bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of different interferon beta products for relapsing-remitting and secondary progressive multiple sclerosis: Decision analysis based on long-term clinical data and switchable treatments
Authors: Nikfar Shekoufeh , Kebriaeezadeh Abbas , Dinarvand Rassoul , Abdollahi Mohammad , Sahraian Mohammad-Ali , Henry David , Akbari Sari Ali
Published: June 2013

Background

Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs).

Methods

A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF β products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model.

Results

ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913.

Conclusions

The Markov pharmacoeconomics model determined that according to suggested threshold for developing countries by world health organization, all brand INF β products are cost effective in Iran except Avonex. The best strategy among INF β therapies is CBP intramuscular INF β-1a (Cinnovex). Results showed that a policy of encouraging accessibility to CBPs and biosimilars could make even high technology products cost-effective in LMICs.
Grass pollen allergy in children and adolescents‐symptoms, health related quality of life and the value of pollen prognosis
Authors: Kiotseridis Hampus , Cilio Corrado M , Bjermer Leif , Tunsäter Alf , Jacobsson Helene , Dahl Åslög
Published: June 2013

Introduction

An association between pollen count (Poaceae) and symptoms is well known, but to a lesser degree the importance of priming and lag effects. Also, threshold levels for changes in symptom severity need to be validated. The present study aims to investigate the relationship between pollen counts, symptoms and health related quality of life (HRQL), and to validate thresholds levels, useful in public pollen warnings.

Material and methods

Children aged 7–18 with grass pollen allergy filled out a symptom diary during the pollen season for nose, eyes and lung symptoms, as well as a HRQL questionnaire every week. Pollen counts were monitored using a volumetric spore trap.

Results

89 (91%) of the included 98 children completed the study. There was a clear association between pollen count, symptom severity and HRQL during the whole pollen season, but no difference in this respect between early and late pollen season. There was a lag effect of 1–3 days after pollen exposure except for lung symptoms. We found only two threshold levels, at 30 and 80 pollen grains/m3 for the total symptom score, not three as is used today. The nose and eyes reacted to low doses, but for the lung symptoms, symptom strength did hardly change until 50 pollen grains/m3.

Conclusion

Grass pollen has an effect on symptoms and HRQL, lasting up to 5 days after exposure. Symptoms from the lungs appear to have higher threshold levels than the eyes and the nose. Overall symptom severity does not appear to change during the course of season. Threshold levels need to be revised. We suggest a traffic light model for public pollen warnings directed to children, where green signifies “no problem”, yellow signifies “can be problems, especially if you are highly sensitive” and red signifies “alert – take action”.
Technical Advance: Actin CytoFRET, a novel FRET flow cytometry method for detection of actin dynamics in resting and activated T cell
Authors: Larbret Frédéric , Dubois Nicholas , Brau Frédéric , Guillemot Elodie , Mahiddine Karim , Tartare-Deckert Sophie , Verhasselt Valérie , Deckert Marcel
Published: June 2013

Actin cytoskeleton plays a critical role in regulating T cell motility and activation. However, the lack of a real-time quantitative method to analyze actin assembly has limited the progress toward understanding actin regulation. Here, we describe a novel approach to probe actin dynamics on living T cells using FRET combined with flow cytometry. We have first generated a Jurkat T cell line stably coexpressing EGFP and mOrange FPs fused to actin. The real-time variation of actin monomer assembly or disassembly into filaments was quantified using a ratiometric flow cytometry method measuring changes in the mOrange/EGFP emission ratio. The method was validated on resting T cells by using chemical compounds with known effects on actin filaments and comparison with conventional microscopy imaging. Our method also detected the rapid and transient actin assembly in T cells stimulated by anti-CD3/CD28-coated beads, demonstrating its robustness and high sensitivity. Finally, we provide evidence that lentiviral-mediated transduction of shRNAs in engineered Jurkat cells could be used as a strategy to identify regulators of actin remodeling. In conclusion, the flow cytometric FRET analysis of actin polymerization represents a new technical advance to study the dynamics of actin regulation in intact cells.
Modulation of granulocyte kinetics by GM-CSF/IFN-γ in a human LPS rechallenge model
Authors: Kamp Vera M , Leentjens Jenneke , Pillay Janesh , Langereis Jeroen D , de Kleijn Stan , Kox Matthijs , Netea Mihai G , Pickkers Peter , Koenderman Leo
Published: June 2013

Inflammation in response to infection or trauma can lead to CARS, which is characterized by leukocyte dysfunction. In this study, we used a human model system for CARS to study the effect of GM-CSF and IFN-γ treatment on this immunoparalyzed state. Healthy human volunteers were treated with GM-CSF (4 μg/kg), IFN-γ (100 μg), or placebo in between two challenges with Escherichia coli LPS/endotoxin (2 ng/kg). Serial leukocyte blood counts were measured. Neutrophil subsets were discriminated using CD16 and CD62L expression. LPS rechallenge resulted in increased mobilization of mature neutrophils, whereas banded neutrophils decreased. GM-CSF and IFN-γ treatment did not restore these changes. GM-CSF treatment did, however, increase the number of CD16bright/CD62Ldim neutrophils that were previously shown be able to suppress T cell proliferation. IFN-γ treatment decreased neutrophilia seen after LPS rechallenge. Our study shows that LPS rechallenge was associated with changes in the distribution of neutrophil subsets, whereas no additional changes in kinetics of other granulocyte populations were observed. GM-CSF and IFN-γ treatment induced a shift in granulocyte composition toward an anti-inflammatory direction by increasing CD16bright/CD62Ldim cells or decreasing neutrophil counts, respectively.
RIP2 activity in inflammatory disease and implications for novel therapeutics
Authors: Jun Janice C , Cominelli Fabio , Abbott Derek W
Published: June 2013

The role of NOD2 and RIP2 in inflammatory disease has been paradoxical. Whereas loss-of-function NOD2 polymorphisms cause CD, a granulomatous disease of the gastrointestinal tract, gain-of-function mutations cause EOS—a granulomatous disease primarily affecting the skin, joints, and eyes. Thus, gain-of-function mutations and loss-of-function polymorphisms cause granulomatous inflammatory disease, only in different anatomic locations. The situation is complicated further by the fact that WT NOD2 and WT RIP2 activity has been implicated in diseases such as asthma, inflammatory arthritis and MS. This article reviews the role that the NOD2:RIP2 complex plays in inflammatory disease, with an emphasis on the inhibition of this signaling pathway as a novel pharmaceutical target in inflammatory disease.
Mannose receptor and macrophage galactose-type lectin are involved inBordetella pertussismast cell interaction
Authors: Vukman Krisztina V , Ravidà Alessandra , Aldridge Allison M , O'Neill Sandra M
Published: June 2013

Mast cells are crucial in the development of immunity against Bordetella pertussis, and the function of TLRs in this process has been investigated. Here, the interaction between mast cells and B. pertussis with an emphasis on the role of CLRs is examined. In this study, two CLRs, MGL and MR, were detected for the first time on the surface of mast cells. The involvement of MR and MGL in the stimulation of mast cells by heat-inactivated BP was investigated by the use of blocking antibodies and specific carbohydrate ligands. The cell wall LOS of BP was also isolated to explore its role in this interaction. Mast cells stimulated with heat-inactivated BP or BP LOS induced TNF-α, IL-6, and IFN-γ secretion, which was suppressed by blocking MR or MGL. Inhibition of CLRs signaling during BP stimulation affected the ability of mast cells to promote cytokine secretion in T cells but had no effect on the cell-surface expression of ICAM1. Blocking MR or MGL suppressed BP-induced NF-κB expression but not ERK phosphorylation. Syk was involved in the CLR-mediated activation of mast cells by BP. Bacterial recognition by immune cells has been predominantly attributed to TLRs; in this study, the novel role of CLRs in the BP–mast cell interaction is highlighted.
Enhancing the low-frequency amplitude of ground force from a seismic vibrator through reduction of harmonic distortion
Authors: Wei Zhouhong , Phillips Thomas F.
Published: June 2013

Extending the vibroseis bandwidth toward low frequencies (below 10 Hz) can bring many benefits for land seismic exploration such as deeper signal penetration and for near-surface inversion techniques. Due to physical limitations in vibrator mechanical and hydraulic systems, the ground force output from a vibrator at low frequencies is limited. This limited ground force output is severely distorted by harmonic distortion such that the ground force in fundamental frequencies is reduced. We focused on reducing harmonic distortion through vibrator control algorithms to improve vibrator performance at low frequencies. The purpose was to show that with only vibrator control algorithms, the fundamental ground force from a vibrator can be noticeably improved at low frequencies. In addition, we demonstrated a synthetic case using the weighted-sum ground force to simulate slip-sweep acquisition. Presumably, reducing source generated harmonic distortion can help decrease the slip time in slip-sweep operations thereby increasing productivity rates.
Effect of nutrient limitation of cyanobacteria on protease inhibitor production and fitness ofDaphnia magna
Authors: Schwarzenberger Anke , Sadler Thomas , Von Elert Eric
Published: June 2013

Herbivore-plant interactions have been well studied in both terrestrial and aquatic ecosystems as they are crucial for the trophic transfer of energy and matter. In nutrient-rich freshwater ecosystems, the interaction between primary producers and herbivores is to a large extent represented by Daphnia and cyanobacteria. The occurrence of cyanobacterial blooms in lakes and ponds has, at least partly, been attributed to cyanotoxins, which negatively affect the major grazer of planktonic cyanobacteria, i.e. Daphnia. Among these cyanotoxins are the wide-spread protease inhibitors. These inhibitors have been shown (both in vitro and in situ) to inhibit the most important group of digestive proteases in the gut of Daphnia, i.e. trypsins and chymotrypsins, and to reduce Daphnia growth. In this study we grew cultures of the cyanobacterium Microcystis aeruginosa strain BM25 on nutrient replete, N-depleted or P-depleted medium. We identified three different micropeptins to be the cause for the inhibitory activity of BM25 against chymotrypsins. The micropeptin content depended on nutrient availability: Whereas N-limitation led to a lower concentration of micropeptins per biomass, P-limitation resulted in a higher production of these chymotrypsin inhibitors. The altered micropeptin content of BM25 was accompanied by changed effects on the fitness of Daphnia: A higher content of micropeptins led to lower IC50 values for Daphnia gut proteases and vice-versa. Following expectations, the lower content of micropeptins in the N-depleted BM25 caused higher somatic growth of Daphnia. Therefore, protease inhibitors can be regarded as a nutrient-dependent defence against grazers. Interestingly, although the P-limitation of the cyanobacterium led to a higher micropeptin content, high growth of D. magna was observed when they were fed with P-depleted BM25. This might be due to reduced digestibility of P-depleted cells with putatively thick mucilaginous sheaths. These findings indicate that both the grazer and the cyanobacterium benefit from P-reduction in light of digestibility and growth inhibition, which is an interesting starting point for further studies.
Political Economy of Public Policies: Insights from Distortions to Agricultural and Food Markets
Authors: Anderson Kym , Rausser Gordon , Swinnen Johan
Published: June 2013

The agricultural and food sector is an ideal case for investigating the political economy of public policies. Many of the policy developments in this sector since the 1950s have been sudden and transformational, while others have been gradual but persistent. This article reviews and synthesizes the literature on trends and fluctuations in market distortions and the political-economy explanations that have been advanced. Based on a rich global data set covering a half-century of evidence on commodities, countries, and policy instruments, we identify hypotheses that have been explored in the literature on the extent of market distortions and the conditions under which reform may be feasible. (JEL F13, Q11, Q17, Q18)
The nuclear cap-binding complex interacts with the U4/U6·U5 tri-snRNP and promotes spliceosome assembly in mammalian cells
Authors: Pabis Marta , Neufeld Noa , Steiner Michaela C. , Bojic Teodora , Shav-Tal Yaron , Neugebauer Karla M.
Published: June 2013

The nuclear cap-binding complex (CBC) binds to the 7-methyl guanosine cap present on every RNA polymerase II transcript. CBC has been implicated in many aspects of RNA biogenesis; in addition to roles in miRNA biogenesis, nonsense-mediated decay, 3′-end formation, and snRNA export from the nucleus, CBC promotes pre-mRNA splicing. An unresolved question is how CBC participates in splicing. To investigate CBC’s role in splicing, we used mass spectrometry to identify proteins that copurify with mammalian CBC. Numerous components of spliceosomal snRNPs were specifically detected. Among these, three U4/U6·U5 snRNP proteins (hBrr2, hPrp4, and hPrp31) copurified with CBC in an RNA-independent fashion, suggesting that a significant fraction of CBC forms a complex with the U4/U6·U5 snRNP and that the activity of CBC might be associated with snRNP recruitment to pre-mRNA. To test this possibility, CBC was depleted from HeLa cells by RNAi. Chromatin immunoprecipitation and live-cell imaging assays revealed decreased cotranscriptional accumulation of U4/U6·U5 snRNPs on active transcription units, consistent with a requirement for CBC in cotranscriptional spliceosome assembly. Surprisingly, recruitment of U1 and U2 snRNPs was also affected, indicating that RNA-mediated interactions between CBC and snRNPs contribute to splicing. On the other hand, CBC depletion did not impair snRNP biogenesis, ruling out the possibility that decreased snRNP recruitment was due to changes in nuclear snRNP concentration. Taken together, the data support a model whereby CBC promotes pre-mRNA splicing through a network of interactions with and among spliceosomal snRNPs during cotranscriptional spliceosome assembly.
A miRNA-responsive cell-free translation system facilitates isolation of hepatitis C virus miRNP complexes
Authors: Bradrick Shelton S. , Nagyal Simardeep , Novatt Hilary
Published: June 2013

Micro(mi)RNAs are 21- to 23-nt RNAs that regulate multiple biological processes. In association with Argonaute (Ago) proteins and other factors that form the RNA-induced silencing complex (RISC), miRNAs typically bind mRNA 3′ untranslated regions (UTRs) and repress protein production through antagonizing translation and transcript stability. For a given mRNA–miRNA interaction,cis-acting RNA elements andtrans-acting RNA-binding proteins (RBPs) may influence mRNA fate. This is particularly true of the hepatitis C virus (HCV) genome which interacts with miR-122, an abundant liver miRNA. miR-122 binding to HCV RNA considerably stimulates virus replication in cultured cells and primates, but the mechanism(s) and associated host factors required for enhancement of HCV replication have not been fully elucidated. We recapitulated miR-122–HCV RNA interactions in a cell-free translation system derived from cells that express miR-122. Specifically, lysates produced from HEK-293 cells that inducibly transcribe and process pri-miR-122 were characterized alongside those from isogenic cells lacking miR-122 expression. We observed a stimulatory effect of miR-122 on HCV reporter mRNAs in a manner that depended on expression of miR-122 and intact target sites within the HCV 5′ UTR. We took advantage of this system to affinity-purify miR-122-HCV RNP complexes. Similar to functional assays, we found that association of immobilized HCV internal ribosome entry site (IRES) RNA with endogenous Ago2 requires both miR-122 expression and intact miR-122 target sites incis. This combined approach may be generalizable to affinity purification of miRNP complexes for selected target mRNAs, allowing identification of miRNP components and RBPs that may contribute to regulation.
Unexpected expansion of tRNA substrate recognition by the yeast m1G9methyltransferase Trm10
Authors: Swinehart William E. , Henderson Jeremy C. , Jackman Jane E.
Published: June 2013

N-1 Methylation of the nearly invariant purine residue found at position 9 of tRNA is a nucleotide modification found in multiple tRNA species throughout Eukarya and Archaea. First discovered inSaccharomyces cerevisiae, the tRNA methyltransferase Trm10 is a highly conserved protein both necessary and sufficient to catalyze all known instances of m1G9modification in yeast. Although there are 19 unique tRNA species that contain a G at position 9 in yeast, and whose fully modified sequence is known, only 9 of these tRNA species are modified with m1G9in wild-type cells. The elements that allow Trm10 to distinguish between structurally similar tRNA species are not known, and sequences that are shared between all substrate or all nonsubstrate tRNAs have not been identified. Here, we demonstrate that the in vitro methylation activity of yeast Trm10 is not sufficient to explain the observed pattern of modification in vivo, as additional tRNA species are substrates for Trm10 m1G9methyltransferase activity. Similarly, overexpression of Trm10 in yeast yields m1G9containing tRNA species that are ordinarily unmodified in vivo. Thus, yeast Trm10 has a significantly broader tRNA substrate specificity than is suggested by the observed pattern of modification in wild-type yeast. These results may shed light onto the suggested involvement of Trm10 in other pathways in other organisms, particularly in higher eukaryotes that contain up to three different genes with sequence similarity to the singleTRM10gene in yeast, and where these other enzymes have been implicated in pathways beyond tRNA processing.
Enzyme engineering through evolution: Thermostable recombinant group II intron reverse transcriptases provide new tools for RNA research and biotechnology
Authors: Collins Kathleen , Nilsen Timothy W.
Published: June 2013

Current investigation of RNA transcriptomes relies heavily on the use of retroviral reverse transcriptases. It is well known that these enzymes have many limitations because of their intrinsic properties. This commentary highlights the recent biochemical characterization of a new family of reverse transcriptases, those encoded by group II intron retrohoming elements. The novel properties of these enzymes endow them with the potential to revolutionize how we approach RNA analyses.
Education in Public Health major at Polish medical universities in the aspect of the Bologna Process
Authors: Stelmach Włodzimierz , Bąk-Walczak Ewa , Zawadzka Magdalena , Kowalska Alina , Bryła Marek
Published: June 2013

Introduction. This article is a continuation of a review paper called “Bologna Process and education towards public health in Poland”. The Bologna Process is still evolving. Since 2007 two consecutive meetings have taken place: in Leuven/Louvain-la-Neuve, Belgium on 28-29 April 2009 and in Budapest/Vienna on 11-12 March 2010.
Aim. The aim of the work is to analyze the education of students of medical universities (medical academies) towards public health in 2000-2009 in Poland in the light of the Bologna Process guidelines.
Material and methods. Eleven universities were included in the study, all of which had public health majors introduced. The research was carried out from July 2009 to July 2010 using a specially designed survey. Despite numerous reminders, only 8 universities sent back their responses. The results were analyzed descriptively and presented in the form of tables and figures. The values of the analyzed parameters, measured in the nominal scale, were characterized using structure indices.
Results. In the light of the conducted study, it turned out that in Poland till 2007 there had been a dynamic development in education towards public health, whereas in the following years there appeared a slight decreasing tendency in the number of students who chose this subject. It ought to be stressed that majority of the universities included in the study pursue to improve the quality of education according to the recommendations of the Bologna Process. However, alarming is the fact that not all universities take good care of the mobility of their students and employees. Majority of the academic centers perceive the changes introduced by the Bologna Process in higher education system as a positive necessity, at the same time postulating that there is too little information about it in the Polish society in general.
Conclusions. Not all institutions implement the guidelines of education towards public health in the same way. Evidence of that can be a varied offer of specializations and a possibility of pursuing students’ training. Majority of universities in which the survey was carried out made the effort to meet the demands of education by creating an organizational body responsible for introduction and implementation of the guidelines of the Bologna Process.
Selected anti-health behaviors of junior high school students diagnosed with allergic disease
Authors: Bednarek Anna , Emeryk Andrzej , Matuszak Joanna ,   Department of Paediatric Nursing, Faculty of Nursing and Health Sciences, Medical University of Lublin, Poland
Published: June 2013

Introduction. A health risk behavior is characteristic of the period of adolescence, both in healthy adolescents as well as in those with a chronic disease, including allergy. It is associated with looking for their own identity and autonomy, as well as ways to cope with difficulties and stress.

Aim. Identification of some anti-healthy behaviors of ju-nior high school students diagnosed with allergic disease.
Material and methods. The study included a group of 100 junior high school students with diagnosed allergic disease in one of the public schools in Lublin, in 2008. The control group (100 persons) were adolescents from the same school, but without allergies. The research tool was authors’ questionnaire. For the comparison of both groups the statistical program SPSS 14.0 PL was used with the numbers, percentage calculations, and chi squared test of conformity and chi squared test of independence.
Results. The attempts of smoking are confirmed by 38.3% of young people with allergy, and up to 61.3% of boys and 58.2% of girls in the control group. Pressure from peers when trying smoking was an important motivating factor to take these risky health behaviors in all patients with allergy, whereas in healthy young people it concerned 68.1% of boys and 78.0% girls. Similarly, alcohol consumption significantly more often was reported in the control group (87.2% in boys) than in adolescents with allergy (38.1% in girls).
Conclusions. The pressure of peers has a significant impact on the occurrence of anti-health behavior in adolescents with allergic disease. Attempts to health risk behaviors in adolescents with allergies were more frequent in girls than in boys. Anti-health behavior strongly dominated in the control group, but its presence in adolescents with allergic disease may be a greater health risk than in the group of healthy adolescents.
The women`s knowledge about the urinary incontinence and ways of controlling the illness
Authors: Derewiecki Tomasz , Duda Marta , Majcher Piotr , Mroczek Krzysztof
Published: June 2013

Introduction. The urinary incontinence (UI) is considered one of the most often occurring chronic diseases in wo-men. It consists in uncontrolled leakage of urine through the urethra. It concerns 17-60% of the female population.
Aim. The main aim of the present work was to investigate women’s knowledge about the problem of urinary incontinence and its practical application dealing with the problem, what would contribute to improving the quality of life.
Material and methods. There were 101 female patients surveyed from the Zamość Rehabilitation Center of University of Management and Administration. The population was diversified with regard to age, place of living and education. The age of the examined women varied from 30 to 87 years. The research tool used was an author`s questionnaire survey. In the statistical analysis of the results Microsoft Excel program was applied. The significance level was accepted for p<0.05.
Results. For 69.31% respondents it was the embarrassing problem, but for 30.69% it was not. According to 35.64% women the age is the factor which influences UI to the highest degree. Next are the previous pregnancies (27.72%), hard physical labor (12.87%), frequent infections of the urinary tract (11.88%), genetic factors (8.91%), and excess weight (2.97%). The methods of dealing with the problem which respondents list most frequently are: exercises (37.62%),
using of inserts/ sanitary towels (27.72%), pharmacotherapy (13.86%), operation (10.89%), avoiding effort (1.98%), frequent emptying, Botox, limiting consumption of drinks (0.99%).
Conclusions. In the opinion of the investigated women, UI was an embarrassing illness, often concealed, so the availability of information should be easier, both in urban and in rural areas. In both tested groups the respondents stated that UI exerted a negative influence on different spheres of life and on a quality of life, so it should be emphasized here that it is a social-economic problem. The tested women knew different methods of dealing with UI, but they didn`t know about such non-invasive methods as electrotherapy or biofeedback therapy. The women especially exposed to UI were those who were multipara. That is why a thoroughly prepared informing program about UI should be conducted among those women.
Photoinduced charge separation in a PtII acetylide donor–acceptor
triad based on 2-(1-pyrazole)-pyridine modified with naphthalene mono-imide
electron acceptor
Authors: Sazanovich Igor V. , Alamiry Mohammed A. H. , Meijer Anthony J. H. M. , Towrie Michael , Davies E. Stephen , Bennett Robert D. , Weinstein Julia A.
Published: June 2013

A class of molecular electron transfer cascades—those based on PtII
complexes of 2-(1-pyrazole)-pyridine (pzpy) ligands—are reported. The synthesis
of a new electron-acceptor imide-modified pzpy ligands is reported, and their
application to transition-metal chemistry demonstrated by the synthesis of the
PtII chloride and acetylide complexes. These donor–acceptor
assemblies are promising models for investigation of photoinduced charge
separation. Accordingly, picosecond time-resolved infrared (TRIR) and
femtosecond transient absorption (TA) studies have been undertaken to elucidate
the nature and dynamics of the lowest excited states in
Pt(NAP-pyr-pyrazole)(–CC–Ph–C7H15)2. It has
been established that the initial population of an MLL'CT excited state in the
chromophoric [Pt(pyridine-pyrazole)(acetylide)] core is followed by an electron
transfer to the naphthalimide (NAP) acceptor, forming a charge-separated state.
This state is characterized by a large shift in ν(CO) vibrations of the NAP
acceptor, as well as by a very intense and broad [×10 times in comparison to
ν(CO)] asymmetric acetylide stretch which incorporates –CC–Pt–CC– framework and
occurs at approximately 300 cm–1 lower in energy than its
ground-state counterpart. In CH2Cl2 at room temperature,
the charge-separated state with the lifetime of 150 ps collapses into an almost
isoenergetic NAP-localized triplet state; the rate of this transformation
changes upon decreasing the temperature to 263 K. This final excited state,
3NAP-(pyr-pyrazole)Pt(–CC–Ph–C7H15)2,
has an unusually long, for PtII complexes, excited-state lifetime of
tens of microseconds. The work demonstrates the possibility of tuning
excited-state properties in this new class of PtII chromophores
designed for electron-transfer cascades.
Glycemic Control in the 12 Months following a Change to SI Hemoglobin A1c Reporting Units
Authors: Kilpatrick Eric S , Rigby Alan S , Atkin Stephen L , Barth Julian H
Published: June 2013

BACKGROUND

Many countries have implemented, or are considering, a change in hemoglobin A1c (Hb A1c) units from traditional percentage values [Diabetes Control and Complications Trial (DCCT)] to the new Système International d'Unités (SI) unit in millimoles per mole. Concern exists that such a large alteration in numeric values might lead, through confusion, to a deterioration in patients' glycemia. This study has assessed Hb A1c in the year before and after the change of units in a UK diabetes population.

METHODS

The Hb A1c in the 12 months immediately before the unit change (October 2010 to September 2011) was compared with the 12 months after (October 2011 to September 2012). Also, the subsequent change in Hb A1c in patients who had poor glycemic control [Hb A1c >8% (64 mmol/mol)], either before or after the unit change, was compared.

RESULTS

Over the 2 years, 44 721 Hb A1c measurements were requested on 13 197 (7247 male, 5950 female) known diabetes patients. The population Hb A1c was no different between years, with a median [interquartile range (IQR)] value of 7.5% (6.6%–8.7%) after the change and 7.5% (6.5–8.7) before (P = 0.34). The subsequent change in Hb A1c following a raised (>8%) result was the same regardless of whether the initial value reported was in DCCT or SI units [median (IQR) change in Hb A1c −0.2% (−0.9% to 0.3%), n = 4316, following a DCCT result, vs −0.2% (−0.8% to 0.3%), n = 4396, following SI; P = 0.44].

CONCLUSIONS

In this UK diabetes population, a move to SI Hb A1c reporting did not lead to any marked short-term deterioration in glycemia or a different Hb A1c outcome in patients with initial poor glucose control.
From algebraic cobordism to motivic cohomology
Authors: Hoyois Marc
Published: June 2013

Let S be an essentially smooth scheme over a field of characteristic exponent c.
We prove that there is a canonical equivalence of motivic spectra over S
MGL/(a
1,a
2,...)[1/c] ≃ Hℤ[1/c]
where Hℤ is the motivic cohomology spectrum, MGL is the algebraic cobordism spectrum, and the elements an
are generators of the Lazard ring. We discuss several applications including the computation of the slices of ℤ[1/c]-local Landweber exact motivic spectra and the convergence of the associated slice spectral sequences.
Differential effects of GH and GH-releasing peptide-6 on astrocytes
Authors: Baquedano Eva , Chowen Julie A , Argente Jesús , Frago Laura M
Published: June 2013

GH and GH secretagogues (GHSs) are involved in many cellular activities such as stimulation of mitosis, proliferation and differentiation. As astrocytes are involved in developmental and protective functions, our aim was to analyse the effects of GH and GH-releasing hexapeptide on astrocyte proliferation and differentiation in the hypothalamus and hippocampus. Treatment of adult male Wistar rats with GH (i.v., 100 μg/day) for 1 week increased the levels of glial fibrillary acidic protein (GFAP) and decreased the levels of vimentin in the hypothalamus and hippocampus. These changes were not accompanied by increased proliferation. By contrast, GH-releasing hexapeptide (i.v., 150 μg/day) did not affect GFAP levels but increased proliferation in the areas studied. To further study the intracellular mechanisms involved in these effects, we treated C6 astrocytoma cells with GH or GH-releasing hexapeptide and the phosphatidylinositol 3′-kinase (PI3K) inhibitor, LY294002, and observed that the presence of this inhibitor reverted the increase in GFAP levels induced by GH and the proliferation induced by GH-releasing hexapeptide. We conclude that although GH-releasing hexapeptide is a GHS, it may exert GH-independent effects centrally on astrocytes when administered i.v., although the effects of both substances appear to be mediated by the PI3K/Akt pathway.
Phospho-Regulation Pathways During Egg Activation in Drosophila melanogaster
Authors: Krauchunas Amber R , Sackton Katharine L , Wolfner Mariana F
Published: June 2013

Egg activation is the series of events that transition a mature oocyte to an egg capable of supporting embryogenesis. Increasing evidence points toward phosphorylation as a critical regulator of these events. We used Drosophila melanogaster to investigate the relationship between known egg activation genes and phosphorylation changes that occur upon egg activation. Using the phosphorylation states of four proteins—Giant Nuclei, Young Arrest, Spindly, and Vap-33-1—as molecular markers, we showed that the egg activation genes sarah, CanB2, and cortex are required for the phospho-regulation of multiple proteins. We show that an additional egg activation gene, prage, regulates the phosphorylation state of a subset of these proteins. Finally, we show that Sarah and calcineurin are required for the Anaphase Promoting Complex/Cyclosome (APC/C)-dependent degradation of Cortex following egg activation. From these data, we present a model in which Sarah, through the activation of calcineurin, positively regulates the APC/C at the time of egg activation, which leads to a change in phosphorylation state of numerous downstream proteins.
UP-TORR: Online Tool for Accurate and Up-to-Date Annotation of RNAi Reagents
Authors: Hu Yanhui , Roesel Charles , Flockhart Ian , Perkins Lizabeth , Perrimon Norbert , Mohr Stephanie E
Published: June 2013

RNA interference (RNAi) is a widely adopted tool for loss-of-function studies but RNAi results only have biological relevance if the reagents are appropriately mapped to genes. Several groups have designed and generated RNAi reagent libraries for studies in cells or in vivo for Drosophila and other species. At first glance, matching RNAi reagents to genes appears to be a simple problem, as each reagent is typically designed to target a single gene. In practice, however, the reagent–gene relationship is complex. Although the sequences of oligonucleotides used to generate most types of RNAi reagents are static, the reference genome and gene annotations are regularly updated. Thus, at the time a researcher chooses an RNAi reagent or analyzes RNAi data, the most current interpretation of the RNAi reagent–gene relationship, as well as related information regarding specificity (e.g., predicted off-target effects), can be different from the original interpretation. Here, we describe a set of strategies and an accompanying online tool, UP-TORR (for Updated Targets of RNAi Reagents; www.flyrnai.org/up-torr), useful for accurate and up-to-date annotation of cell-based and in vivo RNAi reagents. Importantly, UP-TORR automatically synchronizes with gene annotations daily, retrieving the most current information available, and for Drosophila, also synchronizes with the major reagent collections. Thus, UP-TORR allows users to choose the most appropriate RNAi reagents at the onset of a study, as well as to perform the most appropriate analyses of results of RNAi-based studies.
Genome-Wide Variation of Cytosine Modifications Between European and African Populations and the Implications for Complex Traits
Authors: Moen Erika L , Zhang Xu , Mu Wenbo , Delaney Shannon M , Wing Claudia , McQuade Jennifer , Myers Jamie , Godley Lucy A , Dolan M Eileen , Zhang Wei
Published: June 2013

Elucidating cytosine modification differences between human populations can enhance our understanding of ethnic specificity in complex traits. In this study, cytosine modification levels in 133 HapMap lymphoblastoid cell lines derived from individuals of European or African ancestry were profiled using the Illumina HumanMethylation450 BeadChip. Approximately 13% of the analyzed CpG sites showed differential modification between the two populations at a false discovery rate of 1%. The CpG sites with greater modification levels in European descent were enriched in the proximal regulatory regions, while those greater in African descent were biased toward gene bodies. More than half of the detected population-specific cytosine modifications could be explained primarily by local genetic variation. In addition, a substantial proportion of local modification quantitative trait loci exhibited population-specific effects, suggesting that genetic epistasis and/or genotype × environment interactions could be common. Distinct correlations were observed between gene expression levels and cytosine modifications in proximal regions and gene bodies, suggesting epigenetic regulation of interindividual expression variation. Furthermore, quantitative trait loci associated with population-specific modifications can be colocalized with expression quantitative trait loci and single nucleotide polymorphisms previously identified for complex traits with known racial disparities. Our findings revealed abundant population-specific cytosine modifications and the underlying genetic basis, as well as the relatively independent contribution of genetic and epigenetic variations to population differences in gene expression.
Why Do More Divergent Sequences Produce Smaller Nonsynonymous/Synonymous Rate Ratios in Pairwise Sequence Comparisons?
Authors: dos Reis Mario , Yang Ziheng
Published: June 2013

Several studies have reported a negative correlation between estimates of the nonsynonymous to synonymous rate ratio (ω = dN/dS) and the sequence distance d in pairwise comparisons of the same gene from different species. That is, more divergent sequences produce smaller estimates of ω. Explanations for this negative correlation have included segregating nonsynonymous polymorphisms in closely related species and nonlinear dynamics of the ratio of two random variables. Here we study the statistical properties of the maximum-likelihood estimates of ω and d in pairwise alignments and explore the possibility that the negative correlation can be entirely explained by those properties. We show that the ω estimate is positively biased for small d and that the bias decreases with the increase of d. We also show that the estimates of ω and d are negatively correlated when ω < 1 and positively correlated when ω > 1. However, the bias in estimates of ω and the correlation between estimates of ω and d are not enough to explain the much stronger correlation observed in real data sets. We then explore the behavior of the estimates when the model is misspecified and suggest that the observed correlation may be due to protein-level selection that causes very different amino acids to be favored in different domains of the protein. Widely used models fail to account for such among-site heterogeneity and cause underestimation of the nonsynonymous rate and ω, with the bias being much stronger for distant sequences. We point out that tests of positive selection based on the ω ratio are invariant to the parameterization of the model and thus unaffected by bias in the ω estimates or the correlation between estimates of ω and d.
A DNA Damage Checkpoint Pathway Coordinates the Division of Dikaryotic Cells in the Ink Cap MushroomCoprinopsis cinerea
Authors: de Sena-Tomás Carmen , Navarro-González Mónica , Kües Ursula , Pérez-Martín José
Published: June 2013

The fungal fruiting body or mushroom is a multicellular structure essential for sexual reproduction. It is composed of dikaryotic cells that contain one haploid nucleus from each mating partner sharing the same cytoplasm without undergoing nuclear fusion. In the mushroom, the pileus bears the hymenium, a layer of cells that includes the specialized basidia in which nuclear fusion, meiosis, and sporulation occur. Coprinopsis cinerea is a well-known model fungus used to study developmental processes associated with the formation of the fruiting body. Here we describe that knocking down the expression of Atr1 and Chk1, two kinases shown to be involved in the response to DNA damage in a number of eukaryotic organisms, dramatically impairs the ability to develop fruiting bodies in C. cinerea, as well as other developmental decisions such as sclerotia formation. These developmental defects correlated with the impairment in silenced strains to sustain an appropriated dikaryotic cell cycle. Dikaryotic cells in which chk1 or atr1 genes were silenced displayed a higher level of asynchronous mitosis and as a consequence aberrant cells carrying an unbalanced dose of nuclei. Since fruiting body initiation is dependent on the balanced mating-type regulator doses present in the dikaryon, we believe that the observed developmental defects were a consequence of the impaired cell cycle in the dikaryon. Our results suggest a connection between the DNA damage response cascade, cell cycle regulation, and developmental processes in this fungus.
The Jaw of the Worm: GTPase-activating Protein EAT-17 Regulates Grinder Formation in Caenorhabditis elegans
Authors: Straud Sarah , Lee Inhwan , Song Bomi , Avery Leon , You Young-Jai
Published: June 2013

Constitutive transport of cellular materials is essential for cell survival. Although multiple small GTPase Rab proteins are required for the process, few regulators of Rabs are known. Here we report that EAT-17, a novel GTPase-activating protein (GAP), regulates RAB-6.2 function in grinder formation in Caenorhabditis elegans. We identified EAT-17 as a novel RabGAP that interacts with RAB-6.2, a protein that presumably regulates vesicle trafficking between Golgi, the endoplasmic reticulum, and plasma membrane to form a functional grinder. EAT-17 has a canonical GAP domain that is critical for its function. RNA interference against 25 confirmed and/or predicted RABs in C. elegans shows that RNAi against rab-6.2 produces a phenotype identical to eat-17. A directed yeast two-hybrid screen using EAT-17 as bait and each of the 25 RAB proteins as prey identifies RAB-6.2 as the interacting partner of EAT-17, confirming that RAB-6.2 is a specific substrate of EAT-17. Additionally, deletion mutants of rab-6.2 show grinder defects identical to those of eat-17 loss-of-function mutants, and both RAB-6.2 and EAT-17 are expressed in the terminal bulb of the pharynx where the grinder is located. Collectively, these results suggest that EAT-17 is a specific GTPase-activating protein for RAB-6.2. Based on the conserved function of Rab6 in vesicular transport, we propose that EAT-17 regulates the turnover rate of RAB-6.2 activity in cargo trafficking for grinder formation.
Teaching Interviewing Skills to Pediatric House Officers
Authors: Farsad Parichehr , Galliguez Pilarita , Chamberlin Robert , Roghmann Klaus J.
Published: June 2013

Interviewing skills of 34 pediatric house officers were compared with those of five practicing members of the clinical faculty. Interviews with a programmed mother were videotaped to evaluate physician-patient interaction, data gathering, hypothesis formation and provision of therapy education, reassurance, support, and anticipatory guidance. In addition, eight pediatric interns (PL-1s) were assigned to a study group and five to a control group at the beginning of their outpatient department rotation. The study group received feedback after the videotaped interviews and a 1½-hour didactic session designed to teach interviewing skills. The control group received neither feedback nor the didactic session. Both groups were reevaluated at the end of the outpatient department rotation, again using the video-taped interview technique.

Results showed that data-gathering ability increased significantly; that the focus of attention shifted from a more disease-oriented to a more patient-oriented interview; that data were obtained by means of less direct, less leading questions; and that more support and reassurance were provided as the level of training and experience increased. After the outpatient department rotation, members of both the study group and the control group of PL-ls had improved significantly and approached the proficiency level of practicing pediatricians.
Primary Pediatric Care in One Community
Authors: Mclnerny Thomas K. , Roghmann Klaus J. , Sutherland Sydney A.
Published: June 2013

Primary pediatric practice in one community was studied by using a household interview survey, a pediatrician mail questionnaire, and an ambulatory care survey of nine practices reporting on all visits over a four-week period. The results for the study year 1975 are compared with those for 1971 and 1967.

Pediatricians provided an ever-increasing proportion of ambulatory care. Of all the children who had a regular physician in 1967, only 47% had a pediatrician; by 1975, this proportion had increased to 74%. Well-child care continues to be the largest diagnostic category (30%), followed by treatment for upper respiratory tract infections (24%), otitis media (14%), and lower respiratory tract infections (6%). Variations by practice and patient characteristics are examined.

If the observed changes indicate a nationwide trend, a larger number of pediatricians will be needed to cover their growing share in primary care for children. Working in multiple settings and delegating part of the work load to nurse practitioners have helped to meet the growing demand.
Medical Correlates of Infant Development
Authors: Littman Bruce , Parmelee A. H.
Published: June 2013

Attempts to correlate developmental outcome with medical complications affecting the fetus and infant have focused on the prenatal, intrapartum, and postnatal periods. The time beyond the newborn stage has not been explored in detail. The aim of this study was to relate events occurring during the gestational and neonatal periods as well as the infancy periods to later performance by the use of four medical scales. A total of 126 preterm infants were followed up prospectively from birth to 2 years of age. Medical complications occurring during the prenatal, intrapartum, and postnatal periods as well as the first nine months-of life were recorded. No relationship was found between obstetric and neonatal events and developmental outcome. Significant correlations were seen between medical events of later infancy and development at 2 years of age.