bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiences with treprostinil in the treatment of pulmonary arterial hypertension
Authors: Stream Amanda R. , Bull Todd M.
Published: August 2012

Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressures with associated increases in pulmonary vascular resistance leading to right ventricular failure, which was almost uniformly fatal prior to the introduction of pulmonary hypertension specific therapy. Systemic prostacyclin analogs are the first PAH-specific therapies to be made available and are typically recommended as first-line therapy for subjects with severe disease. Treprostinil is a newer prostacyclin analog similar to epoprostenol in its mechanism of action and relative efficacy with the advantage of a longer half life in human serum and room temperature stability. It is unique in that it is available in multiple formulations for alternative routes of delivery, including subcutaneous, intravenous and inhalational routes. Additionally, oral treprostinil is currently under investigation. Both subcutaneous and intravenous forms of treprostinil have demonstrated efficacy in short-term clinical trials and are currently approved for use in subjects with PAH and New York Heart Association functional class (NYHA FC) II–IV symptoms in the USA and for subjects with NYHA FC III and IV in Europe. Inhaled treprostinil has also demonstrated efficacy in short-term clinical trials primarily as add-on therapy and is currently approved for use in subjects with PAH and NYHA FC III–IV symptoms in the USA and Europe. The different formulations of treprostinil have significantly increased the treatment options and opportunities for treatment of patients with PAH.
Preclinical Studies
Authors: Zhu Yinggang , Feng Xiaomei , Lee Jae-Woo
Published: August 2012

Sepsis remains a major cause of morbidity and mortality in hospitalized patients. The pathophysiology of sepsis involves complex interactions between microbial pathogens and the host immune system. Stem cells have the potential to both directly regenerate tissue by virtue of their pluripotency and mitigate injury and inflammation through paracrine mechanisms. These characteristics have stimulated worldwide research efforts to explore the possibility of using stem cells for the treatment of sepsis. A variety of stem cells have been isolated, characterized, and tested experimentally in preclinical animal models of sepsis. In this review, the authors define the various types of stem cells (embryonic, mesenchymal, endothelial progenitor, and hematopoietic progenitor) and describe the results of studies done to date to examine the role of these various stem cell classes in treatment of sepsis and other human diseases.
The Effects of Hypertriglyceridemia on Plasma Free Hemoglobin Levels and Extracorporeal Membrane Oxygenation Support
Authors: Ruiz Julia Dolores , Armijo-Garcia Veronica
Published: August 2012

Exposure of patients to significant hemolysis can lead to serious clinical sequelae. Plasma free hemoglobin (pFHgb) is used during extracorporeal membrane oxygenation (ECMO) support to monitor ongoing hemolysis that is a consequence of mechanical forces applied to the red blood cells. This publication presents the case of a 3-year-old child who required ECMO support due to severe pneumonia. During her ECMO course, she developed severe elevations of pFHgb that were of questionable validity. Additional laboratory findings suggested a concurrent hypertriglyceridemia to be the potential cause for these false elevations. Linear regression analysis was employed and revealed a statistically significant ( P = .006) moderate correlation between pFHgb and triglyceride levels ( R = .69). The analysis reinforces the theory that hypertriglyceridemia may lead to false increases in pFHgb, which may complicate a patient’s clinical picture and influence management decisions. Therefore, it should not be the sole value used to assess hemolysis in patients on ECMO.
Effect of materials position on friction stir lap welding of Al to Cu
Authors: Akbari M , Abdi Behnagh R , Dadvand A
Published: August 2012

Friction stir welding has been successfully used to weld the dissimilar metals. A few investigations have been carried out on the friction stir lap welding of Al to Cu, but the basic issue of how the position of the metals would affect the joint strength is still not resolved. In the present study, the 7070 Al and the commercially pure copper are lap joined using friction stir lap welding technology. Two test cases are considered. The distinction refers to the position of Al with respect to Cu. Microstructural analyses are carried out to gain intermetallic compounds and some microcracks. The effect of position of materials on the heat generation is investigated and justified through the temperature measurements. Mechanical properties of each sample are characterized using both shear and hardness tests. The results reveal that the maximum fracture load of the joint is obtained when Al is placed on the top of Cu.
Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms
Authors: Xu Xiao , Gnatenko Dmitri V. , Ju Jingfang , Hitchcock Ian S. , Martin Dwight W. , Zhu Wei , Bahou Wadie F.
Published: August 2012

Posttranscriptional and translational controls mediated by microRNAs (miRNA) regulate diverse biologic processes. We dissected regulatory effects of miRNAs relevant to megakaryocytopoiesis and platelet biology by analyzing expression patterns in 79 subjects with thrombocytosis and controls, and integrated data with transcriptomic and proteomic platforms. We validated a unique 21-miRNA genetic fingerprint associated with thrombocytosis, and demonstrated that a 3-member subset defines essential thrombocythemia (ET). The genetic signature includes functional guide and passenger strands of the previously uncharacterized miR 490 (5p and 3p), which displayed restricted, low-level expression in megakaryocytes/platelets (compared with leukocytes), and aberrant expression during thrombocytosis, most profound in ET. Overexpression of miR 490 in a bilineage differentiation model of megakaryocyte/erythroid progenitor formation was insufficient for hematopoietic colony differentiation and/or lineage specification. Integration of transcriptomic and mass spectrometric datasets with functional reporter assays identified dishevelled associated activator of morphogenesis 1 (DAAM1) as a miR 490 5p protein target demonstrating decreased expression in ET platelets, putatively by translational control (and not by mRNA target degradation). Our data define a dysregulated miRNA fingerprint in thrombocytosis and support a developmentally restricted function of miR 490 (and its putative DAAM1 target) to conditions associated with exaggerated megakaryocytopoiesis and/or proplatelet formation.
Genome-wide analysis of Acetivibrio cellulolyticus provides a blueprint of an elaborate cellulosome system
Authors: Dassa Bareket , Borovok Ilya , Lamed Raphael , Henrissat Bernard , Coutinho Pedro , Hemme Christopher L , Huang Yue , Zhou Jizhong , Bayer Edward A
Published: August 2012

Background

Microbial degradation of plant cell walls and its conversion to sugars and other byproducts is a key step in the carbon cycle on Earth. In order to process heterogeneous plant-derived biomass, specialized anaerobic bacteria use an elaborate multi-enzyme cellulosome complex to synergistically deconstruct cellulosic substrates. The cellulosome was first discovered in the cellulolytic thermophile, Clostridium thermocellum, and much of our knowledge of this intriguing type of protein composite is based on the cellulosome of this environmentally and biotechnologically important bacterium. The recently sequenced genome of the cellulolytic mesophile, Acetivibrio cellulolyticus, allows detailed comparison of the cellulosomes of these two select cellulosome-producing bacteria.

Results

Comprehensive analysis of the A. cellulolyticus draft genome sequence revealed a very sophisticated cellulosome system. Compared to C. thermocellum, the cellulosomal architecture of A. cellulolyticus is much more extensive, whereby the genome encodes for twice the number of cohesin- and dockerin-containing proteins. The A. cellulolyticus genome has thus evolved an inflated number of 143 dockerin-containing genes, coding for multimodular proteins with distinctive catalytic and carbohydrate-binding modules that play critical roles in biomass degradation. Additionally, 41 putative cohesin modules distributed in 16 different scaffoldin proteins were identified in the genome, representing a broader diversity and modularity than those of Clostridium thermocellum. Although many of the A. cellulolyticus scaffoldins appear in unconventional modular combinations, elements of the basic structural scaffoldins are maintained in both species. In addition, both species exhibit similarly elaborate cell-anchoring and cellulosome-related gene- regulatory elements.

Conclusions

This work portrays a particularly intricate, cell-surface cellulosome system in A. cellulolyticus and provides a blueprint for examining the specific roles of the various cellulosomal components in the degradation of complex carbohydrate substrates of the plant cell wall by the bacterium.
Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation
Authors: Fuchs Mary , Reinhöfer Mike , Ragoschke-Schumm Andreas , Sayer Herbert G , Böer Klas , Witte Otto W , Hochhaus Andreas , Axer Hubertus
Published: August 2012

Background

This case report highlights the relevance of quantifying the BCR-ABL gene in cerebrospinal fluid of patients with suspected relapse of chronic myeloid leukemia in the central nervous system.

Case presentation

We report on a female patient with isolated central nervous system relapse of chronic myeloid leukemia (CML) during peripheral remission after allogeneic hematopoietic stem cell transplantation. The patient showed a progressive cognitive decline as the main symptom. MRI revealed a hydrocephalus and an increase in cell count in the cerebrospinal fluid (CSF) with around 50% immature blasts in the differential count. A highly elevated BCR-ABL/ ABL ratio was detected in the CSF, whilst the ratio for peripheral blood and bone marrow was not altered. On treatment of the malresorptive hydrocephalus with shunt surgery, the patient showed an initial cognitive improvement, followed by a secondary deterioration. At this time, the cranial MRI showed leukemic infiltration of lateral ventricles walls. Hence, intrathecal administration of cytarabine, methotrexate, and dexamethasone was initiated, which caused a significant decrease of cells in the CSF. Soon after, the patient demonstrated significant cognitive improvement with a good participation in daily activities. At a later time point, after the patient had lost the major molecular response of CML, therapy with dasatinib was initiated. In a further follow-up, the patient was neurologically and hematologically stable.

Conclusions

In patients with treated CML, the rare case of an isolated CNS blast crisis has to be taken into account if neurological symptoms evolve. The analysis of BCR-ABL in the CSF is a further option for the reliable detection of primary isolated relapse of CML in these patients.
A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the MECP2 duplication phenotype
Authors: Hanchard Neil A , Carvalho Claudia MB , Bader Patricia , Thome Aaron , Omo-Griffith Lisa , del Gaudio Daniela , Pehlivan Davut , Fang Ping , Schaaf Christian P , Ramocki Melissa B , Lupski James R , Cheung Sau Wai
Published: August 2012

Background

Duplications of the X-linked MECP2 gene are associated with moderate to severe intellectual disability, epilepsy, and neuropsychiatric illness in males, while triplications are associated with a more severe phenotype. Most carrier females show complete skewing of X-inactivation in peripheral blood and an apparent susceptibility to specific personality traits or neuropsychiatric symptoms.

Methods

We describe the clinical phenotype of a pedigree segregating a duplication of MECP2 found on clinical array comparative genomic hybridization. The position, size, and extent of the duplication were delineated in peripheral blood samples from affected individuals using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, as well as targeted high-resolution oligonucleotide microarray analysis and long-range PCR. The molecular consequences of the rearrangement were studied in lymphoblast cell lines using quantitative real-time PCR, reverse transcriptase PCR, and western blot analysis.

Results

We observed a partial MECP2 duplication in an adult male with epilepsy and mild neurocognitive impairment who was able to function independently; this phenotype has not previously been reported among males harboring gains in MECP2 copy number. The same duplication was inherited by this individual’s daughter who was also affected with neurocognitive impairment and epilepsy and carried an additional copy-number variant. The duplicated segment involved all four exons of MECP2, but excluded almost the entire 3' untranslated region (UTR), and the genomic rearrangement resulted in a MECP2-TEX28 fusion gene mRNA transcript. Increased expression of MECP2 and the resulting fusion gene were both confirmed; however, western blot analysis of lysates from lymphoblast cells demonstrated increased MeCP2 protein without evidence of a stable fusion gene protein product.

Conclusion

The observations of a mildly affected adult male with a MECP2 duplication and paternal transmission of this duplication are unique among reported cases with a duplication of MECP2. The clinical and molecular findings imply a minimal critical region for the full neurocognitive expression of the MECP2 duplication syndrome, and suggest a role for the 3′ UTR in mitigating the severity of the disease phenotype.
The development of quality indicators in mental healthcare: a discrete choice experiment
Authors: Schellings Ron , Essers Brigitte AB , Kessels Alfons G , Brunner Florian , van de Ven Tijmen , Robben Paul BM
Published: August 2012

Background

Health care regulatory agencies perform audits or inspections to judge the quality and safety of health care. This judgment is based on the assessment of a large set of health care indicators as accepted by the profession. However, there is a lack of knowledge about the influence of these indicators and whether a smaller number would be sufficient for a quality assessment or audit procedure.

Methods

A discrete choice experiment (DCE) was performed for the assessment of quality of care regarding the management of patients with schizophrenia and drug dependency in psychiatric institutes. Based on multidisciplinary guidelines for the treatment of schizophrenia and a visit of (co)inspectors of the Dutch Healthcare Inspectorate at all 33 integrated mental hospitals a set of 51 indicators were assessed in a subsequent interview. With the analysis of the results, 6 attributes were selected for the DCE as quality indicators.

Results

Seventy-six percent of all health services (co)inspectors (n = 33) involved in the inspection of mental health services, participated in the experiment. Respondents considered an operational elaborate treatment plan the most important indicator for the assessment of quality of care in a psychiatric institute, followed by a general care program, treatment outcome measurement, and involvement in treatment of patients and relatives. Pharmacotherapy and governance responsibility were valued as less important indicators.

Conclusions

The results of this DCE show that there is a prioritisation in the six selected quality indicators. This might help health services (co) inspectors to enhance the efficiency and transparency of the quality of care assessment for patients with schizophrenia and/or drug dependency in psychiatric institutes.
Obesity and elevated blood pressure among adolescents in Lagos, Nigeria: a cross-sectional study
Authors: Oduwole Abiola A , Ladapo Taiwo A , Fajolu Iretiola B , Ekure Ekanem N , Adeniyi Olufunmilayo F
Published: August 2012

Background

Childhood obesity and associated hypertension are major public health concerns globally. This study aimed to determine the prevalence of obesity and the associated risk of high blood pressure among Nigerian adolescents.

Methods

A cross-sectional school-based study of 885 apparently healthy adolescents was performed. Weight, height and blood pressure (BP) were measured using standard methods. Body mass index (BMI) was calculated and categorized by age, sex and percentile. Obesity and overweight were defined as: ≥ 95th and 85th to < 95th percentiles, respectively, for age, sex and height. Subjects were sub-categorized into age 10–13 years (A) and 14–17 years (B). The odds ratio for pre-hypertensive and hypertensive range BP by age and BMI were generated. Significance was set at P < 0.05.

Results

The prevalence of overweight and obesity were 13.8% and 9.4%, respectively. The prevalence of hypertensive range systolic BP in obese versus normal BMI females was 16% versus 23% (p=0.00) and 12.1% versus 6.4% (p=0.27) in males. The prevalence of hypertensive range diastolic BP in obese versus normal BMI females was 12% versus 1.4% (p=0.00) and 15.2% versus 3.5% (p=0.01) in males. BMI in group B was significantly associated with pre-hypertensive and hypertensive range systolic BP in overweight (P = 0.01, P = 0.002) and obese subjects (P = 0.00, P = 0.00) and with hypertensive range diastolic BP (P = 0.00) only in obese subjects. The only significant association in group A was between obesity and pre-hypertensive range diastolic BP (P = 0.00).

Conclusion

The prevalence of hypertensive range BP among obese Nigerian adolescents was high. Screening for childhood obesity and hypertension, and long-term follow-up of obese adolescents into adulthood are recommended.
Neighbourhood socioeconomic inequalities in incidence of acute myocardial infarction: a cohort study quantifying age- and gender-specific differences in relative and absolute terms
Authors: Koopman Carla , van Oeffelen Aloysia AM , Bots Michiel L , Engelfriet Peter M , Verschuren WM Monique , van Rossem Lenie , van Dis Ineke , Capewell Simon , Vaartjes Ilonca
Published: August 2012

Background

Socioeconomic status has a profound effect on the risk of having a first acute myocardial infarction (AMI). Information on socioeconomic inequalities in AMI incidence across age- gender-groups is lacking. Our objective was to examine socioeconomic inequalities in the incidence of AMI considering both relative and absolute measures of risk differences, with a particular focus on age and gender.

Methods

We identified all patients with a first AMI from 1997 to 2007 through linked hospital discharge and death records covering the Dutch population. Relative risks (RR) of AMI incidence were estimated by mean equivalent household income at neighbourhood-level for strata of age and gender using Poisson regression models. Socioeconomic inequalities were also shown within the stratified age-gender groups by calculating the total number of events attributable to socioeconomic disadvantage.

Results

Between 1997 and 2007, 317,564 people had a first AMI. When comparing the most deprived socioeconomic quintile with the most affluent quintile, the overall RR for AMI was 1.34 (95 % confidence interval (CI): 1.32 – 1.36) in men and 1.44 (95 % CI: 1.42 – 1.47) in women. The socioeconomic gradient decreased with age. Relative socioeconomic inequalities were most apparent in men under 35 years and in women under 65 years. The largest number of events attributable to socioeconomic inequalities was found in men aged 45–74 years and in women aged 65–84 years. The total proportion of AMIs that was attributable to socioeconomic inequalities in the Dutch population of 1997 to 2007 was 14 % in men and 18 % in women.

Conclusions

Neighbourhood socioeconomic inequalities were observed in AMI incidence in the Netherlands, but the magnitude across age-gender groups depended on whether inequality was expressed in relative or absolute terms. Relative socioeconomic inequalities were high in young persons and women, where the absolute burden of AMI was low. Absolute socioeconomic inequalities in AMI were highest in the age-gender groups of middle-aged men and elderly women, where the number of cases was largest.
Nutritional status and risk factors of overweight and obesity for children aged 9–15 years in Chengdu, Southwest China
Authors: Li Ping , Yang Fan , Xiong Fei , Huo Tingzhu , Tong Yu , Yang Sufei , Mao Meng
Published: August 2012

Background

Obesity is widespread in the world including developing countries. However malnutrition in poor areas is still a serious problem. Few investigations, especially in a large sample, have been performed in Western area of China. This study aimed to evaluate the nutritional status of school children aged 9–15 years in large Southwest city of China, and identify the differential impact of aberrant birth categories and family history of obesity related disease on childhood overweight and obesity development.

Methods

A multistage random cluster sampling was performed to evaluate the prevalence of thinness, overweight and obesity, which were defined by the new age-, sex-, specific BMI reference developed by World Health Organization (WHO) (2007). And then a frequency matched case–control study was performed to identify the risk factors of overweight and obesity.

Results

7,194 children (3,494 boys, 3,700 girls) were recruited, and 1,282 (17.8%) had excess bodyweight (14.5% overweight, 3.3% obesity). The combined prevalence gradually decreased with age, and were more prevalent among boys than girls (P <0.05). Meanwhile 6.3% were found thinness and there were little differences in genders (P >0.05). Preterm large for gestational age (OR = 2.746), maternal history of obesity related disease (OR = 1.713), paternal history of obesity related disease (OR = 1.583), preterm appropriate for gestational age (OR = 1.564), full term small for gestational age (OR = 1.454) and full term large for gestational age (OR = 1.418) were recognized as significant risk factors in the multivariate regression analysis (P <0.05).

Conclusions

While overweight and obesity was dramatically spreading, malnutrition still remained a serious problem. This unmatched nutritional status should be emphasized in backward cities of China. Children born of both preterm and LGA, whose parents particularly mothers had a history of obesity related disease, should be emphatically intervened as early as possible.
Mortality after low trauma hip fracture: a prospective cohort study
Authors: Valizadeh Majid , Mazloomzadeh Saeideh , Golmohammadi Somayeh , Larijani Bagher
Published: August 2012

Background

Various risk of mortality due to hip fracture has been reported by different studies. There is scarce controlled study on hip fracture mortality from developing countries and no data from Middle East region. The objective of this study is to determine mortality and its risk factors one year after low trauma hip fracture.

Methods

One hundred and two patients after hip fracture not caused by high impact injuries or local bone diseases followed up prospectively for one year. Control group consisted of sex and age matched patients admitted to ophthalmology ward for eye surgery. Data about comorbidity obtained from both groups at baseline. Functional state and health-related quality of life for the participants were measured using RDRS-2 and SF-36 questionnaires, respectively.

Results

The overall survival was 83% in cases and 92% in controls (log rank test 3.62, df = 1, P = 0.057). Early mortality within the first 6 months of observation was significantly higher in patients than controls (13 in patients vs. 2 in controls) (log rank test 8.84, df = 1, P = 0.003). The risk of mortality in the first year after fracture was significantly and independently associated with age and baseline RDRS score. By the end of follow-up, in the patient group, 55.4% of survivors were able to walk without any assistance and 10.8% were not able to walk.

Conclusions

The risk of mortality within the first 6 months of observation was significantly and independently associated with low trauma hip fracture. However, age and baseline RDRS score were independent predictors of mortality in the first year following hip fracture.
Accelerometer-assisted 802.11 rate adaptation on mobile WiFi access
Authors: Lai Yu-Jen , Kuo Wei-Hao , Chiu Wan-Ting , Wei Hung-Yu
Published: August 2012

The expansion of 802.11 AP deployment provides opportunistic Wi-Fi access in underground mass rapid transit (MRT) system. However, such vehicular network faces the challenge of limited time for the MS on the train to connect the base station at the station. Therefore, to maximize the throughput within these several tens of seconds becomes crucial to the network. To achieve this goal, we propose accelerometer-assisted rate adaptation (AARA), a mechanism utilizes the out-of-band information of a train’s acceleration to improve the conventional rate adaptation scheme. AARA consists of two parts: First, AARA divides a train’s movement into four phases and performs real-time estimation on the train’s current movement phase. Second, AARA employs the estimation results to enhance the bit-rate selection during each phase. We conduct experiments on two different Taipei MRT systems: high-capacity MRT and medium-capacity MRT. The experimental results show that the average throughput of AARA outperforms that of the conventional scheme in different scenarios. In addition, we also design a mechanism of power saving with the aid of the movement estimation.
Efficiency and safety of inhalative sedation with sevoflurane in comparison to an intravenous sedation concept with propofol in intensive care patients: study protocol for a randomized controlled trial
Authors: Soukup Jens , Selle Antje , Wienke Andreas , Steighardt Jörg , Wagner Nana-Maria , Kellner Patrick
Published: August 2012

Background

State of the art sedation concepts on intensive care units (ICU) favor propofol for a time period of up to 72 h and midazolam for long-term sedation. However, intravenous sedation is associated with complications such as development of tolerance, insufficient sedation quality, gastrointestinal paralysis, and withdrawal symptoms including cognitive deficits. Therefore, we aimed to investigate whether sevoflurane as a volatile anesthetic technically implemented by the anesthetic-conserving device (ACD) may provide advantages regarding ‘weaning time’, efficiency, and patient’s safety when compared to standard intravenous sedation employing propofol.

Method/Design

This currently ongoing trial is designed as a two-armed, monocentric, randomized prospective phase II study including intubated intensive care patients with an expected necessity for sedation exceeding 48 h. Patients are randomly assigned to either receive intravenous sedation with propofol or sevoflurane employing the ACD. Primary endpoint is the comparison of the ‘weaning time’ defined as the time required from discontinuation of the sedating agent until sufficient spontaneous breathing occurs. Moreover, sedation depth evaluated by Richmond Agitation Sedation Scale and parameters of patient’s safety (that is, vital signs, laboratory monitoring of organ function) as well as the duration of mechanical ventilation and overall stay on the ICU are analyzed and compared. An intention-to-treat analysis will be carried out with all patients for whom it will be possible to define a wake-up time. In addition, a per-protocol analysis is envisaged. Completion of patient recruitment is expected by the end of 2012.

Discussion

This clinical study is designed to evaluate the impact of sevoflurane during long-term sedation of critically ill patients on ‘weaning time’, efficiency, and patient’s safety compared to the standard intravenous sedation concept employing propofol.

Trial registration

EudraCT2007-006087-30; ISCRTN90609144
OSCILLATOR: A system for analysis of diurnal leaf growth using infrared photography combined with wavelet transformation
Authors: Bours Ralph , Muthuraman Manickam , Bouwmeester Harro , van der Krol Alexander
Published: August 2012

Background

Quantification of leaf movement is an important tool for characterising the effects of environmental signals and the circadian clock on plant development. Analysis of leaf movement is currently restricted by the attachment of sensors to the plant or dependent upon visible light for time-lapse photography. The study of leaf growth movement rhythms in mature plants under biological relevant conditions,e.g.diurnal light and dark conditions, is therefore problematic.

Results

Here we present OSCILLATOR, an affordable system for the analysis of rhythmic leaf growth movement in mature plants. The system contains three modules: (1) Infrared time-lapse imaging of growing mature plants (2) measurement of projected distances between leaf tip and plant apex (leaf tip tracking growth-curves) and (3) extraction of phase, period and amplitude of leaf growth oscillations using wavelet analysis. A proof-of-principle is provided by characterising parameters of rhythmic leaf growth movement of differentArabidopsis thalianaaccessions as well as ofPetunia hybridaandSolanum lycopersicumplants under diurnal conditions. The amplitude of leaf oscillations correlated to published data on leaf angles, while amplitude and leaf length did not correlate, suggesting a distinct leaf growth profile for each accession. Arabidopsis mutant accession Landsbergerectadisplayed a late phase (timing of peak oscillation) compared to other accessions and this trait appears unrelated to theERECTAlocus.

Conclusions

OSCILLATOR is a low cost and easy to implement system that can accurately and reproducibly quantify rhythmic growth of mature plants for different species under diurnal light/dark cycling.
Fluorescent property of 3-hydroxymethyl imidazo[1,2-a]pyridine and pyrimidine derivatives
Authors: Velázquez-Olvera Stephania , Salgado-Zamora Héctor , Velázquez-Ponce Manuel , Campos-Aldrete Elena , Reyes-Arellano Alicia , Pérez-González Cuauhtémoc
Published: August 2012

Background

Imidazo[1,2-a]pyridines and pyrimidines are important organic fluorophores which have been investigated as biomarkers and photochemical sensors. The effect on the luminescent property by substituents in the heterocycle and phenyl rings, have been studied as well. In this investigation, series of 3-hydroxymethyl imidazo[1,2-a]pyridines and pyrimidines were synthesized and evaluated in relation to fluorescence emission, based upon the hypothesis that the hydroxymethyl group may act as an enhancer of fluorescence intensity.

Results

Compounds of both series emitted light in organic solvents dilutions as well as in acidic and alkaline media. Quantitative fluorescence spectroscopy determined that both fused heterocycles fluoresced more intensely than the parent unsubstituted imidazo[1,2-a]azine fluorophore. In particular, 3-hydroxymethyl imidazo[1,2-a]pyridines fluoresced more intensely than 3-hydroxymethyl imidazo[1,2-a]pyrimidines, the latter emitting blue light at longer wavelengths, whereas the former emitted purple light.

Conclusion

It was concluded that in most cases the hydroxymethyl moiety did act as an enhancer of the fluorescence intensity, however, a comparison made with the fluorescence emitted by 2-aryl imidazo[1,2-a]azines revealed that in some cases the hydroxymethyl substituent decreased the fluorescence intensity.
Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial
Authors: Fagermoen Even , Sulheim Dag , Winger Anette , Andersen Anders M , Vethe Nils Tore , Saul J Philip , Thaulow Erik , Wyller Vegard Bruun
Published: August 2012

Background

This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.

Findings

Five adolescent CFS patients (14–19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.

After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.

Conclusion

Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).
Proteinases as virulence factors in Leishmania spp. infection in mammals
Authors: Silva-Almeida Mariana , Pereira Bernardo Acácio Santini , Ribeiro-Guimarães Michelle Lopes , Alves Carlos Roberto
Published: August 2012

Leishmaniaparasites cause human tegumentary and visceral infections that are commonly referred to as leishmaniasis. Despite the high incidence and prevalence of cases, leishmaniasis has been a neglected disease because it mainly affects developing countries. The data obtained from the analysis of patients’ biological samples and from assays with animal models confirm the involvement of an array of the parasite’s components in its survival inside the mammalian host.These components are classified as virulence factors. In this review, we focus on studies that have explored the role of proteinases as virulence factors that promote parasite survival and immune modulation in the mammalian host. Additionally, the direct involvement of proteinases from the host in lesion evolution is analyzed. The gathered data shows that both parasite and host proteinases are involved in the clinical manifestation of leishmaniasis. It is interesting to note that although the majority of the classes of proteinases are present inLeishmaniaspp., only cysteine-proteinases, metalloproteinases and, to a lesser scale, serine-proteinases have been adequately studied. Members from these classes have been implicated in tissue invasion, survival in macrophages and immune modulation by parasites. This review reinforces the importance of the parasite proteinases, which are interesting candidates for new chemo or immunotherapies, in the clinical manifestations of leishmaniasis.
Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols
Authors: Greaves Wesley , Xiao Lianchun , Sanchez-Espiridion Beatriz , Kunkalla Kranthi , Dave Kunal S , Liang Cynthia S , Singh Rajesh R , Younes Anas , Medeiros L Jeffrey , Vega Francisco
Published: August 2012

Background

The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2.

Findings

We analyzed for expression of five ABC transporters ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 using immunohistochemistry in 103 pre-treatment tumor specimens obtained from patients with CHL. All patients received first-line standard chemotherapy with doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens. ABCC1 was expressed in Hodgkin and Reed-Sternberg (HRS) cells in 16 of 82 cases (19.5%) and ABCG2 was expressed by HRS cells in 25 of 77 cases (32.5%). All tumors were negative for ABCB1, ABCC2 and ABCC3. ABCC1 expression was associated with refractory disease (p = 0.01) and was marginally associated with poorer failure-free survival (p = 0.06). Multivariate analysis after adjusting for hemoglobin and albumin levels and age showed that patients with CHL with HRS cells positive for ABCC1 had a higher risk of not responding to treatment (HR = 2.84, 95%, CI: 1.12-7.19 p = 0.028).

Conclusions

Expression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens.
MK3 controls Polycomb target gene expression via negative feedback on ERK
Authors: Prickaerts Peggy , Niessen Hanneke EC , Mouchel-Vielh Emmanuèle , Dahlmans Vivian EH , van den Akker Guus GH , Geijselaers Claudia , Adriaens Michiel E , Spaapen Frank , Takihara Yoshihiro , Rapp Ulf R , Peronnet Frédérique , Voncken Jan Willem
Published: August 2012

Background

Gene-environment interactions are mediated by epigenetic mechanisms. Polycomb Group proteins constitute part of an epigenetic cellular transcriptional memory system that is subject to dynamic modulation during differentiation. Molecular insight in processes that control dynamic chromatin association and dissociation of Polycomb repressive complexes during and beyond development is limited. We recently showed that MK3 interacts with Polycomb repressive complex 1 (PRC1). The functional relevance of this interaction, however, remained poorly understood. MK3 is activated downstream of mitogen- and stress-activated protein kinases (M/SAPKs), all of which fulfill crucial roles during development. We here use activation of the immediate-early response gene ATF3, a bona fide PRC1 target gene, as a model to study how MK3 and its effector kinases MAPK/ERK and SAPK/P38 are involved in regulation of PRC1-dependent ATF3 transcription.

Results

Our current data show that mitogenic signaling through ERK, P38 and MK3 regulates ATF3 expression by PRC1/chromatin dissociation and epigenetic modulation. Mitogenic stimulation results in transient P38-dependent H3S28 phosphorylation and ERK-driven PRC1/chromatin dissociation at PRC1 targets. H3S28 phosphorylation by itself appears not sufficient to induce PRC1/chromatin dissociation, nor ATF3 transcription, as inhibition of MEK/ERK signaling blocks BMI1/chromatin dissociation and ATF3 expression, despite induced H3S28 phosphorylation. In addition, we establish that concomitant loss of local H3K27me3 promoter marking is not required for ATF3 activation. We identify pERK as a novel signaling-induced binding partner of PRC1, and provide evidence that MK3 controls ATF3 expression in cultured cells via negative regulatory feedback on M/SAPKs. Dramatically increased ectopic wing vein formation in the absence of Drosophila MK in a Drosophila ERK gain-of-function wing vein patterning model, supports the existence of MK-mediated negative feedback regulation on pERK.

Conclusion

We here identify and characterize important actors in a PRC1-dependent epigenetic signal/response mechanism, some of which appear to be nonspecific global responses, whereas others provide modular specificity. Our findings provide novel insight into a Polycomb-mediated epigenetic mechanism that dynamically controls gene transcription and support a direct link between PRC1 and cellular responses to changes in the microenvironment.
Active induction of experimental autoimmune encephalomyelitis by MOG35-55 peptide immunization is associated with differential responses in separate compartments of the choroid plexus
Authors: Murugesan Nivetha , Paul Debayon , Lemire Yen , Shrestha Bandana , Ge Shujun , Pachter Joel S
Published: August 2012

Background

There is increasing awareness that, aside from producing cerebrospinal fluid, the choroid plexus (CP) might be a key regulator of immune activity in the central nervous system (CNS) during neuroinflammation. Specifically, the CP has recently been posited to control entry of sentinel T cells into the uninflamed CNS during the early stages of neuroinflammatory diseases, like multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). As the CP is compartmentalized into a stromal core containing fenestrated capillaries devoid of typical blood–brain barrier properties, surrounded by a tight junction-expressing choroidal epithelium, each of these compartments might mount unique responses that instigate the neuroinflammatory process.

Methods

To discern responses of the respective CP stromal capillary and choroidal epithelial tissues during evolving neuroinflammation, we investigated morphology andin situexpression of 93 immune-related genes during early stages of EAE induced by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Specifically, 3-D immunofluorescent imaging was employed to gauge morphological changes, and laser capture microdissection was coupled to anImmune PanelTaqMan Low Density Array to detail alterations in gene expression patterns at these separate CP sites on days 9 and 15 post-immunization (p.i.). To resolve CP effects due to autoimmunity against MOG peptide, from those due to complete Freund’s adjuvant (CFA) and pertussis toxin (PTX) included in the immunization, analysis was performed on MOG-CFA/PTX-treated, CFA/PTX-treated, and naïve cohorts.

Results

The CP became swollen and displayed significant molecular changes in response to MOG-CFA/PTX immunization. Both stromal capillary and choroidal epithelial tissues mounted vigorous, yet different, changes in expression of numerous genes over the time course analyzed - including those encoding adhesion molecules, cytokines, chemokines, statins, interleukins, T cell activation markers, costimulatory molecules, cyclooxygenase, pro-inflammatory transcription factors and pro-apoptotic markers. Moreover, CFA/PTX-treatment, alone, resulted in extensive, though less robust, alterations in both CP compartments.

Conclusions

MOG-CFA/PTX immunization significantly affects CP morphology and stimulates distinct expression patterns of immune-related genes in CP stromal capillary and epithelial tissues during evolving EAE. CFA/PTX treatment, alone, causes widespread gene alterations that could prime the CP to unlock the CNS to T cell infiltration during neuroinflammatory disease.
Primary cilia and aberrant cell signaling in epithelial ovarian cancer
Authors: Egeberg Dorte L , Lethan Mette , Manguso Robert , Schneider Linda , Awan Aashir , Jørgensen Tue S , Byskov Anne G , Pedersen Lotte B , Christensen Søren T
Published: August 2012

Background

Ovarian cancer is the fourth leading cause of cancer-related deaths among women in Denmark, largely due to the advanced stage at diagnosis in most patients. Approximately 90% of ovarian cancers originate from the single-layered ovarian surface epithelium (OSE). Defects in the primary cilium, a solitary sensory organelle in most cells types including OSE, were recently implicated in tumorigenesis, mainly due to deregulation of ciliary signaling pathways such as Hedgehog (Hh) signaling. However, a possible link between primary cilia and epithelial ovarian cancer has not previously been investigated.

Methods

The presence of primary cilia was analyzed in sections of fixed human ovarian tissue as well as in cultures of normal human ovarian surface epithelium (OSE) cells and two human OSE-derived cancer cell lines. We also used immunofluorescence microscopy, western blotting, RT-PCR and siRNA to investigate ciliary signaling pathways in these cells.

Results

We show that ovarian cancer cells display significantly reduced numbers of primary cilia. The reduction in ciliation frequency in these cells was not due to a failure to enter growth arrest, and correlated with persistent centrosomal localization of aurora A kinase (AURA). Further, we demonstrate that ovarian cancer cells have deregulated Hh signaling and platelet-derived growth factor receptor alpha (PDGFRα) expression and that promotion of ciliary formation/stability by AURA siRNA depletion decreases Hh signaling in ovarian cancer cells. Lastly, we show that the tumor suppressor protein and negative regulator of AURA, checkpoint with forkhead-associated and ring finger domains (CHFR), localizes to the centrosome/primary cilium axis.

Conclusions

Our results suggest that primary cilia play a role in maintaining OSE homeostasis and that the low frequency of primary cilia in cancer OSE cells may result in part from over-expression of AURA, leading to aberrant Hh signaling and ovarian tumorigenesis.
Inflammation associated anemia and ferritin as disease markers in SLE
Authors: Vanarsa Kamala , Ye Yujin , Han Jie , Xie Chun , Mohan Chandra , Wu Tianfu
Published: August 2012

Introduction

In a recent screening to detect biomarkers in systemic lupus erythematosus (SLE), expression of the iron storage protein, ferritin, was increased. Given that proteins that regulate the storage, transfer and release of iron play an important role in inflammation, this study aims to determine the serum and urine levels of ferritin and of the iron transfer protein, transferrin, in lupus patients and to correlate these levels with disease activity, inflammatory cytokine levels and markers of anemia.

Methods

A protein array was utilized to measure ferritin expression in the urine and serum of SLE patients and healthy controls. To confirm these results as well as the role of the iron transfer pathway in SLE, ELISAs were performed to measure ferritin and transferrin levels in inactive or active SLE patients and healthy controls. The relationship between ferritin/transferrin levels and inflammatory markers and anemia was next analyzed.

Results

Protein array results showed elevated ferritin levels in the serum and urine of lupus patients as compared to controls, which were further validated by ELISA. Increased ferritin levels correlated with measures of disease activity and anemia as well as inflammatory cytokine titers. Though active SLE patients had elevated urine transferrin, serum transferrin was reduced.

Conclusion

Urine ferritin and transferrin levels are elevated significantly in SLE patients and correlate with disease activity, bolstering previous reports. Most importantly, these changes correlated with the inflammatory state of the patients and anemia of chronic disease. Taken together, altered iron handling, inflammation and anemia of chronic disease constitute an ominous triad in SLE.
Elevated cardiac troponin in the early post-operative period and mortality following ruptured abdominal aortic aneurysm: a retrospective population-based cohort study
Authors: Kopolovic Ilana , Simmonds Kimberley , Duggan Shelley , Ewanchuk Mark , Stollery Daniel E , Bagshaw Sean M
Published: August 2012

Introduction

Cardiac complications are potentially life-threatening following emergency repair of ruptured abdominal aortic aneurysms (rAAA). Our objectives were to describe the incidence, risk factors, cardiac outcomes and mortality associated with elevated cardiac-specific troponin (cTnI) following repair of rAAA. We hypothesized that early post-operative cTnI elevation (>0.15 mcg/L) in rAAA patients would identify a high-risk subgroup for cardiovascular complications and adverse outcomes.

Methods

This was a retrospective population-based cohort study of all referrals for emergency repair of rAAA in central and northern Alberta, from 1 January 2002 to 31 December 2009. Demographic, clinical, physiologic and laboratory data were extracted, along with cardiac-specific investigations and events in the 72 hours following rAAA repair.

Results

In total, 55% of patients (n = 77/141) had elevated cTnI, of which 12% (n = 9) had ST segment elevation, 23% (n = 18) had ST segment depression, 5% (n = 4) had other ECG changes, and 61% (n = 47) had no diagnostic ECG changes. Those with positive cTnI were more likely to have coronary artery disease (45.5% vs. 23.4%, P = 0.01) and higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (24.9 vs. 21.4, n = 0.016). cTnI positive patients were more likely to receive vasoactive support (58.4% vs. 14.1%, P < 0.001), had longer intensive care unit (ICU) lengths of stay (8 (3 to 11) vs. 4 (2 to 9) days, P = 0.02) and higher adjusted in-hospital mortality (40.3% vs. 14.1%; OR 4.23; 95% CI, 1.47 to 12.1; P = 0.007).

Conclusions

Elevated cTnI early after rAAA repair is an independent predictor for post-operative complications and death.