bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract S6-1: Menopausal Hormone Therapy Influence on Cancer Incidence and Related Cancer Mortality in the Women's Health Initiative Randomized Trials
Authors: Chlebowski RT
Published: April 2011

The Women's Health Initiative (WHI) has conducted two phase III randomized placebo controlled trials evaluating menopausal hormone therapy. Conjugated equine estrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily (E+P) was evaluated in 16,608 postmenopausal women with no prior hysterectomy and conjugated equine estrogen alone 0.625 mg daily (E alone) was evaluated in 10,738 postmenopausal women with prior hysterectomy. Previous analyses suggested differences in E+P vs E alone influence on incidence and related mortality of several cancers. More recent analyses after additional follow-up clarify these issues and suggest a unifying hypothesis regarding hormone therapy influence on cancer. In cross study comparisons using multivariate Cox regression models statistically significant differences between the two WHI trials regarding E+P vs E alone influence on breast cancer incidence (P=0.01), colorectal cancer incidence (P=0.004) and deaths from non-small cell lung cancer (P=0.03) are seen. In addition, E+P, but not E alone, had a greater adverse influence on mortality attributed to breast cancer, colorectal cancer, and NSCLC then on the incidence of these cancers. Results are summarized below.

Menopausal Hormone Therapy Influence on Incidence and Related Mortality of Selected Cancer

Chlebowski JAMA 2003;289:3243, Chlebowski NEJM 2004;350:991, Stefanick JAMA 2006;242:1048, Ritenbaugh Cancer Epi Bio Prev 2008;17:2609, Prentice Cancer Epi Bio Prev 2009;18:1531, Chlebowski NEJM 2009;360:573, Chlebowski Gynecologic Oncology 2010;117:394; abst, Chlebowski Proc ASCO 2010;abst 1705 As estrogen plus progestin simulates angiogenesis, these findings suggest an hypothesis that, in addition to its influence on cancer incidence, combined E+P use, thru angiogenesis stimulation or other mechanisms, broadly enhances growth of already established cancers, differentially impacting cancer-related survival across several cancer categories.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-1.
Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma
Authors: Tworkoski Kathryn , Singhal Garima , Szpakowski Sebastian , Zito Christina Ivins , Bacchiocchi Antonella , Muthusamy Viswanathan , Bosenberg Marcus , Krauthammer Michael , Halaban Ruth , Stern David F.
Published: April 2011

Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma. Mol Cancer Res; 9(6); 801–12. ©2011 AACR.
Fine-Needle Aspiration in Suspected Inflammatory Breast Cancer: Case Series with Emphasis on Approach to Specimen Adequacy
Authors: Kumar Neeta , Sayed Shahin , Moloo Zahir , Wasike Ronald
Published: April 2011

Objectives: To highlight the utility of a tangential approach in the fine-needle aspiration (FNA) technique for obtaining cellular material adequate for a conclusive diagnosis in diffusely enlarged breast without a discrete lump. Study Design: FNA was performed on 5 women clinically suspected to have inflammatory breast cancer (IBC). All had unilateral diffusely enlarged breasts with peau d’orange changes of the skin. No distinct lump was palpable. The procedure was performed using a 10 cm3 syringe with a tangential approach of a 23-gauge needle in all 4 quadrants with extra passes in the antigravity areas. Rapid on-site evaluation for adequacy was done. Results: All women were of African descent within the age range of 34–57 years. One case had a recent history of lactation. FNA smears showed low-to-moderate cellularity. One case was suspicious and 4 were positive for ductal carcinoma. Core biopsy confirmed IBC in 3 cases. Two cases had a mastectomy; 1 of these cases had preoperative neoadjuvant chemotherapy. Conclusion: The approach of FNA used in these cases helped to establish the diagnosis of IBC in 4 women presenting with a diffusely enlarged and tender breast, resulting in the timely initiation of appropriate management. The technique needs to be assessed in a larger cohort of women with diffusely enlarged breast to evaluate its diagnostic utility.
Pharmacodynamic Evaluation of Pantoprazole Therapy on Clopidogrel Effects
Authors: Ferreiro José Luis , Ueno Masafumi , Tomasello Salvatore D. , Capodanno Davide , Desai Bhaloo , Dharmashankar Kodlipet , Seecheran Naveen , Kodali Murali K. , Darlington Andrew , Pham John-Paul , Tello-Montoliu Antonio , Charlton Ronald K. , Bass Theodore A. , Angiolillo Dominick J.
Published: April 2011

Background—

Safety concerns have recently emerged based on a drug interaction between clopidogrel and proton pump inhibitors leading to reduced pharmacodynamic effects. However, whether such drug interaction is a class effect or a drug effect and if this can be modulated by timing of drug administration remains a matter of debate. The aim of this study was to assess the impact of high-dose pantoprazole therapy, a proton pump inhibitor with low potential to interfere with clopidogrel metabolism, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects.

Methods and Results—

This was a prospective, randomized, crossover study conducted in 20 healthy volunteers. Subjects were randomly assigned to receive pantoprazole (80 mg daily) administered concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy (600-mg loading dose followed by a 75-mg maintenance dose during all phases) in a crossover fashion with a 2- to 4-week washout period between treatments. All subjects had a 1-week treatment phase with a clopidogrel-only regimen with a 2- to 4-week washout period from randomization sequence. Platelet function was assessed by flow cytometric analysis of the status of phosphorylation of the vasodilator-stimulated phosphoprotein, light transmittance aggregometry after adenosine diphosphate stimuli, and VerifyNow P2Y
12
system at 3 time points: baseline, 24 hours after loading dose, and 1 week after maintenance dose. The primary end point was the comparison of P2Y
12
reactivity index assessed by vasodilator-stimulated phosphoprotein at 1 week. After 1 week, there were no significant difference in P2Y
12
reactivity index between the CONC and STAG regimens (least-squares mean±SEM, 56.0±3.9% versus 56.1±3.9%;
P
=0.974), as well as when compared with the clopidogrel-only regimen (61.0±3.9%;
P
=0.100 versus CONC and
P
=0.107 versus STAG). Further, no differences were observed at baseline and 24 hours between regimens. Concordant results were obtained by light transmittance aggregometry and VerifyNow P2Y
12
assays.

Conclusions—

Pantoprazole therapy used at high doses is not associated with modulation of the pharmacodynamic effects of clopidogrel, irrespective of timing of drug administration.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01170533.
Direct Costs of Patients With Stroke Can Be Continuously Monitored on a National Level
Authors: Meretoja Atte , Kaste Markku , Roine Risto O. , Juntunen Merja , Linna Miika , Hillbom Matti , Marttila Reijo , Erilä Terttu , Rissanen Aimo , Sivenius Juhani , Häkkinen Unto
Published: April 2011

Background and Purpose—

Treatment of stroke consumes a significant portion of all healthcare expenditure. We developed a system for monitoring costs from individual patient data on a national level in Finland.

Methods—

Multiple national administrative registers were linked to gain episode-of-care data on all hospital-treated patients with incident stroke over the years 1999 to 2007 (n=94 316). Inpatient and specialist outpatient costs were evaluated with a cost database, long-term care costs with fixed prices, and medication costs with true retail prices.

Results—

For the patients of Year 2007, the mean 1-year costs after an ischemic stroke were $29 580, after an intracerebral hemorrhage $36 220, and after a subarachnoid hemorrhage $42 570, valued in Year 2008 US dollars. Only part of these costs are attributable to stroke, because the annual costs prior to stroke were significant, $8900 before ischemic stroke, $7600 before intracerebral hemorrhage, and $4200 before subarachnoid hemorrhage. Older patients with ischemic stroke, and, among patients with ischemic stroke and subarachnoid hemorrhage, women, incurred higher costs. The mean estimated lifetime costs were $130 000 after ischemic stroke or intracerebral hemorrhage and $80 000 after subarachnoid hemorrhage. Annually $1.6 billion is spent in the care of Finnish patients with stroke, which equals to 7% of the national healthcare expenditure, or 0.6% of the gross domestic product. Costs of patients with stroke are increasing with prolonged survival and the aging population.

Conclusions—

Treatment of patients with stroke is a large national investment. Setting up a nationwide system for continuous monitoring of stroke costs is feasible. Cost data should optimally be evaluated in conjunction with effectiveness and performance indicators.
Water Mass Exchange in the Southern Ocean in Coupled Climate Models
Authors: Downes Stephanie M. , Gnanadesikan Anand , Griffies Stephen M. , Sarmiento Jorge L.
Published: April 2011

The authors estimate water mass transformation rates resulting from surface buoyancy fluxes and interior diapycnal fluxes in the region south of 30°S in the Estimating the Circulation and Climate of the Ocean (ECCO) model-based state estimation and three free-running coupled climate models. The meridional transport of deep and intermediate waters across 30°S agrees well between models and observationally based estimates in the Atlantic Ocean but not in the Indian and Pacific, where the model-based estimates are much smaller. Associated with this, in the models about half the southward-flowing deep water is converted into lighter waters and half is converted to denser bottom waters, whereas the observationally based estimates convert most of the inflowing deep water to bottom waters. In the models, both Antarctic Intermediate Water (AAIW) and Antarctic Bottom Water (AABW) are formed primarily via an interior diapycnal transformation rather than being transformed at the surface via heat or freshwater fluxes. Given the small vertical diffusivity specified in the models in this region, the authors conclude that other processes such as cabbeling and thermobaricity must be playing an important role in water mass transformation. Finally, in the models, the largest contribution of the surface buoyancy fluxes in the Southern Ocean is to convert Upper Circumpolar Deep Water (UCDW) and AAIW into lighter Subantarctic Mode Water (SAMW).
Response to Increasing Southern Hemisphere Winds in CCSM4
Authors: Gent Peter R. , Danabasoglu Gokhan
Published: April 2011

Results from two perturbation experiments using the Community Climate System Model version 4 where the Southern Hemisphere zonal wind stress is increased are described. It is shown that the ocean response is in accord with experiments using much-higher-resolution ocean models that do not use an eddy parameterization. The key to obtaining an appropriate response in the coarse-resolution climate model is to specify a variable coefficient in the Gent and McWilliams eddy parameterization, rather than a constant value. This result contrasts with several recent papers that have suggested that coarse-resolution climate models cannot obtain an appropriate response.
Performance of a Dynamic Initialization Scheme in the Coupled Ocean–Atmosphere Mesoscale Prediction System for Tropical Cyclones (COAMPS-TC)
Authors: Hendricks Eric A. , Peng Melinda S. , Ge Xuyang , Li Tim
Published: April 2011

A dynamic initialization scheme for tropical cyclone structure and intensity in numerical prediction systems is described and tested. The procedure involves the removal of the analyzed vortex and, then, insertion of a new vortex that is dynamically initialized to the observed surface pressure into the numerical model initial conditions. This new vortex has the potential to be more balanced, and to have a more realistic boundary layer structure than by adding synthetic data in the data assimilation procedure to initialize the tropical cyclone in a model. The dynamic initialization scheme was tested on multiple tropical cyclones during 2008 and 2009 in the North Atlantic and western North Pacific Ocean basins using the Naval Research Laboratory’s tropical cyclone version of the Coupled Ocean–Atmosphere Mesoscale Prediction System (COAMPS-TC). The use of this initialization procedure yielded significant improvements in intensity forecasts, with no degradation in track performance. Mean absolute errors in the maximum sustained surface wind were reduced by approximately 5 kt for all lead times up to 72 h.
Pultruded glass fiber- and pultruded carbon fiber-reinforced chemically bonded phosphate ceramics
Authors: Colorado H.A. , Hahn H.T. , Hiel C.
Published: April 2011

The main goal of this article is to present the pultrusion process for glass fiber- and carbon fiber-reinforced chemically bonded phosphate ceramics (CBPCs). Samples were fabricated with 15% of fibers by volume. An improvement (with respect to the matrix) of 29 times for the bending strength of CBPCs pultruded graphite fibers composites and 17 times for CBPCs pultruded glass fiber composites is shown. Bending strength was obtained with the three-point bending test. The CBPCs were fabricated by mixing special formulations of both wollastonite powder and phosphoric acid, through resonant acoustic mixing. The microstructure was analyzed with optical and scanning electron microscopes. X-ray compositional maps were obtained for the cross-section of pultruded samples with SEM-EDS. Pultruded sample response at high temperature and thermal shock were also analyzed. The structural characterization of samples was conducted by using X-ray micro tomography.
When is Democracy an Equilibrium? Theory and Evidence from Colombia’s La Violencia
Authors: Chacón Mario , Robinson James A. , Torvik Ragnar
Published: April 2011

The conventional wisdom is that for a democracy to be consolidated, all groups must have a chance to attain power. If they do not, then they will subvert democracy and choose to fight for power. In this article, the authors show that this wisdom is seriously incomplete because it considers absolute, not relative payoffs. Although the probability of winning an election increases with the size of a group, so does the probability of winning an armed conflict. Thus, in a situation in which all groups have a high chance of winning an election, they may also have a high chance of winning a fight. Indeed, in a natural model, the authors show that democracy may never be consolidated in such a situation. Rather, democracy may only be stable when one group is dominant. The authors explore this key aspect of the theory using data from La Violencia, a political conflict in Colombia during the years 1946—1950 between the Liberal and Conservative parties. Consistent with their results, and contrary to conventional wisdom, the authors show that fighting between the parties was more intense in municipalities where the support of the parties was more evenly balanced.
Identification of Disabilities and Service Receipt Among Preschool Children Living in Poverty
Authors: Peterson Carla A. , Wall Shavaun , Jeon Hyun-Joo , Swanson Mark E. , Carta Judith J. , Luze Gayle J. , Eshbaugh Elaine
Published: April 2011

This study examined the prevalence of indicators of disability or potential disability among preschool-aged children enrolled in the Early Head Start Research and Evaluation Longitudinal Follow-Up. Three categories of indicators were established: received Part B services, developmental risk, and biological risk. The majority of participating children (62%) were classified into at least one category. Children living in poverty from birth through preschool and of minority status were among those most likely to be classified; these children were likely to have received a variety of services. The majority of children who received Part C services (79.8%) received Part B services as preschoolers, but 33% of the children with a developmental risk identified before age 3 continued to have a developmental risk during preschool yet did not receive specialized services. Results highlight the importance of understanding the relations among child and family characteristics and service receipt to inform policy and practice.
Emotion Facilitation and Passive Avoidance Learning in Psychopathic Female Offenders
Authors: Vitale Jennifer E. , Maccoon Donal G. , Newman Joseph P.
Published: April 2011

Research on psychopathy among incarcerated White males has consistently demonstrated deficits in emotion processing and response inhibition. Using the Psychopathy Checklist—Revised to classify participants as psychopathic or nonpsychopathic, this study examined the performance of incarcerated White females on two laboratory tasks: a lexical decision task used to assess emotion processing and a passive avoidance task used to assess response inhibition. Contrary to prediction, deficits in performance typically exhibited by psychopathic males were not exhibited by psychopathic females in this sample. Implications of these findings are discussed and an interpretation of the results in the context of the response modulation hypothesis is presented.
Computed Tomography Is Useful for Preoperative Identification of Nonrecurrent Laryngeal Nerve in Thyroid Cancer Patients
Authors: Lee Yong Sang , Son Eun Ju , Chang Hang‐Seok , Chung Woong Youn , Nam Kee‐Hyun , Park Cheong Soo
Published: April 2011

Objective

Nonrecurrent laryngeal nerve (NRLN) is a risk factor for nerve injury during thyroid or parathyroid surgery and is usually associated with vascular anomalies. This study investigated the usefulness of computed tomography (CT) scans for preoperative identification of NRLN in thyroid cancer patients.

Study Design

Case series with chart review.

Setting

Academic university hospital.

Subjects and Methods

Of the 6546 patients, 20 (0.3%) were intraoperatively identified with NRLN, and the medical records of 20 patients were reviewed retrospectively, with particular focus on preoperative CT findings.

Results

All 20 cases were right‐sided NRLN, and no clinical symptoms were observed preoperatively in any patient. Two patients had type I NRLN and 18 had type II NRLN. NRLN injury occurred in 1 patient at a point where the nerve was close to the superior thyroid artery. Prior to surgery, surgeons identified only 5 suspected NRLN cases based on identification of vascular anomalies on CT scans. However, this review of CT scans revealed that vascular anomalies could be identified on the scans of all patients.

Conclusions

Neck CT scanning appears to be an excellent method for predicting NRLN cases. However, thorough examination of the scans, with particular attention to the neck and mediastinum vascular structures, is required.
Competition and Combative Advertising
Authors: Beard Fred K.
Published: April 2011

This historical study contributes to the research literature on advertising and competition by exploring professional thought and economic theory as explanations for why advertisers might choose to compete in advertising and how combatively. Primary and secondary sources consist of articles published in historic and contemporary advertising trade journals, such as Printers’ Ink and Advertising Age. The findings reveal that during the first half of the twentieth century, statements and beliefs in favor of avoiding competition were often consistent with both the informative economic view and the symbiotic competition associated with expanding markets. During the past fifty to sixty years, however, findings show that the majority advocating more combative advertising predominantly associated it with zero-sum competitive situations and described the use of advertising consistent with the persuasive school of economic thought. Other findings support recent theory and research on combative advertising and both micro- and macroeconomic causes and consequences of competition.
Shifting to the Systemic-Relational Paradigm in Treating Adults Diagnosed With Cancer
Authors: Taylor Jessica Z. , Rocco Cottone R.
Published: April 2011

Numerous existentially based counseling interventions have aimed to help adults diagnosed with cancer find meaning in their lives. All of these interventions have measured only psychological outcome measures while alluding to benefits from social relationships. Shifting from the psychological paradigm to the systemic-relational paradigm in approaching and assessing counseling interventions with this population is discussed. Two measurement tools in the literature are presented as ideas for creating systemically based outcome measurement tools for counseling interventions.
Legislator Uses of Public Performance Reports
Authors: McDavid James C. , Huse Irene
Published: April 2011

A key assumption in efforts to implement and improve cross-government public reporting systems is that legislators will make use of the performance information to enhance accountability and improve program and policy effectiveness. This five-year study is an assessment of expectations and actual uses of annual performance reports by elected decision-makers in British Columbia, Canada. Our findings from three anonymous surveys indicate that while the legislators had high initial expectations, actual usage—measured in two follow-up surveys—showed substantial drops from expectations. Our findings are consistent with a growing body of evidence that there may be a paradox at the core of the public performance reporting movement: public reporting of targeted performance measures, although it may improve symbolic accountability, undermines the usefulness of the reported performance information for performance management. These findings have implications for jurisdictions using whole of government performance measurement and reporting systems for these dual purposes.
The spatial implications of homeworking: a Lefebvrian approach to the rewards and challenges of home-based work
Authors: Wapshott Robert , Mallett Oliver
Published: April 2011

In this theoretical article we propose an approach to the spatial implications of homeworking derived from the work of social theorist Henri Lefebvre. By highlighting the processes involved in the inherently contested and (re)constructed nature of space in the demarcated home/work environment we draw on Lefebvre to suggest a collapse of this demarcation. We consider the impact of such a collapse on questions relating to the rewards and challenges of home-based work for both workers and their co-residents. In contrast to our approach to the spatial implications of home-based work derived from Lefebvre, we argue that a traditional, Euclidean conception of space risks ignoring the important, symbolic nature of social space to the detriment of both the effective research and practice of homeworking.
Transition From Paraprofessionals to Bilingual Teachers: Latino Voices and Experiences in Education
Authors: Bonner Patricia J. , Pacino Maria A. , Hardcastle Stanford Beverly
Published: April 2011

This study explored perceptions of Latino paraprofessionals 10 years after completion of a program that provided financial, academic, and social support to help them complete their bachelor’s degrees and teaching credentials. Findings indicated that they valued education for themselves and their children; they believed they were important role models for Latino children and families; they were proactive in mentoring Latino paraprofessionals to become credentialed teachers; and they viewed the program as critical in enabling them to become educators and leaders in their communities.
Transumbilical Single-Incision Laparoscopic Resection of Ileocecal Junction for Benign Disease: First Report of Two Cases
Authors: Jun Cai  , Zhang Zhong-Tao , Jiabang Sun  , Hongzhi Yu  , Jin Wang  , Lan Jin  , Kangli Wang
Published: April 2011

Background. Transumbilical single-incision laparoscopic surgery (TUSILS) has emerged as an advanced technique for minimally invasive surgery. Recently, the authors performed TUSIL resection of the ileocecal junction for benign lesions. Methods. The authors report the surgical technique and clinical effect of TUSIL resection of the ileocecal junction in 2 patients. Results. The 2 operations were completely successful with satisfactory and scarless recovery. No postoperative complications occurred. Conclusions. TUSIL resection of the ileocecal junction was feasible and safe in the 2 patients and might lead to an expansion of the indications for TUSILS.
Characteristics of Dispositional Mindfulness in Patients With Severe Cardiac Disease
Authors: Salmoirago-Blotcher Elena , Crawford Sybil , Carmody James , Rosenthal Lawrence , Ockene Ira
Published: April 2011

The characteristics of dispositional mindfulness have rarely been explored in unhealthy populations. The authors sought to evaluate its association(s) with psychological morbidity and disease severity in 30 outpatients with implantable cardioverter defibrillators who were naïve to mindfulness training. They used the Five Facets of Mindfulness and the Hospital Anxiety and Depression Scale to measure dispositional mindfulness and anxiety/depression, respectively. Associations were estimated using linear regression models. Higher dispositional mindfulness was observed in patients with lower anxiety scores (β = −1.10, CI = −1.71, −0.49) and no history of depression (β = −7.95; CI = −14.31, −1.6) by univariate analysis. No associations were observed with disease severity or other covariates. In conclusion, psychological well-being and psychological morbidity, and not disease severity, appear to be associated with dispositional mindfulness in patients with implantable cardioverter defibrillators. Further research is needed to confirm these findings.

Accepted for publication March 8, 2011.
DOT1L, the H3K79 methyltransferase, is required for MLL-AF9–mediated leukemogenesis
Authors: Nguyen Anh Tram , Taranova Olena , He Jin , Zhang Yi
Published: April 2011

Chromosomal translocations of the mixed lineage leukemia (MLL) gene are a common cause of acute leukemias. The oncogenic function of MLL fusion proteins is, in part, mediated through aberrant activation of Hoxa genes and Meis1, among others. Here we demonstrate using a tamoxifen-inducible Cre-mediated loss of function mouse model that DOT1L, an H3K79 methyltransferase, is required for both initiation and maintenance of MLL-AF9–induced leukemogenesis in vitro and in vivo. Through gene expression and chromatin immunoprecipitation analysis we demonstrate that mistargeting of DOT1L, subsequent H3K79 methylation, and up-regulation of Hoxa and Meis1 genes underlie the molecular mechanism of how DOT1L contributes to MLL-AF9–mediated leukemogenesis. Our study not only provides the first in vivo evidence for the function of DOT1L in leukemia, but also reveals the molecular mechanism for DOT1L in MLL-AF9 mediated leukemia. Thus, DOT1L may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations.
Genetic variation in TIMP1 but not MMPs predict excess FEV1 decline in two general population-based cohorts
Authors: van Diemen CC , Postma DS , Siedlinski M , Blokstra A , Smit HA , Boezen HM
Published: April 2011

Background

An imbalance in Matrix MetalloProteases (MMPs) and Tissue Inhibitors of MMPs (TIMPs) contributes to Chronic Obstructive Pulmonary Disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in MMPs and TIMPs with respect to COPD development and lung function decline in the general population are lacking.

Methods

We genotyped SNPs in MMP1 (G-1607GG), MMP2 (-1306 C/T), MMP9 (3 tagging SNPs), MMP12 (A-82G and Asn357Ser) and TIMP1 (Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV1 measurements from a prospective cohort study in the general population. FEV1 decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal TIMP1 gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n = 1152).

Results

MMP2 -1306 TT genotype carriers had excess FEV1 decline (-4.0 ml/yr, p = 0.03) compared to wild type carriers. TIMP1 Ile158Ile predicted significant excess FEV1 decline in both males and females. TIMP1 Phe124Phe predicted significant excess FEV1 decline in males only, which was replicated (p = 0.10) in the second cohort. The MMP2 and TIMP1 Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development.

Conclusions

We for the first time show that TIMP1 Phe124Phe contributes to excess FEV1 decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in MMPs evidently do not contribute to FEV1 decline in the general population.
The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism
Authors: Reyes-Zurita Fernando J , Pachón-Peña Gisela , Lizárraga Daneida , Rufino-Palomares Eva E , Cascante Marta , Lupiáñez José A
Published: April 2011

Background

Maslinic acid, a pentacyclic triterpene found in the protective wax-like coating of the leaves and fruit of Olea europaea L., is a promising agent for the prevention of colon cancer. We have shown elsewhere that maslinic acid inhibits cell proliferation to a significant extent and activates mitochondrial apoptosis in colon cancer cells. In our latest work we have investigated further this compound's apoptotic molecular mechanism.

Methods

We used HT29 adenocarcinoma cells. Changes genotoxicity were analyzed by single-cell gel electrophoresis (comet assay). The cell cycle was determined by flow cytometry. Finally, changes in protein expression were examined by western blotting. Student's t-test was used for statistical comparison.

Results

HT29 cells treated with maslinic acid showed significant increases in genotoxicity and cell-cycle arrest during the G0/G1 phase after 72 hours' treatment and an apoptotic sub-G0/G1 peak after 96 hours. Nevertheless, the molecular mechanism for this cytotoxic effect of maslinic acid has never been properly explored. We show here that the anti-tumoral activity of maslinic acid might proceed via p53-mediated apoptosis by acting upon the main signaling components that lead to an increase in p53 activity and the induction of the rest of the factors that participate in the apoptotic pathway. We found that in HT29 cells maslinic acid activated the expression of c-Jun NH2-terminal kinase (JNK), thus inducing p53. Treatment of tumor cells with maslinic acid also resulted in an increase in the expression of Bid and Bax, repression of Bcl-2, release of cytochrome-c and an increase in the expression of caspases -9, -3, and -7. Moreover, maslinic acid produced belated caspase-8 activity, thus amplifying the initial mitochondrial apoptotic signaling.

Conclusion

All these results suggest that maslinic acid induces apoptosis in human HT29 colon-cancer cells through the JNK-Bid-mediated mitochondrial apoptotic pathway via the activation of p53. Thus we propose a plausible sequential molecular mechanism for the expression of the different proteins responsible for the intrinsic mitochondrial apoptotic pathway. Further studies with other cell lines will be needed to confirm the general nature of these findings.
High throughput RNAi assay optimization using adherent cell cytometry
Authors: Nabzdyk Christoph S , Chun Maggie , Pradhan Leena , LoGerfo Frank W
Published: April 2011

Background

siRNA technology is a promising tool for gene therapy of vascular disease. Due to the multitude of reagents and cell types, RNAi experiment optimization can be time-consuming. In this study adherent cell cytometry was used to rapidly optimize siRNA transfection in human aortic vascular smooth muscle cells (AoSMC).

Methods

AoSMC were seeded at a density of 3000-8000 cells/well of a 96well plate. 24 hours later AoSMC were transfected with either non-targeting unlabeled siRNA (50 nM), or non-targeting labeled siRNA, siGLO Red (5 or 50 nM) using no transfection reagent, HiPerfect or Lipofectamine RNAiMax. For counting cells, Hoechst nuclei stain or Cell Tracker green were used. For data analysis an adherent cell cytometer, Celigo® was used. Data was normalized to the transfection reagent alone group and expressed as red pixel count/cell.

Results

After 24 hours, none of the transfection conditions led to cell loss. Red fluorescence counts were normalized to the AoSMC count. RNAiMax was more potent compared to HiPerfect or no transfection reagent at 5 nM siGLO Red (4.12 +/-1.04 vs. 0.70 +/-0.26 vs. 0.15 +/-0.13 red pixel/cell) and 50 nM siGLO Red (6.49 +/-1.81 vs. 2.52 +/-0.67 vs. 0.34 +/-0.19). Fluorescence expression results supported gene knockdown achieved by using MARCKS targeting siRNA in AoSMCs.

Conclusion

This study underscores that RNAi delivery depends heavily on the choice of delivery method. Adherent cell cytometry can be used as a high throughput-screening tool for the optimization of RNAi assays. This technology can accelerate in vitro cell assays and thus save costs.
Frequency distribution of HCV genotypes among chronic hepatitis C patients of Khyber Pakhtunkhwa
Authors: Ali Sajid , Ali Ijaz , Azam Sadiq , Ahmad Bashir
Published: April 2011

Background

Hepatitis C Virus (HCV) genotypes frequency is important for the predication of response to therapy and duration of treatment. Despite variable response rates experienced in the case of Interferon (IFN) -based therapies, there was scarcity of data on HCV genotypes frequency in Khyber Pakhtunkhwa (KPK).

Study Design

A total of 200 blood samples were collected from chronic HCV patients prior to the initiation of anti-viral therapy. The study population included patients from 6 districts of KPK. Active HCV infection was confirmed in case of all the patients by real time PCR. HCV genotypes were determined in each case by Type-specific PCR.

Results

The analysis revealed that out of 200 PCR positive samples; 78 (39%) were 2a, 62 (31%) were 3a, 16 (8%) were 3b, 34 (17%) were untypable while 1a, 2b and 1b were 3 (1.5%), 2 (1%) and 5 (2.5%), respectively.

Conclusion

Genotype determination is not carried out prior to therapy in KPK. Although, the abundantly prevalent types (2a and 3a) of HCV in KPK are susceptible to combination therapy, yet resistance experienced in some of the chronic HCV patients may partly be attributed to the prevalence of less prevalent resistant genotypes (1a, 1b) of HCV among the population.
Comparison of postoperative pulmonary function and air leakage between pleural closure vs. mesh-cover for intersegmental plane in segmentectomy
Authors: Yoshimoto Kentaro , Nomori Hiroaki , Mori Takeshi , Ohba Yasuomi , Shiraishi Kenji , Ikeda Koei
Published: April 2011

Background

To prevent postoperative air leakage after lung segmentectomy, we used two methods for the intersegmental plane: closing it by suturing the pleural edge (pleural closure), or opening it with coverage using polyglycolic acid mesh and fibrin glue (mesh-cover). The preserved forced expiratory volume in one second (FEV1) of each lobe and the postoperative air leakage were compared between the two groups.

Methods

For 61 patients who underwent pleural closure and 36 patients who underwent mesh-cover, FEV1 of the lobe before and after segmentectomy was measured using lung-perfusion single-photon-emission computed tomography and CT (SPECT/CT). The groups' results were compared, revealing differences of the preserved FEV1 of the lobe for several segmentectomy procedures and postoperative duration of chest tube drainage.

Results

Although left upper division segmentectomy showed higher preserved FEV1 of the lobe in the mesh-cover group than in the pleural closure one (p = 0.06), the other segmentectomy procedures showed no differences between the groups. The durations of postoperative chest drainage in the two groups (2.0 ± 2.5 vs. 2.3 ± 2.2 days) were not different.

Conclusions

Mesh-cover preserved the pulmonary function of remaining segments better than the pleural closure method in left upper division segmentectomy, although no superiority was found in the other segmentectomy procedures. However, the data include no results obtained using a stapler, which cuts the segment without recognizing even the intersegmental plane and the intersegmental vein. Mesh-cover prevented postoperative air leakage as well as the pleural closure method did.
Bazooka mediates secondary axon morphology in Drosophila brain lineages
Authors: Spindler Shana R , Hartenstein Volker
Published: April 2011

In the Drosophila brain, neural lineages project bundled axon tracts into a central neuropile. Each lineage exhibits a stereotypical branching pattern and trajectory, which distinguish it from other lineages. In this study, we used a multilineage approach to explore the neural function of the Par-complex member Par3/Bazooka in vivo. Drosophila bazooka is expressed in post-mitotic neurons of the larval brain and localizes within neurons in a lineage-dependent manner. The fact that multiple GAL4 drivers have been mapped to several lineages of the Drosophila brain enables investigation of the role of Bazooka from larval to adult stages Bazooka loss-of-function (LOF) clones had abnormal morphologies, including aberrant pathway choice of ventral projection neurons in the BAla1 lineage, ectopic branching in the DALv2 and BAmv1 lineages, and excess BLD5 lineage axon projections in the optic medulla. Exogenous expression of Bazooka protein in BAla1 neurons rescued defective guidance, supporting an intrinsic requirement for Bazooka in the post-mitotic neuron. Elimination of the Par-complex member Par6 recapitulated Bazooka phenotypes in some but not all lineages, suggesting that the Par complex functions in a lineage-dependent manner, and that Bazooka may act independently in some lineages. Importantly, this study highlights the potential of using a multilineage approach when studying gene function during neural development in Drosophila.
Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism
Authors: Wills Sharifia , Rossi Christy C , Bennett Jeffrey , Martinez-Cerdeño Veronica , Ashwood Paul , Amaral David G , Van de Water Judy
Published: April 2011

Background

Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons.

Methods

We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined.

Results

In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.

Conclusions

These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.
Presentation of lipopeptide by dendritic cells induces anti-tumor responses via an endocytosis-independent pathway in vivo
Authors: Song Ying-Chyi , Chou Ai-Hsiang , Homhuan Atthachai , Huang Ming-Hsi , Chiang Sheng-Kuo , Shen Kuan-Yin , Chuang Po-Wei , Leng Chih-Hsiang , Tao Mi-Hua , Chong Pele , Liu Shih-Jen
Published: April 2011

Cross-presentation by DCs is the major mechanism by which exogenous antigens activate CTLs. However, the mechanisms of entry and presentation of vaccine peptides by DCs remain unclear. In this study, we determined that the mechanisms of antigen presentation differed between nonlipidated and monopalmitoylated peptide antigens. We found that a nonlipidated long peptide could be taken up by DCs and that the peptide could be colocalized with early endosomes. The uptake of nonlipidated peptides by DCs was inhibited at low temperatures or by the depolymerization of actin filaments or microtubules. In contrast, lipidated peptides were internalized by DCs at low temperatures, and internalization was not inhibited when actin filaments or microtubules were depolymerized. Moreover, lipidated peptide, but not nonlipidated peptide, was internalized by nonphagocytic Jurkat cells. The endosomal/lysosomal and proteasomal degradation pathways were necessary for nonlipidated presentation leading to the activation of CD8+ T cells, but the proteasomal degradation pathway alone was sufficient to process lipidated peptides for MHC class I presentation. We further found that lipidated peptides could enhance peptide-specific T cell responses in vitro and in vivo and induced stronger antitumor responses than nonlipidated peptides. Taken together, our results demonstrate that DCs present lipidated peptides through an endocytosis-independent pathway to promote strong anti-tumor effects in vivo.
More good news about the magic ion: lithium may prevent
dementia
Authors: Young Allan H.
Published: April 2011

Lithium is an established treatment for affective disorders with good
evidence of antisuicidal properties. Alzheimer's disease rates are
relatively reduced in patients with bipolar disorder on lithium and a recent
trial of lithium in amnestic minimal cognitive impairment is indicative of
potential benefits. This should stimulate further, larger-scale studies.
Contingency management: what it is and why psychiatrists should want to use it
Authors: Petry Nancy M.
Published: April 2011

Contingency management is a highly effective treatment for substance use and related disorders. However, few psychiatrists are familiar with this intervention or its application to a range of patient behaviours. This paper describes contingency management and evidence of its efficacy for reducing drug use. It then details areas in which contingency management interventions can be applied in the context of psychiatric treatments more generally, including increasing abstinence in individuals with dual diagnoses, encouraging attendance in mental health treatment settings, enhancing adherence to psychiatric medications, reducing weight, and improving exercise. Greater awareness and use of contingency management in practice may improve outcomes across a range of mental health and related conditions.
Impaired CNS Leptin Action Is Implicated in Depression Associated with Obesity
Authors: Yamada Nobuko , Katsuura Goro , Ochi Yukari , Ebihara Ken , Kusakabe Toru , Hosoda Kiminori , Nakao Kazuwa
Published: April 2011

Recent epidemiological studies indicate that obesity increases the incidence of depression. We examined the implication of leptin for obesity-associated depression. Leptin induced antidepressive behavior in normal mice in a forced swimming test (FST), and leptin-overexpressing transgenic mice with hyperleptinemia exhibited more antidepressive behavior in the FST than nontransgenic mice. In contrast, leptin-deficient ob/ob mice showed more severe depressive behavior in the FST than normal mice, and leptin administration substantially ameliorated this depressive behavior. Diet-induced obese (DIO) mice fed a high-fat diet showed more depressive behavior in the FST and in a sucrose preference test compared with mice fed a control diet (CD). In DIO mice, leptin induced neither antidepressive action nor increment of the number of c-Fos immunoreactive cells in the hippocampus. Diet substitution from high-fat diet to CD in DIO mice ameliorated the depressive behavior and restored leptin-induced antidepressive action. Brain-derived neurotrophic factor concentrations in the hippocampus were significantly lower in DIO mice than in CD mice. Leptin administration significantly increased hippocampal brain-derived neurotrophic factor concentrations in CD mice but not in DIO mice. The antidepressant activity of leptin in CD mice was significantly attenuated by treatment with K252a. These findings demonstrated that leptin induces an antidepressive state, and DIO mice, which exhibit severe depressive behavior, did not respond to leptin in both the FST and the biochemical changes in the hippocampus. Thus, depression associated with obesity is due, at least in part, to impaired leptin activity in the hippocampus.