bluuebunny/crossref_metadata_2025_split huggingface dataset:
What predicts enduring intractability in children who appear medically intractable in the first 2 years after diagnosis?
Authors: Wirrell Elaine C. , Wong‐Kisiel Lily C.‐L. , Mandrekar Jay , Nickels Katherine C. 
Published: April 2013

SummaryPurposeIn a population‐based retrospective cohort of children with newly diagnosed epilepsy, to determine (1) what proportion meet criteria for early medical intractability, and (2) predictors of enduring intractability.MethodsChildren with newly diagnosed epilepsy between 1980 and 2009 while resident in Olmsted County, MN, and followed >36 months, were stratified into groups based on both early medical intractability (“apparent” medical intractability in the first 2 years) and enduring intractability (persisting intractability at final follow‐up or having undergone surgery for intractable epilepsy), and variables predicting these outcomes were evaluated.Key FindingsThree hundred eighty‐one children were included, representing 81% of our cohort with newly diagnosed epilepsy. Seventy five (19.7%) had early medical intractability, and predictors of this outcome on multivariable analysis were neuroimaging abnormality (risk ratio, 2.70; p = 0.0004), abnormal neurologic examination at diagnosis (risk ratio, 1.87; p = 0.015), and mode of onset (association was significant for focal vs. generalized onset [risk ratio, 0.25; p < 0.0001] but not unknown vs. generalized onset [p = 0.065]). After a median follow‐up of 11.7 years, 49% remained intractable, 8% had rare seizures (≤ every 6 months), and the remainder were seizure‐free. The only factor predicting enduring intractability on multivariable analysis was neuroimaging abnormality (risk ratio, 7.0; p = 0.0006).SignificanceAlthough a significant minority of children with early medical intractability ultimately achieved seizure control without surgery, those with an abnormal imaging study did poorly. For this subgroup, early surgical intervention is strongly advised to limit comorbidities of ongoing, intractable seizures. Conversely, a cautious approach is suggested for those with normal imaging, as most will remit with time.
Double site saturation mutagenesis of the human cytochrome P450 2D6 results in regioselective steroid hydroxylation
Authors: Geier Martina , Braun Andreas , Fladischer Patrik , Stepniak Piotr , Rudroff Florian , Hametner Christian , Mihovilovic Marko D. , Glieder Anton 
Published: March 2013

The human cytochrome P450 2D6 (CYP2D6) is one of the major human drug metabolizing enzymes and acts preferably on substrates containing a basic nitrogen atom. Testosterone − just as other steroids − is an atypical substrate and only poorly metabolized by CYP2D6. The present study intended to investigate the influence of the two active site residues 216 and 483 on the capability of CYP2D6 to hydroxylate steroids such as for example testosterone. All 400 possible combinatorial mutations at these two positions have been generated and expressed individually in Pichia pastoris. Employing whole‐cell biotransformations coupled with HPLC‐MS analysis the testosterone hydroxylase activity and regioselectivity of every single CYP2D6 variant was determined. Covering the whole sequence space, CYP2D6 variants with improved activity and so far unknown regio‐preference in testosterone hydroxylation were identified. Most intriguingly and in contrast to previous literature reports about mutein F483I, the mutation F483G led to preferred hydroxylation at the 2β‐position, while the slow formation of 6β‐hydroxytestosterone, the main product of wild‐type CYP2D6, was further reduced. Two point mutations have already been sufficient to convert CYP2D6 into a steroid hydroxylase with the highest ever reported testosterone hydroxylation rate for this enzyme, which is of the same order of magnitude as for the conversion of the standard substrate bufuralol by wild‐type CYP2D6. Furthermore, this study is also an example for efficient human CYP engineering in P. pastoris for biocatalytic applications and to study so far unknown pharmacokinetic effects of individual and combined mutations in these key enzymes of the human drug metabolism.
Tolvaptan for improvement of hepatic edema: A phase 3, multicenter, randomized, double‐blind, placebo‐controlled trial
Authors: Sakaida Isao , Kawazoe Seiji , Kajimura Kozo , Saito Takafumi , Okuse Chiaki , Takaguchi Koichi , Okada Mitsuru , Okita Kiwamu ,   ASCITES‐DOUBLEBLIND Study Group
Published: April 2013

AimHepatic edema is manifested by ascites, lower limb edema and intolerable symptoms. Some patients insufficiently respond to the conventional diuretic therapy. Therefore, a novel therapeutic option is required. We conducted a phase 3 study to confirm therapeutic effect of tolvaptan on hepatic edema associated with liver cirrhosis.MethodsIn our multicenter, randomized, double‐blind, placebo‐controlled trial, liver cirrhosis patients who showed insufficient response to conventional diuretics were randomly assigned to 7‐day administration of either tolvaptan at 7.5 mg/day or placebo as an add‐on therapy to conventional diuretics. The primary outcome was change in bodyweight from baseline.ResultsOf 164 eligible patients, 84 were assigned to tolvaptan and 80 to placebo. Change in bodyweight from baseline on the final dosing day was −0.44 kg (standard deviation [SD], 1.93) in the placebo group and −1.95 kg (SD, 1.77) in the tolvaptan group (P < 0.0001). Improvement rates for lower limb edema and ascites‐related clinical symptoms were higher with tolvaptan than with placebo. Even in patients with low serum albumin (<2.5 g/dL), decrease in bodyweight was greater with tolvaptan than with placebo (P = 0.0163). In addition, tolvaptan significantly increased serum sodium concentration from baseline.ConclusionAdd‐on therapy with tolvaptan was effective for the treatment of hepatic edema and ascites‐related clinical symptoms. Furthermore, tolvaptan is expected to improve low serum sodium concentration and to exert its effect regardless of serum albumin level. Add‐on therapy with tolvaptan is therefore considered to be a novel therapeutic option for hepatic edema.
Merger in Higher Education: learning from Experiences
Authors: Drowley Melinda J. , Lewis Duncan , Brooks Simon 
Published: April 2013

AbstractPolitical pressure to reduce the number of higher education institutions in Wales has been sustained for over a decade by three successive ministers for education, two of whom, Jane Davidson and the current incumbent, Leighton Andrews, have left the Welsh sector in no doubt about the strength of their personal commitment to the policy of reconfiguration and collaboration. In this paper, an attempt is made to understand and explain how this policy was experienced by some of the people most closely affected by the recent merger between the Royal Welsh College of Music and Drama and the University of Glamorgan in South East Wales. Some of the lessons learned in this particular context are elucidated in the hope that they might be of assistance to both policy‐makers and members of higher education institutions elsewhere that are contemplating merger.
Immunohistochemistry using the BRAF V600E mutation‐specific monoclonal antibody VE1 is not a useful surrogate for genotyping in colorectal adenocarcinoma
Authors: Adackapara Cheryl A , Sholl Lynette M , Barletta Justine A , Hornick Jason L 
Published: March 2013

AimsThe presence of a BRAF mutation is a strong marker for poor prognosis of colorectal carcinoma (CRC), and can be used as evidence of a sporadic mechanism of mismatch repair deficiency. BRAF mutation may also predict resistance to EGFR‐targeted therapy. A BRAF V600E‐specific antibody has recently become commercially available. The aim of this study was to determine whether immunohistochemistry can predict BRAF mutations in CRC.Methods and resultsImmunohistochemistry was performed on 52 genotyped CRC cases (17 BRAF mutant, 18 KRAS mutant, 17 BRAF/KRAS wild‐type) with monoclonal antibody VE1. Cytoplasmic staining was observed in 71% of BRAF V600E mutant tumours (moderate or strong staining in 50% of these cases). Weak cytoplasmic staining was observed in 17% of KRAS mutant tumours and 35% of wild‐type tumours. Non‐specific nuclear staining was common. The sensitivity and specificity of immunohistochemistry with VE1 for BRAF mutation were 71% and 74%, respectively; when only moderate or strong staining was considered to be positive, the specificity was 100%, but the sensitivity only 35%.ConclusionsImmunohistochemistry with VE1 is not a useful surrogate for genotyping in CRC. Although moderate or strong cytoplasmic staining is specific for BRAF V600E mutations, this antibody is insufficiently sensitive to serve as an effective screening tool.
Structure‐Property Correlation in BaO‐TiO2‐B2O3 Glasses: Glass Stability, Optical, Hydrophobic, and Dielectric Properties
Authors: Paramesh Gadige , Varma Kalidindi B. R. 
Published: April 2013

Glasses in the x(BaO‐TiO2)‐B2O3 (x = 0.25, 0.5, 0.75, and 1 mol.) system were fabricated via the conventional melt‐quenching technique. Thermal stability and glass‐forming ability as determined by differential thermal analysis (DTA) were found to increase with increasing BaO–TiO2 (BT) content. However, there was no noticeable change in the glass transition temperature (Tg). This was attributed to the active participation of TiO2 in the network formation especially at higher BT contents via the conversion of the TiO6 structural units into TiO4 units, which increased the connectivity and resulted in an increase in crystallization temperature. Dielectric and optical properties at room temperature were studied for all the glasses under investigation. Interestingly, these glasses were found to be hydrophobic. The results obtained were correlated with different structural units and their connectivity in the glasses.
Preimplantation genetic diagnosis, an alternative to conventional prenatal diagnosis of the hemoglobinopathies
Authors: Traeger‐Synodinos J. 
Published: April 2013

SummaryPrenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) both represent highly important reproductive choices for couples with a high risk of transmitting a severe disease, such as a severe hemoglobinopathy. Conventional PND for hemoglobinopathies based on molecular analysis of trophoblast or amniocyte DNA has been applied for around 30 years, but the major disadvantages with this approach include ‘invasive’ fetal sampling, and the potential involvement of pregnancy termination when affected. In comparison, the major advantage of PGD over conventional PND is that it supports the initiation of unaffected pregnancies, avoiding the need to terminate affected pregnancies. However, it is a multistep technically demanding procedure requiring the close collaboration of experts from several fields. PGD is also limited by the need to involve assisted reproduction, even in couples without fertility problems. Furthermore, even for fertile couples, pregnancy rates rarely surpass 30–35%. Both PND and PGD have advantages and drawbacks. Before embarking on either procedure, couples should be carefully counseled by experts so that they can select the option most appropriate for them. Finally, whatever their choice, it is paramount that both prenatal and PGD be applied with the highest standards of clinical, laboratory, and ethical practice.
MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer
Authors: Tili Esmerina , Michaille Jean‐Jacques , Croce Carlo M. 
Published: April 2013

SummaryIt is now largely admitted that a pro‐inflammatory environment may curtail anti‐tumor immunity and favor cancer initiation and progression. The discovery that small non‐coding regulatory RNAs, namely microRNAs (miRNAs), regulate all aspects of cell proliferation, differentiation, and function has shed a new light on regulatory mechanisms linking inflammation and cancer. Thus, miRNAs such as miR‐21, miR‐125b, miR‐155, miR‐196, and miR‐210 that are critical for the immune response or hypoxia are often overexpressed in cancers and leukemias. Given the high number of their target transcripts, their deregulation may have a number of deleterious consequences, depending on the cellular context. In this review, we focus on how the factors encoded by transcripts targeted by these five miRNAs, be they transcription factors, tumor‐suppressors, or regulators of different signaling pathways, can deregulate the immune response and favor pro‐tumor immunity. Furthermore, we expose how the misdirected action of the main regulators of these miRNAs, such as nuclear factor κB (NF‐κB), activator protein‐1 (AP‐1), and signal transduction and activators of transcription (STAT) transcription factors, or AKT and transforming growth factor β (TGFβ) signaling pathways, can contribute to decrease anti‐tumor immunity and enhance cell proliferation and oncogenesis. We conclude by briefly discussing about how these discoveries may possibly lead to the development of new miRNA‐based cancer therapies.
Safety and tolerability of a 2009 trivalent inactivated split‐virion influenza vaccine in infants, children and adolescents
Authors: Lambert Stephen B. , Chuk Lai‐man R. , Nissen Michael D. , Nolan Terry M. , McVernon Jodie , Booy Robert , Heron Leon , Richmond Peter C. , Walls Tony , Marshall Helen S. , Reynolds Graham J. , Hartel Gunter F. , Hu Wilson , Lai Michael H. 
Published: April 2013

ObjectiveTo evaluate the safety of CSL's split‐virion inactivated trivalent 2009 Southern Hemisphere formulation influenza vaccine (TIV) in children.MethodsWe enrolled 1992 healthy children into three groups: Cohorts A, ≥6 months to <3 years; B, ≥3 years to <9 years; and C, ≥9 years to <18 years. Children received one or two doses of 0·25 ml (22·5 μg haemagglutinin) or 0·5 ml (45 μg) TIV, depending on age and prior vaccination history. We collected post‐vaccination solicited adverse event (AE) data (days 0–6), including fever (temperature: ≥37·5°C axilla, ≥38·0°C oral), unsolicited AEs (days 0–29) and serious AEs (SAEs) and new‐onset chronic illnesses (NOCIs; to day 180 after last vaccination).ResultsAt least one solicited AE was reported by 80%/78%/78% of children in Cohorts A, B and C, respectively. Systemic AEs were more common among Cohort A (72% of participants), and local AEs were more common among Cohort C (71% of participants). Fever was more common in younger cohorts, in influenza vaccine‐naïve children (29% of Cohort A receiving their first dose), and following first compared with second doses. Severe fever following a first dose prevented 20 participants receiving their second scheduled vaccine dose. A 7‐month‐old participant had a single uncomplicated febrile convulsion on the day of vaccination.ConclusionsNearly 80% of subjects reported at least one solicited AE following immunization. Fever prevalence was highest in vaccine‐naïve Cohort A participants, similar to other paediatric studies using CSL vaccine. Further research to understand fever‐related AEs in children following CSL's TIV is recommended.
Favourable long‐term outcomes with brachytherapy‐based regimens in men ≤60 years with clinically localized prostate cancer
Authors: Kollmeier Marisa A. , Fidaleo Anthony , Pei Xin , Cohen Gil'ad , Zaider Marco , Mo Quincy , Cox Brett , Yamada Yoshiya , Zelefsky Michael J. 
Published: April 2013

What's known on the subject? and What does the study add?
Brachytherapy (BT)‐based treatment for clinically localized prostate cancer is a well‐accepted treatment strategy; however, there is concern that long‐term outcomes and morbidity may not be acceptable in young patients (≤60 years).
We report our long‐term experience with BT in men aged ≤ 60 years with a minimum of 2 years of post‐treatment follow‐up. Our results show low treatment‐related morbidity and excellent long‐term outcomes with BT‐based treatment and suggest that such treatment should be offered to this patient population.
Objective
To report long‐term outcomes of men ≤60 years treated with brachytherapy (BT) for low‐ and intermediate‐risk prostate cancer.
Patients and Methods
Of 1655 patients treated with BT for clinically localized prostate cancer between January 1998 and May 2008 at Memorial Sloan‐Kettering Cancer Center, 236 patients with National Comprehensive Cancer Network low‐ (n = 178) or intermediate‐risk (n = 58) prostate cancer were ≤60 years old with a 3‐year minimum follow‐up, and represent the subjects of this report.
Brachytherapy was given either as monotherapy (n = 169) or with external beam radiation therapy (EBRT; n = 67). Forty‐four patients (19%) received neoadjuvant cytoreductive hormone therapy. The ‘nadir+2’ definition was used for prostate‐specific antigen (PSA) recurrence.
Common Terminology Criteria for Acute Events (CTCAE) v 3.0 was used to grade genitourinary (GU) and gastrointestinal (GI) toxicity. Potency was defined as the ability to obtain an erection suitable for intercourse or an International Index of Erectile Function score ≥ 22.
The Kaplan–Meier method and Cox regression were used for statistical analysis. The median follow‐up was 83 months.
Results
The 8‐year PSA relapse‐free survival (RFS), cancer‐specific and overall survival rates for the entire cohort were 96, 99 and 96%, respectively.
For patients with low‐risk disease, the 8‐year PSA RFS rate was 97% and for intermediate‐risk patients it was 94% (P = 0.34).
There was no difference in PSA RFS between BT alone and combined therapy (P = 0.17). Late grade ≥ 2 GU and GI toxicity was 14 and 3%, respectively.
Of 150 patients potent before treatment, 76 (51%) were potent at last follow‐up, with 50/76 (66%) using no medication.
There was no significant difference in post‐treatment potency between BT alone and BT with EBRT (P = 0.74).
Conclusions
Brachytherapy provides patients aged ≤ 60 years with low‐ and intermediate‐risk prostate cancer with excellent outcomes and has a low risk of significant long‐term GU or GI morbidity.
Erectile function is preserved in >50% of patients and the majority do not require erectile dysfunction medication.
Up‐regulation and activation of the P2Y2 nucleotide receptor mediate neurite extension in IL‐1β‐treated mouse primary cortical neurons
Authors: Peterson Troy S. , Thebeau Christina N. , Ajit Deepa , Camden Jean M. , Woods Lucas T. , Wood W. Gibson , Petris Michael J. , Sun Grace Y. , Erb Laurie , Weisman Gary A. 
Published: March 2013

AbstractThe pro‐inflammatory cytokine interleukin‐1β (IL‐1β), whose levels are elevated in the brain in Alzheimer's and other neurodegenerative diseases, has been shown to have both detrimental and beneficial effects on disease progression. In this article, we demonstrate that incubation of mouse primary cortical neurons (mPCNs) with IL‐1β increases the expression of the P2Y2 nucleotide receptor (P2Y2R) and that activation of the up‐regulated receptor with UTP, a relatively selective agonist of the P2Y2R, increases neurite outgrowth. Consistent with the accepted role of cofilin in the regulation of neurite extension, results indicate that incubation of IL‐1β‐treated mPCNs with UTP increases the phosphorylation of cofilin, a response absent in PCNs isolated from P2Y2R−/− mice. Other findings indicate that function‐blocking anti‐αvβ3/5 integrin antibodies prevent UTP‐induced cofilin activation in IL‐1β‐treated mPCNs, suggesting that established P2Y2R/αvβ3/5 interactions that promote G12‐dependent Rho activation lead to cofilin phosphorylation involved in neurite extension. Cofilin phosphorylation induced by UTP in IL‐1β‐treated mPCNs is also decreased by inhibitors of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), suggesting a role for P2Y2R‐mediated and Gq‐dependent calcium mobilization in neurite outgrowth. Taken together, these studies indicate that up‐regulation of P2Y2Rs in mPCNs under pro‐inflammatory conditions can promote cofilin‐dependent neurite outgrowth, a neuroprotective response that may be a novel pharmacological target in the treatment of neurodegenerative diseases.
Clinical trial recruitment – a complex intervention?
Authors: Tramm Ralph , Daws Karen , Schadewaldt Verena 
Published: April 2013

Aims and objectivesTo discuss the evidence of poor recruitment rates in randomised clinical trials and relate this to existing recruitment methodology before a novel approach to recruitment is suggested.BackgroundRecruitment is crucial to the success of research projects. Effective recruitment leads to effective retention, an increased pool of data and in‐time completion of projects. Robust evidence indicates that recruitment remains a challenge in many clinical trials.DesignDiscursive article.MethodsThe complexity of recruitment is mandated based on the findings from a literature review that summarises common threats to successful recruitment. Nursing theories and models that incorporate recruitment are critically reviewed before recruiting, and its planning is related to existing complex intervention methodology.ConclusionThreats to sufficient recruitment are inherent in the planning of studies, the recruiting process and triadic relationships between institutions, recruiter and participants. Existing nursing theories and models address important recruitment issues but do not account for all aspects that jeopardise sufficient recruitment. Hence, available frameworks for complex intervention planning and evaluation are useful to guide recruitment and its planning as an umbrella methodology.Relevance to clinical practiceUsing complex intervention methodology for recruitment and its planning enhances a nurse researcher's awareness of the challenges and pitfalls recruitment poses and may translate to improved recruitment rates and overall success of clinical trials.
The development and psychometric evaluation of the Chinese version of the maternal attachment inventory
Authors: Chen Chen‐Jung , Sung Huei‐chuan , Chen Yi‐Chang , Chang Ching‐Yuan , Lee Ming‐Shinn 
Published: April 2013

Aims and objectivesTo develop the Maternal Attachment Inventory (MAI) into Chinese and assess its psychometric properties.BackgroundThe MAI measures of maternal affectionate attachment. This scale displays the most appropriate indicators associated with attachment and has been widely adopted in different fields for measuring maternal–infant attachment.DesignCross‐sectional survey design.MethodsThe study was carried out in two clinics. From the accessible population of 507 samples, a simple random sampling method of selection was used to randomly choose 200 names of mothers at 4–8 months after delivery using a computer. One hundred and eighty‐one mothers agreed to participate in the study. The Chinese version of the MAI (CMAI) was developed in five stages: translation, review, back‐translation, a review by a panel of specialists and a pilot test. Regarding the reliability of the CMAI, a test of correlations between the subscales and the entire scale was performed consecutively. With respect to the validity of the MAI, exploratory factor analyses, a test of relationships between items and subscales, and an analysis of concurrent criterion‐related validity were conducted.ResultsThe CMAI contains four factors in its structure. The CMAI and its subscales possess good internal consistency; the Cronbach's α coefficient was 0·94. In addition, the Pearson product‐moment correlation coefficient between the CMAI and the Maternal–Fetal Attachment Inventory (MFAI) and between the CMAI and the Maternal–Infant Attachment Inventory (MIAI) was 0·38 and 0·5, respectively. This suggests significant medium and high respective correlations between the CMAI and these two scales. One major limitation of this study is that participants were recruited from two clinics located in central Taiwan.ConclusionsThe CMAI possesses acceptable reliability and validity for use in measuring the levels of attachment and affectional ties between mothers and their infants.Relevance to clinical practiceThe CMAI provides further evidence of the applicability of the CMAI in clinical maternity care services.