bluuebunny/crossref_metadata_2025 huggingface dataset:
Fast spin echo sequences with very long echo trains: Design of variable refocusing flip angle schedules and generation of clinical T2 contrast
Authors: Busse Reed F. , Hariharan Hari , Vu Anthony , Brittain Jean H.
Published: April 2006

Reducing and continuously varying the flip angle of the refocusing RF pulses in a rapid acquisition with relaxation enhancement (RARE; fast/turbo spin echo) sequence is a useful means of addressing high RF power deposition and modulation transfer function (MTF) distortion due to relaxation. This work presents a streamlined technique to generate a sequence of refocusing flip angles on a per‐prescription basis that produces relatively high SNR and limits blurring in a wide range of materials encountered in vivo. Since the “effective TE” (traditionally defined as the time at which the center of k‐space is sampled) no longer corresponds to the expected amount of spin‐echo T2 contrast due to the mixing of stimulated and spin echoes, a “contrast‐equivalent” TE is defined and experimentally demonstrated that allows annotation of a more accurate effective TE that matches the contrast produced by 180° refocusing. Furthermore, contrast is shown to be manipulable by the addition of magnetization preparation pulse sequence segments, such as T2‐prep, to produce clinically desirable contrast for routine head and body imaging. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
In vivo quantitative three‐dimensional motion mapping of the murine myocardium with PC‐MRI at 17.6 T
Authors: Herold Volker , Mörchel Philipp , Faber Cornelius , Rommel Eberhard , Haase Axel , Jakob Peter M.
Published: April 2006

This work presents a method that allows for the assessment of 3D murine myocardial motion in vivo at microscopic resolution. Phase‐contrast (PC) magnetic resonance imaging (MRI) at 17.6 T was applied to map myocardial motion in healthy mice along three gradient directions. High‐resolution velocity maps were acquired at three different levels in the murine myocardium with an in‐plane resolution of 98 μm, a slice thickness of 0.6 mm, and a temporal resolution of 6 ms. The applied PC‐MRI method was validated with phantom experiments that confirmed the correctness of the method with deviations of <1.7%. Myocardial in‐plane velocities between 0.5 cm/s and 2.2 cm/s were determined for the healthy murine myocardium. Through‐plane velocities of 0.1–0.83 cm/s were measured. Velocity data was also used to calculate the myocardial twist angle during systole at different slices in the short‐axis view. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Quantification of cerebral arterial blood volume using arterial spin labeling with intravoxel incoherent motion‐sensitive gradients
Authors: Kim Tae , Kim Seong‐Gi
Published: April 2006

Quantification of cerebral arterial blood volume (CBVa) is important for understanding vascular regulation. To enable measurement of CBVa with diffusion‐weighted (DW) arterial spin labeling (ASL), a theoretical framework was developed using the effects of intravoxel incoherent motion (IVIM). The pseudo‐diffusion coefficient (D*) in the IVIM model was evaluated at 9.4 T in DW‐ASL of rat brain under isoflurane anesthesia by variations of both post‐labeling delay (w) and magnetization transfer ratio (MTR). D* and its volume fraction decreased at values of w ≥ 0.3 s, and the normalized apparent diffusion coefficient (ADC) increased with MTR, suggesting that D* is closely correlated with CBVa. Thus, the difference between ASL measurements with and without DW gradients is related to CBVa. The CBVa values measured by this approach were compared with values obtained using the modulation of tissue and vessel (MOTIVE) technique with ASL, which varies MT levels without changing spin labeling efficiency. CBVa values from both methods were highly correlated. The measured CBVa values were linearly correlated with cerebral blood flow (CBF) for a PaCO2 range of 25–50 mmHg; ΔCBVa (ml/100 g) = 0.007 (min−1) × ΔCBF (ml/100 g/min). The DW‐ASL approach is simple and easy to implement for human and animal CBVa studies. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
32‐element receiver‐coil array for cardiac imaging
Authors: Hardy Christopher J. , Cline Harvey E. , Giaquinto Randy O. , Niendorf Thoralf , Grant Aaron K. , Sodickson Daniel K.
Published: April 2006

A lightweight 32‐element MRI receiver‐coil array was designed and built for cardiac imaging. It comprises an anterior array of 21 copper rings (75 mm diameter) and a posterior array of 11 rings (107 mm diameter) that are arranged in hexagonal lattices so as to decouple nearest neighbors, and curved around the left side of the torso. Imaging experiments on phantoms and human volunteers show that it yields superior performance relative to an eight‐element cardiac array as well as a 32‐element whole‐torso array for both traditional nonaccelerated cardiac imaging and 3D parallel imaging with acceleration factors as high as 16. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Measurement of brain glutamate and glutamine by spectrally‐selective refocusing at 3 tesla
Authors: Choi Changho , Coupland Nicholas J. , Bhardwaj Paramjit P. , Malykhin Nikolai , Gheorghiu Dan , Allen Peter S.
Published: April 2006

A new single‐voxel proton NMR spectrally‐selective refocusing method for measuring glutamate (Glu) and glutamine (Gln) in the human brain in vivo at 3T is reported. Triple‐resonance selective 180° RF pulses with a bandwidth of 12 Hz were implemented within point‐resolved spectroscopy (PRESS) for selective detection of Glu or Gln, and simultaneous acquisition of creatine singlets for use as a reference in phase correction. The carriers of the spectrally‐selective 180° pulses and the echo times (TEs) were optimized with both numerical and experimental analyses of the filtering performance, which enabled measurements of the target metabolites with negligible contamination from N‐acetylaspartate and glutathione. The concentrations of Glu and Gln in the prefrontal cortex were estimated to be 9.7 ± 0.5 and 3.0 ± 0.7 mM (mean ± SD, N = 7), with reference to Cr at 8 mM. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Manganese‐enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice
Authors: Stieltjes Bram , Klussmann Stefan , Bock Michael , Umathum Reiner , Mangalathu Jain , Letellier Elisabeth , Rittgen Werner , Edler Lutz , Krammer Peter H. , Kauczor Hans‐Ulrich , Martin‐Villalba Ana , Essig Marco
Published: April 2006

In past decades, much effort has been invested in developing therapies for spinal injuries. Lack of standardization of clinical read‐out measures, however, makes direct comparison of experimental therapies difficult. Damage and therapeutic effects in vivo are routinely evaluated using rather subjective behavioral tests. Here we show that manganese‐enhanced magnetic resonance imaging (MEMRI) can be used to examine the extent of damage following spinal cord injury (SCI) in mice in vivo. Injection of MnCl2 solution into the cerebrospinal fluid leads to manganese uptake into the spinal cord. Furthermore, after injury MEMRI‐derived quantitative measures correlate closely with clinical locomotor scores. Improved locomotion due to treating the detrimental effects of SCI with an established therapy (neutralization of CD95Ligand) is reflected in an increase of manganese uptake into the injured spinal cord. Therefore, we demonstrate that MEMRI is a sensitive and objective tool for in vivo visualization and quantification of damage and functional improvement after SCI. Thus, MEMRI can serve as a reproducible surrogate measure of the clinical status of the spinal cord in mice, potentially becoming a standard approach for evaluating experimental therapies. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Pre‐radiation chemotherapy with response‐based radiation therapy in children with central nervous system germ cell tumors: A report from the Children's Oncology Group
Authors: Kretschmar C. , Kleinberg L. , Greenberg M. , Burger P. , Holmes Emi , Wharam M.
Published: April 2006

Background

This Phase II study was designed to determine response to chemotherapy and survival after response‐based radiation (RT) in children with CNS germ cell tumors.

Procedure

Children with germinomas and normal markers received cisplatin 100 mg/m2 + etoposide, alternating with vincristine + cyclophosphamide (CPM) 2 g/m2/d, for four cycles. Children with nongerminomatous tumors or with abnormal markers received doubled doses of cisplatin and CPM. For germinoma patients in complete response (CR), RT was decreased from 50.4 to 30.6 Gy. High‐risk patients received neuraxis RT: 50.4 Gy local + 30.6 Gy neuraxis in CR; 54 Gy local + 36 Gy if less than CR.

Results

Of 12 germinoma patients, 4 had cerebrospinal fluid (CSF) human chorionic gonadotropin (HCG) 6.9–21 mIU/ml. Of 14 nongerminomatous patients, HCG in serum or CSF was >50 mIU/ml in 9, α‐fetoprotein (AFP) abnormal in 9. Four germinoma patients attained CR, six PR, one SD, one not evaluable after resection. Two nongerminomatous patients had CR, three PR, three SD, one PD, four not evaluable after resection; one inadequately treated patient had progressive disease (PD). Both PD patients died; one SD patient died during a seizure. Eleven germinoma patients are PF at median 66 months; one patient in CR refused RT, had PD at 10 months, received RT, and was PF at 56 months. Eleven of 14 nongerminomatous patients were PF at median 58 months.

Conclusion

Response (germinoma, 91%; nongerminomatous, 55%) and survival are encouraging after this regimen plus response‐based RT. Pediatr Blood Cancer 2007;48:285–291. © 2006 Wiley‐Liss, Inc.
How American women's philanthropy helped build economic growth and a democratic society
Authors: Gaudiani Claire
Published: April 2006

Women's philanthropic efforts throughout American history have created a transforming asset in the economic growth of the country, particularly in the arenas of upward mobility and human capital.
Women's philanthropic leadership: How is it different?
Authors: Banducci Bonita
Published: April 2006

Based on the author's research, this chapter gives advice to both volunteers and development professionals about better using women's unique leadership qualities.
Married couples' charitable giving: Who and why
Authors: Brown Eleanor
Published: April 2006

The author discusses new research on married couples' giving and makes predictions about married women's decision‐making trends.
Women philanthropists: Leveraging influence and impact as change makers
Authors: Gary Tracy
Published: April 2006

Women face complex challenges as they move through their philanthropic journey—financial resources being a major one. As women become more informed and work collaboratively, a better society will be created.
Women's philanthropy programs at coeducational colleges and universities
Authors: Lovell Jeanie
Published: April 2006

Many programs that work at universities and colleges to successfully engage more women as donors can be applied to any other nonprofit organization.
Women, wealth, and endowed philanthropy: Trends and innovations in foundations
Authors: Otis Kimberly , Jankowski Katherine
Published: April 2006

Women as donors, board members, and nonprofit executives serve programs and projects that affect women and girls and have the opportunity to build a world that is generous, just, diverse, and equitable for all its members.
Launching new initiatives and raising a call to action
Authors: Taylor Martha A.
Published: April 2006

By working together, women philanthropists and nonprofits can make significant strides to increase giving and improve the quality of life for all.
Core concerns of couples living with early stage breast cancer
Authors: Shands Mary Ellen , Lewis Frances Marcus , Sinsheimer Janet , Cochrane Barbara B.
Published: April 2006

Study objectives: Although clinicians and scientists have a growing awareness of breast cancer as a couple's joint experience, no one has studied the concerns couples choose to address with a professional coach to better manage the impact of the cancer. The purpose of the current study was to describe illness‐related concerns couples worked on together with masters‐educated professional coaches during the first eleven months of the wife's treatment for early stage breast cancer.

Setting and participants: Intervention sessions were conducted with twenty‐nine couples in their homes in the Pacific Northwest.

Design: Data were obtained from single occasion case intensive interviews with couples.

Main results: Inductive coding of the audiorecorded intervention sessions yielded four domains of core concerns: dealing with tension in the relationship; needing to be together as a couple; wondering about the children; and managing the threat of breast cancer.

Conclusion: Over half the couples chose to address and do something about the stress, tension and dissatisfaction they were feeling in their relationship that each attributed to the breast cancer. Future family‐focused cancer care needs to include services that assist couples to address these core concerns. Copyright © 2006 John Wiley & Sons, Ltd.
A combinatorial score to distinguish biological and nonbiological protein–protein interfaces
Authors: Liu Shiyong , Li Qingliang , Lai Luhua
Published: April 2006

With the large amount of protein–protein complex structural data available, to understand the key features governing the specificity of protein–protein recognition and to define a suitable scoring function for protein–protein interaction predictions, we have analyzed the protein interfaces from geometric and energetic points of view. Atom‐based potential of mean force (PMFScore), packing density, contact size, and geometric complementarity are calculated for crystal contacts in 74 homodimers and 91 monomers, which include real biological interactions in dimers and nonbiological contacts in monomers and dimers. Simple cutoffs were developed for single and combinatorial parameters to distinguish biological and nonbiological contacts. The results show that PMFScore is a better discriminator between biological and nonbiological interfaces comparable in size. The combination of PMFScore and contact size is the most powerful pairwise discriminator. A combinatorial score (CFPScore) based on the four parameters was developed, which gives the success rate of the homodimer discrimination of 96.6% and error rate of the monomer discrimination of 6.0% and 19.8% according to Valdar's and our definition, respectively. Compared with other statistical learning models, the cutoffs for the four parameters and their combinations are directly based on physical models, simple, and can be easily applied to protein–protein interface analysis and docking studies. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Crystal structures of the complexes of a group IIA phospholipase A2 with two natural anti‐inflammatory agents, anisic acid, and atropine reveal a similar mode of binding
Authors: Singh Nagendra , Jabeen Talat , Pal Aritra , Sharma Sujata , Perbandt Markus , Betzel Christian , Singh Tej P.
Published: April 2006

Secretory low molecular weight phospholipase A2s (PLA2s) are believed to be involved in the release of arachidonic acid, a precursor for the biosynthesis of pro‐inflammatory eicosanoids. Therefore, the specific inhibitors of these enzymes may act as potent anti‐inflammatory agents. Similarly, the compounds with known anti‐inflammatory properties should act as specific inhibitors. Two plant compounds, (a) anisic acid (4‐methoxy benzoic acid) and (b) atropine (8‐methyl‐8‐azabicyclo oct‐3‐hydroxy‐2‐phenylpropanoate), have been used in various inflammatory disorders. Both compounds (a) and (b) have been found to inhibit PLA2 activity having binding constants of 4.5 × 10−5 M and 2.1 × 10−8 M, respectively. A group IIA PLA2 was isolated and purified from the venom of Daboia russelli pulchella (DRP) and its complexes were made with anisic acid and atropine. The crystal structures of the two complexes (i) and (ii) of PLA2 with compounds (a) and (b) have been determined at 1.3 and 1.2 Å resolutions, respectively. The high‐quality observed electron densities for the two compounds allowed the accurate determinations of their atomic positions. The structures revealed that these compounds bound to the enzyme at the substrate ‐ binding cleft and their positions were stabilized by networks of hydrogen bonds and hydrophobic interactions. The most characteristic interactions involving Asp 49 and His 48 were clearly observed in both complexes, although the residues that formed hydrophobic interactions with these compounds were not identical because their positions did not exactly superimpose in the large substrate‐binding hydrophobic channel. Owing to a relatively small size, the structure of anisic acid did not alter upon binding to PLA2, while that of atropine changed significantly when compared with its native crystal structure. The conformation of the protein also did not show notable changes upon the bindings of these ligands. The mode of binding of anisic acid to the present group II PLA2 is almost identical to its binding with bovine pancreatic PLA2 of group I. On the other hand, the binding of atropine to PLA2 is similar to that of another plant alkaloid aristolochic acid. Proteins 2006. © 2006 Wiley‐Liss, Inc.
A simple measure of native‐state topology and chain connectivity predicts the folding rates of two‐state proteins with and without crosslinks
Authors: Dixit Purushottam D. , Weikl Thomas R.
Published: April 2006

The folding rates of two‐state proteins have been found to correlate with simple measures of native‐state topology. The most prominent among these measures is the relative contact order (CO), which is the average CO, or localness, of all contacts in the native protein structure, divided by the chain length. Here, we test whether such measures can be generalized to capture the effect of chain crosslinks on the folding rate. Crosslinks change the chain connectivity and therefore also the localness of some of the native contacts. These changes in localness can be taken into account by the graph‐theoretical concept of effective contact order (ECO). The relative ECO, however, the natural extension of the relative CO for proteins with crosslinks, overestimates the changes in the folding rates caused by crosslinks. We suggest here a novel measure of native‐state topology, the relative logCO, and its natural extension, the relative logECO. The relative logCO is the average value for the logarithm of the CO of all contacts, divided by the logarithm of the chain length. The relative log(E)CO reproduces the folding rates of a set of 26 two‐state proteins without crosslinks with essentially the same high correlation coefficient as the relative CO. In addition, it also captures the folding rates of eight two‐state proteins with crosslinks. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Microscopy reveals disease control through novel effects on fungal development: a case study with an early‐generation benzophenone fungicide
Authors: Schmitt Mark R , Carzaniga Raffaella , Cotter H Van T , O'Connell Richard , Hollomon Derek
Published: April 2006

The benzophenones are a new class of agricultural fungicides that demonstrate protectant, curative and eradicative/antisporulant activity against powdery mildews. The chemistry is represented in the marketplace by the fungicide metrafenone, recently introduced by BASF and discussed in the following paper. The benzophenones show no evidence of acting by previously identified biochemical mechanisms, nor do they show cross‐resistance with existing fungicides. The value of microscopy in elucidating fungicide mode of action is demonstrated through identification of the effects of an early benzophenone, eBZO, on mildew development. eBZO caused profound alterations in the morphology of powdery mildews of both monocotyledons and dicotyledons, affecting multiple stages of fungal development, including spore germination, appressorial formation, penetration, surface hyphal morphology and sporogenesis. Identification of analogous effects of eBZO on sporulation in the model organismAspergillus nidulans(Eidam) Winter provides a unique opportunity to elucidate important morphogenetic regulatory sites in the economically important obligate pathogens, the powdery mildews. Benzophenones provide a further example of the benefits of whole‐organism testing in the search for novel fungicide modes of action. Copyright © 2006 Society of Chemical Industry
Modelling Toxicity using Molecular Quantum Similarity Measures
Authors: Gironés Xavier , Carbó‐Dorca Ramon
Published: April 2006

In this work, a general procedure for the application of Molecular Quantum Similarity Measures (MQSM) into the Quantitative Structure‐Toxicity Relationships (QSTR) field is presented. The methodology is presented from its theoretical background, beginning with the formulation of MQSM and the role of density functions. Other topics, like molecular modelling, electronic density fitting, similarity scaling and molecular superposition are also analysed. The theoretical part is complemented with three different application examples dealing with acute aquatic toxicity related to different fish species. The molecular sets are constituted by different kinds of benzene derivatives. Acceptable correlations are obtained for the aquatic toxicity using quantum similarity derived descriptors, allowing a fairly confident classification of the studied compounds according to their toxicity level.
A flexible model for multivariate interval‐censored survival times with complex correlation structure
Authors: Falcaro Milena , Pickles Andrew
Published: April 2006

We focus on the analysis of multivariate survival times with highly structured interdependency and subject to interval censoring. Such data are common in developmental genetics and genetic epidemiology. We propose a flexible mixed probit model that deals naturally with complex but uninformative censoring. The recorded ages of onset are treated as possibly censored ordinal outcomes with the interval censoring mechanism seen as arising from a coarsened measurement of a continuous variable observed as falling between subject‐specific thresholds. This bypasses the requirement for the failure times to be observed as falling into non‐overlapping intervals. The assumption of a normal age‐of‐onset distribution of the standard probit model is relaxed by embedding within it a multivariate Box–Cox transformation whose parameters are jointly estimated with the other parameters of the model. Complex decompositions of the underlying multivariate normal covariance matrix of the transformed ages of onset become possible. The new methodology is here applied to a multivariate study of the ages of first use of tobacco and first consumption of alcohol without parental permission in twins. The proposed model allows estimation of the genetic and environmental effects that are shared by both of these risk behaviours as well as those that are specific. Copyright © 2006 John Wiley & Sons, Ltd.
A penalized likelihood approach to magnetic resonance image reconstruction
Authors: Bulaevskaya Vera L. , Oehlert Gary W.
Published: April 2006

Currently, images acquired via magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) technology are reconstructed using the discrete inverse Fourier transform. While computationally convenient, this approach is not able to filter out noise. This is a serious limitation because the amount of noise in MRI and fMRI can be substantial. In this paper, we propose an alternative approach to reconstruction, based on penalized likelihood methodology. In particular, we focus on non‐linear shrinkage estimators and show that this approach achieves a great reduction in integrated mean squared error (IMSE) of the estimated image with respect to the currently used estimator. This approach is extremely fast and easy to implement computationally. In addition, it can be combined with various alternative approaches to MR image reconstruction and can be easily adapted to other, non‐MRI contexts, in which the observed data and the quantities of interest are related via a linear transform. Copyright © 2006 John Wiley & Sons, Ltd.
A method for therapeutic dose selection in a phase II clinical trial using contrast statistics
Authors: Wakana Akira , Yoshimura Isao , Hamada Chikuma
Published: April 2006

This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test‐drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut‐off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut‐off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut‐off value to reduce the expected loss for various response patterns is 0.75 for a 3‐group trial and 0.70 for a 4‐group trial. Using these cut‐off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable. Copyright © 2006 John Wiley & Sons, Ltd.
A comparison of methods for the analysis of recurrent health outcome data with environmental covariates
Authors: Fung Karen Y. , Khan Shahedul , Krewski Daniel , Ramsay Tim
Published: April 2006

Recurrent events such as repeated hospital admissions for the same health outcome occur frequently in environmental health studies. Dewanji and Moolgavkar proposed a flexible parametric model and a conditional likelihood analysis for recurrent events based on a Poisson process formulation. In this paper, we examine the statistical properties of the Dewanji–Moolgavkar (DM) estimator of the risk of an adverse health outcome associated with environmental exposures based on recurrent event data using computer simulation. We also compare the DM approach with both case–crossover analysis for multiple observations and time series analysis when there are no subject‐specific covariates. When using a correctly specified model, the DM method produced better estimates with respect to relative mean square error when each subject had constant or curved baseline intensity functions than it did when baseline intensities were increasing or decreasing in a linear fashion. For under‐specified models, the DM method outperformed case–crossover analysis for decreasing straight line intensity functions, was outperformed by case–crossover analysis for increasing straight line intensity functions, and was roughly equivalent to case–crossover analysis for constant and curved intensity functions. Case–crossover analysis produced superior risk estimates more frequently than the other two methods in the cases considered here, especially for linear representations of the baseline intensities. Copyright © 2006 John Wiley & Sons, Ltd.
Gaussianization‐based quasi‐imputation and expansion strategies for incomplete correlated binary responses
Authors: Demirtas Hakan , Hedeker Donald
Published: April 2006

New quasi‐imputation and expansion strategies for correlated binary responses are proposed by borrowing ideas from random number generation. The core idea is to convert correlated binary outcomes to multivariate normal outcomes in a sensible way so that re‐conversion to the binary scale, after performing multiple imputation, yields the original specified marginal expectations and correlations. This conversion process ensures that the correlations are transformed reasonably which in turn allows us to take advantage of well‐developed imputation techniques for Gaussian outcomes. We use the phrase ‘quasi’ because the original observations are not guaranteed to be preserved. We argue that if the inferential goals are well‐defined, it is not necessary to strictly adhere to the established definition of multiple imputation. Our expansion scheme employs a similar strategy where imputation is used as an intermediate step. It leads to proportionally inflated observed patterns, forcing the data set to a complete rectangular format. The plausibility of the proposed methodology is examined by applying it to a wide range of simulated data sets that reflect alternative assumptions on complete data populations and missing‐data mechanisms. We also present an application using a data set from obesity research. We conclude that the proposed method is a promising tool for handling incomplete longitudinal or clustered binary outcomes under ignorable non‐response mechanisms. Copyright © 2006 John Wiley & Sons, Ltd.
Supporting the analysis of clones in software systems
Authors: Kapser Cory J. , Godfrey Michael W.
Published: April 2006

Code duplication is a well‐documented problem in industrial software systems. There has been considerable research into techniques for detecting duplication in software, and there are several effective tools to perform this task. However, there have been few detailed qualitative studies into how cloning actually manifests itself within software systems. This is primarily due to the large result sets that many clone‐detection tools return; these result sets are very difficult to manage without complementary tool support that can scale to the size of the problem, and this kind of support does not currently exist. In this paper we present an in‐depth case study of cloning in a large software system that is in wide use, the Apache Web server; we provide insights into cloning as it exists in this system, and we demonstrate techniques to manage and make effective use of the large result sets of clone‐detection tools. In our case study, we found several interesting types of cloning occurrences, such as ‘cloning hotspots’, where a single subsystem comprising only 17% of the system code contained 38.8% of the clones. We also found several examples of cloning behavior that were beneficial to the development of the system, in particular cloning as a way to add experimental functionality. Copyright © 2006 John Wiley & Sons, Ltd.
How do APIs evolve? A story of refactoring
Authors: Dig Danny , Johnson Ralph
Published: April 2006

Frameworks and libraries change their APIs. Migrating an application to the new API is tedious and disrupts the development process. Although some tools and ideas have been proposed to solve the evolution of APIs, most updates are done manually. To better understand the requirements for migration tools, we studied the API changes of four frameworks and one library. We discovered that the changes that break existing applications are not random, but tend to fall into particular categories. Over 80% of these changes are refactorings. This suggests that refactoring‐based migration tools should be used to update applications. Copyright © 2006 John Wiley & Sons, Ltd.
Refactoring a legacy component for reuse in a software product line: a case study
Authors: Kolb Ronny , Muthig Dirk , Patzke Thomas , Yamauchi Kazuyuki
Published: April 2006

Product lines are a promising approach to improve conceptually the productivity of the software development process and thus to reduce both the cost and time of developing and maintaining increasingly complex systems. An important issue in the adoption of the product‐line approach is the migration of legacy software components, which have not been designed for reuse, systematically into reusable product‐line components. This article describes activities performed to improve systematically the design and implementation of an existing software component in order to reuse it in a software product line. The activities are embedded in the application of Fraunhofer PuLSE™‐DSSA—an approach for defining domain‐specific software architectures (DSSA) and product‐line architectures. The component under investigation is the so‐called Image Memory Handler (IMH), which is used in Ricoh's current products of office appliances such as copier machines, printers, and multi‐functional peripherals. It is responsible for controlling memory usage and compressing and decompressing image data. Improvement of both the component's design and implementation are based on a systematic analysis and focused on increasing maintainability and reusability and hence suitability for use in a product line. As a result of the analysis and refactoring activities, the documentation and implementation of the component has been considerably improved as shown by quantitative data collected at the end of the activities. Despite a number of changes to the code, the external behavior of the component has been preserved without significantly affecting the performance. Copyright © 2006 John Wiley & Sons, Ltd.
The first patient diagnosed with cytochrome c oxidase deficient Leigh syndrome: Progress report
Authors: Coenen M. J. H. , Smeitink J. A. M. , Farhoud M. H. , Nijtmans L. G. J. , Rodenburg R. , Janssen A. , van Kaauwen E. P. M. , Trijbels F. J. M. , van den Heuvel L. P.
Published: April 2006

Mutations in SURF1, an assembly gene for cytochrome c oxidase (COX), the fourth complex of the oxidative phosphorylation system, are most frequently encountered in patients with COX deficiency. We describe a patient with Leigh syndrome harbouring a mutation in SURF1 who was reported decades ago with a tissue‐specific cytochrome c oxidase deficiency.
Inefficient cleavage of palmitoyl‐protein thioesterase (PPT) substrates by aminothiols: Implications for treatment of infantile neuronal ceroid lipofuscinosis
Authors: Lu J.‐Y. , Hofmann S. L.
Published: April 2006

Infantile neuronal ceroid lipofuscinosis (INCL, also known as infantile Batten disease) is a devastating neurodegenerative disorder caused by deficiency in the lysosomal enzyme palmitoyl‐protein thioesterase (PPT, or CLN1), which functions to remove long‐chain fatty acids from cysteine residues in proteins. A previous study suggested that the drug cysteamine, a simple aminothiol used in the treatment of cystinosis, may have utility in the treatment of INCL. In the current study, we compared the catalytic rate constants for the conversion of palmitoyl‐CoA (a PPT substrate) and cystine (which accumulates in cystinosis) by cysteamine. We found that while cysteamine can react with palmitoyl‐CoA, the rate constant is 103‐fold less than the reaction with cystine. Structure–activity studies suggested that it is the thiolate ion that is reactive in the cleavage reaction and that the amino group probably facilitates lysosomal entry. A modest effect of cysteamine (and two related aminothiols, WR 1065 and dimethylaminoethanethiol, DMAET) on PPT substrate accumulation in INCL lymphoblasts was observed. However, at optimum concentration a paradoxical increase in saposin immunoreactivity was seen, indicating possible lysosomal dysfunction. Improvements are needed in the design of small molecules for the treatment of INCL disease.
Dietary compliance in ornithine aminotransferase deficiency
Authors: Santos Lucia , Fiona White J. , Walter John H.
Published: April 2006

Ornithine δ‐aminotransferase (OAT) deficiency (McKusick 258870) is associated with hyperornithinaemia, thought to be the cause of the progressive retinal degeneration that occurs in this disorder. For the large majority of cases unresponsive to the co‐factor pyridoxine, treatment is based on reducing ornithine plasma levels below 400 μ mol/L with an arginine‐restricted diet. This has been shown to slow the progression of retinal disease. (Santinelli et al 2004). In Table 1 we present our experience in the dietary management of 12 patients (7 female) from 8 families. Compliance was defined as good, intermediate or poor according to plasma ornithine levels. Only one patient could be categorized as a good complier, 5 were intermediate, and 6 were poor. The age at start of treatment was the most important factor as regards ability to comply with diet. Our study emphasizes the difficulty with dietary treatment and need for early diagnosis. For the older patients, alternative treatments such as the use of oral lysine to increase renal losses of ornithine need to be investigated further (Peltola et al 2000).
Effect of sample type, and timing of assay, on feline blood potassium concentration
Authors: Gunn-Moore Danièlle A , Reed Nicola , Simpson Kerry E , Milne Elspeth M
Published: April 2006

Blood samples were collected from 41 cats presented for pre-anaesthetic assessments, routine geriatric screening, or re-assessment of ongoing chronic medical disorders. Samples were either left to clot or anticoagulated with lithium heparin, then assessed for their potassium concentration within 1 h of collection, and again after remaining in contact with their cell pellet for 48 h. There was a significantly higher potassium concentration in the serum samples compared to the plasma samples, both in the basal and 48-h samples (although this difference was most marked in the basal samples). Ageing of both serum and plasma samples also resulted in an increase in the potassium concentration when compared with the basal values for each sample type. The mean difference (basal serum minus basal plasma) in potassium concentration was 0.47 mmol/l. While it is probable that the potassium came from either leukocytes and/or thrombocytes the mean total leukocyte count and the mean thrombocyte count were below the upper limit of the reference intervals for our laboratory and the rise in the potassium level did not appear to be directly related to either of these values.
Population characteristics of feral cats admitted to seven trap-neuter-return programs in the United States
Authors: Wallace Jennifer L. , Levy Julie K.
Published: April 2006

Internationally, large populations of feral cats constitute an important and controversial issue due to their impact on cat overpopulation, animal welfare, public health, and the environment, and to disagreement about what are the best methods for their control. Trap-neuter-return (TNR) programs are an increasingly popular alternative to mass euthanasia. The objective of this study was to determine the population characteristics of feral cats admitted to large-scale TNR programs from geographically diverse locations in the United States. Data from 103,643 feral cats admitted to TNR programs from 1993 to 2004 were evaluated. All groups reported more intact females (53.4%) than intact males (44.3%); only 2.3% of the cats were found to be previously sterilized. Overall, 15.9% of female cats were pregnant at the time of surgery. Pregnancy was highly seasonal and peaked between March and April for all of the groups. The average prenatal litter size was 4.1±0.1 fetuses per litter. Cryptorchidism was observed in 1.3% of male cats admitted for sterilization. A total of 0.4% of cats was euthanased because of the presence of debilitating conditions, and 0.4% died during the TNR clinics. Remarkably similar populations of cats with comparable seasonal variability were seen at each program, despite their wide geographical distribution. These results suggest that it is feasible to safely sterilize large numbers of feral cats and that the experiences of existing programs are a consistent source of information upon which to model new TNR programs.
Ammonia volatilization from surface-applied livestock slurry as affected by slurry composition and slurry infiltration depth
Authors: SOMMER S. G. , JENSEN L. S. , CLAUSEN S. B. , SØGAARD H. T.
Published: April 2006

Volatilization of ammonia (NH3) from slurry applied in the field is considered a risk to the environment and reduces the fertilizer value of the slurry. To reduce volatilization a better understanding of the slurry–soil interaction is needed. Therefore, the present study focuses on measuring NH3 volatilization as affected by differences in infiltration. Livestock slurries with different dry matter (DM) composition and viscosity were included in the experiments by using untreated cattle and pig slurry, pig slurry anaerobically digested in a biogas plant and pig slurry anaerobically digested and physically separated. NH3 volatilization was measured using dynamic chambers and related to infiltration of the livestock slurries in the soil by measuring chloride (Cl−) and Total Ammoniacal Nitrogen (TAN=ammonium (NH4+)+NH3) concentrations in soil at different depths from 0·5 to 6·0 cm from the soil surface. The slurries were applied to sandy and sandy-loam soils packed in boxes within the chambers. There were no significant differences in relative volatilization of NH3 from untreated cattle and pig slurries, but anaerobic digestion of pig slurry increased volatilization due to increases in pH. However, physical separation of the digested slurry reduced the volatilization compared with untreated slurry, due to increased infiltration. In general, the volatilization decreased significantly with increased infiltration. The present study shows that NH3 volatilization from applied slurry can be related to infiltration and that infiltration is related to slurry composition (i.e. DM content and particle size distribution) and soil water content. The infiltration of liquid (measured by Cl− infiltration) was affected by soil water potential, therefore, Cl− infiltrated deeper into the sandy loam soil than the sandy soil at similar gravimetric soil water values. Dry matter (DM) and large particles (>1 mm) of the slurry reduced infiltration of liquid. A high proportion of small particles (<0·025 mm) facilitated infiltration of TAN.
Cognitive reserve in neuropsychiatry
Authors: BARNETT J. H. , SALMOND C. H. , JONES P. B. , SAHAKIAN B. J.
Published: April 2006

Background. The idea that superior cognitive function acts as a protective factor against dementia and the consequences of head injury is well established. Here we suggest the hypothesis that cognitive reserve is also important in neuropsychiatric disorders including schizophrenia, bipolar disorder and depression.

Method. We review the history of passive and active models of reserve, and apply the concept to neuropsychiatric disorders. Schizophrenia is used as an exemplar because the effects of premorbid IQ and cognitive function in this disorder have been extensively studied.

Results. Cognitive reserve may impact on neuropsychiatric disorders in three ways: by affecting the risk for developing the disorder, in the expression of symptoms within disorders, and in patients' functional outcome. Cognitive failure below a certain threshold may alone, or in combination with common psychiatric symptoms, produce neuropsychiatric syndromes.

Conclusions. Consideration of cognitive reserve may considerably improve our understanding of individual differences in the causes and consequences of neuropsychiatric disorders. For these reasons, the concept of cognitive reserve should be incorporated in future studies of neuropsychiatric disorder. It may be possible to enhance cognitive reserve through pharmacological or non-pharmacological means, such as education, neurocognitive activation or other treatment programmes.
Transduction of biochemical signals across cell membranes
Authors: Hendrickson Wayne A.
Published: April 2006

1. Introduction 321

2. Tyrosine kinase receptors 322

3. Histidine kinase sensors 325

4. G-protein coupled receptors 327

5. Principles 328

6. Acknowledgments 329

7. References 330

Biological cells need to be responsive to various stimuli, primarily chemical ligands from their environments. Specific receptor molecules embedded in the plasma membrane detect the different biochemical signals that impact the cell, and these receptors are the conduits for transmission of this information to the cell interior for action. There are several classes of signal transduction receptors and many specific receptors within each of the major classes. This review emphasizes the structural biology of three major classes of transmembrane receptors – tyrosine kinase receptors, histidine kinase sensors, and G-protein coupled receptors. Biophysical principles that govern the processes of signal transduction across cell membranes are also discussed.
Addressing the challenges of cellular delivery and bioavailability of peptide nucleic acids (PNA)
Authors: Nielsen Peter E.
Published: April 2006

1. Introduction 345

2. Peptide nucleic acid (PNA) 346

3. ‘Cell penetrating peptides’ (CPPs) 346

4. Endosomal escape 347

5. Cellular delivery of PNA 347

6.In vivobioavailability of PNA 349

7. References 350

Recent results on the cellular delivery of antisense peptide nucleic acids (PNA) via peptide conjugation is briefly discussed, in particular in the context of endosomal entrapment and escape.
Nature, Nation-Building, and the Seasons of Justice in Rousseau's Political Thought
Authors: Smith Jeffrey A.
Published: April 2006

Examining the special relations between On the Social Contract and the Constitutional Project for Corsica, this essay argues that Rousseau conceives of constitutionalism on the basis of his understanding of the “natural development” of any state. What is “natural” is a certain order in which developmental periods best emerge, such that any state's disordered development will always result in its premature “death.” The essay explains four aspects of Rousseau's conception of properly ordered political development: the nature of a state's beginning; the relation between the two “great springs” of human conduct; the influence of external nature on human nature and justice; and the inevitable “end” of even the best state.
Allocation of Attention by Fishing Vessel Watchkeepers
Authors: Findlay Malcolm
Published: April 2006

This study examines the way in which attention is allocated by watchkeepers on fishing vessels and identifies differences in the approach displayed by individuals with different levels of training and experience. A method of analysing the way in which attention is allocated on a sample of UK fishing vessels is described. It was found that both skippers and mates allocated disproportionate amounts of attention to fishfinding equipment at certain stages of the fishing trip, while crewmen were heavily reliant upon the track plotter both while fishing and on passage. Those with more training and experience appeared to treat the array of navigation and control components as an integrated system, while untrained crewmen dealt with each aspect in isolation.
Syntactic change in Anglo-Norman and continental French chronicles: was there a ‘Middle’ Anglo-Norman?
Authors: INGHAM RICHARD
Published: April 2006

Anglo-Norman (AN) showed a tendency to lose Old French conjugation and gender inflectional distinctions, but is thought to have largely maintained the syntax of Old French. This study considers whether in the early 14th century AN syntax continued to follow continental French (CF) by moving towards new word-order patterns, namely XSV order and subject-verb inversion after et, which were to typify Middle French. Using corpora of CF and AN historical writing, especially chronicles, it is found that AN to some extent shadowed developments found in later 13th and in 14th century CF. In both AN and CF, XSV order was widespread with time adjuncts, but avoided with place adjuncts and direct and indirect objects. This dissociation was not calqued on Old/Middle English subject-verb inversion, which showed a different dissociation, i.e. inversion of verb and nominal subjects, but not pronominal subjects; AN showed no influence of this contrast. Inversion after et was found in AN, but only with unaccusative verbs, whereas in CF by the late 13th century it was spreading to other verbs as well, having initially shown a similar limitation as in AN. It is concluded that underlying syntactic processes of change began to affect AN as well as CF, but that they were interrupted by the switch away from French in England in the later 14th century.