bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts: a possible defense against transforming growth factor-β mediated fibrosis
Authors: Watson Chris J , Phelan Dermot , Xu Maojia , Collier Patrick , Neary Roisin , Smolenski Albert , Ledwidge Mark , McDonald Kenneth , Baugh John
Published: July 2012

Background

Mechanical overload of the heart is associated with excessive deposition of extracellular matrix proteins and the development of cardiac fibrosis. This can result in reduced ventricular compliance, diastolic dysfunction, and heart failure. Extracellular matrix synthesis is regulated primarily by cardiac fibroblasts, more specifically, the active myofibroblast. The influence of mechanical stretch on human cardiac fibroblasts’ response to pro-fibrotic stimuli, such as transforming growth factor beta (TGFβ), is unknown as is the impact of stretch on B-type natriuretic peptide (BNP) and natriuretic peptide receptor A (NPRA) expression. BNP, acting via NPRA, has been shown to play a role in modulation of cardiac fibrosis.

Methods and results

The effect of cyclical mechanical stretch on TGFβ induction of myofibroblast differentiation in primary human cardiac fibroblasts and whether differences in response to stretch were associated with changes in the natriuretic peptide system were investigated. Cyclical mechanical stretch attenuated the effectiveness of TGFβ in inducing myofibroblast differentiation. This finding was associated with a novel observation that mechanical stretch can increase BNP and NPRA expression in human cardiac fibroblasts, which could have important implications in modulating myocardial fibrosis. Exogenous BNP treatment further reduced the potency of TGFβ on mechanically stretched fibroblasts.

Conclusion

We postulate that stretch induced up-regulation of the natriuretic peptide system may contribute to the observed reduction in myofibroblast differentiation.
First analysis of the secretome of the canine heartworm, Dirofilaria immitis
Authors: Geary James , Satti Mohamed , Moreno Yovany , Madrill Nicole , Whitten Doug , Headley Selwyn A , Agnew Dalen , Geary Timothy , Mackenzie Charles
Published: July 2012

Background

The characterization of proteins released from filariae is an important step in addressing many of the needs in the diagnosis and treatment of these clinically important parasites, as well as contributing to a clearer understanding of their biology. This report describes findings on the proteins released during in vitro cultivation of adult Dirofilaria immitis , the causative agent of canine and feline heartworm disease. Differences in protein secretion among nematodes in vivo may relate to the ecological niche of each parasite and the pathological changes that they induce.

Methods

The proteins in the secretions of cultured adult worms were run on Tris-Glycine gels, bands separated and peptides from each band analysed by ultra mass spectrometry and compared with a FastA dataset of predicted tryptic peptides derived from a genome sequence of D. immitis.

Results

This study identified 110 proteins. Of these proteins, 52 were unique to D. immitis . A total of 23 (44%) were recognized as proteins likely to be secreted. Although these proteins were unique, the motifs were conserved compared with proteins secreted by other nematodes.

Conclusion

The present data indicate that D. immitis secretes proteins that are unique to this species, when compared with Brugia malayi. The two major functional groups of molecules represented were those representing cellular and of metabolic processes. Unique proteins might be important for maintaining an infection in the host environment, intimately involved in the pathogenesis of disease and may also provide new tools for the diagnosis of heartworm infection.
Clinical and laboratory characteristics of systemic anaplastic large cell lymphoma in Chinese patients
Authors: Wang Yan-Fang , Yang Yan-Li , Gao Zi-Fen , Zhou Chun-Ju , Gregg Xylina , Shi Yun-Fei , Wang Jing , Yang Xiao-Feng , Ke Xiao-Yan
Published: July 2012

Background

Systemic anaplastic large cell lymphoma (S-ALCL) is a rare disease with a highly variable prognosis and no standard chemotherapy regimen. Anaplastic lymphoma kinase (ALK) has been reported as an important prognostic factor correlated with S-ALCL in many but not all studies. In our study, we retrospectively analyzed 92 patients with S-ALCL from the Peking University Lymphoma Center for clinical and molecular prognostic factors to make clear the role of ALK and other prognostic factors in Han Chinese S-ALCL.

Results

The majority of Chinese S-ALCL patients were young male patients (median age 26, male/female ratio 1.7) and the median age was younger than previous reports regardless of ALK expression status. The only statistically significant different clinical characteristic in S-ALCL between ALK positive (ALK+) and ALK negative (ALK-) was age, with a younger median age of 22 for ALK+compared with 30 for ALK-. However, when pediatric patients (≤18) were excluded, there was no age difference between ALK+and ALK-. The groups did not differ in the proportion of males, those with clinical stage III/IV (49 vs 51%) or those with extranodal disease (53 vs 59%). Of 73 evaluable patients, the 3-year and 5-year survival rates were 60% and 47%, respectively. Univariate analysis showed that three factors: advanced stage III/IV, lack of expression of ALK, and high Ki-67 expression, were associated with treatment failure in patients with S-ALCL. However, ALK expression correlated with improved survival only in patients younger than 14 years, while not in adult patients. In multivariate analysis, only clinical stage was an independent prognostic factor for survival. Expressions of Wilms tumor 1 (WT1) and B-cell lymphoma 2 protein (BCL-2) correlated with the expression of ALK, but they did not have prognostic significance. High Ki-67 expression was also a poor prognostic factor.

Conclusions

Our results show that ALK expression alone is not sufficient to determine the outcome of ALCL and other prognostic factors must be considered. Clinical stage is an independent prognostic factor. Ki-67 expression is a promising prognostic factor.
Prognostic impact of fecal pH in critically ill patients
Authors: Osuka Akinori , Shimizu Kentaro , Ogura Hiroshi , Tasaki Osamu , Hamasaki Toshimitsu , Asahara Takashi , Nomoto Koji , Morotomi Masami , Kuwagata Yasuyuki , Shimazu Takeshi
Published: July 2012

Introduction

We have reported that altered gut flora is associated with septic complications and eventual death in critically ill patients with systemic inflammatory response syndrome. It is unclear how fecal pH affects these patients. We sought to determine whether fecal pH can be used as an assessment tool for the clinical course of critically ill patients.

Methods

Four hundred ninety-one fecal samples were collected from 138 patients who were admitted to the Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Japan. These patients were treated in the intensive care unit for more than 2 days. Fecal pH, fecal organic acids, and fecal bacteria counts were measured and compared by survived group and nonsurvived group, or nonbacteremia group and bacteremia group. Logistic regression was used to estimate relations between fecal pH, age, sex, or APACHE II score and mortality, and incidence of bacteremia. Differences in fecal organic acids or fecal bacteria counts among acidic, neutral, and alkaline feces were analyzed.

Results

The increase of fecal pH 6.6 was significantly associated with the increased mortality (odds ratio, 2.46; 95% confidence interval, 1.25 to 4.82) or incidence of bacteremia (3.25; 1.67 to 6.30). Total organic acid was increased in acidic feces and decreased in alkaline feces. Lactic acid, succinic acid, and formic acid were the main contributors to acidity in acidic feces. In alkaline feces, acetic acid was significantly decreased. Propionic acid was markedly decreased in both acidic and alkaline feces compared with neutral feces. No differences were noted among the groups in bacterial counts.

Conclusions

The data presented here demonstrate that the fecal pH range that extended beyond the normal range was associated with the clinical course and prognosis of critically ill patients.
Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate
Authors: Molenaar Nienke , Bijkerk Ronald M , Beishuizen Albertus , Hempen Christel M , de Jong Margriet FC , Vermes Istvan , van der Sluijs Veer Gertjan , Girbes Armand RJ , Groeneveld AB Johan
Published: July 2012

Introduction

This study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account.

Method

This was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded.

Results

At the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions.

Conclusions

A single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.
3D inversion of airborne electromagnetic data
Authors: Cox Leif H. , Wilson Glenn A. , Zhdanov Michael S.
Published: July 2012

Time-domain airborne surveys gather hundreds of thousands of multichannel, multicomponent samples. The volume of data and other complications have made 1D inversions and transforms the only viable method to interpret these data, in spite of their limitations. We have developed a practical methodology to perform full 3D inversions of entire time- or frequency-domain airborne electromagnetic (AEM) surveys. Our methodology is based on the concept of a moving footprint that reduces the computation requirements by several orders of magnitude. The 3D AEM responses and sensitivities are computed using a frequency-domain total field integral equation technique. For time-domain AEM responses and sensitivities, the frequency-domain responses and sensitivities are transformed to the time domain via a cosine transform and convolution with the system waveform. We demonstrate the efficiency of our methodology with a model study relevant to the Abitibi greenstone belt and a case study from the Reid-Mahaffy test site in Ontario, Canada, which provided an excellent practical opportunity to compare 3D inversions for different AEM systems. In particular, we compared 3D inversions of VTEM-35 (time-domain helicopter), MEGATEM II (time-domain fixed-wing), and DIGHEM (frequency-domain helicopter) data. Our comparison showed that each system is able to image the conductive overburden and to varying degrees, detect and delineate the bedrock conductors, and, as expected, that the DIGHEM system best resolved the conductive overburden, whereas the time-domain systems most clearly delineated the bedrock conductors. Our comparisons of the helicopter and fixed-wing time-domain systems revealed that the often-cited disadvantages of a fixed-wing system (i.e., response asymmetry) are not inherent in the system, but rather reflect a limitation of the 1D interpretation methods used to date.
Feasibility of monitoring hydraulic fracturing using time-lapse audio-magnetotellurics
Authors: He Lanfang , Hu Xiumian , Xu Ligui , He Zhanxiang , Li Weili
Published: July 2012

Hydraulic fracturing is widely used for initiating and subsequently propagating fractures in reservoir strata by means of a pressurized fluid to release oil and gas or to store industry waste. Downhole or surface microseismic monitoring is commonly used to characterize the hydraulically induced fractures. However, in some cases, downhole microseismic monitoring can be difficult due to the limitation imposed by boreholes. Surface microseismic monitoring often faces difficulties acquiring high signal-to-noise ratio data because of the on-site noise from hydraulic fracturing process. Research and field observations indicate that injecting conductive slurry or water into a strata may generate distinct time-lapse electromagnetic anomalies between pre- and posthydraulic fracturing. These anomalies provide a means for characterizing the hydraulic fracturing using time-lapse electromagnetic methods. We examined the time-lapse variation over an hour, one day, one month, and two years of observed audio-magnetotellurics (AMT) resistivity and the 1D and 3D AMT modeling result of the variation pre- and posthydraulic fracturing. There is also a successful case history of applying the time-lapse AMT to map hydraulic fractures. Observed data indicate that the variation of AMT resistivity is normally less than 6% apart from the data of the dead band and some noisy data. Modeling results show the variation pre- and posthydraulic fracturing is larger than 30% at the frequency point lower than 100 Hz. The case history indicates that time-lapse magnetotelluric monitoring may form a new way to characterize the hydraulic fracture.
A global measure for depth of investigation
Authors: Vest Christiansen Anders , Auken Esben
Published: July 2012

We tested a new robust concept for the calculation of depth of investigation (DOI) that is valid for any 1D electromagnetic (EM) geophysical model. A good estimate of DOI is crucial when building geologic and hydrological models from EM data sets because the validity of the models varies strongly with data noise and the resistivity of the layers themselves. For diffusive methods, such as ground-based and airborne electromagnetic, it is not possible to define an unambiguous depth below which there is no information on the resistivity structure and a measure of DOI is therefore to what depth the model can be considered reliable. The method we presented is based on the actual model output from the inversion process and we used the actual system response, contrary to assuming, e.g., planar waves over a homogeneous half-space, the widely used skin depth calculation. Equally important, the data noise and the number of data points are integrated into the calculation. Our methodology is based on a recalculated sensitivity (Jacobian) matrix of the final model and thus it can be used on any model type for which a sensitivity matrix can be calculated. Unlike other sensitivity matrix methods, we defined a global and absolute threshold value contrary to defining a relative (such as 5%), sensitivity limit. The threshold value will apply to all 1D inverted data and will thus produce comparable numbers of DOI.
A Mediterranean petroleum province on the North Africa Plate margin: The Sicily Channel
Authors: Fink Paul , Zimmer Wolfgang , Punch Sonya
Published: July 2012

Increased exploration of the multiplay hydrocarbon providence between Sicily and Tunisia has resulted in large gas discoveries offshore Sicily (Italy), Tunisia's first deep-water well (ADX 2010), and several recently acquired 2D and 3D dual-sensor seismic surveys. While the area is well known to be tectonically complex, it is at the same time considered a highly attractive exploration basin offering large structural anticlines, medium-sized transtensional horst blocks, stratigraphic traps, and a range of hydrocarbon play types with already discovered accumulations. However, some geologic uncertainties that have stunted exploration in this area for the past 25 years, especially in northern Tunisian waters, still require risk reduction. This paper gives several examples of some risks and uncertainties in this area and explains how better seismic imaging can significantly reduce risk. A large dual-sensor 3D survey acquired by ADX in 2010 with PGS dual-sensor technology (Geostreamer) serves as an illustration.
Incomplete Intrapulmonary Lymph Node Retrieval After Routine Pathologic Examination of Resected Lung Cancer
Authors: Ramirez Robert A. , Wang Christopher G. , Miller Laura E. , Adair Courtney A. , Berry Allen , Yu Xinhua , O'Brien Thomas F. , Osarogiagbon Raymond U.
Published: July 2012

Purpose

Pathologic nodal stage affects prognosis in patients with surgically resected non–small-cell lung cancer (NSCLC). Unlike examination of mediastinal lymph nodes (LNs), which depends on surgical practice, accurate examination of intrapulmonary (N1) nodes depends primarily on pathology practice. We investigated the completeness of N1 LN examination in NSCLC resection specimens and its potential impact on stage.

Patients and Methods

We performed a case-control study of a special pathologic examination (SPE) protocol using thin gross dissection with retrieval and microscopic examination of all LN-like material on remnant NSCLC resection specimens after routine pathologic examination (RPE). We compared LNs retrieved by the SPE protocol with nodes examined after RPE of the same lung specimens and with those of an external control cohort.

Results

We retrieved additional LNs in 66 (90%) of 73 patient cases and discovered metastasis in 56 (11%) of 514 retrieved LNs from 27% of all patients. We found unexpected LN metastasis in six (12%) of 50 node-negative patients. Three other patients had undetected satellite metastatic nodules. Pathologic stage was upgraded in eight (11%) of 73 patients. The time required for the SPE protocol decreased significantly with experience, with no change in the number of LNs found.

Conclusion

Standard pathology practice frequently leaves large numbers of N1 LNs unexamined, a clinically significant proportion of which harbor metastasis. By improving N1 LN examination, SPE can have an impact on prognosis and adjuvant management. We suggest adoption of the SPE to improve pathologic staging of resected NSCLC.
First-Line Erlotinib Followed by Second-Line Cisplatin-Gemcitabine Chemotherapy in Advanced Non–Small-Cell Lung Cancer: The TORCH Randomized Trial
Authors: Gridelli Cesare , Ciardiello Fortunato , Gallo Ciro , Feld Ronald , Butts Charles , Gebbia Vittorio , Maione Paolo , Morgillo Floriana , Genestreti Giovenzio , Favaretto Adolfo , Leighl Natasha , Wierzbicki Rafal , Cinieri Saverio , Alam Yasmin , Siena Salvatore , Tortora Giampaolo , Felletti Raffaella , Riccardi Ferdinando , Mancuso Gianfranco , Rossi Antonio , Cantile Flavia , Tsao Ming-Sound , Saieg Mauro , da Cunha Santos Gilda , Piccirillo Maria Carmela , Di Maio Massimo , Morabito Alessandro , Perrone Francesco
Published: July 2012

Purpose

Erlotinib prolonged survival of unselected patients with advanced non–small-cell lung cancer (NSCLC) who were not eligible for further chemotherapy, and two phase II studies suggested it might be an alternative to first-line chemotherapy. A randomized phase III trial was designed to test whether first-line erlotinib followed at progression by cisplatin-gemcitabine was not inferior in terms of survival to the standard inverse sequence.

Patients and Methods

Patients with stage IIIB (with pleural effusion or supraclavicular nodes) to IV NSCLC and performance status of 0 to 1 were eligible. With a 95% CI upper limit of 1.25 for the hazard ratio (HR) for death, 80% power, a one-sided α = .025, and two interim analyses, a sample size of 900 patients was planned.

Results

At the first planned interim analysis with half the events, the inferiority boundary was crossed, and the Independent Data Monitoring Committee recommended early termination of the study. Seven hundred sixty patients (median age, 62 years; range, 27 to 81 years) had been randomly assigned. Baseline characteristics were balanced between study arms. As of June 1, 2011, median follow-up was 24.3 months, and 536 deaths were recorded (263 in the standard treatment arm and 273 in the experimental arm). Median survival was 11.6 months (95% CI, 10.2 to 13.3 months) in the standard arm and 8.7 months (95% CI, 7.4 to 10.5 months) in the experimental arm. Adjusted HR of death in the experimental arm was 1.24 (95% CI, 1.04 to 1.47). There was no heterogeneity across sex, smoking habit, histotype, and epidermal growth factor receptor (EGFR) mutation.

Conclusion

In unselected patients with advanced NSCLC, first-line erlotinib followed at progression by cisplatin-gemcitabine was significantly inferior in terms of overall survival compared with the standard sequence of first-line chemotherapy followed by erlotinib.
American Society of Clinical Oncology Clinical Practice Guidelines: Formal Systematic Review–Based Consensus Methodology
Authors: Loblaw D. Andrew , Prestrud Ann Alexis , Somerfield Mark R. , Oliver Thomas K. , Brouwers Melissa C. , Nam Robert K. , Lyman Gary H. , Basch Ethan
Published: July 2012

The American Society of Clinical Oncology (ASCO) guidelines program employs a systematic review–based methodology to produce evidence-based guidelines. This is consistent with the stance of the Institute of Medicine on guideline development, which is that high-quality evidence syntheses form the basis for recommendation development.

In the absence of high-quality evidence, recommendation development becomes more complex. One option is to provide no recommendations or withdraw a guideline topic. However, it is often the areas of greatest uncertainty in which the evidentiary base is incomplete, and thus, guidelines are needed most. To provide recommendations in such circumstances, an explicit methodology is needed to ensure that a credible process is undertaken, and rigorous, reliable advice is provided.

In 2010, the ASCO Board of Directors approved development of guideline recommendations using consensus methodology. A modified Delphi approach to recommendation development, based on the best available data identified in a systematic review, was piloted with an ASCO guideline. Consensus was achieved through the rating of a series of recommendations by a large group of clinicians, including academic and community-based content and methodology experts. A prespecified threshold of agreement was determined to indicate when consensus was achieved. Consensus was defined as agreement by ≥ 75% of raters.

The formal consensus methodology used by ASCO enabled development of guideline recommendations on a challenging clinical issue based on limited evidence using a rigorous, transparent, and explicit method. This methodology is proposed for development of future ASCO guidelines on topics for which limited evidence is available.
Progesterone Increases the Release of Brain-Derived Neurotrophic Factor from Glia via Progesterone Receptor Membrane Component 1 (Pgrmc1)-Dependent ERK5 Signaling
Authors: Su Chang , Cunningham Rebecca L. , Rybalchenko Nataliya , Singh Meharvan
Published: July 2012

Progesterone (P4) is cytoprotective in various experimental models, but our understanding of the mechanisms involved is still incomplete. Our laboratory has implicated brain-derived neurotrophic factor (BDNF) signaling as an important mediator of P4's protective actions. We have shown that P4 increases the expression of BDNF, an effect mediated by the classical P4 receptor (PR), and that the protective effects of P4 were abolished using inhibitors of Trk receptor signaling. In an effort to extend our understanding of the interrelationship between P4 and BDNF signaling, we determined whether P4 influenced BDNF release and examined the role of the classical PR and a putative membrane PR, progesterone receptor membrane component-1 (Pgrmc1), as mediators of this response. Given recent data from our laboratory that supported the role of ERK5 in BDNF release, we also tested whether P4-induced BDNF release was mediated by ERK5. In this study, we found that P4 and the membrane-impermeable P4 (P4-BSA) both induced BDNF release from cultured C6 glial cells and primary astrocytes. Both these cells lack the classical nuclear/intracellular PR but express high levels of membrane-associated PR, including Pgrmc1. Using RNA interference-mediated knockdown of Pgrmc1 expression, we determined that P4-induced BDNF release was dependent on the expression of Pgrmc1, although pharmacological inhibition of the PR failed to alter the effects of P4. Furthermore, the BDNF release elicited by P4 was mediated by ERK5, and not ERK1/2. Collectively, our data describe that P4 elicits an increase in BDNF release from glia via a Pgrmc1-induced ERK5 signaling mechanism and identify Pgrmc1 as a potential therapeutic target for future hormone-based drug development for the treatment of such degenerative diseases as Alzheimer's disease as well as other diseases wherein neurotrophin dysregulation is noted.
Differentiation of Human Embryonic Stem Cells and Human Induced Pluripotent Stem Cells into Steroid-Producing Cells
Authors: Sonoyama Takuhiro , Sone Masakatsu , Honda Kyoko , Taura Daisuke , Kojima Katsutoshi , Inuzuka Megumi , Kanamoto Naotetsu , Tamura Naohisa , Nakao Kazuwa
Published: July 2012

Although there have been reports of the differentiation of mesenchymal stem cells and mouse embryonic stem (ES) cells into steroid-producing cells, the differentiation of human ES/induced pluripotent stem (iPS) cells into steroid-producing cells has not been reported. The purpose of our present study was to establish a method for inducing differentiation of human ES/iPS cells into steroid-producing cells. The first approach we tried was embryoid body formation and further culture on adherent plates. The resultant differentiated cells expressed mRNA encoding the steroidogenic enzymes steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, cytochrome P450-containing enzyme (CYP)-11A1, CYP17A1, and CYP19, and secreted progesterone was detected in the cell medium. However, expression of human chorionic gonadotropin was also detected, suggesting the differentiated cells were trophoblast like. We next tried a multistep approach. As a first step, human ES/iPS cells were induced to differentiate into the mesodermal lineage. After 7 d of differentiation induced by 6-bromoindirubin-3′-oxime (a glycogen synthase kinase-3β inhibitor), the human ES/iPS cells had differentiated into fetal liver kinase-1- and platelet derived growth factor receptor-α-expressing mesodermal lineage cells. As a second step, plasmid DNA encoding steroidogenic factor-1, a master regulator of steroidogenesis, was introduced into these mesodermal cells. The forced expression of steroidogenic factor-1 and subsequent addition of 8-bromoadenosine 3′,5′-cyclic monophosphate induced the mesodermal cells to differentiate into the steroidogenic cell lineage, and expression of CYP21A2 and CYP11B1, in addition to steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, CYP11A1, and CYP17A1, was detected. Moreover, secreted cortisol was detected in the medium, but human chorionic gonadotropin was not. These findings indicate that the steroid-producing cells obtained through the described multistep method are not trophoblast like; instead, they exhibit characteristics of adrenal cortical cells.
β-Endorphin Antagonizes the Effects of α-MSH on Food Intake and Body Weight
Authors: Dutia Roxanne , Meece Kana , Dighe Shveta , Kim Andrea J. , Wardlaw Sharon L.
Published: July 2012

Proopiomelanocortin (POMC) is posttranslationally processed to several peptides including α-MSH, a primary regulator of energy balance that inhibits food intake and stimulates energy expenditure. However, another POMC-derived peptide, β-endorphin (β-EP), has been shown to stimulate food intake. In this study we examined the effects of intracerebroventricular (icv) β-EP on food intake and its ability to antagonize the negative effects of α-MSH on energy balance in male rats. A single icv injection of β-EP stimulated food intake over a 2- to 6-h period during both the light and dark cycles. This effect was, however, not sustained with chronic icv β-EP infusion. In the next study, a subthreshold dose of β-EP was injected together with Nle4, d-Phe7 (NDP)-MSH after a 16-h fast, and the negative effects of NDP-MSH on refeeding and body weight gain were partially reversed. Finally, peptide interactions were studied in a chronic icv infusion model. Weight gain and food intake were significantly suppressed in the NDP-MSH group during the entire study. A subthreshold dose of β-EP antagonized these suppressive effects on food intake and weight gain for the first 3 d. However on d 4–7, β-EP no longer blocked these effects. Of note, the stimulatory effect of β-EP on feeding and its ability to antagonize MSH were specific for β-EP1–31 and were not observed with β-EP1–27. This study highlights the importance of understanding how the balance between α-MSH and β-EP is maintained and the potential role of differential POMC processing in regulating energy balance.
Minireview: Hair Cortisol: A Novel Biomarker of Hypothalamic-Pituitary-Adrenocortical Activity
Authors: Meyer Jerrold S. , Novak Melinda A.
Published: July 2012

Activity of the hypothalamic-pituitary-adrenocortical (HPA) axis is commonly assessed by measuring glucocorticoids such as cortisol (CORT). For many years, CORT was obtained primarily from blood plasma or urine, whereas later approaches added saliva and feces for noninvasive monitoring of HPA functioning. Despite the value of all these sample matrices for answering many research questions, they remain limited in the temporal range of assessment. Plasma and saliva are point samples that vary as a function of circadian rhythmicity and are susceptible to confounding by environmental disturbances. Even urine and feces generally assess HPA activity over a period of only 24 h or less. We and others have recently developed and validated methods for measuring the concentration of CORT in the body hair of animals (e.g. rhesus monkeys) and scalp hair of humans. CORT is constantly deposited in the growing hair shaft, as a consequence of which such deposition can serve as a biomarker of integrated HPA activity over weeks and months instead of minutes or hours. Since the advent of this methodological advance, hair CORT has already been used as an index of chronic HPA activity and stress in human clinical and nonclinical populations, in a variety of laboratory-housed and wild-living animal species, and in archival specimens that are many decades or even centuries old. Moreover, because human hair is known to grow at an average rate of about 1 cm/month, several studies suggest that CORT levels in hair segments that differ in proximity to the scalp can, under certain conditions, be used as a retrospective calendar of HPA activity during specific time periods preceding sample collection.
Minireview: Translational Animal Models of Human Menopause: Challenges and Emerging Opportunities
Authors: Diaz Brinton Roberta
Published: July 2012

Increasing importance is placed on the translational validity of animal models of human menopause to discern risk vs. benefit for prediction of outcomes after therapeutic interventions and to develop new therapeutic strategies to promote health. Basic discovery research conducted over many decades has built an extensive body of knowledge regarding reproductive senescence across mammalian species upon which to advance animal models of human menopause. Modifications to existing animal models could rapidly address translational gaps relevant to clinical issues in human menopausal health, which include the impact of 1) chronic ovarian hormone deprivation and hormone therapy, 2) clinically relevant hormone therapy regimens (cyclic vs. continuous combined), 3) clinically relevant hormone therapy formulations, and 4) windows of opportunity and optimal duration of interventions. Modifications in existing animal models to more accurately represent human menopause and clinical interventions could rapidly provide preclinical translational data to predict outcomes regarding unresolved clinical issues relevant to women's menopausal health. Development of the next generation of animal models of human menopause could leverage advances in identifying genotypic variations in estrogen and progesterone receptors to develop personalized menopausal care and to predict outcomes of interventions for protection against or vulnerability to disease. Key to the success of these models is the close coupling between the translational target and the range of predictive validity. Preclinical translational animal models of human menopause need to keep pace with changes in clinical practice. With focus on predictive validity and strategic use of advances in genetic and epigenetic science, new animal models of human menopause have the opportunity to set new directions for menopausal clinical care for women worldwide.
Estrogenic Compounds Are Not Always Cardioprotective and Can Be Lethal in Males with Genetic Heart Disease
Authors: Haines Christopher D. , Harvey Pamela A. , Luczak Elizabeth D. , Barthel Kristen K. B. , Konhilas John P. , Watson Peter A. , Stauffer Brian L. , Leinwand Leslie A.
Published: July 2012

Hypertrophic cardiomyopathy (HCM) is more severe in male than female mice eating a soy-based diet. We sought to determine whether the detrimental effects are mediated by the phytoestrogens present in soy, the mechanism by which phytoestrogens act, and to test whether estrogen modulates the sexually dimorphic phenotype. A soy-free diet (casein based) supplemented with the predominant phytoestrogens in soy, genistein and daidzein, recapitulated the fibrotic, proapoptotic and negative hemodynamic effects of soy in male hearts. As with the soy diet, the hearts of female HCM mice were not negatively affected by the phytoestrogen-containing diet. To determine the role of estrogen in the sex differences mediated by diet in HCM, gonadectomies were performed and estrogen was administered to male and female HCM mice on a casein- or phytoestrogen-supplemented diet. Somewhat surprisingly, estrogen was not protective in male or female mice with HCM and, in fact, was lethal in phytoestrogen-fed male mice with HCM. Because genistein is a potent tyrosine kinase inhibitor and tyrosine kinase inhibition has been associated with cardiotoxicity, we tested its effects in isolated adult cardiac myocytes. Genistein inhibited different tyrosine kinases depending on sex and, in combination with estrogen, resulted in apoptosis only in adult male cardiac myocytes. Finally, we show that phytoestrogens led to distinct programs of gene expression in hearts from males vs. females with HCM, suggesting mechanisms by which males are more sensitive to the detrimental effects of phytoestrogens and females are protected. These results implicate the phytoestrogen genistein in mediating cardiac pathology in males with HCM and, importantly, establish that estrogen is not protective in the setting of HCM.
EGFR-dependent network interactions that pattern Drosophila eggshell appendages
Authors: Simakov David S. A. , Cheung Lily S. , Pismen Len M. , Shvartsman Stanislav Y.
Published: July 2012

Similar to other organisms, Drosophila uses its Epidermal Growth Factor Receptor (EGFR) multiple times throughout development. One crucial EGFR-dependent event is patterning of the follicular epithelium during oogenesis. In addition to providing inductive cues necessary for body axes specification, patterning of the follicle cells initiates the formation of two respiratory eggshell appendages. Each appendage is derived from a primordium comprising a patch of cells expressing broad (br) and an adjacent stripe of cells expressing rhomboid (rho). Several mechanisms of eggshell patterning have been proposed in the past, but none of them can explain the highly coordinated expression of br and rho. To address some of the outstanding issues in this system, we synthesized the existing information into a revised mathematical model of follicle cell patterning. Based on the computational model analysis, we propose that dorsal appendage primordia are established by sequential action of feed-forward loops and juxtacrine signals activated by the gradient of EGFR signaling. The model describes pattern formation in a large number of mutants and points to several unanswered questions related to the dynamic interaction of the EGFR and Notch pathways.
Toward a blueprint for regeneration
Authors: Nachtrab Gregory , Poss Kenneth D.
Published: July 2012

Tissue regeneration has been studied for hundreds of years, yet remains one of the less understood topics in developmental biology. The recent Keystone Symposium on Mechanisms of Whole Organ Regeneration brought together biologists, clinicians and bioengineers representing an impressive breadth of model systems and perspectives. Members of the growing regeneration community discussed classic and new ideas on mechanisms of regeneration and how these can be applied to regenerative medicine.
How Labor Won in Ohio
Authors: Burstein Rachel
Published: July 2012

We Are Ohio was successful because it assembled a true coalition of Democrats and Republicans, unionists and nonunionized workers, those hailing from union strongholds like Toledo and conservative regions like Butler County in Ohio’s southwest corner, and those from both rural and urban areas of the state. It framed workers’ rights as a common good and a service to the community, not a budget line or the prerogative of special interests. We Are Ohio focused on cultivating television and press coverage throughout the state and drew on social media to publicize its campaign and develop a cohesive network.
Charting a Democratic Future in China
Authors: Stark Andrew
Published: July 2012

Is there a path toward a democratic future for China? There are plenty of reasons to be pessimistic, at least in the near term. But if there is a way forward, then the first steps are being mapped by a group of thinkers who aim to show how Chinese cultural and institutional resources can be deployed as the initial building blocks of a western-style democracy
Letters
Authors: Stein Jonathan M.
Published: July 2012

Response to lack of attention to hunger and poverty related issues in the “Food” section of Dissent’s Spring issue
Editor’s Page
Authors: Kazin Michael
Published: July 2012

Obama, like every other major party nominee, must raise millions of dollars from wealthy Americans and thus cannot alienate all of them if he expects to hold onto the presidency. But Obama has also signed bills that aim to prevent the kind of financial abuses that largely brought about the Great Recession—as well as a major reform and expansion of the health care system. And he has appointed thousands of men and women who, away from the media’s glare, are working to carry out a progressive agenda. One result is that far more Wall Street executives this year are donating to Mitt Romney, who is one of their own, than to Obama.
Immigrants and the Road to Power
Authors: Milkman Ruth
Published: July 2012

The once conventional wisdom that immigrants, especially the unauthorized, are unlikely candidates for labor organizing has turned out to be not so much wrong as incomplete. It overlooked several factors that make low-wage immigrants more “organizable” in the workplace than many of their U.S.-born counterparts. First, because new arrivals find jobs through social networks made up of other immigrants from the same place (and often from the same extended family), many workplaces contain within them an unusual potential for solidarity rooted in those very networks—a relatively rare phenomenon among U.S.-born workers. Further contributing to that potential is the shared racialization and stigmatization that many immigrants experience, which often serves as a unifying force. And while organizing is risky, the risks it involves are relatively modest compared, for example, to crossing the border without papers or, for that matter, labor organizing in many of the countries where immigrants grew up.
Pakistani Conundrum: Public, Private, and Female
Authors: Zakaria Rafia
Published: July 2012

That evening, the rally, held at the Baghe-Jinnah, a huge park surrounding the white mausoleum of Pakistan’s founder, Muhammad Ali Jinnah, drew thousands of women—young and not so young. Many wore burkas or headscarves or chadors that cocooned their bodies against the open air. The MQM’s white-clad volunteers could be seen filing in and out of the orderly queues, directing women to tents providing water, refreshments, bangles, and even tricolor wraps for those nipped by the chill of the February evening.
From American Exceptionalism to Self-Knowledge
Authors: Scialabba George
Published: July 2012

A review of Andrew Bacevich’s The Short American Century: A Post-Mortem
The World as Database: On the Relation of Software Development, Query Methods, and Interpretative Independence
Authors: Gugerli David
Published: July 2012

In the early 1970s, conventional database management systems were challenged by relational database models. Relational search procedures, as proposed by Edgar F. Codd, offered both improved data independence and an enhanced combinatorial freedom for the user. At the same time, late modern concepts of an open text boosted a reader's interpretative independence, bringing to an end the heyday of hermeneutics. This politically significant change of technocultural patterns led to wild debates, and not only among intellectuals. Likewise, the change meant big trouble for software engineers. Advocates of user independence tried to promote their concepts, destabilize adversative suggestions, and gain allies by aggressive claims, heroic narratives, and cooperative publication strategies.
Deaf Education Policy as Language Policy: A Comparative Analysis of Sweden and the United States
Authors: Hult Francis M. , Compton Sarah E.
Published: July 2012

The present study offers a cross-national, comparative analysis of deafeducation policies in Sweden and the United States and examines the ways in which these countries address status planning and acquisition planning for sign languages. Major policy documents were selected from each polity, reflecting key national legislative policies, as well as the primary texts that guide educational implementation: for Sweden, the Ordinance for Special Schools, the Education Act, and the national syllabi for special schools; for the United States, the Individuals with Disabilities Education Act and Title 34 of the Code of Federal Regulations. Analysis of these texts shows that such planning tends to be explicit in Sweden but implicit in the United States. Moreover, the Swedish policies focus on the development of sign language/national-language bilingualism, whereas the policies of the United States foreground assimilation to the hearing world; however, implementational space for sign language and multilingualism are present in the policies of both countries to varying degrees.
Comprehensive One-Step Molecular Analyses of Mitochondrial Genome by Massively Parallel Sequencing
Authors: Zhang Wei , Cui Hong , Wong Lee-Jun C
Published: July 2012

BACKGROUND

Mitochondrial diseases are clinically and genetically heterogeneous, with variable penetrance, expressivity, and differing age of onset. Disease-causing point mutations and large deletions in the mitochondrial genome often exist in a heteroplasmic state. Current molecular analyses require multiple different and complementary methods for the detection and quantification of mitochondrial DNA (mtDNA) mutations. We developed a novel approach to analyze the mtDNA in 1 step.

METHODS

The entire human mitochondrial genome was enriched by a single amplicon long-range PCR followed by massively parallel sequencing to simultaneously detect mtDNA point mutations and large deletions with heteroplasmic levels of the mutations and variants quantified. QC samples were designed and analyzed along with each sample. A total of 45 samples were analyzed for the evaluation of analytic sensitivity and specificity.

RESULTS

Our analysis demonstrated 100% diagnostic sensitivity and specificity of base calls compared to the results from Sanger sequencing. The deep coverage allowed the detection and quantification of heteroplasmy at every single nucleotide position of the 16 569-bp mitochondrial genome. Moreover, the method also detected large deletions with the breakpoints mapped.

CONCLUSIONS

This “deep” sequencing approach provides a 1-step comprehensive molecular analysis of the whole mitochondrial genome for patients in whom a mitochondrial disease is suspected.
Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan
Authors: Tseng Chin-Hsiao
Published: July 2012

Objective

A retrospective cohort study, using a population-based reimbursement database, was conducted for investigating the relationship between diabetes and colon cancer and assessing whether metformin had a protective effect.

Methods

Overall, 493 704 men and 502 139 women, covered by the National Health Insurance, without colon cancer were followed from 2003 to 2005. Cox regression evaluated the adjusted relative risk (RR), considering confounders and detection examinations.

Results

Even though diabetes patients had a significantly higher probability of receiving examinations that could lead to the detection of colon cancer, they had a significantly higher risk (24%) of this cancer after adjustment. Metformin users had a significantly lower risk (27%) of colon cancer. While comparing patients with diabetes for <1, 1–3, and ≥3 years to nondiabetes individuals, the adjusted RR (95% confidence interval) was 1.308 (1.020–1.679), 1.087 (0.900–1.313), and 1.185 (1.055–1.330) respectively. The higher risk among those with diabetes for <1 year suggested a possible reverse causality or a link with prediabetes. However, diabetes still might play some role in the development of colon cancer in those with diabetes for ≥3 years. The duration of metformin use showed an inverse trend, with a significant RR of 0.643 (0.490–0.845) in users for ≥3 years, when compared with nonusers. In addition, metformin may reduce colon cancer risk associated with chronic obstructive pulmonary disease (a surrogate for smoking).

Conclusions

Following adjustment for potential detection bias and other covariates, diabetes remains a significant risk factor for colon cancer. Metformin may protect against colon cancer.