bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemopreventive effect of Korean Angelica root extract on TRAMP carcinogenesis and integrative “omic” profiling of affected neuroendocrine carcinomas
Authors: Zhang Jinhui , Wang Lei , Zhang Yong , Li Li , Tang Suni , Xing Chengguo , Kim Sung‐Hoon , Jiang Cheng , Lü Junxuan
Published: October 2014

Angelica gigas Nakai (AGN) root ethanol extract exerts anti‐cancer activity in several allograft and xenograft models. Here we examined its chemopreventive efficacy through gavage administration against primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Male C57BL/6 TRAMP mice and wild type littermates were given a daily gavage (5 mg/mouse, Monday–Friday) of AGN or vehicle, beginning at 8 wk of age (WOA). All mice were terminated at 24 WOA, unless earlier euthanasia was necessitated by large tumors. Whereas AGN‐treated TRAMP mice decreased dorsolateral prostate lesion growth by 30% (P = 0.009), they developed fewer and smaller neuroendocrine‐carcinomas (NE‐Ca) (0.12 g/mouse) than vehicle‐treated counterparts (0.81 g/mouse, P = 0.037). We analyzed the proteome and transcriptome of banked NE‐Ca to gain molecular insights. Angiogenesis‐antibody array detected a substantial reduction in AGN‐treated NE‐Ca of basic fibroblast growth factor (FGF2), an angiogenesis stimulator. iTRAQ proteomics plus data mining suggested changes of genes upstream and downstream of FGF2 functionally consistent with AGN inhibiting FGF2/FGFR1 signaling at different levels of the transduction cascade. Moreover, AGN upregulated mRNA of genes related to immune responses, restored expression of many tumor suppressor genes, and prostate function and muscle differentiation genes. On the other hand, AGN down‐regulated mRNA of genes related to neuron signaling, oncofetal antigens, inflammation, and mast cells, Wnt signaling, embryonic morphogenesis, biosynthesis, cell adhesion, motility, invasion, and angiogenesis. These changes suggest not only multiple cancer cell targeting actions of AGN but also impact on the tumor microenvironments such as angiogenesis, inflammation, and immune surveillance. © 2014 Wiley Periodicals, Inc.
Fast iterative algorithm for the reconstruction of multishot non‐cartesian diffusion data
Authors: Mani Merry , Jacob Mathews , Magnotta Vincent , Zhong Jianhui
Published: October 2014

Purpose

To accelerate the motion‐compensated iterative reconstruction of multishot non‐Cartesian diffusion data.

Method

The motion‐compensated recovery of multishot non‐Cartesian diffusion data is often performed using a modified iterative sensitivity‐encoded algorithm. Specifically, the encoding matrix is replaced with a combination of nonuniform Fourier transforms and composite sensitivity functions, which account for the motion‐induced phase errors. The main challenge with this scheme is the significantly increased computational complexity, which is directly related to the total number of composite sensitivity functions (number of shots × number of coils). The dimensionality of the composite sensitivity functions and hence the number of Fourier transforms within each iteration is reduced using a principal component analysis‐based scheme. Using a Toeplitz‐based conjugate gradient approach in combination with an augmented Lagrangian optimization scheme, a fast algorithm is proposed for the sparse recovery of diffusion data.

Results

The proposed simplifications considerably reduce the computation time, especially in the recovery of diffusion data from under‐sampled reconstructions using sparse optimization. By choosing appropriate number of basis functions to approximate the composite sensitivities, faster reconstruction (close to 9 times) with effective motion compensation is achieved.

Conclusion

The proposed enhancements can offer fast motion‐compensated reconstruction of multishot diffusion data for arbitrary k‐space trajectories. Magn Reson Med 74:1086–1094, 2015. © 2014 Wiley Periodicals, Inc.
Accelerated three‐dimensional cine phase contrast imaging using randomly undersampled echo planar imaging with compressed sensing reconstruction
Authors: Basha Tamer A. , Akçakaya Mehmet , Goddu Beth , Berg Sophie , Nezafat Reza
Published: October 2014

The aim of this study was to implement and evaluate an accelerated three‐dimensional (3D) cine phase contrast MRI sequence by combining a randomly sampled 3D k‐space acquisition sequence with an echo planar imaging (EPI) readout. An accelerated 3D cine phase contrast MRI sequence was implemented by combining EPI readout with randomly undersampled 3D k‐space data suitable for compressed sensing (CS) reconstruction. The undersampled data were then reconstructed using low‐dimensional structural self‐learning and thresholding (LOST). 3D phase contrast MRI was acquired in 11 healthy adults using an overall acceleration of 7 (EPI factor of 3 and CS rate of 3). For comparison, a single two‐dimensional (2D) cine phase contrast scan was also performed with sensitivity encoding (SENSE) rate 2 and approximately at the level of the pulmonary artery bifurcation. The stroke volume and mean velocity in both the ascending and descending aorta were measured and compared between two sequences using Bland–Altman plots. An average scan time of 3 min and 30 s, corresponding to an acceleration rate of 7, was achieved for 3D cine phase contrast scan with one direction flow encoding, voxel size of 2 × 2 × 3 mm3, foot–head coverage of 6 cm and temporal resolution of 30 ms. The mean velocity and stroke volume in both the ascending and descending aorta were statistically equivalent between the proposed 3D sequence and the standard 2D cine phase contrast sequence. The combination of EPI with a randomly undersampled 3D k‐space sampling sequence using LOST reconstruction allows a seven‐fold reduction in scan time of 3D cine phase contrast MRI without compromising blood flow quantification. Copyright © 2014 John Wiley & Sons, Ltd.
Symptom Distress Profiles in Hospitalized Patients in Sweden: A Cross‐Sectional Study
Authors: Henoch Ingela , Sawatzky Richard , Falk Hanna , Fridh Isabell , Jakobsson Ung Eva , Sarenmalm Elisabeth Kenne , Ozanne Anneli , Öhlén Joakim , Falk Kristin
Published: October 2014

Symptom distress profiles of patients with a variety of diagnoses at two hospitals in Sweden were examined using a point‐prevalence cross‐sectional survey design. The sample included 710 patients present on internal medicine, surgery, geriatric, and oncology acute care hospital wards of each hospital on a single day. Symptom distress data were collected via structured interviews using a 0–10 numeric rating scale (NRS). Fatigue was the most prevalent symptom, experienced by 76.2% of the patients, followed by pain (65.2%) and sleeping difficulties (52.8%). Symptoms were fairly distressing (median NRS 5–6). Patients experiencing high distress from fatigue and pain were more likely to be female, living alone, and to have more symptoms. Latent class analysis revealed three symptom distress profiles that differed with respect to the degree of distress and number of symptoms. The profiles were not substantially differentiated by diagnoses. Symptom distress needs to be assessed and treated on an individual basis, rather than predicting distress levels based on diagnosis alone. © 2014 Wiley Periodicals, Inc.
Increase in visceral fat per se does not induce insulin resistance in the canine model
Authors: Castro Ana V.B. , Woolcott Orison O. , Iyer Malini S. , Kabir Morvarid , Ionut Viorica , Stefanovski Darko , Kolka Cathryn M. , Szczepaniak Lidia S. , Szczepaniak Edward W. , Asare‐Bediako Isaac , Paszkiewicz Rebecca L. , Broussard Josiane L. , Kim Stella P. , Kirkman Erlinda L. , Rios Hernan C. , Mkrtchyan Hasmik , Wu Qiang , Ader Marilyn , Bergman Richard N.
Published: October 2014

Objectives

To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance.

Methods

Sympathetic denervation of the omental fat was performed under general inhalant anesthesia by injecting 6‐hydroxydopamine in the omental fat of lean mongrel dogs (n = 11). In the conscious animal, whole‐body insulin sensitivity was assessed by the minimal model (SI) and the euglycemic hyperinsulinemic clamp (SICLAMP). Changes in abdominal fat were monitored by magnetic resonance. All assessments were determined before (Wk0) and 2 weeks (Wk2) after denervation. Data are medians (upper and lower interquartile).

Results

Denervation of omental fat resulted in increased percentage (and content) of visceral fat [Wk0: 10.2% (8.5‐11.4); Wk2: 12.4% (10.4‐13.6); P < 0.01]. Abdominal subcutaneous fat remained unchanged. However, no changes were found in SI [Wk0: 4.7 (mU/l)−1 min−1 (3.1‐8.8); Wk2: 5.3 (mU/l)−1 min−1 (4.5‐7.2); P = 0.59] or SICLAMP [Wk0: 42.0 × 10−4 dl kg−1 min−1 (mU/l)−1 (41.0‐51.0); Wk2: 40.0 × 10−4 dl kg−1 min−1 (mU/l) −1 (34.0‐52.0); P = 0.67].

Conclusions

Despite a selective increase in visceral adiposity in dogs, insulin sensitivity in vivo did not change, which argues against the concept that accumulation of visceral adipose tissue contributes to insulin resistance.
Elevated secreted frizzled‐related protein 4 in obesity: A potential role in adipose tissue dysfunction
Authors: Garufi Gabriella , Seyhan Attila A. , Pasarica Magdalena
Published: October 2014

Objectives

Rarefaction and inflammation of adipose tissue contributes to insulin resistance in obesity. It was hypothesized that angiostatic secreted frizzled‐related protein 4 (SFRP4) causes adipose tissue rarefaction and leads to inflammation and ultimately insulin resistance in obese patients.

Methods

Abdominal subcutaneous adipose tissue (AbdAT), gluteal subcutaneous adipose tissue (GlutAT), and blood from 15 lean and obese subjects were collected. Circulating‐SFRP4 was measured by ELISA. Body composition was measured by DEXA and insulin sensitivity by the euglycemic hyperinsulinemic clamp. Adipose tissue was analyzed using qRT‐PCR for mRNA gene expression, Luminex system for tissue cytokine release, immunohistochemistry for labeling adipose capillaries, and osmium fixation and Coulter counting for adipocyte sizing.

Results

Circulating‐SFRP4 was higher in obese vs. lean subjects (137.8 ± 33.6 ng ml−1 vs. 64.1 ± 23.8 ng ml−1, P < 0.05). Circulating‐SFRP4 significantly (P < 0.05) correlated with body fat percentage (R = 0.07), body mass index (R = 0.07), insulin sensitivity (R = −0.66). Circulating‐SFRP4 correlated with AbdAT‐VEGF (R = −0.67, P < 0.05), AbdAT‐capillary density (R = −0.65, P < 0.05), secreted‐MIP1α (R = 0.74), and AbdAT‐SFRP4 mRNA (R = 0.60). AbdAT‐SFRP4 mRNA significantly correlated with AbdAT‐capillary density (R = 0.71, P < 0.05), but not with AbdAT mean adipocyte size. There was no difference between AbdAT‐SFRP4 and GlutAT‐SFRP4 mRNA. Interestingly, GlutAT‐SFRP4 correlated with AbdAT mean adipocyte size (P < 0.05).

Conclusions

The results suggested that AbdAT is a major contributor for circulating‐SFRP4 and that SFRP4 has an important role in obese adipose tissue pathophysiology.
Shared decision making for hydroxyurea treatment initiation in children with sickle cell anemia
Authors: Crosby Lori E. , Shook Lisa M. , Ware Russell E. , Brinkman William B.
Published: October 2014

Clinical trials have demonstrated hydroxyurea's efficacy in improving health outcomes for children with sickle cell anemia (SCA) who have medical complications. New NHLBI clinical guidelines will recommend offering hydroxyurea to young patients regardless of clinical severity. Shared decision making may be an effective approach for implementing this practice change. Decision aids that help patients/parents feel empowered to make this decision and help providers feel comfortable in discussing hydroxyurea as a preventive treatment may facilitate shared discussions between families and providers. We recommend six strategies providers can use to facilitate these discussions while decision aids and tools are being developed. Pediatr Blood Cancer 2015;62:184–185. © 2014 Wiley Periodicals, Inc.
Treatment and outcomes of immune cytopenias following solid organ transplant in children
Authors: Schoettler Michelle , Elisofon Scott A. , Kim Heung Bae , Blume Elizabeth D. , Rodig Nancy , Boyer Debra , Neufeld Ellis J. , Grace Rachael F.
Published: October 2014

Background

Immune cytopenias are a recognized life‐threatening complication following pediatric solid organ transplants (SOT), but treatment responses and overall outcome are not well described. The aim of this study was to evaluate the demographic characteristics, response to treatments, and outcomes of a cohort of patients who developed immune cytopenias following SOT.

Procedure

In this single center retrospective review, patients with immune cytopenias after SOT were identified by electronic medical record (EMR) search and transplant databases from 1995–2012.

Results

Of 764 SOT patients, 19 (2.4%) developed immune cytopenias. Incidence varied widely by transplant type from 1.2% (renal) to 23.5% (multivisceral). Autoimmune hemolytic anemia (AIHA) was the most common immune cytopenia. Overall median time from transplant to immune cytopenia was 8 m and varied by transplant type from 3 m (liver) to 74 m (heart). Standard therapies for immune cytopenias were often used and ineffective. The most effective therapy for the immune cytopenia was changing immunosuppression from tacrolimus to another agent. Three of 19 patients died; none directly attributed to the immune cytopenia.

Conclusions

Immune cytopenias are not rare after SOT, and patients usually do not respond well to traditional first line therapies. Provided that the risk of organ rejection is otherwise manageable, temporary cessation of tacrolimus could be more widely explored in this challenging clinical context. Pediatr Blood Cancer 2015;62:214–218. © 2014 Wiley Periodicals, Inc.
Successful treatment of kaposiform hemangioendothelioma with everolimus
Authors: Uno Teruaki , Ito Shuichi , Nakazawa Atsuko , Miyazaki Osamu , Mori Tetsuya , Terashima Keita
Published: October 2014

There is currently no consensus on the second‐line management of Kaposiform hemangioendothelioma (KHE) that was resistant to prednisolone and vincristine. We described an eight‐year‐old male with KHE in the right femur that was resistant to prednisolone, vincristine and propranolol. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) at the dosage of 0.1 mg/kg/day, successfully decreased the tumor size and controlled the symptoms. Everolimus should be further studied as an alternative agent to sirolimus in the management of KHE. Pediatr Blood Cancer 2015;62:536–538. © 2014 Wiley Periodicals, Inc.
Comparison of continuous and twice‐daily infusions of cyclosporine A for graft‐versus‐host‐disease prophylaxis in pediatric hematopoietic stem cell transplantation
Authors: Umeda Katsutsugu , Adachi Souichi , Tanaka Shiro , Ogawa Atsushi , Hatakeyama Naoki , Kudo Kazuko , Sakata Naoki , Igarashi Shunji , Ohshima Kumi , Hyakuna Nobuyuki , Chin Motoaki , Goto Hiroaki , Takahashi Yoshiyuki , Azuma Eiichi , Koh Katsuyoshi , Sawada Akihisa , Kato Koji , Inoue Masami , Atsuta Yoshiko , Takami Akiyoshi , Murata Makoto ,   on behalf of the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation
Published: October 2014

Background

Cyclosporine A (CsA) is used widely for graft‐versus‐host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation (HSCT); however, the optimal schedule of its administration has not been established. Although comparative studies of adult patients undergoing HSCT have demonstrated enhanced efficacy and safety of twice‐daily infusion (TD) compared with continuous infusion (CIF) of CsA, to our knowledge, similar studies have not yet been performed in pediatric groups.

Procedure

A self‐administered questionnaire was used to retrospectively compare the clinical outcome and incidence of CsA‐associated adverse events of 70 pediatric acute myelogenous leukemia patients who were receiving CsA by TD (n = 36) or CIF (n = 34) as GVHD prophylaxis for their first allogeneic HSCT.

Results

The cumulative incidences of grade II–IV acute GVHD and chronic GVHD, as well as the overall survival and event‐free survival rates, did not differ significantly between the TD and CIF groups; however, the incidence of severe hypertension was significantly higher in the CIF group than the TD group.

Conclusions

The analysis presented here indicates that TD and CIF administration of CsA have similar prophylactic effect on pediatric GVHD and suggest that TD is associated with a lower rate of toxicity than CIF in pediatric patients undergoing HSCT. Pediatr Blood Cancer 2015;62:291–298. © 2014 Wiley Periodicals, Inc.
Humanism and professionalism education for pediatric hematology‐oncology fellows: A model for pediatric subspecialty training
Authors: Kesselheim Jennifer C. , Atlas Mark , Adams Denise , Aygun Banu , Barfield Ray , Eisenman Kristen , Fulbright Joy , Garvey Katharine , Kersun Leslie , Nageswara Rao Amulya , Reilly Anne , Sharma Mukta , Shereck Evan , Wang Michael , Watt Tanya , Leavey Patrick
Published: October 2014

Background

Humanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence‐based approach for teaching and evaluation. Pediatric hematology‐oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training.

Procedure

We electronically surveyed a national sample of PHO fellows to identify fellows' educational needs in humanism and professionalism. Next, we developed a case‐based, faculty‐facilitated discussion curriculum to teach this content within pilot fellowship programs. We assessed whether fellowships would decide to offer the curriculum, feasibility of administering the curriculum, and satisfaction of fellow and faculty participants.

Results

Surveys were completed by 187 fellows (35%). A minority (29%) reported that their training program offers a formal curriculum in humanism and/or professionalism. A majority desires more formal teaching on balancing clinical practice and research (85%), coping with death/dying (85%), bereavement (78%), balancing work and personal life (75%), navigating challenging relationships with patients (74%), and depression/burn out (71%). These six topics were condensed into four case‐based modules, which proved feasible to deliver at all pilot sites. Ten fellowship programs agreed to administer the novel curriculum. The majority (90%) of responding fellows and faculty reported the sessions touched on issues important for training, stimulated reflective communication, and were valuable.

Conclusions

Pediatric hematology‐oncology fellows identify numerous gaps in their training related to humanism and professionalism. This curriculum offers an opportunity to systematically address these educational needs and can serve as a model for wider implementation. Pediatr Blood Cancer 2015;62:335–340. © 2014 Wiley Periodicals, Inc.
Kaposiform lymphangiomatosis: Unifying features of a heterogeneous disorder
Authors: Fernandes Violet M. , Fargo John H. , Saini Surbhi , Guerrera Michael F. , Marcus Leigh , Luchtman‐Jones Lori , Adams Denise , Meier Emily Riehm
Published: October 2014

Kaposiform lymphangiomatosis (KLA) is a rare proliferation of abnormal lymphatic vessels often complicated by pleural/pericardial effusions and a consumptive coagulopathy that may lead to life threatening hemorrhage. Establishing the diagnosis is challenging due to the clinical heterogeneity and variable findings in laboratory values, radiographic features, and pathologic characteristics. We report three patients who had slowly progressive symptoms and presented with pleural or pericardial effusions, evidence of a consumptive coagulopathy and anemia. Despite being a rare and challenging diagnosis, KLA should be considered in patients presenting with non‐specific indolent symptoms, pleural or pericardial effusions and laboratory evidence of a consumptive coagulopathy. Pediatr Blood Cancer 2015;62:901–904. © 2014 Wiley Periodicals, Inc.
Evaluating diabetes integrated care pathways
Authors: Grant Paul , Chika‐Ezerioha Ifyunaya
Published: October 2014

The delivery of chronic disease care within new models of integration is an increasing reality. Currently, there is no clear evidence that community or tiered systems of care delivery are superior to existing diabetes services in terms of hard outcomes; however, it is apparent that they offer other potential benefits that can enhance the system of care. Examples include better communication between primary and secondary care, shared IT to enable clearer care planning and greater user satisfaction.

Integrated care pathways (ICPs) are tools designed to ensure that the system of care is functioning and incorporates all the relevant factors necessary for good care, and that evaluation of the system itself can be reviewed – as a form of performance management. This article looks at how in practice we can monitor, measure and learn from ICPs. Copyright © 2014 John Wiley & Sons, Ltd.
Observations on age at diagnosis of type 1 diabetes and family history in a small population: the Winchester cohort
Authors: Brooks AP , Li Voon Chong JSW
Published: October 2014

Clinical and demographic data from the records of 694 white Caucasian patients with type 1 diabetes attending a secondary care diabetes clinic between 1983 and 2010 have been audited to give information on age at diagnosis of type 1 diabetes and frequency of a family history of diabetes in their first degree relatives over five chronological decades between 1961 and 2010.

All patients in the cohort lived in 12 postcode areas (six urban and six rural) in west Hampshire, and, although ascertainment is thought to be at least 90%, the exact at‐risk populations are not accurately known, so no incidence nor prevalence figures can be given.

Mean age at diagnosis rose from 18.5 years in the decade 1961–70 to 26.7 years in 1991–2000, falling again to 21.9 in 2001–10. The ranges of ages at diagnosis were 0.7–53.5 years in the decade 1961–70, and 0.7–73.1 in the decade 1991–2000. Sixty‐three of the 694 patients (9.1%) were diagnosed over the age of 45 years. This is important in the initial management of people presenting with new‐onset diabetes at any age and for screening programmes to consider. Eighty‐eight patients had a first degree relative with diagnosed diabetes, giving an overall risk of 1 in 8 (12.7%). Possible genetic mechanisms operating in this group, and their investigation, are put forward on a hypothetical basis. Copyright © 2014 John Wiley & Sons, Ltd.
A simple method for introducing care planning into specialist diabetes clinics. The WICKED project
Authors: Gillani SMR , Singh BM
Published: October 2014

Diabetes care planning is a systematic way of establishing a partnership between people with diabetes and health care services. We piloted a systematic patient‐driven care planning consultation process in our routine specialist diabetes clinics.

A document based on all key care processes was given to and completed by patients prior to their consultation. The completed document was used to structure the clinic consultation. Patient and doctor outcomes were assessed by post consultation questionnaires.

Of 148 patients, 101 responded; 55 male, age 60 ± 12 years, duration of diabetes 12 ± 9 years, 67 on insulin, 3 new and 98 review patients; 63% were Caucasian, 14% Asian, 4% Afro Caribbean and 19% unknown ethnicity. In global assessment by patients, the process scored ‘good’ or ‘very good’ in 80%, as it did in the other more specific domains (n = 7). Among doctors, 10 of 12 rated the structured patient‐driven consultation process good or very good, reporting increased patient engagement, shared decision making and communication; they felt it was more time consuming though worthwhile. Crucially, it increased insight into patients’ needs.

In patient‐centric consultations: patients did use the opportunity to assess, categorise and prioritise their health concerns with a high degree of satisfaction; health professionals found that of benefit; this was implementable within busy routine specialist diabetes clinics. Copyright © 2014 John Wiley & Sons, Ltd.
CHILD‐CENTERED PLAY THERAPY IN THE SCHOOLS: REVIEW AND META‐ANALYSIS
Authors: Ray Dee C. , Armstrong Stephen A. , Balkin Richard S. , Jayne Kimberly M.
Published: October 2014

The authors conducted a meta‐analysis and systematic review that examined 23 studies evaluating the effectiveness of child centered play therapy (CCPT) conducted in elementary schools. Meta‐analysis results were explored using a random effects model for mean difference and mean gain effect size estimates. Results revealed statistically significant effects for outcome constructs, including externalizing problems (d = 0.34), internalizing problems (d = 0.21), total problems (d = 0.34), self‐efficacy (d = 0.29), academic (d = 0.36), and other behaviors (d = 0.38). Further, a systematic review was conducted on all studies compared with Outcome Research Coding Protocol criteria. Results indicated that CCPT studies provided quantitative support and qualitatively promising to strong evidence in support of its use in the schools.
Refined phosphopeptide enrichment by phosphate additive and the analysis of human brain phosphoproteome
Authors: Tan Haiyan , Wu Zhiping , Wang Hong , Bai Bing , Li Yuxin , Wang Xusheng , Zhai Bo , Beach Thomas G. , Peng Junmin
Published: October 2014

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive loss of cognitive function. One of the pathological hallmarks of AD is the formation of neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein, but global deregulation of protein phosphorylation in AD is not well analyzed. Here, we report a pilot investigation of AD phosphoproteome by titanium dioxide enrichment coupled with high resolution LC‐MS/MS. During the optimization of the enrichment method, we found that phosphate ion at a low concentration (e.g. 1 mM) worked efficiently as a nonphosphopeptide competitor to reduce background. The procedure was further tuned with respect to peptide‐to‐bead ratio, phosphopeptide recovery, and purity. Using this refined method and 9 h LC‐MS/MS, we analyzed phosphoproteome in one milligram of digested AD brain lysate, identifying 5243 phosphopeptides containing 3715 nonredundant phosphosites on 1455 proteins, including 31 phosphosites on the tau protein. This modified enrichment method is simple and highly efficient. The AD case study demonstrates its feasibility of dissecting phosphoproteome in a limited amount of postmortem human brain. All MS data have been deposited in the ProteomeXchange with identifier PXD001180 (http://proteomecentral.proteomexchange.org/dataset/PXD001180).
Analysis of the tryptic search space in UniProt databases
Authors: Alpi Emanuele , Griss Johannes , da Silva Alan Wilter Sousa , Bely Benoit , Antunes Ricardo , Zellner Hermann , Ríos Daniel , O'Donovan Claire , Vizcaíno Juan Antonio , Martin Maria J.
Published: October 2014

In this article, we provide a comprehensive study of the content of the Universal Protein Resource (UniProt) protein data sets for human and mouse. The tryptic search spaces of the UniProtKB (UniProt knowledgebase) complete proteome sets were compared with other data sets from UniProtKB and with the corresponding International Protein Index, reference sequence, Ensembl, and UniRef100 (where UniRef is UniProt reference clusters) organism‐specific data sets. All protein forms annotated in UniProtKB (both the canonical sequences and isoforms) were evaluated in this study. In addition, natural and disease‐associated amino acid variants annotated in UniProtKB were included in the evaluation. The peptide unicity was also evaluated for each data set. Furthermore, the peptide information in the UniProtKB data sets was also compared against the available peptide‐level identifications in the main MS‐based proteomics repositories. Identifying the peptides observed in these repositories is an important resource of information for protein databases as they provide supporting evidence for the existence of otherwise predicted proteins. Likewise, the repositories could use the information available in UniProtKB to direct reprocessing efforts on specific sets of peptides/proteins of interest. In summary, we provide comprehensive information about the different organism‐specific sequence data sets available from UniProt, together with the pros and cons for each, in terms of search space for MS‐based bottom‐up proteomics workflows. The aim of the analysis is to provide a clear view of the tryptic search space of UniProt and other protein databases to enable scientists to select those most appropriate for their purposes.
Adaptive graph‐based multiple testing procedures
Authors: Klinglmueller Florian , Posch Martin , Koenig Franz
Published: October 2014

Multiple testing procedures defined by directed, weighted graphs have recently been proposed as an intuitive visual tool for constructing multiple testing strategies that reflect the often complex contextual relations between hypotheses in clinical trials. Many well‐known sequentially rejective tests, such as (parallel) gatekeeping tests or hierarchical testing procedures are special cases of the graph based tests. We generalize these graph‐based multiple testing procedures to adaptive trial designs with an interim analysis. These designs permit mid‐trial design modifications based on unblinded interim data as well as external information, while providing strong family wise error rate control. To maintain the familywise error rate, it is not required to prespecify the adaption rule in detail. Because the adaptive test does not require knowledge of the multivariate distribution of test statistics, it is applicable in a wide range of scenarios including trials with multiple treatment comparisons, endpoints or subgroups, or combinations thereof. Examples of adaptations are dropping of treatment arms, selection of subpopulations, and sample size reassessment. If, in the interim analysis, it is decided to continue the trial as planned, the adaptive test reduces to the originally planned multiple testing procedure. Only if adaptations are actually implemented, an adjusted test needs to be applied. The procedure is illustrated with a case study and its operating characteristics are investigated by simulations. Copyright © 2014 John Wiley & Sons, Ltd.
Control of type 1 error in a hybrid complete two‐period vaccine efficacy trial
Authors: Dunning Andrew J. , Reeves John
Published: October 2014

A complete two‐period experimental design has been defined as one in which subjects are randomized to treatment, observed for the occurrence of an event of interest, re‐randomized, and observed again for the event in a second period. A 4‐year vaccine efficacy trial was planned to compare a high‐dose vaccine with a standard dose vaccine. Subjects would be randomized each year, and subjects who had participated in a previous year would be allowed to re‐enroll in a subsequent year and would be re‐randomized. A question of interest is whether positive correlation between observations on subjects who re‐enrolled would inflate the variance of test statistics. The effect of re‐enrollment and correlation on type 1 error in a 4‐year trial is investigated by simulation. As conducted, the trial met its power requirements after two years. Subjects therefore included some who participated for a single year and others who participated in both years. Those who participated in both years constituted a complete two‐period design. An algebraic expression for the variance of the treatment difference in a complete two‐period design is derived. It is shown that under a ‘no difference’ null, correlation does not result in variance inflation in this design. When there is a treatment difference, there is variance inflation but it is small. In the vaccine efficacy trial, the effect of correlation on the statistical inference was negligible. Copyright © 2014 John Wiley & Sons, Ltd.
Aqueous Extract of Rosmarinus officinalis L. Inhibits Neutrophil Influx and Cytokine Secretion
Authors: Silva Ana Mara de Oliveira e , Machado Isabel Daufenback , Santin José Roberto , de Melo Illana Louise Pereira , Pedrosa Gabriela Vieira , Genovese Maria Ines , Farsky Sandra Helena Poliselli , Mancini‐Filho Jorge
Published: October 2014

Rosmarinus officinalis L. phenolic compounds have attracted considerable attention because of their antioxidant and antimicrobial properties, including its ability to treat inflammatory disorders. In this work, we investigated the in vivo and in vitro effects of R. officinalis aqueous extract on neutrophil trafficking from the blood into an inflamed tissue, on cell‐derived secretion of chemical mediators, and on oxidative stress. Anti‐inflammatory activity was investigated using carrageenan‐induced inflammation in the subcutaneous tissue of male Wistar rats orally treated with the R. officinalis extract (100, 200, or 400 mg/kg). The leukocyte influx (optical microscopy), secretion of chemical mediators (prostaglandin E2 (PGE2), TNF‐α, interleukin 6 (IL‐6), leukotriene B4 (LTB4), and cytokine‐induced neutrophil chemoattractant 1 by enzyme‐linked immunosorbent assay), and the anti‐oxidative profile (super oxide dismutase (SOD), glutathione peroxidase, and thiobarbituric acid reactive substance (TBARS) spectrophotometry) were quantified in the inflamed exudate. N‐Formyl‐methionine‐leucine‐phenylalanine‐induced chemotaxis, lipopolysaccharide‐induced NO2− production (Greiss reaction), and adhesion molecule expression (flow cytometry) were in vitro quantified using oyster glycogen recruited peritoneal neutrophils previous treated with the extract (1, 10, or 100 µg/mL). Animals orally treated with phosphate‐buffered saline and neutrophils incubated with Hank's balanced salt solution were used as control. R. officinalis extract oral treatment caused a dose‐dependent reduction in the neutrophil migration as well as decreased SOD, TBARS, LTB4, PGE2, IL‐6, and TNF‐α levels in the inflamed exudate. In vitro treatment with R. officinalis decreased neutrophil chemotaxis, NO2− production, and shedding of L‐selectin and β2 integrin expressions. Results here presented show that R. officinalis aqueous extract displays important in vivo and in vitro anti‐inflammatory actions by blocking pathways of neutrophil migration and secretion, suggesting its therapeutic application to acute inflammatory reactions. Copyright © 2014 John Wiley & Sons, Ltd.
Cycle packing
Authors: Conlon David , Fox Jacob , Sudakov Benny
Published: October 2014

In the 1960s, Erdős and Gallai conjectured that the edge set of every graph on n vertices can be partitioned into O(n) cycles and edges. They observed that one can easily get an O(nlogn) upper bound by repeatedly removing the edges of the longest cycle. We make the first progress on this problem, showing that O(nloglogn) cycles and edges suffice. We also prove the Erdős‐Gallai conjecture for random graphs and for graphs with linear minimum degree. © 2014 Wiley Periodicals, Inc. Random Struct. Alg., 45, 608–626, 2014
Spline‐based procedures for dose‐finding studies with active control
Authors: Helms Hans‐Joachim , Benda Norbert , Zinserling Jörg , Kneib Thomas , Friede Tim
Published: October 2014

In a dose‐finding study with an active control, several doses of a new drug are compared with an established drug (the so‐called active control). One goal of such studies is to characterize the dose–response relationship and to find the smallest target dose concentrationd*, which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose–response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline‐based method for deriving an estimator of the target dose without assuming a specific dose–response function. Furthermore, the construction of a spline‐based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline‐based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. © 2014 The Authors.Statistics in MedicinePublished by John Wiley & Sons Ltd.
Comparative optimization study for chemical synthesis of hydroxypropyl starch from native corn and taro starch through evolutionary operation (EVOP) factorial design technique
Authors: Chattopadhyay Jayati , Banerjee Soumitra , Bhattacharyya A. K.
Published: October 2014

Modification of native starch is aimed at tailor‐making functional properties of starch to overcome its inherent shortcomings which will enhance its versatility for different food‐uses. Optimization of chemical synthesis of hydroxypropyl starch from two native starch sources, corn and taro, was explored through application of evolutionary operation (EVOP) factorial design technique. Concentrations of starch slurry, propylene oxide, and sodium sulfate were considered as process variables and these were optimized in order to maximize swelling power of hydroxypropyl starch. EVOP factorial designing technique was applied consecutively and the results were analyzed statistically. Maximization of swelling power was achieved by corn starch after two sets of experiments of EVOP and the maximum value obtained was 36.17 at 20% sodium sulfate, 50% starch slurry, and 3.2% propylene oxide concentrations. The highest value of swelling power for hydroxypropyl taro starch was measured to be 62.33 after two sets of experiments and there was still scope for increasing its value in further set of experiments. Final conditions for taro starch were found to be optimum at 30% sodium sulfate, 40% starch slurry, and 5.6% propylene oxide concentrations, evaluated through EVOP method.
The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit
Authors: O'Leary Conor J. , Bradford DanaKai , Chen Min , White Amanda , Blackmore Daniel G. , Cooper Helen M.
Published: October 2014

A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neogt/gt) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neogt/gt olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S-phase neuroblasts within the Neogt/gt RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS. Stem Cells  2015;33:503–514
Evidence for a Subventricular Zone Neural Stem Cell Phagocytic Activity Stimulated by the Vitamin K-Dependent Factor Protein S
Authors: Ginisty Aurélie , Gély-Pernot Aurore , Abaamrane Loubna , Morel Franck , Arnault Patricia , Coronas Valérie , Benzakour Omar
Published: October 2014

Neural stem cells, whose major reservoir in the adult mammalian brain is the subventricular zone (SVZ), ensure neuropoiesis, a process during which many generated cells die. Removal of dead cells and debris by phagocytes is necessary for tissue homeostasis. Using confocal and electron microscopy, we demonstrate that cultured SVZ cells phagocytose both 1 and 2 µm latex beads and apoptotic cell-derived fragments. We determine by flow cytometry that phagocytic cells represent more than 10% of SVZ cultured cells. Phenotyping of SVZ cells using nestin, GFAP, Sox2, or LeX/SSEA and quantification of aldehyde dehydrogenase (ALDH) activity, reveals that cells with neural stem-cell features phagocytose and represent more than 30% of SVZ phagocytic cells. In vivo, nestin-, Sox2-, and ALDH-expressing neural stem-like cells engulfed latex beads or apoptotic cell-derived fragments that were injected into mice lateral brain ventricles. We show also that SVZ cell phagocytic activity is an active process, which depends both on cytoskeleton dynamic and on recognition of phosphatidylserine eat-me signal, and is stimulated by the vitamin K-dependent factor protein S (ProS). ProS neutralizing antibodies inhibit SVZ cell phagocytic activity and exposure of SVZ cells to apoptotic cell-derived fragments induces a transient Mer tyrosine kinase receptor (MerTK) phosphorylation. Conversely, MerTK blocking antibodies impair both basal and ProS-stimulated SVZ cell phagocytic activity. By revealing that neural stem-like cells act within the SVZ neurogenic niche as phagocytes and that the ProS/MerTK path represents an endogenous regulatory mechanism for SVZ cell phagocytic activity, the present report opens-up new perspectives for both stem cell biology and brain physiopathology. Stem Cells  2015;33:515–525
Cervical length in prediction of preterm birth after laser surgery for twin–twin transfusion syndrome
Authors: Papanna R. , Mann L. K. , Baschat A. A. , Bebbington M. W. , Khalek N. , Johnson A. , Snowise S. , Moise K. J.
Published: October 2014

Objectives

To determine the risk factors for spontaneous preterm delivery (PTD) or preterm prelabor rupture of membranes (PPROM) at < 34 weeks' gestation after fetoscopic laser surgery for twin–twin transfusion syndrome and to identify the optimal threshold for preoperative cervical length (CL) that indicates a high risk for spontaneous PTD.

Methods

This was a secondary analysis of data prospectively collected from 449 patients at three fetal centers. CL measurements were obtained by preoperative transvaginal ultrasound, at a gestational age of 16–26 weeks. The risk factors associated with spontaneous PTD before 34 weeks' gestation were determined using multivariable logistic regression analysis. We excluded patients with dual fetal demise and those with maternal or fetal indications for delivery without PPROM (n = 63). The optimal threshold for cervical length to predict spontaneous PTD before 34 weeks was determined using a receiver–operating characteristics (ROC) curve and Youden index. Additionally, the CL threshold for spontaneous PTD at 2‐week intervals between 24 and 34 weeks was determined.

Results

Spontaneous PTD before 34 weeks occurred in 206 (53.4%) of the included patients. Only the preoperative CL was significantly associated with spontaneous PTD. The preoperative CL was normally distributed with a mean of 37.6 ± 10.3 mm (range, 5–66 mm). Maternal age and parity were positively associated, and gestational age at procedure and anterior placenta were negatively associated, with CL on multivariable linear regression analysis. The area under the ROC curve for predicting spontaneous PTD with CL measurements was 0.61 (P = 0.02) and the optimal threshold was 28 mm with a Youden index of 0.19 (sensitivity and specificity of 92% and 27%, respectively). A CL measurement of < 28 mm increased the risk of spontaneous PTD for all gestational age thresholds.

Conclusions

Spontaneous PTD at < 34 weeks' gestation is associated with a preoperative CL of < 28 mm. Preventive strategies should focus on this high‐risk group. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Maternal cardiac function, uteroplacental Doppler flow parameters and pregnancy outcome: a systematic review
Authors: Kampman M. A. M. , Bilardo C. M. , Mulder B. J. M. , Aarnoudse J. G. , Ris‐Stalpers C. , van Veldhuisen D. J. , Pieper P. G.
Published: October 2014

Objective

To investigate the existing evidence for a link between maternal cardiac function, abnormal uteroplacental flow and poor perinatal outcome in women with and without known cardiac disease.

Methods

PubMed and EMBASE databases were searched systematically for studies relating cardiac functional parameters and uteroplacental Doppler flow with pregnancy outcome in women with pre‐existing congenital cardiac disease and women without known cardiac disease. Only studies based on echocardiography were included.

Results

From 1732 citations, 10 articles were included. In women with known congenital heart disease, a relationship was found between abnormal uteroplacental Doppler flow patterns and cardiac function before and during pregnancy. Conversely, women without a history of congenital heart disease, but with abnormal uterine artery resistance and pregnancy complications, more often showed global left ventricular diastolic dysfunction (33%; P = 0.0001), impaired myocardial relaxation (72%; P < 0.0001) and left ventricular systolic dysfunction (17%; P = 0.006), even up to 1 year postpartum.

Conclusion

There is increasing evidence for an association between pre‐existing subclinical cardiac dysfunction, poor placentation (reflected by uteroplacental Doppler flow abnormalities) and poor pregnancy outcome. It may be postulated that pre‐existing suboptimal cardiac performance, as a result of either congenital heart disease or a subclinical latent condition, is one of the common denominators of poor placentation, leading to poor pregnancy outcome. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Measuring the economic costs of discrimination experienced by people with mental health problems: development of the Costs of Discrimination Assessment (CODA)
Authors: Wright Steve , Henderson Claire , Thornicroft Graham , Sharac Jessica , McCrone Paul
Published: October 2014

Purpose

Stigma and discrimination are faced by many with mental health problems and this may affect the uptake of services and engagement in leisure and recreational activities. The aims of this study were to develop a schedule to measure the impact of stigma and discrimination on service use, employment and leisure activities and to estimate the value of such reductions.

Methods

A questionnaire, the Cost of Discrimination Assessment, was developed and piloted in a sample people with mental health problems. Costs were calculated and test–retest reliability assessed.

Results

Test–retest reliability was good for most items. A substantial proportion of the sample had experienced negative impacts on employment as a result of stigma and discrimination. Around one-fifth had reduced contacts with general practitioners in the previous 6 months due to stigma and discrimination and the leisure activity most affected was visiting pubs/restaurants/café.

Conclusions

In conclusion, stigma and discrimination result in reduced use of services and reduced engagement in leisure activities. This represents a welfare loss to individuals.