bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Three Elementary Mathematics Programs for Presence of Eight Research-Based Instructional Design Principles
Authors: Doabler Christian T. , Fien Hank , Nelson-Walker Nancy J. , Baker Scott K.
Published: September 2012

The present review builds on earlier research that evaluated the curricular features of core math programs to improve the performances of students with or at risk for mathematics difficulties. In this review, three elementary math programs, at Grades 2 and 4, were evaluated for the presence of eight instructional principles. Math intervention studies have empirically validated these principles for promoting math proficiency of students struggling with mathematics. Data were collected via a researcher-developed scoring rubric. Findings indicate that adherence to the instructional principles varied markedly within and across programs. In addition, the results indicated that the current textbooks contain a general lack of explicit instruction and provide too few practice opportunities to teach material to mastery. Implications for future curricular reviews and enhancing core math instruction are discussed.
Patulin in apple juice and its risk assessments on albino mice
Authors: Al-Hazmi Mansour A
Published: September 2012

The contamination of apple juice with patulin mycotoxin is a major risk factor in food safety. This study focuses to assess the biochemical and histopathological effects of patulin in apple juice samples collected from different outlets retailing in Jeddah, Kingdom of Saudi Arabia. On the basis of the selected dose level, 152.5 ppb patulin/ml was administered daily orally for up to 6 weeks to male albino mice. The exposure to contaminated samples revealed significant elevation of all the studied blood parameters (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities as well as creatinine, urea and uric acid contents). On the other hand, and with regard to the accumulated neuronal toxicity of the tested dose level, the toxic signs were recorded as significant increase in the aggressive and locomotor behavioral changes. In addition, the brain areas monoamines concentration revealed variable increased changes. The potential maximal changes in norepinephrine, dopamine and serotonin5-hydroxytryptamine levels attained in cortex, hypothalamus, striatum, hippocampus, midbrain and pons and medulla were assessed. Moreover, the histological examination revealed degeneration and necrosis in liver tissues and degenerated glomeruli and hemorrhage between the tubules of the cortical region in kidney tissues. The study declared that patulin-contaminated (152.5 ppb) apple juice exhibited liver, kidney and neurotoxicological effects in 6 weeks orally administered mice.
Health hazards associated with nanomaterials
Authors: Pattan Gurulingappa , Kaul Gautam
Published: September 2012

Nanotechnology is a major scientific and economic growth area and presents a variety of hazards for human health and environment. It is widely believed that engineered nanomaterials will be increasingly used in biomedical applications (as therapeutics and as diagnostic tools). However, before these novel materials can be safely applied in a clinical setting, their toxicity needs to be carefully assessed. Nanoscale materials often behave different from the materials with a larger structure, even when the basic material is same. Many mammals get exposed to these nanomaterials, which can reach almost every cell of the mammalian body, causing the cells to respond against nanoparticles (NPs) resulting in cytotoxicity and/or genotoxicity. The important key to understand the toxicity of nanomaterials is that their minute size, smaller than cellular organelles, allows them to penetrate the basic biological structures, disrupting their normal function. There is a wealth of evidence for the noxious and harmful effects of engineered NPs as well as other nanomaterials. The rapid commercialization of nanotechnology field requires thoughtful, attentive environmental, animal and human health safety research and should be an open discussion for broader societal impacts and urgent toxicological oversight action. While ‘nanotoxicity’ is a relatively new concept to science, this comprehensive review focuses on the nanomaterials exposure through the skin, respiratory tract, and gastrointestinal tract and their mechanism of toxicity and effect on various organs of the body.
Expect the Unexpected? Testing for Minimally Counterintuitive (MCI) Bias in the Transmission of Contemporary Legends
Authors: Stubbersfield Joseph , Tehrani Jamshid
Published: September 2012

In this study, we use computational methods for analyzing cultural transmission to examine the role of cognitive selection pressures on the evolution of narratives, the first use of computational phylogenetic analysis in the study of contemporary legends. It has been suggested that a number of biases in transmission may alter the content and structure of narrative so as to maximize how transmittable it is. One bias that has attracted much attention is Boyer’s minimally counterintuitive (MCI) bias, which suggests that a cognitively optimal number of counterintuitive concepts increase the salience and, therefore, the transmission of a narrative. Previous research has used traditional folklore and religious texts to examine this bias and a cognitively optimum number of 1–2 or 2–3 counterintuitive concepts has been suggested. The present research uses the legend of “Bloody Mary,” a contemporary (or urban) legend with MCI elements in a computational phylogenetic analysis to examine the influence of MCI on cultural transmission and evolution. Counterintuitive and intuitive concepts were found to be equally stable in transmission, suggesting that MCI bias may function on the narrative as a whole, rather than individual concepts within it.
Experimental and statistical analysis of cutting force acting on diamond sawblade in sawing of granitic rocks
Authors: Karakurt Izzet , Aydin Gokhan , Aydiner Kerim
Published: September 2012

In this study, sawability analyses of granitic rocks were carried out using segmented circular diamond sawblades. In the experimentations, a computer controlled cutting machine was used and the experiments were performed with the same-direction cutting mode. Effects and contribution of each operating variable (the peripheral speed, workpiece traverse speed, cutting depth and flowrate of cooling fluid) on the cutting force were determined and cutting forces were correlated with rock properties. Moreover, models were built depending on the operating variables and the rock properties (physico-mechanical and mineralogical properties) for the estimation of cutting force. The results indicated that the higher cutting forces were obtained for higher cutting depth and traverse speed and for lower peripheral speed and flowrate of cooling fluid. The most significant operating variable affecting the cutting force was determined as cutting depth. It was concluded that rather than the physico-mechanical properties, mineralogical properties (such as quarts, plagioclase and feldspar content) is the dominant rock properties affecting the cutting force. Results also revealed that the predictive models derived from operating variables and materials properties have high potentials for practical applications.
‘Theory of mind’ III: the unbearable idea of other minds
Authors: Plastow Michael
Published: September 2012

Objective:

In order to give an alternative explanation for the phenomena described by ‘theory of mind’, this topic is approached firstly by an examination of literary productions and then by reference to psychoanalysis.

Conclusions:

In literature there are many references to the apprehension of the other in terms of a mirror image of the self. The difficulty of grasping the other is described in a passage by the author Ian McEwan as ‘the unbearable idea of other minds’. The notion that this difficulty can in part be overcome through both spoken and written language is also salient in the novels examined here. The concept of an entrapment within one’s image of oneself was elaborated by Freud in his notion of narcissism. Lacan further developed this notion as foundational in one’s relation to the other, but clarified that such mirroring relations to others are always imbued with jealousy and rivalry. Lacan’s notion of “paranoid knowledge”, an imagined knowledge of what the other is thinking, is precisely a ‘theory of mind’ that is able to account for the way one subject attempts, and ultimately fails, to read the mind of another.
An exploration of the ability of routine outcome measurement to represent clinically meaningful information regarding individual consumers
Authors: McKay Rod , Coombs Tim
Published: September 2012

Objective:

Evidence that feedback on outcome measures can improve consumer outcomes is building but clinician engagement remains inconsistent. Clinicians can interpret and utilize familiar measures but have difficulty in relating to routine outcome measures like the Health of the Nation Outcomes Scales (HoNOS). This paper aims to explore and illustrate how these measures can represent clinically meaningful information regarding individual consumers.

Method:

Exploration of the aspects of individual clinical states and scenarios that can be represented using the HoNOS and Kessler-10 (K-10) will be used to illustrate their utility in clinical practice.

Results:

Routine outcome measures have the capacity to represent aspects of consumer symptoms, individual functioning and the need for support relevant to clinical care. These measures may be considered using pattern recognition and reflective practice to answer the following questions. Have we adequately assessed the consumer? Is there agreement between the consumer and clinician? Has anything changed?

Conclusions:

While it may be difficult to relate to the total scores on outcome measures, information from within such measures, individual items and subscales can be presented in a manner that is clinically meaningful. Where clinicians are familiar with the measures, this ability is already being used. The challenge is to make it ‘routine’.
Perceived body weight, eating and exercise problems of different groups of women
Authors: Coker Elise , Telfer James , Abraham Suzanne
Published: September 2012

Objective:

To compare prevalence of problems with body weight, eating and exercise (past or present) of female psychiatric inpatients with routine care, gynaecological and obstetric female outpatients, and eating disorder inpatients.

Method:

One thousand and thirty-eight females aged 18–55 years from routine care ( n=99), gynaecological ( n=263) and obstetric ( n=271) outpatient clinics, and eating disorder ( n=223) and general psychiatric units ( n=182) participated. Participants self-reported past or current problems with weight, eating and exercise using a short survey. A sub-sample of women completed the Eating and Exercise Examination (EEE) which includes the Quality of Life for Eating Disorders (QOL ED).

Results:

The prevalence of self-reported problems controlling weight (52%), disordered eating and eating disorders (43%) for the psychiatric patients was significantly greater than for the routine care and gynaecological and obstetrics outpatients. The psychiatric group had a significantly higher mean body mass index (BMI) of 27.3 kg/m2 (standard deviation (SD)=6.7) and prevalence of self-reported obesity (28%) than the other groups.

Conclusion:

Treatment of women with psychiatric problems should include assessment and concurrent attention to body weight, eating disorder and exercise problems in association with appropriate medical, psychiatric, psychological and medication treatment of their presenting disorder.
Clinical Practice Improvement Payments: incentives for delivery of quality care
Authors: Plever Sally , McCarthy Irene , Emmerson Brett , Groves Aaron
Published: September 2012

Objective:

In 2008, Queensland Health mental health services participated in a quality incentive payment scheme referred to as the Clinical Practice Improvement Payment. Services across the state engaged in local improvement projects with the collective aim of improving the number of consumers, diagnosed with schizophrenia, followed up within seven days post discharge. This paper describes the application of this approach over two and a half years.

Method:

Sixteen mental health services across Queensland participated and were provided with the opportunity to receive incentive payments during the period between January 2009 and June 2011. Data collection was conducted using information available on existing Queensland Health databases. Services were provided with regular updates on their progress through a secure intranet site, state-wide forums and individual service presentations, enabling them to compare their individual service data with peer and state data.

Results:

State-wide results showed steady and continual improvement in the indicator over the reporting period.

Conclusions:

The results suggest that the implementation of incentive payments for routine clinical work in mental health can assist with state-wide service improvement. The impact of target setting and supporting activities remains unclear and improvements appeared to be robust to administrative challenges and unexpected external events.
Microencapsulation of conjugated linolenic acid–rich pomegranate seed oil by an emulsion method
Authors: Gupta Surashree Sen , Ghosh Santinath , Maiti Prabir , Ghosh Mahua
Published: September 2012

Controlled release of food ingredients and their protection from oxidation are the key functionality provided by microencapsulation. In the present study, pomegranate seed oil, rich in conjugated linolenic acid, was microencapsulated. As encapsulating agent, sodium alginate or trehalose was used. Calcium caseinate was used as the emulsifier. Performances of the two encapsulants were compared in respect of the rate of release of core material from the microcapsules and stability of microcapsules against harsh conditions. Microencapsulation was carried out by preparation of an emulsion containing calcium caseinate as the emulsion stabilizer and a water-soluble carbohydrate (either sodium alginate or trehalose) as the encapsulant. An oil-in-water emulsion was prepared with pomegranate seed oil as the inner core material. The emulsion was thereby freeze-dried and the dried product pulverized. External morphology of the microcapsules was studied under scanning electron microscope. Micrographs showed that both types of microcapsules had uneven surface morphology. Release rate of the microcapsules was studied using UV-spectrophotometer. Trehalose-based microcapsules showed higher release rate. On subjecting the microcapsules at 110 °C for specific time periods, it was observed that sodium alginate microcapsules retained their original properties. Hence, we can say that sodium alginate microcapsules are more heat resistant than trehalose microcapsules.
Effects of optimized mixtures containing phenolic compounds on the oxidative stability of sausages
Authors: Capitani CD , Hatano MK , Marques MF , Castro IA
Published: September 2012

Phenolic compounds were applied in a sausage formulation as a substitute for artificial sodium erythorbate used as antioxidant. Five assays were prepared in which sodium erythorbate control at 0.05 g/100 g was replaced with a hydrosoluble mixture containing caffeic acid + carnosic acid (47% + 53%) and a liposoluble mixture containing quercetin + rutin (67% + 33%) in two final concentrations (0.05 g/100 g and 0.08 g/100 g). Physico-chemical, color, texture, and sensory parameters were measured on the first day and after 45 days of storage at 4 °C. All phenolic compound mixtures were able to maintain oxidative stability in the sausages when measured by the malondialdehyde concentration, which was expressed as TBARS. The mixture containing quercetin + rutin at 0.05 g/100 g showed lower malondialdehyde formation after 45 days of storage, and no sensory differences from the sausage adopted as control.
Anatomy of the temporomandibular joint in the cat: a study by microdissection, cryosection and vascular injection
Authors: Arredondo Jorge , Agut Amalia , Rodríguez María Jesús , Sarriá Ricardo , Latorre Rafael
Published: September 2012

The minute anatomy of the temporomandibular joint (TMJ) is of great clinical relevance in cats owing to a high number of lesions involving this articulation. However, the precise anatomy is poorly documented in textbooks and scientific articles. The aim of this study was to describe, in detail, the TMJ anatomy and its relationship with other adjacent anatomical structures in the cat. Different anatomical preparations, including vascular and articular injection, microdissection, cryosection and plastination, were performed in 12 cadaveric cats. All TMJ anatomical structures were identified and described in detail. A thorough understanding of the TMJ anatomy is essential to understand the clinical signs associated with TMJ disorders, to locate lesions precisely and to accurately interpret the results in all diagnostic imaging techniques.
Factors Associated with False-Positive Results from Fingerstick OraQuick ADVANCE Rapid HIV 1/2 Antibody Test
Authors: Rifkin Samara B. , Owens Lauren E. , Greenwald Jeffrey L.
Published: September 2012

Objective:

Identify factors associated with false-positive rapid HIV antibody tests.

Design:

This retrospective cohort study with nested case–controls involved patients tested for HIV by Boston Medical Center (BMC) affiliates.

Methods:

Cases had a reactive fingerstick OraQuick ADVANCE rapid HIV 1/2 antibody test and a negative Western blot. Controls had nonreactive rapid tests. We compared the prevalence of HIV risk factors between cases and the total nonreactive population and the prevalence of other clinical factors between cases and controls.

Results:

Of the 15 094 tests, 14 937 (98.9%) were negative and 11 (0.07%) were false positives (specificity of 99.9%). Cases were more likely to have had an HIV-infected sex partner and to be tested at certain sites compared to true negatives. More cases than controls had O-negative blood type.

Conclusion:

O-negative blood type and sex with an HIV-infected person may increase false-positive HIV fingerstick results. More targeted studies should examine these risk factors.
The Validity of the MSCEIT: Additional Analyses and Evidence
Authors: Mayer John D. , Salovey Peter , Caruso David R.
Published: September 2012

We address concerns raised by Maul (2012) regarding the validity of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). We respond to requests for clarifications of our model, and explain why the MSCEIT’s scoring methods stand up to scrutiny and why many reported reliabilities of the MSCEIT may be underestimates, using reanalyses of the test’s standardization sample of N = 5,000 to illustrate our point. We also organize findings from four recent articles that provide evidence for the MSCEIT’s validity based on its relations with other tests.
Definitions Come in Many Kinds: Reply to Comments
Authors: Mulligan Kevin , Scherer Klaus R.
Published: September 2012

We conclude that the commentators seem to fundamentally agree on the substance of our proposal of a partial real definition of emotion as a dynamic episode which has to fulfill a certain number of conditions to count as a member of the class. We raise the issue of prescriptive functions of a definition, suggesting parallels to biomedical ontologies. We also clarify the issues of linguistic and cultural relativity and of differences in the nature of individual emotions.
Bath Concentration of Anionic Contrast Agents Does Not Affect Their Diffusion and Distribution in Articular Cartilage In Vitro
Authors: Silvast Tuomo S. , Jurvelin Jukka S. , Tiitu Virpi , Quinn Thomas M. , Töyräs Juha
Published: September 2012

Objective:

Differences in contrast agent diffusion reflect changes in composition and structure of articular cartilage. However, in clinical application the contrast agent concentration in the joint capsule varies, which may affect the reliability of contrast enhanced cartilage tomography (CECT). In the present study, effects of concentration of x-ray contrast agents on their diffusion and equilibrium distribution in cartilage were investigated.

Design:

Full-thickness cartilage discs ( d = 4.0 mm, n = 120) were detached from bovine patellae ( n = 24). The diffusion of various concentrations of ioxaglate (5, 10, 21, 50 mM) and iodide (30, 60, 126, 300 mM) was allowed only through the articular surface. Samples were imaged with a clinical peripheral quantitative computed tomography scanner before immersion in contrast agent, and after 1, 5, 9, 16, 25, and 29 hours in the bath.

Results:

Diffusion and partition coefficients were similar between different contrast agent concentrations. The diffusion coefficient of iodide (473 ± 133 µm2/s) was greater ( P ≤ 0.001) than that of ioxaglate (92 ± 46 µm2/s). In full-thickness cartilage, the partition coefficient (at 29 h) of iodide (71 ± 5%) was greater ( P ≤ 0.02 with most concentrations) than that of ioxaglate (62 ± 6%).

Conclusions:

Significant differences in partition and diffusion coefficient of two similarly charged (−1) contrast agents were detected, which shows the effect of steric interactions. However, the increase in solute concentration did not increase its partition coefficient. In clinical application, it is important that contrast agent concentration does not affect the interpretation of CECT imaging.
Zinc-finger nuclease-mediated correction of α-thalassemia in iPS cells
Authors: Chang Chan-Jung , Bouhassira Eric E.
Published: September 2012

Induced pluripotent stem (iPS) cell technology holds vast promises for a cure to the hemoglobinopathies. Constructs and methods to safely insert therapeutic genes to correct the genetic defect need to be developed. Site-specific insertion is a very attractive method for gene therapy because the risks of insertional mutagenesis are eliminated provided that a “safe harbor” is identified, and because a single set of validated constructs can be used to correct a large variety of mutations simplifying eventual clinical use. We report here the correction of α-thalassemia major hydrops fetalis in transgene-free iPS cells using zinc finger–mediated insertion of a globin transgene in the AAVS1 site on human chromosome 19. Homozygous insertion of the best of the 4 constructs tested led to complete correction of globin chain imbalance in erythroid cells differentiated from the corrected iPS cells.
The VPS33B-binding protein VPS16B is required in megakaryocyte and platelet α-granule biogenesis
Authors: Urban Denisa , Li Ling , Christensen Hilary , Pluthero Fred G. , Chen Shao Zun , Puhacz Michael , Garg Parvesh M. , Lanka Kiran K. , Cummings James J. , Kramer Helmut , Wasmuth James D. , Parkinson John , Kahr Walter H. A.
Published: September 2012

Patients with platelet α or dense δ-granule defects have bleeding problems. Although several proteins are known to be required for δ-granule development, less is known about α-granule biogenesis. Our previous work showed that the BEACH protein NBEAL2 and the Sec1/Munc18 protein VPS33B are required for α-granule biogenesis. Using a yeast two-hybrid screen, mass spectrometry, coimmunoprecipitation, and bioinformatics studies, we identified VPS16B as a VPS33B-binding protein. Immunoblotting confirmed VPS16B expression in various human tissues and cells including megakaryocytes and platelets, and also in megakaryocytic Dami cells. Characterization of platelets from a patient with arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome containing mutations in C14orf133 encoding VPS16B revealed pale-appearing platelets in blood films and electron microscopy revealed a complete absence of α-granules, whereas δ-granules were observed. Soluble and membrane-bound α-granule proteins were reduced or undetectable, suggesting that both releasable and membrane-bound α-granule constituents were absent. Immunofluorescence microscopy of Dami cells stably expressing GFP-VPS16B revealed that similar to VPS33B, GFP-VPS16B colocalized with markers of the trans-Golgi network, late endosomes and α-granules. We conclude that VPS16B, similar to its binding partner VPS33B, is essential for megakaryocyte and platelet α-granule biogenesis.
A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission
Authors: Vey Norbert , Bourhis Jean-Henri , Boissel Nicolas , Bordessoule Dominique , Prebet Thomas , Charbonnier Aude , Etienne Anne , Andre Pascale , Romagne François , Benson Don , Dombret Herve , Olive Daniel
Published: September 2012

IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIR-mediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenty-three patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. Registered with the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) as 2005-005298-31.
IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4–, MyD88-, and TIRAP- but not UNC-93B–deficient patients
Authors: Weller Sandra , Bonnet Mélanie , Delagreverie Héloïse , Israel Laura , Chrabieh Maya , Maródi László , Rodriguez-Gallego Carlos , Garty Ben-Zion , Roifman Chaim , Issekutz Andrew C. , Zitnik Simona Eva , Hoarau Cyrille , Camcioglu Yildiz , Vasconcelos Júlia , Rodrigo Carlos , Arkwright Peter D. , Cerutti Andrea , Meffre Eric , Zhang Shen-Ying , Alcais Alexandre , Puel Anne , Casanova Jean-Laurent , Picard Capucine , Weill Jean-Claude , Reynaud Claude-Agnès
Published: September 2012

We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel
Authors: Dawood Ban B. , Lowe Gillian C. , Lordkipanidzé Marie , Bem Danai , Daly Martina E. , Makris Mike , Mumford Andrew , Wilde Jonathan T. , Watson Steve P.
Published: September 2012

Light transmission aggregometry (LTA) is used worldwide for the investigation of heritable platelet function disorders (PFDs), but interpretation of results is complicated by the feedback effects of ADP and thromboxane A2 (TxA2) and by the overlap with the response of healthy volunteers. Over 5 years, we have performed lumi-aggregometry on 9 platelet agonists in 111 unrelated research participants with suspected PFDs and in 70 healthy volunteers. Abnormal LTA or ATP secretion test results were identified in 58% of participants. In 84% of these, the patterns of response were consistent with defects in Gi receptor signaling, the TxA2 pathway, and dense granule secretion. Participants with defects in signaling to Gq-coupled receptor agonists and to collagen were also identified. Targeted genotyping identified 3 participants with function-disrupting mutations in the P2Y12 ADP and TxA2 receptors. The results of the present study illustrate that detailed phenotypic analysis using LTA and ATP secretion is a powerful tool for the diagnosis of PFDs. Our data also enable subdivision at the level of platelet-signaling pathways and in some cases to individual receptors. We further demonstrate that most PFDs can be reliably diagnosed using a streamlined panel of key platelet agonists and specified concentrations suitable for testing in most clinical diagnostic laboratories.
High-resolution genotyping and mapping of recombination and gene conversion in the protozoan Theileria parva using whole genome sequencing
Authors: Henson Sonal , Bishop Richard P , Morzaria Subhash , Spooner Paul R , Pelle Roger , Poveda Lucy , Ebeling Martin , Küng Erich , Certa Ulrich , Daubenberger Claudia A , Qi Weihong
Published: September 2012

Background

Theileria parva is a tick-borne protozoan parasite, which causes East Coast Fever, a disease of cattle in sub-Saharan Africa. Like Plasmodium falciparum, the parasite undergoes a transient diploid life-cycle stage in the gut of the arthropod vector, which involves an obligate sexual cycle. As assessed using low-resolution VNTR markers, the crossover (CO) rate in T. parva is relatively high and has been reported to vary across different regions of the genome; non-crossovers (NCOs) and CO-associated gene conversions have not yet been characterised due to the lack of informative markers. To examine all recombination events at high marker resolution, we sequenced the haploid genomes of two parental strains, and two recombinant clones derived from ticks fed on cattle that had been simultaneously co-infected with two different parasite isolates.

Results

By comparing the genome sequences, we were able to genotype over 64 thousand SNP markers with an average spacing of 127 bp in the two progeny clones. Previously unrecognized COs in sub-telomeric regions were detected. About 50% of CO breakpoints were accompanied by gene conversion events. Such a high fraction of COs accompanied by gene conversions demonstrated the contributions of meiotic recombination to the diversity and evolutionary success of T. parva, as the process not only redistributed existing genetic variations, but also altered allelic frequencies. Compared to COs, NCOs were more frequently observed and more uniformly distributed across the genome. In both progeny clones, genomic regions with more SNP markers had a reduced frequency of COs or NCOs, suggesting that the sequence divergence between the parental strains was high enough to adversely affect recombination frequencies. Intra-species polymorphism analysis identified 81 loci as likely to be under selection in the sequenced genomes.

Conclusions

Using whole genome sequencing of two recombinant clones and their parents, we generated maps of COs, NCOs, and CO-associated gene conversion events for T. parva. The data comprises one of the highest-resolution genome-wide analyses of the multiple outcomes of meiotic recombination for this pathogen. The study also demonstrates the usefulness of high throughput sequencing typing for detailed analysis of recombination in organisms in which conventional genetic analysis is technically difficult.
Diagnostic value of urine sCD163 levels for sepsis and relevant acute kidney injury: a prospective study
Authors: Su Longxiang , Feng Lin , Liu Changting , Jiang Zhaoxu , Li Ming , Xiao Kun , Yan Peng , Jia Yanhong , Feng Dan , Xie Lixin
Published: September 2012

Background

Sepsis is a common syndrome in critically ill patients and easily leads to the occurrence of acute kidney injury (AKI), with high mortality rates. This study aimed to investigate the diagnostic value of urine soluble CD163 (sCD163) for identification of sepsis, severity of sepsis, and for secondary AKI, and to assess the patients’ prognosis.

Methods

We enrolled 20 cases with systemic inflammatory response syndrome (SIRS), 40 cases with sepsis (further divided into 17 sepsis cases and 23 severe sepsis cases) admitted to the intensive care unit (ICU), and 20 control cases. Results for urine sCD163 were recorded on the day of admission to the ICU, and AKI occurrence was noted.

Results

On the day of ICU admission, the sepsis group exhibited higher levels of urine sCD163 (74.8 ng/ml; range: 47.9-148.3 ng/ml) compared with those in the SIRS group (31.9 ng/ml; 16.8-48.0, P < 0.001). The area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.72-0.94, P < 0.001) the sensitivity was 0.83, and the specificity was 0.75 (based on a cut-off point of 43.0 ng/ml). Moreover, the severe sepsis group appeared to have a higher level of sCD163 compared with that in the sepsis group (76.2; 47.2-167.5 ng/ml vs. 74.2; 46.2-131.6 ng/ml), but this was not significant. For 15 patients with AKI, urine sCD163 levels at AKI diagnosis were significantly higher than those of the remaining 35 sepsis patients upon ICU admission (121.0; 74.6-299.1 ng/ml vs. 61.8; 42.8-128.3 ng/ml, P = 0.049). The AUC for urine sCD163 was 0.688 (95% CI: 0.51-0.87, P = 0.049). Sepsis patients with a poor prognosis showed a higher urine sCD163 level at ICU admission (98.6; 50.3-275.6 ng/ml vs. 68.0; 44.8-114.5 ng/ml), but this was not significant. Patients with AKI with a poor prognosis had higher sCD163 levels than those in patients with a better prognosis (205.9; 38.6-766.0 ng/ml vs. 80.9; 74.9-141.0 ng/ml), but this was not significant.

Conclusions

This study shows, for the first time, the potential value of urine sCD163 levels for identifying sepsis and diagnosing AKI, as well as for assessment of patients’ prognosis.

Trial Registration

ChiCTR-ONC-10000812
Crystal structure of HutZ, a heme storage protein from Vibrio cholerae: A structural mismatch observed in the region of high sequence conservation
Authors: Liu Xiuhua , Gong Jing , Wei Tiandi , Wang Zhi , Du Qian , Zhu Deyu , Huang Yan , Xu Sujuan , Gu Lichuan
Published: September 2012

Background

HutZ is the sole heme storage protein identified in the pathogenic bacterium Vibrio cholerae and is required for optimal heme utilization. However, no heme oxygenase activity has been observed with this protein. Thus far, HutZ’s structure and heme-binding mechanism are unknown.

Results

We report the first crystal structure of HutZ in a homodimer determined at 2.0 Å resolution. The HutZ structure adopted a typical split-barrel fold. Through a docking study and site-directed mutagenesis, a heme-binding model for the HutZ dimer is proposed. Very interestingly, structural superimposition of HutZ and its homologous protein HugZ, a heme oxygenase from Helicobacter pylori, exhibited a structural mismatch of one amino acid residue in β6 of HutZ, although residues involved in this region are highly conserved in both proteins. Derived homologous models of different single point variants with model evaluations suggested that Pro140 of HutZ, corresponding to Phe215 of HugZ, might have been the main contributor to the structural mismatch. This mismatch initiates more divergent structural characteristics towards their C-terminal regions, which are essential features for the heme-binding of HugZ as a heme oxygenase.

Conclusions

HutZ’s deficiency in heme oxygenase activity might derive from its residue shift relative to the heme oxygenase HugZ. This residue shift also emphasized a limitation of the traditional template selection criterion for homology modeling.
Cyclotron resonance in HgTe/CdTe-based heterostructures in high magnetic fields
Authors: Zholudev Maxim S , Ikonnikov Anton V , Teppe Frederic , Orlita Milan , Maremyanin Kirill V , Spirin Kirill E , Gavrilenko Vladimir I , Knap Wojciech , Dvoretskiy Sergey A , Mihailov Nikolay N
Published: September 2012

Cyclotron resonance study of HgTe/CdTe-based quantum wells with both inverted and normal band structures in quantizing magnetic fields was performed. In semimetallic HgTe quantum wells with inverted band structure, a hole cyclotron resonance line was observed for the first time. In the samples with normal band structure, interband transitions were observed with wide line width due to quantum well width fluctuations. In all samples, impurity-related magnetoabsorption lines were revealed. The obtained results were interpreted within the Kane 8·8 model, the valence band offset of CdTe and HgTe, and the Kane parameter E

P
being adjusted.
Mechanism of cellular uptake of genotoxic silica nanoparticles
Authors: Mu Qingshan , Hondow Nicole S , Krzemiński Łukasz , Brown Andy P , Jeuken Lars JC , Routledge Michael N
Published: September 2012

Mechanisms for cellular uptake of nanoparticles have important implications for nanoparticulate drug delivery and toxicity. We have explored the mechanism of uptake of amorphous silica nanoparticles of 14 nm diameter, which agglomerate in culture medium to hydrodynamic diameters around 500 nm. In HT29, HaCat and A549 cells, cytotoxicity was observed at nanoparticle concentrations ≥ 1 μg/ml, but DNA damage was evident at 0.1 μg/ml and above. Transmission electron microscopy (TEM) combined with energy-dispersive X-ray spectroscopy confirmed entry of the silica particles into A549 cells exposed to 10 μg/ml of nanoparticles. The particles were observed in the cytoplasm but not within membrane bound vesicles or in the nucleus. TEM of cells exposed to nanoparticles at 4°C for 30 minutes showed particles enter cells when activity is low, suggesting a passive mode of entry. Plasma lipid membrane models identified physical interactions between the membrane and the silica NPs. Quartz crystal microbalance experiments on tethered bilayer lipid membrane systems show that the nanoparticles strongly bind to lipid membranes, forming an adherent monolayer on the membrane. Leakage assays on large unilamellar vesicles (400 nm diameter) indicate that binding of the silica NPs transiently disrupts the vesicles which rapidly self-seal. We suggest that an adhesive interaction between silica nanoparticles and lipid membranes could cause passive cellular uptake of the particles.
A case report of para-esophageal bronchogenic cyst with esophageal communication
Authors: Wang Wuping , Ni Yunfeng , Zhang LiWang , Li Xiaofei , Ke Changkang , Lu Qiang , Cheng Qingshu
Published: September 2012

Paraesophageal bronchogenic cyst was one of common mediastinal congenital cystic lesions of foregut origin. Because of an intimate embryologic relationship with the esophagus, they were usually found intramural (intramural esophageal bronchogenic cysts) with the local esophageal mucosa being intact and the paraesophageal bronchogenic cysts were rarely communicated with esophageal lumen. We report a case of para-esophageal bronchogenic cyst communicating to the esophageal lumen thorough a pedicle of canal, which looked liked a diverticulum on X-ray. During the operation, a communication of paraesophageal bronchogenic cyst with esophageal was found and the pathology diagnosis were made then. The symptoms of chest pain and dysphagia were relieved immediately after operation. The follow-up was well 2 years after the surgery.
Daily administration of low molecular weight heparin increases Hepatocyte Growth Factor serum levels in gynaecological patients: pharmacokinetic parameters and clinical implications
Authors: Surbone Anna , Fuso Luca , Passera Roberto , Ferrero Annamaria , Marchese Cristiana , Martino Cosimo , Luchin Annalisa , Di Renzo Maria Flavia , Zola Paolo
Published: September 2012

Background

Hepatocyte Growth Factor (HGF) enhances cytotoxicity of paclitaxel (PTX) and cisplatin (CDDP) in human ovarian cancer cells. Because of potential pitfalls of HGF exogenous administration, we investigated whether HGF serum concentration might be alternatively raised in vivo by administering low molecular weight heparin (LMWH).

Methods

The main HGF pharmacokinetic parameters were evaluated following acute and chronic LMWH treatment. First, women, operated on for gynaecological tumors, were treated with a single dose of calcium nadroparin and studied for 12 hours. Next, women operated on for benign or malignant gynaecological tumors were treated daily with calcic nadroparin for one month. Subsequently, the biological activity of the measured HGF serum levels was tested in assays of ovarian cancer cell sensitization to drugs.

Results

In the short-term treated group, median HGF AUCss, Cmax and Caverage were about four-fold that of the control group, whereas Cmin was three-fold. In the patients treated chronically median HGF serum levels rose about six-fold in the first week, and decreased but remained significantly higher after one month. The pharmacokinetic of nadroparin-dependent HGF increase were similar in the two groups. The HGF concentrations measured after both acute and chronic treatment were found to be effective in sensitising ovarian cancer cells to chemotherapeutics.

Conclusions

This study raises the possibility of using LMWH to increase HGF serum concentration and to take advantage of its biological activities. In particular, nadroparin might be used as a chemo-potentiating agent in epithelial cell ovarian carcinoma through its action on HGF serum concentration.

Trial registration

ClinicalTrials.gov ID: NCT01523652
Circadian Gating of Epithelial-to-Mesenchymal Transition in Breast Cancer Cells Via Melatonin-Regulation of GSK3β
Authors: Mao Lulu , Dauchy Robert T. , Blask David E. , Slakey Lauren M. , Xiang Shulin , Yuan Lin , Dauchy Erin M. , Shan Bin , Brainard George C. , Hanifin John P. , Frasch Tripp , Duplessis Tamika T. , Hill Steven M.
Published: September 2012

Disturbed sleep-wake cycle and circadian rhythmicity are associated with cancer, but the underlying mechanisms are unknown. Employing a tissue-isolated human breast xenograft tumor nude rat model, we observed that glycogen synthase kinase 3β (GSK3β), an enzyme critical in metabolism and cell proliferation/survival, exhibits a circadian rhythm of phosphorylation in human breast tumors. Exposure to light-at-night suppresses the nocturnal pineal melatonin synthesis, disrupting the circadian rhythm of GSK3β phosphorylation. Melatonin activates GSK3β by inhibiting the serine-threonine kinase Akt phosphorylation, inducing β-catenin degradation and inhibiting epithelial-to-mesenchymal transition, a fundamental process underlying cancer metastasis. Thus, chronic circadian disruption by light-at-night via occupational exposure or age-related sleep disturbances may contribute to cancer incidence and the metastatic spread of breast cancer by inhibiting GSK3β activity and driving epithelial-to-mesenchymal transition in breast cancer patients.
Temporal deletion of Arl13b reveals that a mispatterned neural tube corrects cell fate over time
Authors: Su Chen-Ying , Bay Sarah N. , Mariani Laura E. , Hillman Michael J. , Caspary Tamara
Published: September 2012

Cilia are necessary for sonic hedgehog (Shh) signaling, which is required to pattern the neural tube. We know that ventral neural cell fates are defined by a specific cohort of transcription factors that are induced by distinct thresholds of Shh activity mediated by opposing gradients of Gli activator (GliA) and Gli repressor (GliR). Despite this understanding, the role of Shh as an instructive morphogen is viewed as increasingly complex, with current models integrating positive inputs in terms of ligand concentration and time, along with negative feedback via the downstream gene regulatory network. To investigate the relative contributions of the positive and negative inputs from Shh signaling in neural patterning, we took advantage of a protein that uncouples the regulation of GliA and GliR: the cilia protein ADP-ribosylation factor-like 13b (Arl13b). By deleting Arl13b in mouse, we induced low-level constitutive GliA function at specific developmental stages and defined a crucial period prior to E10.5 when shifts in the level of GliA cause cells to change their fate. Strikingly, we found that improperly patterned cells in these mice converted to the wild-type pattern by E12.5. We further showed that the recovery of patterning did not occur when we also deleted Gli3, the primary GliR in the neural tube, revealing a crucial role of Gli3 in the maintenance of neural patterning.
Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling
Authors: Zhang Ling-juan , Bhattacharya Shreya , Leid Mark , Ganguli-Indra Gitali , Indra Arup K.
Published: September 2012

Epidermal morphogenesis results from a delicate balance between keratinocyte proliferation and differentiation, and this balance is perturbed upon deletion of transcription factor Ctip2. Here we demonstrate that Ctip2, in a cell autonomous manner, controls keratinocyte proliferation and cytoskeletal organization, and regulates the onset and maintenance of differentiation in keratinocytes in culture. Ctip2 integrates keratinocyte proliferation and the switch to differentiation by directly and positively regulating EGFR transcription in proliferating cells and Notch1 transcription in differentiating cells. In proliferative cells, the EGFR promoter is occupied by Ctip2, whereas Ctip2 is only recruited to the Notch1 promoter under differentiating conditions. Activation of EGFR signaling downregulates Ctip2 at the transcript level, whereas high calcium signaling triggers SUMOylation, ubiquitination and proteasomal degradation of Ctip2 at the protein level. Together, our findings demonstrate a novel mechanism(s) of Ctip2-mediated, coordinated control of epidermal proliferation and terminal differentiation, and identify a pathway of negative feedback regulation of Ctip2 during epidermal development.