bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function
Authors: Marathe Chinmay S. , Rayner Christopher K. , Jones Karen L. , Horowitz Michael
Published: June 2011

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper.
Antibody-Dependent Cell Cytotoxicity Synapses Form in Mice during Tumor-Specific Antibody Immunotherapy
Authors: Hubert Pascale , Heitzmann Adèle , Viel Sophie , Nicolas André , Sastre-Garau Xavier , Oppezzo Pablo , Pritsch Otto , Osinaga Eduardo , Amigorena Sebastian
Published: June 2011

Antibody-dependent cell cytotoxicity (ADCC) plays a critical role in monoclonal antibody (mAb)-mediated cancer therapy. ADCC, however, has not been directly shown in vivo but inferred from the requirement for IgG Fc receptors (FcγR) in tumor rejection in mice. Here, we investigated the mechanism of action of a Tn antigen-specific chimeric mAb (Chi-Tn), which binds selectively to a wide variety of carcinomas, but not to normal tissues, in both humans and mice. Chi-Tn mAb showed no direct toxicity against carcinomas cell lines in vitro but induced the rejection of a murine breast tumor in 80% to 100% of immunocompetent mice, when associated with cyclophosphamide. Tumor rejection was abolished in Fc receptors–associated γ chain (FcR-γ)–deficient mice, suggesting a role for ADCC. Indeed, tumor cells formed stable conjugates in vivo with FcR-γ chain-expressing macrophages and neutrophils in Chi-Tn mAb-treated but not in control mAb-treated mice. The contact zone between tumor cells and ADCC effectors accumulated actin, FcγR and phospho-tyrosines. The in vivo formed ADCC synapses were organized in multifocal supra-molecular activation clusters. These results show that in vivo ADCC mediated by macrophages and neutrophils during tumor rejection by Chi-Tn mAb involves a novel type of multifocal immune synapse between effectors of innate immunity and tumor cells. Cancer Res; 71(15); 5134–43. ©2011 AACR.
Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer
Authors: Labidi-Galy Sana Intidhar , Sisirak Vanja , Meeus Pierre , Gobert Michael , Treilleux Isabelle , Bajard Agathe , Combes Jean-Damien , Faget Julien , Mithieux François , Cassignol Alexandre , Tredan Olivier , Durand Isabelle , Ménétrier-Caux Christine , Caux Christophe , Blay Jean-Yves , Ray-Coquard Isabelle , Bendriss-Vermare Nathalie
Published: June 2011

In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4+CD123+BDCA2+ pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4+ T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. Cancer Res; 71(16); 5423–34. ©2011 AACR.
Histone Deacetylase Cytoplasmic Trapping by a Novel Fluorescent HDAC Inhibitor
Authors: Kong Yali , Jung Mira , Wang Kan , Grindrod Scott , Velena Alfredo , Lee Sung A. , Dakshanamurthy Sivanesan , Yang Yonghong , Miessau Matthew , Zheng Chaoyi , Dritschilo Anatoly , Brown Milton L.
Published: June 2011

Inhibitors of histone deacetylases (HDAC) are an important emerging class of drugs for the treatment of cancers. HDAC inhibitors are currently under evaluation in clinical trials as single agents and as sensitizers in combinations with chemotherapies and radiation therapy. Although these drugs have important effects on cancer cell growth and functions, the mechanisms underlying HDAC inhibitor activities remain to be fully defined. By using rational drug design, compound 2, a fluorescent class II HDAC targeting inhibitor, was synthesized and observed to accumulate in the cytoplasmic compartments of treated cells, but not in the nuclei. Furthermore, immunostaining of inhibitor exposed cells for HDAC4 showed accumulation of this enzyme in the cytoplasmic compartment with concomitant increased acetylation of tubulin and nuclear histones. These observations support a mechanism by which nuclear histone acetylation is increased as a result of HDAC4 trapping and sequestration in the cytoplasm after binding to compound 2. The HDAC inhibitor offers potential as a novel theranostic agent, combining diagnostic and therapeutic properties in the same molecule. Mol Cancer Ther; 10(9); 1591–9. ©2011 AACR.
Linear Chain PEGylated Recombinant Bacillus Thiaminolyticus Thiaminase I Enzyme Has Growth Inhibitory Activity against Lymphoid Leukemia Cell Lines
Authors: Daily Abigail , Liu Shuqian , Bae Younsoo , Bhatnagar Saloni , Moscow Jeffrey A.
Published: June 2011

Cancer cells acquire abnormalities in energy metabolism, collectively known as the Warburg effect, affecting substrate availability of thiamine-dependent enzymes. To investigate a strategy to exploit abnormal cancer-associated metabolism related to thiamine, we tested the cytotoxicity of native Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, in the NCI60 cell line drug cytotoxicity screening program and found that leukemia cell lines were among the most sensitive to thiaminase I. We obtained additional lymphoid leukemia cell lines and confirmed that native thiaminase I and linear chain PEGylated thiaminase I enzyme (LCPTE) have cytotoxic activity in these cell lines. In addition, the IC50 of 3 of the 5 leukemia cell lines (Reh, RS4, and Jurkat) were at least 1,000-fold more sensitive than Molt-4 cells, which in turn, were among the most sensitive in the NCI60 panel. The 3 LCPTE-sensitive leukemia cell lines were also sensitive to removal of thiamine from the medium, thus suggesting the mechanism of action of LCPTE involves extracellular thiamine starvation. Surprisingly, rapamycin showed a protective effect against LCPTE toxicity in the 3 LCPTE-sensitive cell lines but not in the other 2 cell lines, suggesting involvement of an mTOR-dependent pathway. Immunoblot analysis of the LCPTE-sensitive cell lines after LCPTE exposure revealed changes in mTOR pathway phosphorylation. Nude mice bearing RS4 leukemia xenografts showed both tumor growth delay and prolonged survival after a single dose of LCPTE. Therefore, disruption of thiamine-dependent metabolism may be a novel therapeutic approach to target altered energy metabolism in leukemia and other cancers. Mol Cancer Ther; 10(9); 1563–70. ©2011 AACR.
Extended-Spectrum Beta-Lactamase-Mediated Resistance among Bacterial Isolates Recovered from Ocular Infections
Authors: Jayahar Bharathi M. , Ramakrishnan R. , Ramesh S. , Murugan N.
Published: June 2011

Purpose: To evaluate resistances mediated by extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases among Gram-negative bacteria recovered from ocular infections. Methods: As per the Clinical Laboratory Standards Institute M100-S-16 document, a total of 135 Gram-negative bacilli were recovered from ocular specimens and were subjected to phenotypic confirmation for ESBL production by the double-disc synergy test, cephalosporin and clavulanate combination disc test and E test, and, for AmpC β-lactamase, the modified double-disc approximation method and AmpC disc test. Results: In the double-disc synergy test, 21 (15.5%) isolates showed positive results against the cefpodoxime disc, 19 (14%) against cefpodoxime and cefotaxime, 15 (11%) against cefpodoxime, cefotaxime and ceftriaxone and 10 (7%) isolates were against cefpodoxime, cefotaxime, ceftriaxone and ceftazidime discs. In the cephalosporin/clavulanate combination disc test, 19 (14%) isolates showed positive results against cefotaxime with clavulanic acid and 10 (7%) isolates against ceftazidime with clavulanic acid. In the E test, 10 (7%) isolates displayed positive results against ceftazidime and 19 (14%) against cefotaxime. In the AmpC disc test for phenotypic confirmation, indentations were observed in 15 (11%) isolates with flattening also occurring in 10 (7%) isolates. Conclusion: The incidences of ESBL- and AmpC β-lactamase-mediated resistances are found to be 7 and 18.5% among ocular isolates, respectively, and are more prevalent among the strains of Escherichia coli and Klebsiella pneumoniae.
Symptomatic Secondary Vesical Calculus Formed on an Intrauterine Contraceptive Device Inserted 25 Years Previously
Authors: Al-Awadi Khaleel A. , Zaghloul Ahmed S. , Kehinde Elijah O.
Published: June 2011

A 57-year-old postmenopausal woman presented with vague lower abdominal symptoms, dysuria and recurrent urinary tract infection of a year’s duration. She had an intrauterine contraceptive device (IUCD) inserted 25 years previously and denied having any significant gynecological or urinary tract symptoms since the device was inserted. CT scan of her pelvis confirmed the presence of an IUCD that had migrated into the urinary bladder and on which a calculus had formed. An attempt at removal of the calculus and IUCD during cystoscopy failed. At cystolithotomy, the IUCD and the calculus were removed intact. IUCDs may produce complications several years after insertion.
Evaluation of IgE Antibodies to Recombinant Peanut Allergens in Patients with Reported Reactions to Peanut
Authors: Movérare Robert , Ahlstedt Staffan , Bengtsson Ulf , Borres Magnus P. , van Hage Marianne , Poorafshar Maryam , Sjölander Sigrid , Åkerström Johanna , van Odijk Jenny
Published: June 2011

Background: Peanut may cause severe reactions in allergic individuals. The objective was to evaluate IgE antibodies to various recombinant (r) peanut and birch pollen allergens in relation to IgE levels to whole peanut extract and severe allergic reactions to peanut. Methods: Seventy-four Swedish peanut-allergic patients (age: 14–61 years) reported previous peanut exposure and associated symptoms using a questionnaire. Their IgE reactivity to peanut, birch pollen and individual allergen components was analyzed using ImmunoCAP®. Results: Of the 48 subjects sensitized to Ara h 1, 2 or 3, 60% had peanut-specific IgE levels >15 kUA/l, while 100% of the subjects without detectable IgE to these allergens had low peanut-specific IgE levels (<10 kUA/l). The levels of IgE to rAra h 8, rBet v 1 and birch pollen were highly correlated (rS = 0.94, p < 0.0001). Fifty-eight patients reported adverse reactions after accidental or deliberate peanut exposure (oral, inhalation or skin) of whom 41 had IgE to rAra h 1, 2 or 3. Symptoms of respiratory distress were associated with sensitization to Ara h 1, 2 or 3 (56 vs. 18%, p < 0.01). Two cases of anaphylaxis were reported among the individuals sensitized to Ara h 1–3. IgE to rAra h 8, rAra h 9, profilin or cross-reactive carbohydrate determinants were not associated with severe symptoms. Conclusions: The results indicate that IgE reactivity to Ara h 1, 2 and 3 is associated with severe reactions after exposure to peanut in Swedish patients.
Patients’ Satisfaction with Diagnostic Drug Provocation Tests and Perception of Its Usefulness
Authors: Gomes Eva R. , Kvedariene Violeta , Demoly Pascal , Bousquet Philippe-Jean
Published: June 2011

Background and Aim: Although still controversial, drug provocation tests (DPTs) are considered by many as the gold standard for diagnosis of drug hypersensitivity. No studies have addressed the opinion of patients submitted to DPT. We aimed to determine patient satisfaction with diagnostic DPT and their perception of its usefulness. Methods: Surveys were supplied to patients submitted to diagnostic DPT in 3 different drug allergy clinics which used the same diagnostic protocols for drug hypersensitivity evaluation. Seventy-three patients (33.6%) were enrolled in Porto (Portugal), 102 (47%) in Montpellier (France) and 42 (19.4%) in Vilnius (Lithuania). The patients filled in a written questionnaire within 15 days after the diagnostic procedure, and satisfaction was assessed on a 1 (very unsatisfied) to 5 (very satisfied) score. Results: A total of 217 surveys were collected; 144 female patients (66.4%). The most prevalent studied reactions were cutaneous (70.1%), but 17.9% of the patients had had a systemic reaction. β-Lactam antibiotics were the main culprit drugs (44.3%) tested in all centres and 25.3% of the patients had a positive DPT. No patients were unsatisfied (8.8% were neither unsatisfied nor satisfied and the others were satisfied or very satisfied). The level of satisfaction did not depend on the results of the DPT; 207 (95.4%) believed DPTs were useful and almost all the patients would recommend DPTs to others. Conclusions: Most patients were satisfied with DPT for diagnostic purposes. Satisfaction with the procedure was independent of the results of the provocation tests and did not depend on the country.
In vivo Aneuploidization during the Expansion of Renal Adenocarcinoma
Authors: Di Capua Sacoto C. , Budia Alba A. , Alapont Alacreu J.M. , Ruiz Cerda J.L. , Jimenez Cruz J.F.
Published: June 2011

Background/Aims: A correlation has been observed between DNA ploidy and other prognostic parameters such as tumor stage and grade. The present study evaluates tumor aneuploidization during renal adenocarcinoma expansion and growth. Methods: A total of 252 renal tumors were analyzed between 1969 and 2001. Evaluated variables were age, TNM, Fuhrman classification, histology, size and DNA. A tumor was homogeneous when all the samples were diploid or aneuploid, and a heterogeneous tumor was the coexistence of aneuploid and diploid samples, or all-aneuploid with different aneuploid clones. Results: A total of 224 tumors were included (coefficient of variation <8). The DNA study classified 129 (57.6%) as diploid and 95 (42.4%) as aneuploid. The percentage of aneuploid tumors increased significantly with the pathological stage. Both aneuploid patterns were also significantly more frequent in advanced pathological stages. Tumors with multiple aneuploid clones (n = 17) were significantly more frequent in tumors measuring `4 cm. Both aneuploid patterns showed no differences in survival (p = 0.83), indicating that the heterogeneous pattern probably represents an intermediate step between diploid and homogeneous aneuploid tumor status. Conclusions: The aneuploid pattern is more common in more advanced stages of the disease, with no clear correlation to primary tumor size. This suggests gradual aneuploidization with tumor expansion and growth.
Centromere Conversion and Retention in Somatic Cell Hybrids
Authors: Brown J.D. , Carone D.M. , Flynn B.L. , Finn C.E. , Mlynarski E.E. , O’Neill R.J.
Published: June 2011

The generation of somatic cell hybridization-derived cell lines between highly divergent species affords the opportunity to examine the concept of ‘genome dominance’ in the context of genetic and epigenetic changes. While whole-scale genome dominance has been well documented in natural hybrids among closely related species, an examination of centromere position and sequence retention in 2 marsupial-eutherian hybrids has revealed a mechanism for ‘centromere dominance’ as a driving force in the generation of stable somatic cell hybrids following an initial period of genomic instability. While one somatic cell hybrid cell line appeared to retain marsupial centromere sequences which remained competent to recruit the centromere-specific histone variant CENP-A in a Chinese hamster background, fusion events between marsupial and mouse-derived chromosomes in another hybrid line led to a centromere sequence conversion from one species to the other. We postulate that the necessity to maintain an epigenetically defined centromere following genome hybridization may be responsible for retention of specific chromosomes and may result in rapid sequence turnover to facilitate the recruitment of CENP-A containing histones.
Molecular Cytogenetic Mapping of Humulus lupulus Sex Chromosomes
Authors: Divashuk M.G. , Alexandrov O.S. , Kroupin P.Y. , Karlov G.I.
Published: June 2011

Dioecy is relatively rare in plants and sex determination systems vary among such species. A good example of a plant with heteromorphic sex chromosomes is hop (Humulus lupulus). The genotypes carrying XX or XY chromosomes correspond to female and male plants, respectively. Until now no clear cytogenetic markers for the sex chromosomes of hop have been established. Here, for the first time the sex chromosomes of hop are clearly identified and characterized. The high copy sequence of hop (HSR1) has been cloned and localized on chromosomes by fluorescence in situ hybridization. The HSR1 repeat has shown subtelomeric location on autosomes with the same intensity of the signal. The signal has been present in the subtelomeric region of the long arm and in the near-centromeric region but absent in the telomeric region of the short arm of the X chromosome. At the same time the signal has been found in the telomeric region only of the long arm of the Y chromosome. This finding indicates that the sex chromosomes of hop have evolved from a pair of autosomes via ancient translocation or inversion. The observation of the meiotic configuration of the sex bivalents shows the location of a pseudoautosomal region on the long arms of X and Y chromosomes.
Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel
Authors: Frelinger III Andrew L. , Michelson Alan D. , Wiviott Stephen D. , Trenk Dietmar , Neumann Franz-Josef , Miller Debra L. , Jakubowski Joseph A. , Costigan Timothy M. , McCabe Carolyn H. , Antman Elliott M. , Braunwald Eugene
Published: June 2011

It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18–24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18–24 h and 15 day reactivity to ADP (correlations 0.24–0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.
Care Processes Associated With Quicker Door-In–Door-Out Times for Patients With ST-Elevation–Myocardial Infarction Requiring Transfer
Authors: Glickman Seth W. , Lytle Barbara L. , Ou Fang-Shu , Mears Greg , O'Brien Sean , Cairns Charles B. , Garvey J. Lee , Bohle David J. , Peterson Eric D. , Jollis James G. , Granger Christopher B.
Published: June 2011

Background—

The ability to rapidly identify patients with ST-segment elevation–myocardial infarction (STEMI) at hospitals without percutaneous coronary intervention (PCI) and transfer them to hospitals with PCI capability is critical to STEMI regionalization efforts. Our objective was to assess the association of prehospital, emergency department (ED), and hospital processes of care implemented as part of a statewide STEMI regionalization program with door-in–door-out times at non-PCI hospitals.

Methods and Results—

Door-in–door-out times for 436 STEMI patients at 55 non-PCI hospitals were determined before (July 2005 to September 2005) and after (January 2007 to March 2007) a year-long implementation of standardized protocols as part of a statewide regionalization program (Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments, RACE). The association of 8 system care processes (encompassing emergency medical services [EMS], ED, and hospital settings) with door-in–door-out times was determined using multivariable linear regression. Median door-in–door-out times improved significantly with the intervention (before: 97.0 minutes, interquartile range, 56.0 to 160.0 minutes; after: 58.0 minutes, interquartile range, 35.0 to 90.0 minutes;
P
<0.0001). Hospital, ED, and EMS care processes were each independently associated with shorter door-in–door-out times (−17.7 [95% confidence interval, −27.5 to −7.9]; −10.1 [95% confidence interval, −19.0 to −1.1], and −7.3 [95% confidence interval, −13.0 to −1.5] minutes for each additional hospital, ED, and EMS process, respectively). Combined, adoption of EMS processes was associated with the shortest median treatment times (44 versus 138 minutes for hospitals that adopted all EMS processes versus none).

Conclusions—

Prehospital, ED, and hospital processes of care were independently associated with shorter door-in–door-out times for STEMI patients requiring transfer. Adoption of several EMS processes was associated with the largest reduction in treatment times. These findings highlight the need for an integrated, system-based approach to improving STEMI care.
A Hydroclimatological Assessment of Regional Drought Vulnerability: A Case Study of Indiana Droughts
Authors: Charusombat Umarporn , Niyogi Dev
Published: June 2011

Characterizing and developing drought climatology continues to be a challenging problem. As decision makers seek guidance on water management strategies, there is a need for assessing the performance of drought indices. This requires the adaptation of appropriate drought indices that aid in monitoring droughts and hydrological vulnerability on a regional scale. This study aims to assist the process of developing a statewide water shortage and assessment plan (WSP) for the state of Indiana by conducting a focused hydroclimatological assessment of drought variability. Drought climatology was assessed using in situ observations and regional reanalysis data. A summary of precipitation and evaporation trends, estimated drought variability, worst-case drought scenarios, drought return period, and frequency and duration was undertaken, using multiple drought indices and streamflow analysis. Results indicated a regional and local variability in drought susceptibility. The worst-case (200-yr return period) prediction showed that Indiana has a 0.5% probability of receiving 45% of normal precipitation over a 12-month drought in any year. Consistent with other studies, the standardized precipitation index (SPI) was found to be appropriate for detecting short-term drought conditions over Indiana. This recommendation has now been incorporated in the 2009 Indiana water shortage plan. This study also highlights the difficulties in identifying past droughts from available climatic data, and the authors’ results suggest a persistent, high degree of uncertainty in making drought predictions using future climatic projections.
Modeling the Miocene Climatic Optimum. Part I: Land and Atmosphere*
Authors: Herold N. , Huber M. , Müller R. D.
Published: June 2011

This study presents results from the Community Climate System Model 3 (CCSM3) forced with early to middle Miocene (~20–14 Ma) vegetation, topography, bathymetry, and modern CO2. A decrease in the meridional temperature gradient of 6.5°C and an increase in global mean temperature of 1.5°C are modeled in comparison with a control simulation forced with modern boundary conditions. Seasonal poleward displacements of the subtropical jet streams and storm tracks compared to the control simulation are associated with changes in Hadley circulation and significant cooling of the polar stratosphere, consistent with previously predicted effects of global warming. Energy budget calculations indicate that reduced albedo and topography were responsible for Miocene warmth in the high-latitude Northern Hemisphere while a combination of increased ocean heat transport and reduced albedo was responsible for relative warmth in the high-latitude Southern Hemisphere, compared to the present. Model–data analysis suggests Miocene climate was significantly warmer and wetter than simulated here, consistent with previous uncoupled Miocene models and supports recent reconstructions of Miocene CO2 substantially higher than present.
Properties of Steady Geostrophic Turbulence with Isopycnal Outcropping
Authors: Roullet G. , McWilliams J. C. , Capet X. , Molemaker M. J.
Published: June 2011

High-resolution simulations of β-channel, zonal-jet, baroclinic turbulence with a three-dimensional quasigeostrophic (QG) model including surface potential vorticity (PV) are analyzed with emphasis on the competing role of interior and surface PV (associated with isopycnal outcropping). Two distinct regimes are considered: a Phillips case, where the PV gradient changes sign twice in the interior, and a Charney case, where the PV gradient changes sign in the interior and at the surface. The Phillips case is typical of the simplified turbulence test beds that have been widely used to investigate the effect of ocean eddies on ocean tracer distribution and fluxes. The Charney case shares many similarities with recent high-resolution primitive equation simulations. The main difference between the two regimes is indeed an energization of submesoscale turbulence near the surface. The energy cycle is analyzed in the (k, z) plane, where k is the horizontal wavenumber. In the two regimes, the large-scale buoyancy forcing is the primary source of mechanical energy. It sustains an energy cycle in which baroclinic instability converts more available potential energy (APE) to kinetic energy (KE) than the APE directly injected by the forcing. This is due to a conversion of KE to APE at the scale of arrest. All the KE is dissipated at the bottom at large scales, in the limit of infinite resolution and despite the submesoscales energizing in the Charney case. The eddy PV flux is largest at the scale of arrest in both cases. The eddy diffusivity is very smooth but highly nonuniform. The eddy-induced circulation acts to flatten the mean isopycnals in both cases.
Steady‐State Pharmacokinetic Interactions of Darunavir/Ritonavir With Lipid‐Lowering Agent Rosuvastatin
Authors: Samineni Divya , Desai Pankaj B. , Sallans Larry , Fichtenbaum Carl J.
Published: June 2011

HIV‐1 protease inhibitors often cause dyslipidemia, necessitating the use of lipid‐lowering agents such as rosuvastatin. However, when given concomitantly, these therapeutic agents often exhibit adverse drug interactions. In this study (phase I open‐label trial, n = 12 HIV‐1 seronegative participants), the authors assessed the drug interactions between darunavir/ritonavir given in combination with rosuvastatin. Participants were randomized to receive rosuvastatin (10 mg/day) or darunavir/ritonavir (600/100 mg twice daily) alone for 7 days in a crossover design followed by combination therapy for 7 days with intervening 7‐day washout periods. Intensive blood sampling for pharmacokinetics and fasting lipids was performed on days 7, 21, and 35. The geometric mean AUC0–24 h of rosuvastatin increased from 109 to 161 ng·h/mL (P < .005) and Cmax increased 6.7 to 16.3 ng/mL (P < .001) when coadministered with darunavir/ritonavir. In the presence of darunavir/ritonavir and rosuvastatin, total cholesterol and triglyceride levels increased by 10% (P = .007) and 56% (P = .011), whereas the high‐density lipoprotein cholesterol levels decreased by 13% (P = .006) relative to rosuvastatin administration alone. There were no significant adverse events attributable to the coadministration of these drugs. Rosuvastatin levels increase in the presence of darunavir/ritonavir coadministration, whereas the lipid‐lowering benefits are blunted. The clinical significance of these changes requires further investigation.
More Than 25 Years of the American Journal of Evaluation
Authors: Gargani John
Published: June 2011

This article explores the important role that past editors of the American Journal of Evaluation and its predecessors, Evaluation Practice and Evaluation News, played in the development of the American Evaluation Association (AEA). In interviews presented here, the editors recount the history of the association, the journal, and the field as they experienced it. Using a variety of sources, the author provides additional context for their remarks, describing the pioneering efforts of early evaluation associations, the contentious mergers that resulted in a single national association, the emergence of dedicated evaluation publications, and the challenges posed by an increasingly diverse membership. The author concludes by discussing the ways in which the editors, throughout their 35 years of service, strengthened not only professional associations but the larger field of evaluation.
Using Ryodoraku Measurement to Evaluate the Impact of Environmental Noise on Human Physiological Response
Authors: Chiang Che Ming , Liu Chien Chih , Lin Fang Ming , Wang Wei , Chou Po Cheng
Published: June 2011

According to relevant studies on the influence of indoor sound environment on human responses, long-term exposure to excessive indoor noise can have a significant effect on human physiological responses, such as heart rate variability, electroencephalography and blood pressure. Moreover, it may cause tinnitus, palpitation and headache. In order to find out the impact of noise environment on human physiological response changes, this study undertook experiments in a Lab with a precise control of environmental factors and based on the viewpoint of meridian of traditional Chinese medicine, the changes in human autonomic nervous response and the degree of effect on corresponding meridians after 45 min stimulation of white noise environment at 40 dB (A), 50 dB (A), 60 dB (A) and 70 dB (A) sound pressure levels, were evaluated. The analysis of the experimental results found that, the human Heart Constrictor meridians, Heart meridians and Triple Heater meridians were related to pericardium, blood vessel and blood circulation system; and are likely to be influenced by the noise environment stimulation. When the noise sound pressure level exceeded 60 dB (A), the human Bladder meridians and Gall Bladder meridians related to ears, eyes, shoulder joints, digestive system and endocrine system could be influenced significantly.
High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation
Authors: Gökbuget Nicola , Basara Nadezda , Baurmann Herrad , Beck Joachim , Brüggemann Monika , Diedrich Helmut , Güldenzoph Björn , Hartung Gernot , Horst Heinz-August , Hüttmann Andreas , Kobbe Guido , Naumann Ralph , Ratei Richard , Reichle Albrecht , Serve Hubert , Stelljes Matthias , Viardot Andreas , Wattad Mohammed , Hoelzer Dieter
Published: June 2011

Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.
The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility
Authors: Wu Yu-Hsuan , Hu Tzu-Fang , Chen Yu-Chieh , Tsai Ya-Ni , Tsai Yuan-Hau , Cheng Cheng-Chung , Wang Hsei-Wei
Published: June 2011

miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is up-regulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.
Silencing of RhoA nucleotide exchange factor, ARHGEF3, reveals its unexpected role in iron uptake
Authors: Serbanovic-Canic Jovana , Cvejic Ana , Soranzo Nicole , Stemple Derek L. , Ouwehand Willem H. , Freson Kathleen
Published: June 2011

Genomewide association meta-analysis studies have identified > 100 independent genetic loci associated with blood cell indices, including volume and count of platelets and erythrocytes. Although several of these loci encode known regulators of hematopoiesis, the mechanism by which most sequence variants exert their effect on blood cell formation remains elusive. An example is the Rho guanine nucleotide exchange factor, ARHGEF3, which was previously implicated by genomewide association meta-analysis studies in bone cell biology. Here, we report on the unexpected role of ARHGEF3 in regulation of iron uptake and erythroid cell maturation. Although early erythroid differentiation progressed normally, silencing of arhgef3 in Danio rerio resulted in microcytic and hypochromic anemia. This was rescued by intracellular supplementation of iron, showing that arhgef3-depleted erythroid cells are fully capable of hemoglobinization. Disruption of the arhgef3 target, RhoA, also produced severe anemia, which was, again, corrected by iron injection. Moreover, silencing of ARHGEF3 in erythromyeloblastoid cells K562 showed that the uptake of transferrin was severely impaired. Taken together, this is the first study to provide evidence for ARHGEF3 being a regulator of transferrin uptake in erythroid cells, through activation of RHOA.
Unresolved orthology and peculiar coding sequence properties of lamprey genes: the KCNA gene family as test case
Authors: Qiu Huan , Hildebrand Falk , Kuraku Shigehiro , Meyer Axel
Published: June 2011

Background

In understanding the evolutionary process of vertebrates, cyclostomes (hagfishes and lamprey) occupy crucial positions. Resolving molecular phylogenetic relationships of cyclostome genes with gnathostomes (jawed vertebrates) genes is indispensable in deciphering both the species tree and gene trees. However, molecular phylogenetic analyses, especially those including lamprey genes, have produced highly discordant results between gene families. To efficiently scrutinize this problem using partial genome assemblies of early vertebrates, we focused on the potassium voltage-gated channel, shaker-related (KCNA) family, whose members are mostly single-exon.

Results

Seven sea lampreyKCNAgenes as well as six elephant shark genes were identified, and their orthologies to bony vertebrate subgroups were assessed. In contrast to robustly supported orthology of the elephant shark genes to gnathostome subgroups, clear orthology of any sea lamprey gene could not be established. Notably, sea lampreyKCNAsequences displayed unique codon usage pattern and amino acid composition, probably associated with exceptionally high GC-content in their coding regions. This lamprey-specific property of coding sequences was also observed generally for genes outside this gene family.

Conclusions

Our results suggest that secondary modifications of sequence properties unique to the lamprey lineage may be one of the factors preventing robust orthology assessments of lamprey genes, which deserves further genome-wide validation. The lamprey lineage-specific alteration of protein-coding sequence properties needs to be taken into consideration in tackling the key questions about early vertebrate evolution.
Attitude toward contraception and abortion among Curaçao women. Ineffective contraception due to limited sexual education?
Authors: van den Brink Maaike J , Boersma Adriana A , Meyboom-de Jong Betty , de Bruijn Jeanne GM
Published: June 2011

Background

In Curaçao is a high incidence of unintended pregnancies and induced abortions. Most of the induced abortions in Curaçao are on request of the woman and performed by general practitioners. In Curaçao, induced abortion is strictly prohibited, but since 1999 there has been a policy of connivance. We present data on the relevance of economic and socio-cultural factors for the high abortion-rates and the ineffective use of contraception.

Methods

Structured interviews to investigate knowledge and attitudes toward sexuality, contraception and abortion and reasons for ineffective use of contraceptives among women, visiting general practitioners.

Results

Of 158 women, 146 (92%) participated and 82% reported that their education on sexuality and about contraception was of good quality. However 'knowledge of reliable contraceptive methods' appeared to be - in almost 50% of the cases - false information, misjudgements or erroneous views on the chance of getting pregnant using coitus interruptus and about the reliability and health effects of oral contraceptive pills. Almost half of the interviewed women had incorrect or no knowledge about reliability of condom use and IUD. 42% of the respondents risked by their behavior an unplanned pregnancy. Most respondents considered abortion as an emergency procedure, not as contraception. Almost two third experienced emotional, physical or social problems after the abortion.

Conclusions

Respondents had a negative attitude toward reliable contraceptives due to socio-cultural determined ideas about health consequences and limited sexual education. Main economic factors were costs of contraceptive methods, because most health insurances in Curaçao do not cover contraceptives. To improve the effective use of reliable contraceptives, more adequate information should be given, targeting the wrong beliefs and false information. The government should encourage health insurance companies to reimburse contraceptives. Furthermore, improvement of counseling during the abortion procedure is important.
A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis
Authors: Sarasola Esther , Rodríguez Jose A , Garrote Elisa , Arístegui Javier , García-Barcina Maria J
Published: June 2011

Background

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF).

Case Presentation

We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G>A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A>G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G>A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A>G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain.

Conclusions

We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.
Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation
Authors: Cui Juan , Miner Brooke M , Eldredge Joanna B , Warrenfeltz Susanne W , Dam Phuongan , Xu Ying , Puett David
Published: June 2011

Background

Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells.

Methods

The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses.

Results

Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive mediation of ovarian cancer growth.

Conclusion

Overall, the present study elucidates the extensive transcriptomic changes of ovarian cancer cells in response to LH receptor activation, which provides a comprehensive and objective assessment for determining new cancer therapies and potential serum markers, of which over 100 are suggested.