of Rio Grande do Norte, Brazil. Methods: A descriptive, longitudinal study of 85 aged individuals via an interview conducted following the application of a classification form and the Mini-Mental State Examination (MMSE), with different cutoff points according to the level of education. The study was approved by the Research Ethics Committee of the Universidad Federal do Rio Grande do Norte (164/2011). Results: The mean age of the elderly studied was 76.8 years, 48.3% were single and 62.0% women, with an average of 3.27 children and 3 years of schooling; cognitive losses were recorded over a 6-month period following the 1st assessment, declining from 18.8 to 16.9% at the 2nd assessment for the following items: orientation to space (p = 0.02), language (p = 0.02) and repetition (p = 0.01). Conclusion: The results show significant cognitive changes among elderly subjects, with 64.6% exhibiting cognitive impairment. The findings suggest systematic evaluations in elders as a mean to establish prevention measures for health losses, taking into account that the referred deficits are capable of causing damage in the everyday life of these elderly residents of institutions.
Impact of CYP2D6 and CYP3A4 Genetic Polymorphism on Combined Cholinesterase Inhibitors and Memantine Treatment in Mild to Moderate Alzheimer's Disease
Authors: Sonali Nirmal , Tripathi Manjari , Sagar Rajesh , Velpandian Thirumurthy , Subbiah Vivekanandhan
Published: October 2013

Aim: The impact of CYP2D6 and CYP3A4 polymorphism on the steady-state plasma concentrations and therapeutic outcome of donepezil monotherapy and combination therapy in Alzheimer's disease (AD) patients. Methods: A total of 38 patients for donepezil and 17 patients for donepezil and memantine therapy, aged ≥55 years, were recruited meeting inclusion and exclusion criteria. Polymerase chain reaction-restriction fragment length polymorphism was performed. The liquid chromatography-tandem mass spectrometry method was used for estimation of drug levels of donepezil and memantine. Results: Significant allele frequency was observed for CYP2D6*3 polymorphism in patients on donepezil monotherapy and combination therapy. Significant allele frequency for CYP2D6*4 was observed in the patients on donepezil monotherapy. Conclusion: CYP2D6 polymorphism, though not significant, might partially be involved in the plasma concentration of AD drug.
Self-Efficacy Partially Mediates between Social Support and Health-Related Quality of Life in Family Caregivers for Dementia Patients in Shanghai
Authors: Zhang Shuying , Edwards Helen , Yates Patsy , Li Chunbo , Guo Qihao
Published: October 2013

Background: There is a paucity of research assessing health-related quality of life (HRQoL) and self-efficacy in caregivers of relatives with dementia in mainland China. Aims: To compare the level of HRQoL between caregivers and the general population in mainland China and to assess the role of caregiver self-efficacy in the relationship between caregiver social support and HRQoL. Methods: A cross-sectional study was conducted in Shanghai, China. The caregivers were recruited from the outpatient department of a teaching hospital. A total of 195 participants were interviewed, using a survey package including the Chinese version of the 36-Item Short-Form Health Survey (SF-36), demographic data, the variables associated with the impairments of care recipients, perceived social support and caregiver self-efficacy. The caregivers' SF-36 scores were compared with those of the general population in China. Results: The results indicated that the HRQoL of the caregivers was poorer compared with that of the general population when matched for age and gender. Multiple regression analyses revealed that caregiver self-efficacy is a partial mediator between social support and HRQoL, and a partial mediator between behavioral and psychological symptoms of dementia (BPSD) and caregiver mental health. Conclusion: Assisting with managing BPSD and enhancing caregiver self-efficacy can be considered integral parts of interventions to improve caregiver HRQoL.
Memantine in Patients with Moderate to Severe Alzheimer's Disease: Meta-Analyses Using Realistic Definitions of Response
Authors: Wilkinson David , Wirth Yvonne , Goebel Claus
Published: October 2013

Background/Aims: We aimed to develop realistic definitions of clinical worsening in advanced Alzheimer's disease (AD) and to use them in a post hoc responder analysis of memantine. Methods: 2,340 patients with moderate to severe AD (Mini-Mental State Examination <20) were included from 9 multicentre, 16- to 28-week, randomised, double-blind, placebo-controlled studies of memantine 20 mg/day versus placebo. Responder meta-analyses were performed, with definitions of response based on minimally important differences (MIDs) on cognitive, functional, and global assessment scales. Validated or established MIDs were used where available; otherwise, MIDs were estimated by a data-driven approach, using data from our moderate to severe AD population. Results: Patients with moderate to severe AD treated with memantine had a lower incidence of worsening from baseline to endpoint than patients treated with placebo, in cognition [24.4 vs. 35.0%; odds ratio (OR) = 0.60; p < 0.001], function (38.1 vs. 43.4%; OR = 0.81; p = 0.01), global status (39.8 vs. 48.6%; OR = 0.70; p < 0.001), and in a combined ‘triple' worsening measure (9.4 vs. 16.1%; OR = 0.54; p < 0.001). Conclusions: New definitions of clinical worsening based on MIDs represent a more realistic functional decline in advanced stages of AD. Results of this new analysis show that memantine reduces the incidence of clinical worsening in key symptomatic domains in moderate to severe AD.
Confrontation Naming Errors in Alzheimer's Disease
Authors: Lin Chi-Ying , Chen Ting-Bin , Lin Ker-Neng , Yeh Yen-Chi , Chen Wei-Ta , Wang Kuo-Shu , Wang Pei-Ning
Published: October 2013

Background/Aims: Impairment in visual interpretation, semantic conception, or word retrieval may contribute to the naming errors identified in the Boston Naming Test (BNT). We investigated the possible cognitive mechanism of the naming difficulty in Alzheimer's disease (AD) by analyzing the error patterns presented in the BNT. Methods: The Chinese version of the 30-item BNT (BNT-30) was performed on 115 normal control (NC) subjects and 104 mild-to-moderate AD patients. Accurate rates after semantic and phonemic cues were analyzed. The frequencies of 7 types of error patterns in the AD patients and the NC subjects were compared. Results: The accurate rate after semantic cues was significantly lower in the AD than in the NC groups, but phonemic cues were more helpful than semantic cues to achieve accurate naming in both groups. The AD patients made more errors in all error patterns. Particularly, the frequency of nonresponse errors (n = 806) in the AD group significantly exceeded that in the NC group (n = 382). However, the distribution of the error patterns did not differ between the two groups. Conclusion: Naming difficulties in AD might be attributed to progressive semantic knowledge degradation. The AD and the NC groups differ quantitatively but not qualitatively in the error patterns in confrontation naming.
Octreotide-Induced Long QT Syndrome in a Child with Congenital Hyperinsulinemia and a Novel Missense Mutation (p.Met115Val) in the ABCC8 Gene
Authors: Çelik Nurullah , Cinaz Peyami , Emeksiz Hamdi Cihan , Hussain Khalid , Çamurdan Orhun , Bideci Aysun , Döğer Esra , Yüce Özge , Türkyılmaz Zafer , Oğuz Ayşe Deniz
Published: October 2013

Background/Aims: Congenital hyperinsulinism (CHI) denotes an inappropriate secretion of insulin from pancreatic β-cells in the presence of a low blood glucose level due to various genetic causes. Diazoxide is the first-line medical treatment for CHI. In case of failure, a somatostatin analogue called octreotide is used. A prolonged QT interval is an unusual side effect of octreotide which can be lethal if unrecognized. Case Presentation: We report on a 35-day-old infant who was diagnosed with CHI on the 3rd day of his life and underwent pancreatectomy due to failure of medical treatment at 8 months. His genetic analysis revealed a compound heterozygosity for a novel missense mutation (p.Met115Val) and a nonsense mutation (p.Trp1339X) in the ABCC8 gene. Furthermore, at the 6th month of follow-up, a long QT (0.49 s) was determined by ECG examination, which was normalized following discontinuation of octreotide treatment after pancreatectomy. Thus, the long QT was considered to be secondary to octreotide medication. Conclusion: We recommend ECG monitoring before and during octreotide treatment in order to recognize a prolonged QT interval and to prevent related complications in cases with congenital hyperinsulinemia.
Tetramethylpyrazine Analogue CXC195 Protects against Cerebral Ischemia/Reperfusion Injury in the Rat by an Antioxidant Action via Inhibition of NADPH Oxidase and iNOS Expression
Authors: Liu Huiqing , Wei Xinbing , Chen Lin , Liu Xiaoqian , Li Senpeng , Liu Xinyong , Zhang Xiumei
Published: October 2013

Aims: This study was conducted to investigate the protective effects of CXC195, a tetramethylpyrazine analogue, in acute focal cerebral ischemia/reperfusion (I/R) injury in rats and to elucidate the potential mechanism. Methods: Middle cerebral artery occlusion for 2 h followed by reperfusion for 24 h was conducted in male Wistar rats and different doses of tetramethylpyrazine and CXC195 were intraperitoneally injected at 30 min after reperfusion. Results: Our results demonstrated that CXC195 at the dosage of 3 and 10 mg/kg significantly reduced the neurological deficit score and the infarct volume compared to the vehicle-treated group. In addition, CXC195 exhibited a protective effect against hippocampus neuronal cell death and significantly restored the brain ATP content. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidative capability (T-AOC), as well as production of malondialdehyde (MDA) and reactive oxygen species (ROS) were assayed in ipsilateral hemisphere homogenates to evaluate the redox status after I/R injury. Treatment with CXC195 significantly attenuated the decrease of SOD, GPx and T-AOC activities and inhibited the elevation of MDA content and ROS generation. Furthermore, CXC195 prevented the upregulation of the NADPH oxidase (NOX) 2 and NOX4, and reduced inducible nitric oxide synthase (iNOS) induction and production of nitric oxide induced by I/R. Conclusion: These results suggest that CXC195 has a neuroprotective effect in transient focal ischemia, which is most likely due to its antioxidant activity by inhibiting NOX and iNOS expression.
Interplay Between Mitral Regurgitation and Transcatheter Aortic Valve Replacement With the CoreValve Revalving System
Authors: Bedogni Francesco , Latib Azeem , De Marco Federico , Agnifili Mauro , Oreglia Jacopo , Pizzocri Samuele , Latini Roberto A. , Lanotte Stefania , Petronio Anna Sonia , De Carlo Marco , Ettori Federica , Fiorina Claudia , Poli Arnaldo , Cirri Silvia , De Servi Stefano , Ramondo Angelo , Tarantini Giuseppe , Marzocchi Antonio , Fiorilli Rosario , Klugmann Silvio , Ussia Gian Paolo , Tamburino Corrado , Maisano Francesco , Brambilla Nedy , Colombo Antonio , Testa Luca
Published: October 2013

Background—

Little is known of the prognostic significance of mitral regurgitation (MR) on transcatheter aortic valve replacement (TAVR), the impact of TAVR on MR severity, and the variables associated with possible post-TAVR improvement in MR. We evaluated these issues in a multicenter registry of patients undergoing CoreValve Revalving System–TAVR.

Methods and Results—

Among 1007 consecutive patients, 670 (66.5%), 243 (24.1%), and 94 (9.3%) presented with no/mild, moderate, and severe MR, respectively. At 1 month after TAVR, patients with severe or moderate MR showed comparable mortality rates (odds ratio, 1.1; 95% confidence interval [95% CI], 0.7–1.55;
P
=0.2), but both were significantly higher compared with patients with mild/no MR (odds ratio, 2.2; 95% CI, 1.78–3.28;
P
<0.001; and odds ratio, 1.9; 95% CI, 1.1–3.3;
P
=0.02, respectively).

One-year mortality was also similar between patients with severe and those with moderate MR (hazard ratio, 1.4; 95% CI, 0.94–2.4;
P
=0.06) and still significantly higher compared with patients with mild/no MR (hazard ratio, 1.7; 95% CI, 1.2–3.41;
P
<0.001; and hazard ratio, 1.4; 95% CI, 1.2–2.2;
P
=0.03, respectively). Severe pulmonary hypertension, atrial fibrillation, and MR more than mild, but not an improvement of ≥1 grade in MR severity, were independent predictors of mortality at 1 year. At 1 year, an improved MR was observed in 47% and 35% of patients with severe and moderate MR, respectively. The rate of low implantation was consistent across groups with improved, unchanged, or worsened MR. A functional type of MR and the absence of severe pulmonary hypertension and atrial fibrillation independently predicted the improvement in MR severity.

Conclusions—

Baseline MR greater than mild is associated with higher mortality after CoreValve Revalving System–TAVR. A significant improvement in MR was more likely in patients with functional MR and without severe pulmonary hypertension or atrial fibrillation. The improvement in MR did not independently predict mortality.
Chronic Heart Failure Is Associated With Transforming Growth Factor Beta‐Dependent Yield and Functional Decline in Atrial Explant‐Derived c‐Kit+ Cells
Authors: Zakharova Liudmila , Nural‐Guvener Hikmet , Nimlos James , Popovic Snjezana , Gaballa Mohamed A.
Published: October 2013

Background

Cardiac c‐Kit+ cells isolated from cardiac explant‐derived cells modestly improve cardiac functions after myocardial infarction; however, their full potential has not yet been realized. For instance, the majority of potential candidates for cell therapy suffer from chronic heart failure (
CHF
), and it is unclear how this disease affects the explant‐derived progenitor cells. Therefore, the objective of this study was to determine the effect of
CHF
on the number and phenotype of cardiac explant c‐Kit+ progenitors and elucidate mechanisms of their regulation.

Methods and Results

Myocardial infarction was created by left anterior descending coronary artery occlusion. Sham‐operated animals were used as a control group.
CHF
‐developed infarcted animals were selected on the basis of left ventricle end‐diastolic pressure ≥20 mm Hg and scar size ≥30%. Here, we found that
CHF
atrial explants produced less c‐Kit+ cells than sham explants.
CHF
‐derived c‐Kit+ cells exhibited upregulated transforming growth factor–β (
TGF
‐β) signaling, increased level of epithelial to mesenchymal transition markers, and diminished expression of pluripotency markers compared with shams. We show that intervention with
TGF
‐β signaling by inhibiting
TGF
‐β receptor type I or Smad 2/3 using small‐molecule inhibitors improved c‐Kit+ cell yield, attenuated epithelial to mesenchymal transition markers, stimulated the pluripotency marker Nanog, and improved efficiency of c‐Kit+ cell differentiation toward cardiomyocyte‐like cells in vitro.

Conclusions

Taken together, our findings suggest that
TGF
‐β inhibition positively modulates c‐Kit+ cell phenotype and function in vitro, and this strategy may be considered in optimizing cardiac progenitor function and cell expansion protocols for clinical application.
Twenty‐Two‐Year Population Trends in Sodium and Potassium Consumption: The Minnesota Heart Survey
Authors: Meyer Katie A. , Harnack Lisa J. , Luepker Russell V. , Zhou Xia , Jacobs David R. , Steffen Lyn M.
Published: October 2013

Background

Limiting dietary sodium consumption is a core lifestyle recommendation for the prevention of hypertension. There is increasing evidence that low potassium consumption also increases hypertension risk. We estimated sex‐specific 22‐year trends in sodium and potassium consumption.

Methods and Results

We used data from the
M
innesota
H
eart
S
urvey, which performs surveillance of risk factors for cardiovascular disease in the
M
inneapolis–
S
t.
P
aul metropolitan area. The
M
innesota
H
eart
S
urvey is a random population‐based sample of free‐living adults aged 25 to 74. Surveys were conducted in 1985–1987 (n=2273), 1990–1992 (n=2487), 1995–1997 (n=1842), 2000–2002 (n=2759), and 2007–2009 (n=1502). Dietary intake of sodium and potassium was estimated from one 24‐hour dietary recall. Over 22 years, age‐adjusted sodium and potassium intake among men remained relatively stable in 1985–1987 and 2007–2009 (
P
trend
=0.41 and 0.29, respectively); sodium ranged from 3820 mg/day (1995–1997) to 3968 mg/day (2007–2009) and potassium from 3111 mg/day (2000–2002) to 3249 mg/day (1995–1997). Sodium and potassium intake increased among women, from 2531 mg/day in 1985–1987 to 2854 mg/day in 2007–2009 (
P
trend
=0.001) for sodium and from 2285 to 2533 mg/day (
P
trend
<0.0001) for potassium. We observed stable or increasing sodium and potassium intake within some strata of age, education, and body mass index.

Conclusions

Despite long‐standing public health recommendations to limit sodium intake to <2300 mg/day, high sodium intake levels have persisted over the past 22 years. Furthermore, although potassium consumption increased in some subgroups over the study period, mean consumption remained significantly lower than the recommended 4700 mg/day in all groups.
Studies of Madagascan Ptiliidae (Coleoptera) 1: The Tribe Discheramocephalini including eighteen new species
Authors: DARBY MICHAEL
Published: October 2013

This is the first report detailing Ptiliidae collected from forest leaf litter by the Moravian Museum expeditions to Madagascar 2010-2011.18 new species in three genera are described and figured: Discheramocephalus bisulcatus sp. n.; D. vasilii sp. n.; Cissidium banari sp. n.; Dacrysoma andasibense sp. n.; D. imitatum sp. n.; D. delicatum sp. n.; D. denticulatum sp. n.; D. dolorosum sp. n.; D. fabrum sp. n.; D. fusum sp. n.; D. longulum sp. n.; D. nigerrimum sp. n.; D. pilosum sp. n.; D. rahanitriniainae sp. n.; D. ranomafanense sp. n.; D. ravelosoni sp. n.; D. subinsulsum sp. n.; and D. varium sp. n..
On the correct name of Icterus bullockii (Passeriformes: Icteridae)
Authors: CHESSER R. TERRY
Published: October 2013

William Bullock was an Englishman who owned the Egyptian Hall (also known as the London Museum or Bullock’s Museum) at Piccadilly in London, a museum opened in 1812 to display his collection of antiquities, artifacts, and natural history specimens.  Following the sale of Bullock’s collection in 1819, the Egyptian Hall served as an exhibition space.  Bullock and his son, William Bullock, Jr., both enthusiastic naturalists, travelled in Mexico in 1822–1823, spending some six months together collecting natural history specimens and other artifacts for exhibition and investigating mining and other business opportunities (Costeloe 2006).  The elder Bullock returned to London with the collections in 1823, but his son, while ostensibly managing the silver mine his father had purchased in Temascaltepec, outside of Mexico City, continued to travel in Mexico and collect specimens, often in the company of German naturalist Ferdinand Deppe (Costeloe 2006).  William Bullock, Sr., meanwhile prepared the Mexican collection for exhibition at the Egyptian Hall.  Twin exhibitions on ancient and modern Mexico opened, with much fanfare, in April 1824, and were a great success, remaining open until September 1825 (Costeloe 2006).  Afterwards, the contents of the exhibitions were dispersed via auction, but not before Bullock had made the bird specimens available to English naturalist William Swainson for “recording this portion of his discoveries” (Swainson 1827: 365).
The advertisement call and clutch size of the Golden-capped Boulder-frog Cophixalus pakayakulangun (Anura: Microhylidae)
Authors: ALAND KIERAN V. , HOSKIN CONRAD J.
Published: October 2013

In Australia, the family Microhylidae consists of 19 species of Cophixalus Boettger 1892 and 5 species of Austrochaperina Fry 1912 (Hoskin 2012; Hoskin, submitted). Most of these species have highly localized distributions in the rainforests and boulder-fields of north-east Australia (Zweifel 1985; Hoskin 2004; Hoskin & Aland 2011). Australian microhylid frogs are terrestrial breeders with direct development (Zweifel 1985; Hoskin 2004; Anstis et al. 2011). The natural history of Australia’s microhylids is fairly well known, with the basics of breeding biology such as calls and clutch sizes published for most species (Zweifel 1985; Hoskin 2004; Anstis et al. 2011; Hoskin & Aland 2011; Hoskin 2012; Hoskin, submitted). Hoskin & Aland (2011) described two new species from Cape York Peninsula, C. pakayakulangun and C. kulakula, each restricted to boulder-field areas only 30 km apart but readily distinguished by morphology and genetics. Calls could not be compared because the call of C. pakayakulangun was not known at that time. Clutch information for C. pakayakulangun was also not available at the time of description.
The Fast Longwave and Shortwave Flux (FLASHFlux) Data Product: Single-Scanner Footprint Fluxes
Authors: Kratz David P. , Stackhouse Paul W. , Gupta Shashi K. , Wilber Anne C. , Sawaengphokhai Parnchai , McGarragh Greg R.
Published: October 2013

The Clouds and the Earth’s Radiant Energy Systems (CERES) project utilizes radiometric measurements taken aboard the Terra and Aqua spacecrafts to derive the world-class data products needed for climate research. Achieving the exceptional fidelity of the CERES data products, however, requires a considerable amount of processing to assure quality and to verify accuracy and precision, which results in the CERES data being released more than 6 months after the satellite observations. For most climate studies such delays are of little consequence; however, there are a significant number of near–real time uses for CERES data products. The Fast Longwave and Shortwave Radiative Flux (FLASHFlux) data product was therefore developed to provide a rapid release version of the CERES results, which could be made available to the research and applications communities within 1 week of the satellite observations by exchanging some accuracy for speed. FLASHFlux has both achieved this 1-week processing objective and demonstrated the ability to provide remarkably good agreement when compared with the CERES data products for both the instantaneous single-scanner footprint (SSF) fluxes and the time- and space-averaged (TISA) fluxes. This paper describes the methods used to expedite the production of the FLASHFlux SSF fluxes by utilizing data from the CERES and Moderate Resolution Imaging Spectroradiometer instruments, as well as other meteorological sources. This paper also reports on the validation of the FLASHFlux SSF results against ground-truth measurements and the intercomparison of FLASHFlux and CERES SSF results. A complementary paper will discuss the production and validation of the FLASHFlux TISA fluxes.
Introducing an Irrigation Scheme to a Regional Climate Model: A Case Study over West Africa
Authors: Marcella Marc P. , Eltahir Elfatih A. B.
Published: October 2013

This article presents a new irrigation scheme and biome to the dynamic vegetation model, Integrated Biosphere Simulator (IBIS), coupled to version 3 of the Regional Climate Model (RegCM3-IBIS). The new land cover allows for only the plant functional type (crop) to exist in an irrigated grid cell. Irrigation water (i.e., negative runoff) is applied until the soil root zone reaches relative field capacity. The new scheme allows for irrigation scheduling (i.e., when to apply water) and for the user to determine the crop to be grown. Initial simulations show a large sensitivity of the scheme to soil texture types, how the water is applied, and the climatic conditions over the region. Application of the new scheme is tested over West Africa, specifically Mali and Niger, to simulate the potential irrigation of the Niger River. A realistic representation of irrigation of the Niger River is performed by constraining the land irrigated by the annual flow of the Niger River and the amount of arable land in the region as reported by the Food and Agriculture Organization of the United Nations (FAO). A 30-yr simulation including irrigated cropland is compared to a 30-yr simulation that is identical but with no irrigation of the Niger. Results indicate a significant greening of the irrigated land as evapotranspiration over the crop fields largely increases—mostly via increases in transpiration from plant growth. The increase in the evapotranspiration, or latent heat flux (by 65–150 W m−2), causes a significant decrease in the sensible heat flux while surface temperatures cool on average by nearly 5°C. This cooling is felt downwind, where average daily temperatures outside the irrigation are reduced by 0.5°–1.0°C. Likewise, large increases in 2-m specific humidity are experienced across the irrigated cropland (on the order of 5 g kg−1) but also extend farther north and east, reflecting the prevailing surface southwesterlies. Changes (decreases) in rainfall are found only over the irrigated lands of west Mali. The decrease in rainfall can be explained by the large surface cooling and collapse of the boundary layer (by approximately 500 m). Both lead to a reduction in the triggering of convection as the convective inhibition, or negative buoyant energy, is never breached. Nevertheless, the new scheme and land cover allows for a novel line of research that can accurately reflect the effects of irrigation on climate and the surrounding environment using a dynamic vegetation model coupled to a regional climate model.
Two Stable Equilibria of the Atlantic Subpolar Gyre
Authors: Born Andreas , Stocker Thomas F.
Published: October 2013

The cyclonic circulation of the Atlantic subpolar gyre is a key mechanism for North Atlantic climate variability on a wide range of time scales. It is generally accepted that it is driven by both cyclonic winds and buoyancy forcing, yet the individual importance and dynamical interactions of the two contributions remain unclear. The authors propose a simplified four-box model representing the convective basin of the Labrador Sea and its shallow and deep boundary current system, the western subpolar gyre. Convective heat loss drives a baroclinic flow of relatively light water around the dense center. Eddy salt flux from the boundary current to the center increases with a stronger circulation, favors the formation of dense waters, and thereby sustains a strong baroclinic flow, approximately 10%–25% of the total. In contrast, when the baroclinic flow is not active, surface waters may be too fresh to convect, and a buoyancy-driven circulation cannot develop. This situation corresponds to a second stable circulation mode. A hysteresis is found for variations in surface freshwater flux and the salinity of the near-surface boundary current. An analytical solution is presented and analyzed.
Periosteum
Authors: Lin Z. , Fateh A. , Salem D.M. , Intini G.
Published: October 2013

The bone-regenerative potentials of the periosteum have been explored as early as the 17th century. Over the past few years, however, much has been discovered in terms of the molecular and cellular mechanisms that control the periosteal contribution to bone regeneration. Lineage tracing analyses and knock-in transgenic mice have helped define the relative contributions of the periosteum and endosteum to bone regeneration. Additional studies have shed light on the critical roles that BMP, FGF, Hedgehog, Notch, PDGF, Wnt, and inflammation signaling have or may have in periosteal-mediated bone regeneration, fostering the path to novel approaches in bone-regenerative therapy. Thus, by examining the role that each pathway has in periosteal-mediated bone regeneration, in this review we analyze the status of the current research on the regenerative potential of the periosteum. The provided analysis aims to inform both clinician-scientists who may have interest in the current studies about the biology of the periosteum as well as dental surgeons who may find this review useful to perform periosteal-harnessing bone-regenerative procedures.